WO2025164161A1 - Solvate of cannabidiol and method for purifying cannabidiol - Google Patents

Abstract

The present invention provides a solvate of cannabidiol.　In this solvate of cannabidiol, a solvent S1 of the solvate comprises an aprotic polar solvent.

Description

Solvates of cannabidiol and methods for purifying cannabidiol

The present invention relates to a solvate of cannabidiol and a method for purifying cannabidiol.

Cannabidiol (CBD), for example, is represented by the following formula and is one of the cannabinoids contained in hemp, and is used for various purposes such as pharmaceuticals.
For example, Patent Document 1 discloses a stable pharmaceutical formulation for oral administration containing about 0.1 to about 40% cannabinoid; and about 10 to about 95% lipid.

Special Publication No. 2018-516281

The object of the present invention is to provide solvates of cannabidiol, etc.

Cannabidiol (CBD) can be chemically (artificially) synthesized, for example, by reacting menthadienol with olivetol, but such reactions typically produce by-products (by-products, reaction by-products) in addition to CBD.

These by-products mainly include positional isomers (hereinafter referred to as abn-CBD), adducts (an adduct in which 2 moles of menthadienol are added to 1 mole of olivetol, hereinafter referred to as a 2:1 adduct), and tetrahydrocannabinol (THC) [particularly, Δ9-THC (Δ ⁹ -THC) and Δ8-THC (Δ ⁸ -THC)] (for example, as represented by the following formula):

Positional isomer (abn-CBD)

Adduct (2:1 adduct)

Δ9-THC

Δ8-THC

The production of such by-products reduces the yield of CBD and reduces the efficiency of CBD recovery (purification).

Furthermore, according to the inventors' investigations, when such by-products are produced (for example, when they are produced in relatively large amounts or when by-products that are difficult to separate from CBD are produced), separation (purification) may become difficult even using conventional purification techniques, or even if separation (purification) is possible, the separation (purification) process may become complicated.

Furthermore, if separation is not sufficient and by-products are mixed into CBD, this may interfere with the function of CBD or result in other effects or side effects (for example, THC is the main component of marijuana).

Therefore, it is preferable to minimize the production of such by-products during the reaction process.

However, it is difficult to find reaction (manufacturing) conditions that produce CBD while suppressing these by-products. In particular, there are cases where suppressing the production of one by-product makes it easier for other by-products to be produced, so it has been extremely difficult to find conditions that suppress all by-products (for example, suppressing the by-production of abn-CBD and 2:1 adducts, as well as the by-production of THC).
Furthermore, it is difficult to simultaneously suppress the formation of by-products (suppress the formation of by-products at a high level) and completely react olivetol, and there are cases where unreacted olivetol remains in the reaction mixture.

In light of this, the inventors have discovered that by reacting menthadienol with olivetol under specific conditions (methods), it is possible to produce CBD while efficiently suppressing the production of by-products, and that by subjecting a mixture containing CBD as well as other components such as olivetol and abn-CBD to specific treatment, it is possible to efficiently purify CBD (separate the other components).

The method discovered by the inventors allows for high levels of separation of components other than CBD (olivetol, by-products). However, even with this method, it is difficult to completely separate the other components, and CBD may still contain trace amounts of other components.

Furthermore, according to the inventor's research, there are circumstances unique to CBD, such as the lack of solvents in which CBD dissolves poorly, the similarity in structure between CBD and by-products, and the tendency of highly polar components (such as olivetol) to interfere with CBD crystallization. Therefore, unless other components are separated at an extremely high level, it can be difficult to obtain highly purified CBD using conventional methods such as crystallization, or to efficiently obtain CBD with sufficient yield or recovery efficiency.

Furthermore, these problems can arise even when CBD is not chemically (artificially) synthesized. For example, while CBD derived from natural ingredients (e.g., CBD purified from hemp) does not (is unlikely to) contain components derived solely from chemical synthesis (e.g., raw material components such as olivetol), it may still contain other components (e.g., other cannabinoids other than CBD [e.g., cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), cannabidivarin (CBDV), THC (Δ9-THC, etc.)]). In particular, these components often cannot be easily separated (or are difficult to separate) from CBD using conventional methods such as crystallization, or even if separation is possible, it is often extremely inefficient and impractical.

Under these circumstances, the inventors investigated whether it was possible to purify CBD from a mixture (crude CBD) containing CBD and other components (trace amounts of other components) from an entirely different perspective. They discovered that CBD forms solvates with specific solvents, and that by forming (utilizing) such solvates, it is possible to efficiently separate the other components. After further investigation, they completed the present invention.

That is, the present invention relates to the following inventions.
[1]
A solvate of cannabidiol, wherein the solvent S1 of the solvate comprises an aprotic polar solvent.
[2]
The solvate according to [1], wherein the solvent S1 comprises an amide solvent (amides).
[3]
The solvate according to [1] or [2], wherein the solvent S1 comprises dimethylacetamide.
[4]
The solvate according to any one of [1] to [3], which is a solvate in which dimethylacetamide is solvated in a ratio of 2 moles per mole of cannabidiol.
[5]
The solvate according to any one of [1] to [4], which is a crystal.
[6]
A method for producing a solvate of cannabidiol, wherein the solvent S1 of the solvate comprises an aprotic polar solvent, by forming the solvate in a mixture comprising cannabidiol and solvent S1 (solvent S1 mixture).
[7]
The method according to [6], wherein the solvent S1 comprises an amide-based solvent (amides).
[8]
The method according to [6] or [7], wherein solvent S1 contains dimethylacetamide, and the solvate is a solvate in which dimethylacetamide is solvated in a ratio of 2 moles per mole of cannabidiol.
[9]
The method according to any one of [6] to [8], wherein the mixture further comprises a solvent S2 different from the solvent S1.
[10]
The method according to any one of [6] to [9], wherein the mixture further comprises an aliphatic hydrocarbon.
[11]
The method according to any one of [6] to [10], wherein the mixture contains dimethylacetamide and an aliphatic hydrocarbon, and a solvate in which dimethylacetamide is solvated in a ratio of 2 moles per mole of cannabidiol is precipitated (crystallized) (to obtain a precipitate/solid/crystal containing the solvate, or to form the solvate in the form of a precipitate/solid/crystal containing the solvate).
[12]
The method according to any one of [6] to [11], wherein the mixture further contains other cannabinoids.
[13]
The method according to any one of [6] to [12], wherein the mixture contains at least one other cannabinoid selected from cannabigerol, cannabinol, cannabichromene, cannabidivarin, and tetrahydrocannabinol.
[14]
the mixture further comprises at least one other cannabinoid selected from cannabigerol, cannabinol, delta-9-tetrahydrocannabinol and delta-8-tetrahydrocannabinol;
The method according to any one of [6] to [13], wherein the ratio of cannabigerol, cannabinol, Δ-9-tetrahydrocannabinol and Δ-8-tetrahydrocannabinol to the total amount of cannabidiol, cannabigerol, cannabinol, Δ-9-tetrahydrocannabinol and Δ-8-tetrahydrocannabinol is 0.1% or more based on the area of HPLC.
[15]
The method according to any one of [6] to [14], wherein the mixture (or cannabidiol) is derived from hemp (particularly, cannabis).
[16]
The method according to any one of [6] to [15], wherein the mixture further contains at least one selected from olivetol, a positional isomer of cannabidiol (abn-CBD), an adduct in which 2 moles of menthadienol are added to 1 mole of olivetol (2:1 adduct), Δ-9-tetrahydrocannabinol (Δ9-THC), and Δ-8-tetrahydrocannabinol (Δ8-THC).
[17]
The mixture comprises cannabidiol (CBD) and an adduct of 2 moles of menthadienol to 1 mole of olivetol (2:1 adduct),
the ratio of cannabidiol (CBD) to the total amount of cannabidiol (CBD), olivetol, a positional isomer of cannabidiol (abn-CBD), an adduct in which 2 moles of menthadienol are added to 1 mole of olivetol (2:1 adduct), Δ-9-tetrahydrocannabinol (Δ9-THC), and Δ-8-tetrahydrocannabinol (Δ8-THC) is 60% or more based on the area of HPLC;
Olivetol is not contained or is contained in a ratio of 0.03 or less to cannabidiol (CBD) on an HPLC area basis;
The composition is free of cannabidiol positional isomers (abn-CBD) or contains them at a ratio of 0.3 or less based on the area of cannabidiol (CBD) by HPLC;
The method according to any one of [6] to [16], wherein an adduct in which 2 moles of menthadienol are added to 1 mole of olivetol (2:1 adduct) is contained in a ratio of 0.0001 to 0.5 based on an HPLC area standard relative to cannabidiol (CBD).
[18]
The method further comprises a step of subjecting a mixture containing cannabidiol and at least one selected from olivetol and a positional isomer of cannabidiol (abn-CBD) to an adsorption treatment to produce a purified product containing cannabidiol;
The method according to any one of [6] to [17], wherein a solvate is formed in a mixture containing the purified product obtained through this step and solvent S1 (solvent S1 mixture).
[19]
moreover,
Menthadienol and olivetol,
In the presence of at least one catalyst (acid, acid catalyst) selected from non-boron Lewis acids and Bronsted acids (e.g., organic acids, inorganic acids),
At temperatures above 40°C,
A step of reacting at a water content of 5% by mass or less in the reaction system at the start of the reaction (e.g., 4% by mass or less, 3% by mass or less, 2% by mass or less, 1.5% by mass or less, 1% by mass or less, 0.5% by mass or less, 0.3% by mass or less, 0.25% by mass or less, 0.2% by mass or less, 0.18% by mass or less, 0.15% by mass or less, 0.12% by mass or less, 0.1% by mass or less, 0.08% by mass or less, 0.05% by mass or less, etc.) to produce a reaction mixture containing cannabidiol;
The reaction mixture obtained through this step is subjected to an adsorption treatment to produce a purified product containing cannabidiol,
The method according to any one of [6] to [18], wherein a solvate is formed in a mixture containing the purified product obtained through this step and solvent S1 (solvent S1 mixture).
[20]
A method for producing (regenerating) cannabidiol by desolvating the solvate according to any one of [1] to [5].
[21]
A method for producing (regenerating) cannabidiol by mixing (mixing and desolvating) the solvate according to any one of [1] to [5] with water.
[22]
A method of mixing (mixing and desolvating) the solvate according to any one of [1] to [5] with water and a hydrophobic solvent capable of dissolving cannabidiol, and extracting (liquid-liquid separation) cannabidiol (desolvated cannabidiol) into a layer of the hydrophobic solvent (a layer containing the hydrophobic solvent, a layer separated from water, a separation layer).
[23]
an extraction step of mixing (mixing and desolvating) the solvate according to any one of [1] to [5] with water and a hydrophobic solvent capable of dissolving cannabidiol, and extracting (liquid-liquid separation) the cannabidiol (desolvated cannabidiol) into a layer of the hydrophobic solvent (a layer containing the hydrophobic solvent, a layer separated from water, a separation layer);
and a crystallization step of crystallizing (e.g., crystallizing) the cannabidiol (regenerated cannabidiol) obtained through the extraction step.
[24]
Cannabidiol obtained by the method according to any one of [20] to [23].
[25]
The cannabidiol according to [24], wherein the proportion of cannabidiol to the total amount of cannabidiol, cannabigerol, cannabinol, Δ-9-tetrahydrocannabinol and Δ-8-tetrahydrocannabinol is 97% or more based on the area of HPLC.
[26]
The cannabidiol according to [24] or [25], wherein the proportion of cannabidiol (CBD) relative to the total amount of cannabidiol (CBD), olivetol, a positional isomer of cannabidiol (abn-CBD), an adduct in which 2 moles of menthadienol are added to 1 mole of olivetol (2:1 adduct), Δ-9-tetrahydrocannabinol (Δ9-THC), and Δ-8-tetrahydrocannabinol (Δ8-THC) is 97% or more based on the area standard of HPLC.
[27]
[24] - [26], wherein the solvent S1 (dimethylacetamide, etc.) of the solvate is not contained or the ratio of the solvent S1 of the solvate is 3% by mass or less.
[28]
The cannabidiol according to any one of [24] to [27], containing 0.001% by mass or more of the solvent S1 of the solvate.
[29]
[24] - [28] Cannabidiol according to any one of the above, containing 0.001% by mass or more of the solvent S1 of the solvate and 0.001% by mass or more of a hydrocarbon (for example, an aliphatic hydrocarbon such as heptane).

The present invention provides a solvate of cannabidiol.

Such solvates are useful, for example, for separating CBD (as a solvate) from a mixture containing CBD and other components (trace amounts of other components) [crude CBD, CBD containing (trace amounts of) other components (purified product, crude CBD)].

As mentioned above, it is difficult to completely separate CBD from other components, but these solvates, unlike CBD, appear to be easier to separate from other components. Therefore, by using such solvates (treating the CBD contained in crude CBD as a solvate), it is easier to efficiently separate it from other components.

Furthermore, while the solvate is stable, it can also be easily desolvated (thus regenerating the CBD).

Therefore, by using such solvates, it is possible to efficiently (and easily) obtain CBD (especially high-purity CBD).

<Solvate>
The solvate of the present invention is a solvate of cannabidiol (CBD) (CBD solvate, solvate of CBD).

In CBD solvates, the solvent (sometimes referred to as the solvent of the solvate, the solvent that forms the solvate, solvent S1, etc.) may typically include an aprotic polar solvent.

Specific examples of solvents (solvent S1) for CBD solvates include nitrogen-containing solvents (e.g., amides [amide-based solvents, e.g., N-substituted linear amides (e.g., N-substituted (e.g., N-alkyl) alkanamides such as N,N-dimethylformamide and N,N-dimethylacetamide; N,N-diphenylacetamide; etc.), cyclic amides (e.g., 2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone); etc.], nitriles (e.g., acetonitrile), etc.), sulfur-containing solvents (e.g., sulfoxides such as dimethyl sulfoxide; sulfones such as dimethyl sulfone and sulfolane), etc.).

CBD solvates may contain one or more solvents (e.g., aprotic polar solvents).

Furthermore, in the solvate of CBD, the solvent containing an aprotic polar solvent (solvent S1) may consist solely of an aprotic polar solvent, or may contain solvents other than aprotic polar solvents, and in particular may consist solely of an aprotic polar solvent.

Preferred solvents for CBD solvates include amides (amide-based solvents), particularly N-substituted alkanamides such as N,N-dimethylacetamide (dimethylacetamide), from the viewpoint of ease of precipitation and separation in a mixture.

In addition, in the CBD solvate, the molar ratio of CBD to solvent (solvent S1) is not particularly limited, as long as a solvate is formed.

CBD solvates may, in particular, be crystalline (crystalline form).

An example of a CBD solvate is a solvate formed with dimethylacetamide (sometimes referred to as DMA).

In a solvate solvated with dimethylacetamide (sometimes referred to as CBD-DMA, CBD-DMA solvate, CBD-DMA, etc.), the ratio of CBD to dimethylacetamide by mass is not limited, but may be, for example, a solvate solvated with 2 moles of dimethylacetamide per 1 mole of CBD (sometimes referred to as CBD-2DMA, CBD-2DMA, etc.) (which may contain at least CBD-2DMA).

Such CBD-2DMA may, for example, exhibit at least one of the following physical properties (characteristics):

・Powder X-ray (2θ)
It may have at least the characteristic peak shown in (A) below, and has at least the characteristic peak shown in (B) or (C) below (characteristic peaks including the peak shown in (A) below).

(A) (approximately 5 peaks)
8.3±0.2°, 8.5±0.2°, 10.6±0.2°, 16.4±0.2°, 17.0±0.2°

(B) (approximately 10 peaks)
8.3±0.2°, 8.5±0.2°, 10.6±0.2°, 13.4±0.2°, 16.4±0.2°, 17.0±0.2°, 18.9±0.2°, 22.7±0.2°, 24.6±0.2°, 26.5±0.2°

(C) (approximately 20 peaks)
8.3±0.2°, 8.5±0.2°, 10.6±0.2°, 11.8±0.2°, 13.4±0.2°, 15.4±0.2°, 15.8±0.2°, 16.4±0.2°, 17.0±0.2°, 18.9±0.2°, 19.9±0.2°, 21.4±0.2°, 22.7±0.2°, 22.9±0.2°, 23.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.5±0.2°, 27.1±0.2°, 27.7±0.2°

¹ H-NMR (e.g., 400 MHz, CDCl ₃ ): δppm: 0.88 (t, J=7.2Hz, 3H), 1.22-1.36 (m, 2H), 1.52-1.60 (m, 2H), 1.64-1. 67 (m, 3H), 1.75-1.85 (m, 2H), 1.78-1.80 (m, 3H), 2.07-2.13 (m, 2H), 2.08 (s, 6 H), 2.18-2.28 (m, 3H), 2.37-2.46 (m, 3H), 2.94 (s, 6H), 3.01 (s, 6H), 3.82-3.8 7 (m, 1H), 4.56 (s, 1H), 4.65-4.67 (m, 1H), 5.56-5.58 (m, 1H), 6.13-6.30 (m, 1H)

Melting point: 52-55°C [by DSC (differential scanning calorimetry)]

CBD-2DMA generally has lower solubility in various solvents, such as heptane, than CBD. Therefore, CBD-2DMA generally appears to crystallize more easily than CBD. Therefore, such solvates are particularly effective for efficiently separating (purifying) CBD from mixtures containing CBD and other components (e.g., by-products, olivetol).

Furthermore, CBD-2DMA appears to be relatively easy to release (desolvate) DMA in water, etc. Therefore, such solvates are also effective in generating (regenerating) CBD.

[Method for producing CBD solvates]
The solvate of CBD is not particularly limited and can be produced by contacting (mixing) CBD with a solvent for the solvate (solvent that forms the solvate, solvent S1).

Typically, a solvate can be formed in a mixture containing CBD and solvent S1 (solvent S1 mixture), and in particular, a solvate is precipitated (crystallized) in a mixture containing CBD and solvent S1 (solvent S1 mixture) (obtaining a precipitate/solid/crystal containing the solvate, or forming the solvate in the form of a precipitate/solid/crystal containing the solvate). This method makes it easy to efficiently separate CBD as a solvate.

As for CBD (CBD used in production, CBD source), CBD (high-purity CBD) may be used, or a mixture containing CBD and other components (trace amounts of other components) may also be used.

In particular, when a mixture containing CBD and other components is used (especially when a mixture containing CBD and other components is used to precipitate a solvate), CBD can be easily separated from the other components as a solvate.

Other components may include cannabinoids (cannabinoids other than CBD, other cannabinoids), olivetol, menthadienol, abn-CBD, 2:1 adducts, etc., depending on the source of the CBD (e.g., natural (hemp, etc.) or synthetic), etc.).

Other cannabinoids include, for example, cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), cannabidivarin (CBDV), THC (Δ8-THC, Δ9-THC, Δ10-THC, etc.), cannabiolic acid (CBDA), cannabigerolic acid (CBGA), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), cannabicyclol (CBL), cannabinodiol (CBND), cannabielsoin (CBE), cannabinotriol (CBT), etc.

The other components may be contained in the mixture alone or in combination of two or more.

Among these other components, other cannabinoids (e.g., CBG, CBN, CBC, CBDV, THC, especially CBG, CBN, and THC), olivetol, abn-CBD, 2:1 adducts, etc., are likely to be contained in the mixture.

In addition, olivetol, menthadienol, abn-CBD, and 2:1 adducts are often found in synthetically derived CBD (mixtures), and other cannabinoids may be found in mixtures regardless of whether they are naturally derived or synthetically derived.

Mixtures containing CBD and other ingredients are not particularly limited, and include mixtures of natural origin (for example, hemp (cannabis, etc.) extracts, purified products of such extracts (mixtures with a higher proportion of CBD), etc.), and mixtures derived from reactions (chemical synthesis) (mixtures that have undergone chemical synthesis).

Examples of mixtures of natural origin (other components in mixtures of natural origin) include mixtures containing other cannabinoids (mixtures containing CBD and other cannabinoids).

Examples of the reaction-derived mixture include the reaction mixture and first purified product (crude CBD) described below. Of the reaction mixture and first purified product, it is particularly preferable to use the first purified product (crude product, first purified product that has undergone the adsorption treatment described below) from the perspectives of ease of precipitating CBD solvates and efficient production of highly pure CBD.

The solvent S1 mixture may contain at least solvent S1 as the solvent, but from the perspective of facilitating efficient formation (precipitation) of a CBD solvate, it may also contain a solvent for the solvate and a solvent (sometimes referred to as solvent S2, etc.) different from the solvent for the solvate (e.g., an amide such as DMA) (solvent S1 may be used in combination with solvent S2).

Solvent S2 may be any solvent that does not form a solvate when combined with solvent S1, and solvent S2 itself may be a solvent that can form a solvate.

Solvent S2 may be any solvent different from solvent S1, but it is preferable that it does not (substantially) dissolve the CBD solvate (a poor solvent for the CBD solvate).

Solvent S2 can be selected depending on the type of solvent S1 and solvate, but examples include hydrocarbons [e.g., aliphatic hydrocarbons (e.g., pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, ethylbenzene, etc.)], halogenated solvents (e.g., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), esters (e.g., aliphatic esters such as methyl acetate, ethyl acetate, butyl acetate, etc.), carbonates (e.g., ethylene carbonate, propylene carbonate, etc.), ethers [e.g., chain ethers (e.g., diethyl ether, methyl t-butyl ether, etc.), cyclic ethers (e.g., tetrahydrofuran, etc.], etc.]. furan, dioxane, etc.), glycol ethers (e.g., ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, propylene glycol monomethyl ether, diethylene glycol monoethyl ether, etc.), glycol ether esters (e.g., ethylene glycol monomethyl ether acetate, etc.), nitrogen-containing solvents {e.g., amides [e.g., N-substituted linear amides (e.g., N-alkyl-substituted alkanamides such as N,N-dimethylformamide), cyclic amides (e.g., 2-pyrrolidone, etc.)], nitriles (e.g., acetonitrile, etc.), sulfur-containing solvents (e.g., sulfoxides such as dimethyl sulfoxide; sulfones such as dimethyl sulfone and sulfolane), alcohols [e.g., alkanols (e.g., methanol, ethanol, isopropanol), etc.], polyols (e.g., alkanediols such as ethylene glycol and propylene glycol; glycerin, etc.), water, etc.

Typical solvents S2 include hydrocarbons [e.g., aliphatic hydrocarbons (e.g., pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, ethylbenzene, etc.)], ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), ethers [e.g., chain ethers (e.g., diethyl ether, methyl t-butyl ether, etc.), cyclic ethers (e.g., tetrahydrofuran, dioxane, etc.)], etc.].

Among these, solvent S2 may particularly contain at least an aliphatic hydrocarbon {e.g., pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, etc. [e.g., aliphatic hydrocarbons having 5 or more carbon atoms (e.g., 5 to 18 carbon atoms, 6 to 12 carbon atoms, 6 to 10 carbon atoms, etc.) (e.g., linear or cyclic aliphatic hydrocarbons, saturated or unsaturated hydrocarbons, linear or cyclic saturated aliphatic hydrocarbons), etc.], etc.}.

Solvent S2 may be used alone or in combination of two or more types.

When solvent S2 contains aliphatic hydrocarbons, the proportion of aliphatic hydrocarbons (e.g., heptane, etc.) relative to the total solvent S2 may be selected from a range of, for example, 1 vol.% or more (e.g., 3 vol.% or more), preferably 5 vol.% or more (e.g., 10 vol.% or more), and more preferably 15 vol.% or more (e.g., 20 vol.% or more), and may be 25 vol.% or more [e.g., 30 vol.% or more, 35 vol.% or more, 40 vol.% or more, 50 vol.% or more, more than 50 vol.%, 60 vol.% or more, 70 vol.% or more, 80 vol.% or more, 85 vol.% or more, 90 vol.% or more, 95 vol.% or more, or (substantially) 100 vol.% (almost) only aliphatic hydrocarbons].

Aliphatic hydrocarbons may be used in combination with other solvents (solvents other than aliphatic hydrocarbons, for example, ethers). In such cases, the proportion of the other solvent in the total solvent S2 may be selected from the range of, for example, 99% by volume or less (e.g., 97% by volume or less, 95% by volume or less), 90% by volume or less (e.g., 80% by volume or less), preferably 70% by volume or less (e.g., 60% by volume or less), and more preferably 50% by volume or less (e.g., 40% by volume or less), or 1% by volume or more (e.g., 3% by volume or more, 5% by volume or more, 10% by volume or more), etc.

The proportion of solvent S1 in the total solvent is not particularly limited, but may be, for example, 0.1% by volume or more (e.g., 0.5% by volume or more), preferably 1% by volume or more (e.g., 2% by volume or more), and more preferably 3% by volume or more (e.g., 5% by volume or more).

When the solvent contains solvent S2, the proportion of solvent S2 in the entire solvent is not particularly limited, but may be selected from a range of, for example, 1 vol.% or more (e.g., 3 vol.% or more), preferably 5 vol.% or more (e.g., 10 vol.% or more), and more preferably 15 vol.% or more (e.g., 20 vol.% or more), or may be 25 vol.% or more (e.g., 30 vol.% or more, 35 vol.% or more, 40 vol.% or more, 50 vol.% or more, more than 50 vol.%, 60 vol.% or more, 70 vol.% or more, 80 vol.% or more, 85 vol.% or more, 90 vol.% or more), etc.

The solvent (e.g., solvent S2) may or may not contain a protic solvent (e.g., water, alcohols, etc.). However, from the viewpoint of facilitating efficient formation (precipitation) of CBD solvates, it is preferable that the solvent does not contain any protic solvent, or contains only a small amount of water [e.g., 10% by volume or less of the solvent (e.g., 5% by volume or less, 3% by volume or less, 1% by volume or less, 0.5% by volume or less, 0.1% by volume or less), etc.]. In particular, the solvent may not contain any water, or may contain only a small amount of water [e.g., 10% by volume or less of the solvent (e.g., 5% by volume or less, 3% by volume or less, 1% by volume or less, 0.5% by volume or less, 0.1% by volume or less), etc.].

In the mixture (solvent S1 mixture), the proportion (concentration) of components other than the solvent (solids) relative to the total amount of the solvent and components other than the solvent is not particularly limited, but may be, for example, approximately 0.1% by mass or more (e.g., 0.5% by mass or more, 1% by mass or more, 3% by mass or more, 5% by mass or more), or 99% by mass or less (e.g., 95% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 45% by mass or less, 40% by mass or less, 35% by mass or less, 30% by mass or less, 25% by mass or less, 20% by mass or less, 15% by mass or less, 12% by mass or less, 10% by mass or less), etc.

In the mixture (solvent S1 mixture), the ratio of solvent to CBD1 may be approximately 0.01 or more (e.g., 0.05 or more, 0.1 or more, 0.3 or more, 0.5 or more) by volume, or may be 1000 or less (e.g., 800 or less, 500 or less, 300 or less, 200 or less, 150 or less, 120 or less, 100 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less), etc.

In the mixture, the ratio of solvent S1 to CBD may be, for example, 1 molar equivalent or more, more than 1 molar equivalent (e.g., 1.05 molar equivalents), preferably 1.1 molar equivalents or more (e.g., 1.2 molar equivalents or more), more preferably 1.5 molar equivalents or more (e.g., 1.8 molar equivalents or more), or may be 2 molar equivalents or more (e.g., 2.5 molar equivalents or more, 3 molar equivalents or more), etc.

Note that 1 molar equivalent means that when the solvate is formed by solvating X moles of solvent with 1 mole of CBD (for example, 2 moles in the case of CBD-2DMA), the amount is X moles with respect to 1 mole of CBD (for example, 2 moles in the case of CBD-2DMA).

CBD solvates can be formed (manufactured) by reacting (contacting) CBD with solvent S1 in a mixture (solvent S1 mixture). The formation of such solvates may typically be accompanied by crystallization (crystallization).

In such a reaction (solvation reaction), the method for mixing the raw materials (components) used is not particularly limited; they may all be mixed together, mixed in stages, mixed partially, multiple components may be mixed in advance, or these may be combined.

In particular, from the viewpoint of facilitating efficient formation of a solvate of CBD, solvent S1 may be mixed (e.g., added dropwise) into a system (mixture) containing CBD (e.g., reaction mixture, first purified product) [solvation may be achieved by mixing (e.g., adding dropwise)].

Mixing may be carried out all at once or in stages, preferably in stages. Such mixing (staged mixing) may be intermittent, continuous (continuous), or a combination of these.

Furthermore, in such mixing (step-by-step mixing), the time required for mixing (mixing time, total time, time until mixing is complete) depends on the amount of the other component, etc., but can be selected from a range of, for example, 30 seconds or more (e.g., 40 seconds or more), and may be 1 minute or more (e.g., 2 minutes or more, 3 minutes or more, 5 minutes or more, 10 minutes or more, 30 minutes or more), etc.

The reaction (crystallization) may be carried out in the presence or absence of seed crystals. The use of seed crystals often facilitates crystallization under milder conditions (e.g., crystallization can be easily achieved without low temperatures). The seed crystals may be, for example, a solvate of CBD. Such seed crystals may be pre-prepared, for example, produced using high-purity CBD (using the method of the present invention), or may be produced (using the method of the present invention) using a mixture containing CBD and other components (reaction mixture, first purified product, etc.).

The reaction (crystallization) may be carried out at room temperature (or normal temperature), under heating, or under cooling.

Specific reaction (crystallization) temperatures include, for example, -100°C or higher (e.g., -80°C or higher, -60°C or higher, -40°C or higher, -20°C or higher, -10°C or higher, 0°C or higher, 10°C or higher, 20°C or higher, 30°C or higher, 35°C or higher, 40°C or higher), and 150°C or lower (e.g., 140°C or lower, 130°C or lower, 120°C or lower, 110°C or lower, 100°C or lower, 90°C or lower, 80°C or lower, 70°C or lower, 60°C or lower, 50°C or lower).

In particular, from the viewpoint of facilitating efficient solvate formation and precipitation, the reaction (crystallization) temperature may be relatively low or not too high (e.g., 40°C or less, 35°C or less, 30°C or less, 25°C or less, 20°C or less, 15°C or less, 10°C or less, 5°C or less).

The reaction (crystallization) time can be selected appropriately depending on the degree of progress of the solvation reaction (crystallization), various reaction (crystallization) conditions, etc., and is not particularly limited, but may be, for example, 30 seconds or more (e.g., 1 minute or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 20 minutes or more, 25 minutes or more, 30 minutes or more, 40 minutes or more, 60 minutes or more, 1.5 hours or more, 2 hours or more), etc., or 48 hours or less (e.g., 36 hours or less, 24 hours or less, 18 hours or less, 12 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less), etc.

The reaction (crystallization) may be carried out with stirring or by leaving the mixture to stand.

The reaction (crystallization) may also be carried out in an inert atmosphere (e.g., under nitrogen or argon).

There are no particular restrictions on the container used in the reaction (crystallization), and conventional containers can be used.

Through the above reaction (crystallization), a solvate of CBD is formed (manufactured).

The CBD solvate can be separated (recovered) from the reaction (crystallization) mixture using conventional methods. For example, the crystallized (crystallized, precipitated) CBD solvate (crystals, crystallized product, solid content, solid) can be separated (recovered) by filtration, decantation, etc.

Furthermore, the separated CBD solvate (crystals, crystallized material, solid content, solid) may be washed (washing treatment) if necessary.

The cleaning solvent is not particularly limited, and the solvents exemplified above (e.g., solvent S2) may be used. The preferred solvents are also the same as those described above. For example, hydrocarbons (especially aliphatic hydrocarbons), preferably solvents containing at least aliphatic hydrocarbons, may be used.

The amount of washing solvent used can be selected appropriately depending on the amount of CBD solvate (crystals, crystallized material, solid content, solid), and may be, for example, 0.1 parts by mass or more (e.g., 0.3 parts by mass or more, 0.5 parts by mass or more, 1 part by mass or more) or 100 parts by mass or less (e.g., 50 parts by mass or less, 10 parts by mass or less, 5 parts by mass or less) per part by mass of CBD solvate (crystals, crystallized material).

Furthermore, in solids (crystals, crystallized material, solid content, second purified product (e.g., purified product obtained via the first purified product), CBD solvate), CBD can be recovered almost entirely as a CBD solvate. For example, when the mass of CBD in the mixture (solvent S1 mixture) is A1 and the mass of CBD in the second purified product (the mass of CBD in the solvate) is A2, the value of A2/A1 can be selected, for example, from a range of approximately 0.7 or more, and may be approximately 0.8 or more (e.g., 0.85 or more, 0.88 or more, 0.9 or more, 0.92 or more, 0.93 or more, 0.94 or more, 0.95 or more, 0.96 or more, 0.97 or more, 0.98 or more, 0.99 or more, substantially 1).

Furthermore, the solid (crystal, crystallized product, solid content, second purified product, solvate of CBD) may or may not contain other components (e.g., olivetol, components derived from the reaction (chemical synthesis) such as by-products; other cannabinoids, etc.); however, by undergoing the purification process described above (crystallization, formation of solvates), even if it does contain other components, it is often only in trace amounts (highly purified).

For example, in a solid (crystal, crystallized product, solid content, second purified product, solvate of CBD), the ratio of CBD (or solvate of CBD) to the total amount of CBD (or solvate of CBD), olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC [for example, based on the HPLC (high performance liquid chromatography) area (or peak area, for example, the area measured at a measurement wavelength of 210 nm; the same applies hereinafter to the HPLC area)] The [proportion] can be selected, for example, from a range of 80% or more (e.g., 85% or more), and may be 88% or more (e.g., 89% or more), preferably 90% or more (e.g., 91% or more), more preferably 92% or more (e.g., 93% or more), and particularly 94% or more (e.g., 95% or more, 96% or more, 96.5% or more, 97% or more, 97.5% or more, 98% or more, 98.5% or more, 99% or more, 99.2% or more, 99.5% or more, 99.9% or more).

In a solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly one derived from naturally occurring CBD), the ratio of CBD (or solvate of CBD) to the total amount of CBD (or solvate of CBD) and other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] (e.g., HPLC area (peak area) ) standard) can be selected, for example, from a range of 80% or more (e.g., 85% or more), and may be 88% or more (e.g., 89% or more), preferably 90% or more (e.g., 91% or more), more preferably 92% or more (e.g., 93% or more), and particularly 94% or more (e.g., 95% or more, 96% or more, 96.5% or more, 97% or more, 97.5% or more, 98% or more, 98.5% or more, 99% or more, 99.2% or more, 99.5% or more, 99.9% or more).

In a mixture (e.g., a mixture containing naturally-occurring CBD and other cannabinoids, a mixture before the second purification, or a solvent S1 mixture), the ratio of CBD (e.g., the ratio based on HPLC area (peak area)) to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC is M1; in the second purified product, the ratio based on HPLC area (peak area) to the total amount of CBD (or solvates of CBD), olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC is M2. When the proportion of CBD (or CBD solvate) (for example, the proportion based on the HPLC area (peak area)) is taken as M2, the value of M2-M1 may be greater than 0%, or may be selected from a range of approximately 1% or more (for example, 2% or more), and may be 3% or more (for example, 4% or more), preferably 5% or more (for example, 8% or more), more preferably 10% or more (for example, 12% or more), and particularly 15% or more (for example, 16% or more, 17% or more, 18% or more, 19% or more, 20% or more).

In a mixture (e.g., a mixture containing naturally-occurring CBD and other cannabinoids, a mixture before the second purification, a solvent S1 mixture), the ratio of CBD (or solvates of CBD) and other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] to the total amount of CBD (or solvates of CBD) and other cannabinoids [or CBG, CBN] is defined as M1. In a solid (crystal, crystallized product, solid fraction, second purification product, solvates of CBD, particularly those derived from nature), the ratio of CBD (or solvates of CBD) and other cannabinoids [or CBG, CBN] is defined as M2. When the ratio (e.g., the ratio based on HPLC area (peak area)) of CBD (or CBD solvate) to the total amount of CBG, CBC, CBDV, and THC (e.g., Δ9-THC, Δ8-THC) [or CBG, CBN, and THC (e.g., Δ9-THC, Δ8-THC)] is taken as M2, the value of M2-M1 may be greater than 0%, may be selected from a range of approximately 1% or more (e.g., 2% or more), may be 3% or more (e.g., 4% or more), preferably 5% or more (e.g., 8% or more), more preferably 10% or more (e.g., 12% or more), and particularly 15% or more (e.g., 16% or more, 17% or more, 18% or more, 19% or more, 20% or more).

The solid (crystals, crystallized matter, solid content, second purified product, solvate of CBD, especially the second purified product) may or may not contain olivetol, but if it does contain olivetol, it will often contain small amounts. For example, in the solid (crystal, crystallized product, solid content, second purified product, CBD solvate, particularly the second purified product), the ratio of olivetol (e.g., ratio on an HPLC area basis) to the total amount of CBD (or CBD solvate), olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC may be, for example, 10% or less (e.g., 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less), etc.

In a mixture (e.g., a mixture containing naturally-occurring CBD and other cannabinoids, a mixture before the second purification, or a solvent S1 mixture), the ratio of olivetol (e.g., the ratio based on HPLC area (peak area)) to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC is designated M1; in a second purified product, the ratio of olivetol (e.g., the ratio based on HPLC area (peak area)) to the total amount of CBD (or CBD solvates), olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC is designated M2. When the ratio based on the area (peak area) of M1 is taken as M2, the value of M1-M2 may be greater than 0%, and may be selected from a range of about 0.01% or more (e.g., 0.02% or more), 0.03% or more (e.g., 0.05% or more), preferably 0.07% or more (e.g., 0.08% or more), more preferably 0.1% or more (e.g., 0.12% or more, 0.15% or more), or 0.2% or more (e.g., 0.5% or more, 1% or more, 1.5% or more, 2% or more, 2.5% or more, 3% or more, 3.5% or more).

The solid (crystals, crystallized product, solid content, second purified product, solvate of CBD, especially the second purified product) may or may not contain abn-CBD, but if it does contain abn-CBD, it will often contain only small amounts. For example, in the solid (crystal, crystallized product, solid content, second purified product, CBD solvate, particularly the second purified product), the ratio of abn-CBD to the total amount of CBD (or CBD solvate), olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC (e.g., ratio on an HPLC area basis) may be, for example, 10% or less (e.g., 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less), etc.

In a mixture (e.g., a mixture containing naturally occurring CBD and other cannabinoids, a mixture before the second purification, or a solvent S1 mixture), the ratio of abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., the ratio based on HPLC area (peak area)) is defined as M1; in the second purified product, the ratio of abn-CBD to the total amount of CBD (or solvates of CBD), olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC is defined as M2. When the proportion of -CBD (for example, the proportion based on the HPLC area (peak area)) is M2, the value of M1-M2 may be greater than 0%, or may be selected from a range of approximately 0.1% or more (for example, 0.5% or more), or may be 1% or more (for example, 1.2% or more), preferably 1.5% or more (for example, 1.8% or more), more preferably 2% or more (for example, 2.2% or more), and particularly 2.5% or more (for example, 2.8% or more, 3% or more, 3.2% or more, 3.5% or more, 3.8% or more, 4% or more).

The solid (crystals, crystallized product, solid content, second purified product, solvate of CBD, especially the second purified product) may or may not contain the 2:1 adduct, but if it does contain it, it will often be in small amounts. For example, in the solid (crystal, crystallized product, solid fraction, second purified product, CBD solvate, particularly the second purified product), the ratio of the 2:1 adduct to the total amount of CBD (or CBD solvate), olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC (e.g., the ratio on an HPLC area basis) may be, for example, 3% or less (e.g., 2.5% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.0001% or less), etc.

Solids (crystals, crystallized products, solids, second-purified products, solvates of CBD, especially those of natural origin) may or may not contain other cannabinoids, but if they do, they often contain small amounts. For example, in a solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly one derived from naturally occurring CBD), the ratio of the other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] to the total amount of CBD (or solvate of CBD) and other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] The proportion (e.g., proportion based on HPLC area (peak area)) of CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC) [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] may be, for example, 20% or less (e.g., 18% or less, 16% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less), etc.

The solid (crystals, crystallized matter, solid content, second purified product, solvate of CBD, especially the second purified product) may or may not contain Δ9-THC, but even if it does contain it, it will often be in small amounts. For example, in the solid (crystal, crystallized product, solid content, second purified product, CBD solvate, particularly the second purified product), the ratio of Δ9-THC to the total amount of CBD (or CBD solvate), olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC (e.g., ratio on an HPLC area basis) may be, for example, 1% or less (e.g., 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.0001% or less), etc.

The solid (crystals, crystallized matter, solid content, second purified product, solvate of CBD, especially the second purified product) may or may not contain Δ8-THC, but if it does contain any, it will often contain only small amounts. For example, in the solid (crystal, crystallized product, solid content, second purified product, CBD solvate, particularly the second purified product), the ratio of Δ8-THC to the total amount of CBD (or CBD solvate), olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC (e.g., ratio on an HPLC area basis) may be, for example, 1% or less (e.g., 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.0001% or less), etc.

The solid (crystals, crystallized matter, solid content, second purified product, solvate of CBD, particularly the second purified product) may or may not contain Δ9-THC and Δ8-THC, but even if it does contain them, they will often contain small amounts. For example, in the solid (crystal, crystallized product, solid content, second purified product, CBD solvate, particularly the second purified product), the ratio of Δ9-THC and Δ8-THC to the total amount of CBD (or CBD solvate), olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC (e.g., ratio on an HPLC area basis) may be, for example, 1% or less (e.g., 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.0001% or less), etc.

When the solid (crystals, crystallized product, solid content, second purified product, CBD solvate, particularly the second purified product) contains olivetol, the ratio of olivetol to CBD (or CBD solvate) in the solid (crystals, crystallized product, solid content, second purified product, CBD solvate, particularly the second purified product) (i.e., the ratio of olivetol/CBD (or CBD solvate)) (e.g., the ratio on an HPLC area basis) can be selected from a range of, for example, about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less), etc.

When the solid (crystals, crystallized product, solid content, second purified product, solvate of CBD, particularly the second purified product) contains abn-CBD, the ratio of abn-CBD to CBD (or solvate of CBD) in the solid (crystals, crystallized product, solid content, second purified product, solvate of CBD, particularly the second purified product) (i.e., ratio of abn-CBD/ratio of CBD (or solvate of CBD)) (e.g., ratio on an HPLC area basis) can be selected from a range of, for example, about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less), etc.

When a solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) contains a 2:1 adduct, the ratio of the 2:1 adduct to CBD (or solvate of CBD) in the solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) (i.e., the ratio of the 2:1 adduct/CBD (or solvate of CBD)) (e.g., the ratio on an HPLC area basis) is For example, it can be selected from a range of about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

When a solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) contains Δ9-THC, the ratio of Δ9-THC to CBD (or solvate of CBD) in the solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) (i.e., ratio of Δ9-THC/ratio of CBD (or solvate of CBD)) (e.g., ratio on an HPLC area basis) is: For example, it can be selected from a range of about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

When a solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) contains Δ8-THC, the ratio of Δ8-THC to CBD (or solvate of CBD) in the solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) (i.e., the ratio of Δ8-THC/CBD (or solvate of CBD)) (e.g., the ratio on an HPLC area basis) is: For example, it can be selected from a range of about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

When the solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) contains Δ9-THC and Δ8-THC, the ratio of Δ9-THC and Δ8-THC to CBD (or solvate of CBD) in the solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly the second purified product) [i.e., (total of the ratio of Δ9-THC and the ratio of Δ8-THC)/the ratio of CBD (or solvate of CBD)] (e.g., The ratio (based on HPLC area) can be selected, for example, from a range of about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

In a solid (crystal, crystallized product, solid fraction, second purified product, solvate of CBD, particularly second purified product), the ratio of olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC to CBD (or solvate of CBD) [i.e., the sum of (the ratio of olivetol, the ratio of abn-CBD, the ratio of 2:1 adduct, the ratio of Δ9-THC, and the ratio of Δ8-THC)/CBD (or solvate of CBD) The ratio of the solvate (e.g., ratio based on HPLC area) can be selected, for example, from a range of about 0.5 or less (e.g., 0.3 or less), and may be 0.1 or less (e.g., 0.08 or less), preferably 0.05 or less (e.g., 0.03 or less), more preferably 0.02 or less (e.g., 0.015 or less), and particularly 0.01 or less (e.g., 0.008 or less, 0.006 or less, 0.004 or less), etc.

[Mixtures containing CBD and other ingredients]
As described above, in the production of a CBD solvate, a mixture (e.g., a naturally occurring mixture or a reaction-derived mixture) containing CBD and other components (trace amounts of other components) may be used as the CBD (CBD used in the production, CBD source). Such mixtures [mainly reaction (chemical synthesis)-derived mixtures (mixtures obtained via chemical synthesis)] will be described in detail below.

Other components include unreacted raw materials (e.g., olivetol, menthadienol), by-products (abn-CBD, 2:1 adducts, Δ9-THC, Δ8-THC, etc.), and other components used in the reaction (e.g., catalysts). The other components may also be other cannabinoids.

The other components may typically include at least one selected from olivetol and by-products (abn-CBD, 2:1 adducts, Δ9-THC, Δ8-THC, etc.). Note that such other components are often contained in the reaction-derived mixture.

The mixture may also typically contain other cannabinoids as other components [e.g., one selected from CBG, CBN, CBC, CBDV, and THC (e.g., Δ9-THC, Δ8-THC), particularly one selected from CBG, CBN, and THC (e.g., Δ9-THC, Δ8-THC)]. Such other cannabinoids are often contained in naturally occurring mixtures, but cannabinoids such as THC are also often contained in reaction-derived mixtures, as described above.

An example of such a mixture (one embodiment) is a mixture containing other cannabinoids. Note that such a mixture may be either a naturally occurring mixture or a reaction-derived mixture, and may particularly be a naturally occurring mixture.

The mixture containing other cannabinoids may be, for example, obtained by isolating (purifying) CBD from a naturally occurring source (e.g., hemp), or may be a commercially available product.

In such a mixture, the proportion of CBD (e.g., the proportion based on HPLC area (peak area)) relative to the total amount of CBD and other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] can be selected from a range of, for example, 40% or more (e.g., 45% or more), 50% or more (e.g., 52% or more), preferably 55% or more (e.g., 58% or more), more preferably 60% or more (e.g., 62% or more), and particularly 65% or more (e.g., 66% or more, 67% or more). or higher, 68% or more, 69% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more), or 99.99% or less (for example, 99.9% or less, 99.8% or less, 99.5% or less, 99% or less, 98% or less, 97% or less, 95% or less, 92% or less, 90% or less, 88% or less), etc.

In a mixture (a mixture containing other cannabinoids), the proportion (e.g., the proportion based on HPLC area (peak area)) of other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] relative to the total amount of CBD and other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] can be selected from a range of, for example, 0.01% or more (e.g., 0.03% or more), and can be 0.05% or more (e.g., 0.1% or more). ), preferably 0.2% or more (e.g., 0.3% or more), more preferably 0.5% or more (e.g., 0.7% or more, 0.8% or more), particularly 1% or more (e.g., 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, 2% or more, 2.5% or more, 3% or more, 3.5% or more, 4% or more, 5% or more), or may be 20% or less (e.g., 18% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4.5% or less, 4% or less, 3.5% or less, 3% or less, 2.8% or less, 2.5% or less, 2.2% or less, 2% or less, 1.5% or less, 1% or less), etc.

Furthermore, examples of the mixture (one embodiment of a mixture, a mixture derived from a reaction) include the reaction mixture and the first purified product (crude CBD). In particular, among the reaction mixture and the first purified product (e.g., a purified product obtained by subjecting a reaction mixture to an adsorption treatment), it is preferable to use the first purified product (crude product, first purified product that has undergone the adsorption treatment described below) from the viewpoints that it is easy to precipitate CBD solvates and it is easy to efficiently obtain highly pure CBD.

Below, we will discuss in detail such mixtures (especially reaction-derived mixtures) containing CBD and other components (trace amounts of other components).

(Reaction mixture)
The reaction mixture (CBD-containing reaction mixture, CBD) is not particularly limited, but is usually obtained by reacting menthadienol with olivetol. CBD is produced (generated) by such a reaction.

The ratio (usage ratio) of menthadienol and olivetol is not particularly limited and may be equal or either may be used in excess. For example, the ratio may be selected from a range of approximately 0.3 moles or more (e.g., 0.5 moles or more) of olivetol per mole of menthadienol, 0.6 moles or more (e.g., 0.7 moles or more), preferably 0.8 moles or more (e.g., 0.85 moles or more), and more preferably 0.9 moles or more (e.g., 0.95 moles or more, 0.97 moles or more, 0.99 moles or more), or 1 mole or more (e.g., more than 1 mole, 1.01 moles or more, 1.02 moles or more, 1.03 moles or more, 1.04 moles or more, 1.05 moles or more, etc.).

The ratio (upper limit) of olivetol to 1 mole of menthadienol is not particularly limited, but may be selected from a range of approximately 5 moles or less (e.g., 4 moles or less), preferably 3 moles or less (e.g., 2 moles or less), more preferably 1.5 moles or less (e.g., 1.3 moles or less, 1.25 moles or less, 1.2 moles or less, 1.15 moles or less, 1.12 moles or less, 1.1 moles or less, etc.), or may be 1 mole or less (e.g., 0.99 moles or less, 0.98 moles or less, 0.97 moles or less, 0.95 moles or less, 0.93 moles or less, 0.9 moles or less, etc.).

The ratio of olivetol to 1 mole of menthadienol may be within a range combining the upper and lower limits (e.g., 0.3 to 1 mole, or more than 1 mole and up to 1.5 moles, etc.) (the same applies below).

In the present invention, a specific catalyst [at least one selected from non-boron Lewis acids and Bronsted acids (protonic acids)] may be present (or may be used) in the reaction.

Non-boron Lewis acids include non-boron compounds such as oxides (e.g., metal oxides), halides (e.g., fluorides, chlorides, bromides, iodides, etc.) (e.g., metal halides), alkoxides (e.g., metal alkoxides), triflates (e.g., metal triflates), and other complexes (e.g., acetylacetonate complexes, acetoacetate ester complexes).

Metals (non-boron-based metals, non-boron metals) include typical metals (elements) and transition metals (transition elements), such as metals (elements) from Groups 3 to 12 of the periodic table (e.g., scandium, yttrium, lanthanum, titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc, cadmium, etc.) and metals (elements) from Groups 1 to 17 of the periodic table, such as metals from Groups 13 to 16 of the periodic table (e.g., aluminum, gallium, indium, thallium, tin, lead, arsenic, antimony, bismuth, etc.).

Specific examples of non-boron Lewis acids include oxides (e.g., metal oxides such as aluminum oxide), halides [e.g., metal halides such as zinc halides (e.g., zinc chloride, zinc bromide, zinc iodide)], alkoxides [e.g., metal alkoxides such as titanium alkoxides (titanium tetramethoxide, titanium tetraethoxide), zirconium alkoxide], triflates (e.g., metal triflates such as scandium triflate, silver triflate, zinc triflate), acetylacetone complexes (e.g., metal acetylacetonates such as aluminum acetylacetonate), acetoacetate complexes (e.g., metal acetoacetate complexes such as aluminum ethylacetoacetate diisopropylate), etc.

Brønsted acids include organic acids and inorganic acids.

Examples of organic acids include carboxylic acids (e.g., fatty acids [e.g., monocarboxylic acids (e.g., alkanoic acids) such as formic acid, acetic acid, propionic acid, lactic acid, and trifluoroacetic acid; polycarboxylic acids (e.g., alkanoic acids) such as oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, malic acid, and citric acid], aromatic carboxylic acids (e.g., benzoic acid, phthalic acid, and terephthalic acid), etc.), sulfonic acids (e.g., alkanesulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; arenesulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid), etc.).

Examples of inorganic acids include hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide), sulfuric acid, nitric acid, phosphoric acid, etc.

The catalyst (acid catalyst) may be used alone or in combination of two or more types.

Typical catalysts include non-boron Lewis acids [e.g., metal oxides, metal halides, metal triflates], carboxylic acids, sulfonic acids, inorganic acids, etc.

Among these catalysts, non-boron Lewis acids may be preferably used from the viewpoint of suppressing the formation of by-products and achieving good reactivity (and, in combination with other conditions, easily achieving efficient suppression of by-product formation and good reactivity), and among these, metal halides (e.g., zinc halides such as zinc chloride, zinc bromide, and zinc iodide) may be preferably used.

Therefore, the catalyst may contain at least a non-boron Lewis acid [for example, a metal halide (e.g., a zinc halide such as zinc chloride, zinc bromide, or zinc iodide, particularly zinc iodide)].

As mentioned above, the reaction is usually carried out in the presence of a specific catalyst [at least one selected from non-boron Lewis acids and Bronsted acids (protonic acids)].

In such cases, a specific catalyst may be used in combination with a boron-based Lewis acid [for example, a boron trifluoride complex (for example, boron trifluoride diethyl ether complex, boron trifluoride monoalkylamine complex, boron trifluoride hydrate, etc.)], but from the standpoint of suppressing the formation of by-products and achieving good reactivity (and further, in combination with other conditions, suppressing the formation of by-products and achieving good reactivity efficiently), it is not necessary to use [in combination, substantially not used (in combination)].

The proportion (usage proportion) of the catalyst (specific catalyst) may be selected depending on the type of catalyst and other conditions, but may be selected, for example, from a range of approximately 0.0001 moles (or molar equivalent, the same applies below) or more per mole of menthadienol or olivetol (e.g., menthadienol). From the standpoint of suppressing the production of by-products and achieving good reactivity (and, in combination with other conditions, easily achieving efficient suppression of by-product production and good reactivity), the proportion may be approximately 0.001 moles or more (e.g., 0.003 moles or more), preferably 0.005 moles or more (e.g., 0.007 moles or more), and even more preferably 0.01 moles or more (e.g., 0.03 moles or more), or may be approximately 0.05 moles or more (e.g., 0.07 moles or more, 0.08 moles or more, 0.1 moles or more).

The proportion (upper limit) of the catalyst (specific catalyst) may be selected, for example, from a range of about 20 moles or less (e.g., 15 moles or less, 10 moles or less, 8 moles or less) per mole of menthadienol or olivetol (e.g., menthadienol). From the standpoint of suppressing the production of by-products and achieving good reactivity (and, in combination with other conditions, easily achieving efficient suppression of by-product production and good reactivity), the proportion may be about 5 moles or less (e.g., 3 moles or less), preferably 2 moles or less (e.g., 1.2 moles or less), and more preferably 1 mole or less (e.g., less than 1 mole, 0.8 moles or less), or may be 0.5 moles or less (e.g., 0.4 moles or less, 0.3 moles or less, 0.2 moles or less, 0.15 moles or less, 0.1 moles or less).

The reaction may be carried out in the presence of a solvent.

Solvents include, for example, hydrocarbons [e.g., aliphatic hydrocarbons (e.g., hexane, heptane, cyclohexane, methylcyclohexane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, ethylbenzene, etc.)], halogenated solvents (e.g., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), esters (e.g., aliphatic esters such as methyl acetate, ethyl acetate, butyl acetate, etc.), carbonates (e.g., ethylene carbonate, propylene carbonate, etc.), ethers [e.g., chain ethers (e.g., diethyl ether, methyl t-butyl ether, etc.), cyclic ethers (e.g., tetrahydrofuran, dioxane, etc.)], glycol ethers (e.g., ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, propylene glycol, etc.), ethanol monomethyl ether, diethylene glycol monoethyl ether, etc.), glycol ether esters (e.g., ethylene glycol monomethyl ether acetate, etc.), nitrogen-containing solvents {e.g., amides [e.g., N-substituted linear amides (e.g., N-alkyl-substituted alkanamides such as N,N-dimethylformamide and N,N-dimethylacetamide; N,N-diphenylacetamide, etc.), cyclic amides (e.g., 2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone, etc.)], nitriles (e.g., acetonitrile, etc.)], sulfur-containing solvents (e.g., sulfoxides such as dimethyl sulfoxide; sulfones such as dimethyl sulfone and sulfolane), alcohols [e.g., alkanols (e.g., methanol, ethanol, isopropanol), etc.], polyols (e.g., alkanediols such as ethylene glycol and propylene glycol; glycerin, etc.)], water, etc.

The aforementioned Bronsted acid [e.g., organic acid (e.g., acetic acid)] may also be used as a solvent.

The solvent may be, for example, an aprotic solvent, a protic solvent (water, alcohols, organic acids, etc.), a polar solvent, a non-polar (non-)polar solvent, etc. (or any solvent classified into any category). An aprotic solvent may be preferably used as the solvent.

Solvents may be used alone or in combination of two or more.

Among these solvents, aprotic solvents may be preferably used from the viewpoint of suppressing the formation of by-products and achieving good reactivity (and, in combination with other conditions, easily achieving efficient suppression of by-product formation and good reactivity), and hydrocarbons (especially aromatic hydrocarbons such as toluene) may be preferably used.

Therefore, the solvent may contain at least an aprotic solvent or a hydrocarbon (especially an aromatic hydrocarbon such as toluene).

The solvent may or may not contain a protic solvent (e.g., water, alcohols, organic acids, etc.), but from the standpoint of suppressing the production of by-products and achieving good reactivity (and, in combination with other conditions, making it easier to efficiently achieve suppression of by-product production and good reactivity), it is preferable that the solvent does not contain any protic solvent, or if it does contain any protic solvent, it may contain only a small amount [e.g., 10% by mass or less of the solvent (e.g., 5% by mass or less, 3% by mass or less, 1% by mass or less, 0.5% by mass or less, 0.1% by mass or less)].

In particular, it is preferable that the solvent (reaction system) does not contain water, or contains only a small amount of water, from the perspective of suppressing the formation of by-products and achieving good reactivity (and, in combination with other conditions, making it easier to efficiently achieve suppression of by-product formation and good reactivity).

When the solvent (reaction system) contains water, the proportion of water may be selected from a range of approximately 10% by mass or less (e.g., 8% by mass or less) of the reaction system (e.g., the total amount of menthadienol, olivetol, catalyst, and solvent), 5% by mass or less (e.g., 4% by mass or less, 3.5% by mass or less), preferably 3% by mass or less (e.g., 2.5% by mass or less), more preferably 2% by mass or less (e.g., 1.5% by mass or less), particularly 1.2% by mass or less (e.g., 1% by mass or less, 0.9% by mass or less, 0.8% by mass or less, 0.7% by mass or less, 0.6% by mass or less, 0.5% by mass or less, 0.4% by mass or less, 0.3% by mass or less, 0.28% by mass or less), particularly preferably 0.25% by mass or less (for example, 0.22% by mass or less, 0.2% by mass or less, 0.18% by mass or less, 0 .15 mass% or less, 0.12 mass% or less, 0.1 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.01 mass% or less.

When the solvent (reaction system) contains water, the proportion of water may be selected from a range of approximately 10% by mass or less of the solvent, and may be 5% by mass or less (e.g., 3% by mass or less), preferably 2% by mass or less (e.g., 1.5% by mass or less), and more preferably 1% by mass or less (e.g., 0.5% by mass or less, 0.1% by mass or less), etc.

When the solvent (reaction system) contains water, the proportion of water may be selected from a range of approximately 20 parts by mass or less (e.g., 15 parts by mass or less) per 100 parts by mass of menthadienol or olivetol (e.g., menthadienol), and may be 10 parts by mass or less (e.g., 8 parts by mass or less), preferably 5 parts by mass or less (e.g., 3 parts by mass or less), and more preferably 2 parts by mass or less (e.g., 1.5 parts by mass or less, 1 part by mass or less, 0.5 parts by mass or less, 0.3 parts by mass or less, 0.1 parts by mass or less), etc.

Note that the reaction between menthadienol and olivetol produces water (as a by-product). Therefore, the above water ratio may be the water ratio before the reaction (or at the start of the reaction, or at the initial stage of the reaction, or when by-product water is excluded).

Furthermore, during the reaction, the proportion of water may be maintained (retained) at a relatively low proportion (range) as described above. For example, during the reaction, the proportion of water may be 10% by mass or less (e.g., 5% by mass or less, 3% by mass or less, 2% by mass or less, 1% by mass or less, 0.8% by mass or less, 0.5% by mass or less, 0.4% by mass or less, 0.3% by mass or less, 0.2% by mass or less, 0.1% by mass or less) of the reaction system (e.g., the total amount of menthadienol, olivetol, catalyst, and solvent) or solvent.

Note that protic solvents (such as water) may already be contained in the raw materials (components) used in the reaction [e.g., Olivetol, catalyst (such as Bronsted acid), aprotic solvent, etc.].

In this way, when the raw materials already contain water and it is necessary to reduce the protic solvent (water, etc.), the protic solvent may be separated or removed from the raw materials or reaction system by conventional methods (e.g., distillation, etc.) (the water ratio may be adjusted to the above-mentioned level by separating or removing it).

As mentioned above, water is produced as a by-product in the reaction, but the reaction may be carried out while this by-product water is separated and removed by an appropriate method.

When a solvent is used, the proportion (concentration) of components other than the solvent (solids) relative to the total amount of the solvent and components other than the solvent (e.g., menthadienol, olivetol, and catalyst) may be, for example, about 0.1% by mass or more (e.g., 0.5% by mass or more, 1% by mass or more, 3% by mass or more, 5% by mass or more), or may be 99% by mass or less (e.g., 95% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 45% by mass or less, 40% by mass or less, 35% by mass or less, 30% by mass or less, 25% by mass or less, 20% by mass or less, 15% by mass or less, 12% by mass or less, 10% by mass or less), etc.

When a solvent is used, the ratio of solvent to olivetol or menthadienol (e.g., menthadienol) may be approximately 0.01 or more (e.g., 0.05 or more, 0.1 or more, 0.3 or more, 0.5 or more) by volume, or may be 1000 or less (e.g., 800 or less, 500 or less, 300 or less, 200 or less, 150 or less, 120 or less, 100 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less), etc.

The method for mixing the raw materials (components) used in the reaction (olivetol, menthadienol, catalyst, solvent, etc.) is not particularly limited; they may be mixed all together, mixed in stages, mixed partially, multiple components may be mixed in advance, or these may be combined.

In particular, from the viewpoint of suppressing the production of by-products and achieving good reactivity (and furthermore, in combination with other conditions, it is easy to efficiently achieve suppression of the production of by-products and good reactivity), one of the components of menthadienol or olivetol (e.g., olivetol) may be mixed (e.g., added dropwise) into a system (mixture) containing one of the components of menthadienol or olivetol (e.g., olivetol) and a catalyst (and further a solvent) [the menthadienol and olivetol may be reacted by mixing (e.g., adding dropwise)].
In particular, from the viewpoint of efficiently reacting (allowing the catalyst to function), a mixture containing olivetol and the catalyst may be mixed with menthadienol (for example, menthadienol may be added dropwise to a system (mixture) containing olivetol and the catalyst).

Mixing may be done all at once or in stages, preferably in stages.

Such mixing (staged mixing) may be intermittent, continuous (continuous), or a combination of these.

Furthermore, in such mixing (stepwise mixing), the time required for mixing (mixing time, total time, time until mixing is complete) depends on the amount of the other component, etc., but can be selected from a range of, for example, 30 seconds or more (e.g., 40 seconds or more), and may be 1 minute or more (e.g., 2 minutes or more), preferably 3 minutes or more (e.g., 4 minutes or more), and more preferably 5 minutes or more (e.g., 7 minutes or more), or may be 8 minutes or more (e.g., 10 minutes or more, 12 minutes or more, 15 minutes or more, 18 minutes or more, 20 minutes or more, 25 minutes or more, 30 minutes or more), etc.

The reaction may be carried out at room temperature (or normal temperature), heated, or cooled.

Specific reaction temperatures include, for example, -100°C or higher (e.g., -80°C or higher, -60°C or higher, -40°C or higher, -20°C or higher, 0°C or higher, 10°C or higher, 20°C or higher, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher, 60°C or higher, 65°C or higher, 70°C or higher, 75°C or higher, 80°C or higher, 85°C or higher, 90°C or higher, 95°C or higher, 100°C or higher, 105°C or higher, 110°C or higher), and 300°C or lower (e.g., 250°C or lower, 200°C or lower, 180°C or lower, 160°C or lower, 150°C or lower, 140°C or lower, 130°C or lower, 120°C or lower, 110°C or lower, 100°C or lower, 95°C or lower, 90°C or lower, 85°C or lower, 80°C or lower).

In particular, from the standpoint of suppressing the formation of by-products and achieving good reactivity (and, in combination with other conditions, making it easier to efficiently achieve suppression of by-product formation and good reactivity), the reaction temperature may be relatively high (for example, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher, 60°C or higher, 65°C or higher, 70°C or higher, 75°C or higher, 80°C or higher, 85°C or higher, 90°C or higher, 95°C or higher, 100°C or higher, 105°C or higher, 110°C or higher).

The reaction time can be appropriately selected depending on the degree of reaction progress (reaction rate, conversion rate), the type of catalyst, various reaction conditions, etc., and is not particularly limited. For example, it may be 1 second or more (e.g., 3 seconds or more, 5 seconds or more, 10 seconds or more, 20 seconds or more, 30 seconds or more, 40 seconds or more, 50 seconds or more, 1 minute or more, 1.5 minutes or more, 2 minutes or more, 2.5 minutes or more, 3 minutes or more, 3.5 minutes or more, 4 minutes or more, 4.5 minutes or more, 5 minutes or more, 8 minutes or more, 10 minutes or more, 15 minutes or more, 20 minutes or more, 25 minutes or more, 30 minutes or more), etc., or 24 hours or less (e.g., 18 hours or less, 12 hours or less, 10 hours or less, 8 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1.5 hours or less, 1.2 hours or less, 1 hour or less, 50 minutes or less, 40 minutes or less, 30 minutes or less), etc.

The reaction begins when menthadienol and olivetol (and furthermore the catalyst) coexist and are ready to react, and ends when the reaction no longer progresses (when all of the menthadienol or olivetol has reacted or been consumed) or when an operation (treatment) to slow (quench) the reaction is performed.

For example, as mentioned above, if stepwise mixing is performed, the reaction starts when mixing begins, and if the reaction is carried out under heating, the reaction ends when heating is stopped or cooling begins, and the time from the start of the reaction to the end of the reaction is defined as the reaction time.

The reaction may be carried out with stirring.

The reaction may also be carried out under an inert atmosphere (e.g., under nitrogen or argon).

The reaction may be batch or continuous.

There are no particular restrictions on the reaction vessel used in the reaction, and conventional vessels can be used.

Cannabidiol is produced (manufactured) through the above reaction. Cannabidiol is usually obtained as a mixture containing cannabidiol (reaction mixture, reaction liquid). The present invention also encompasses such mixtures (reaction mixtures).

The mixture (reaction mixture) may be concentrated (solvent removed), filtered, etc.

In the reaction mixture [after the reaction (completion), reaction system after the reaction (completion)], the reaction rate (conversion rate) of menthadienol or olivetol [when either one of the components (e.g., olivetol) is used in excess, the other component (e.g., menthadienol)] will vary depending on the timing of reaction completion, etc., but can be selected from a range of, for example, 20 mol% or more (e.g., 30 mol% or more, 40 mol% or more), and may be 50 mol% or more (e.g., 60 mol% or more), preferably 70 mol% or more (e.g., 80 mol% or more), more preferably 90 mol% or more (e.g., 95 mol% or more), or even 97 mol% or more (e.g., 98 mol% or more, 99 mol% or more, 100 mol%).

In the reaction mixture, the production rate (yield) of cannabidiol (CBD) can be selected from a range of, for example, 10 mol% or more (e.g., 15 mol% or more), and may be 20 mol% or more (e.g., 25 mol% or more), preferably 30 mol% or more (e.g., 35 mol% or more), more preferably 40 mol% or more (e.g., 45 mol% or more), and particularly 50 mol% or more (e.g., 52 mol% or more, 55 mol% or more, 58 mol% or more, 60 mol% or more).

The CBD production rate (upper limit) can be selected from a range of, for example, approximately 99 mol% or less (e.g., 97 mol% or less, 95 mol% or less, 90 mol% or less), and may typically be 85 mol% or less (e.g., 80 mol% or less, 75 mol% or less, 70 mol% or less, 65 mol% or less), etc.

The CBD production rate refers to the proportion (mol %) of menthadienol or olivetol that produced cannabidiol (reacted to become cannabidiol) out of the menthadienol or olivetol used as raw material (if either component (e.g., olivetol) is used in excess, the other component (e.g., menthadienol)).

The mixture (particularly the reaction mixture) contains CBD and other ingredients, as described above.

In the mixture (reaction mixture, etc.), the proportion of CBD (e.g., the proportion based on HPLC area (peak area)) relative to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC can be selected from a range of, for example, 10% or more (e.g., 15% or more), and may be 20% or more (e.g., 25% or more), preferably 30% or more (e.g., 35% or more), more preferably 40% or more (e.g., 45% or more), particularly 50% or more (e.g., 52% or more, 55% or more, 58% or more, 60% or more), or may be 99% or less (e.g., 97% or less, 95% or less, 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 65% or less), etc.

When a mixture (e.g., a reaction mixture) contains olivetol, the proportion of olivetol (e.g., the proportion on an HPLC area basis) relative to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the mixture can be selected from a range of, for example, 0.1% or more (e.g., 0.5% or more), and may be 1% or more (e.g., 2% or more), preferably 3% or more (e.g., 4% or more), more preferably 5% or more (e.g., 6% or more), particularly 7% or more (e.g., 8% or more, 9% or more, 10% or more, 11% or more, 12% or more), or 50% or less (e.g., 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 22% or less, 20% or less, 18% or less, 15% or less), etc.

When a mixture (e.g., a reaction mixture) contains abn-CBD, the proportion of abn-CBD (e.g., the proportion on an HPLC area basis) relative to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the mixture can be selected, for example, from a range of 0.1% or more (e.g., 0.5% or more), and may be 1% or more (e.g., 2% or more), preferably 3% or more (e.g., 4% or more), more preferably 5% or more (e.g., 6% or more), particularly 7% or more (e.g., 8% or more, 9% or more, 10% or more, 11% or more, 12% or more), or may be 70% or less (e.g., 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 22% or less, 20% or less, 18% or less, 15% or less), etc.

When a mixture (e.g., a reaction mixture) contains olivetol and abn-CBD, the ratio of olivetol and abn-CBD to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the mixture (e.g., the ratio based on HPLC area) can be selected from a range of, for example, 0.2% or more (e.g., 1% or more), and may be 2% or more (e.g., 4% or more), preferably 5% or more (e.g., 8% or more), more preferably 10% or more (e.g., 12% or more), particularly 15% or more (e.g., 16% or more, 18% or more, 20% or more, 22% or more, 24% or more, 25% or more), or 80% or less (e.g., 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less), etc.

When a mixture (such as a reaction mixture) contains a 2:1 adduct, the ratio of the 2:1 adduct to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the mixture (e.g., the ratio based on HPLC area) can be selected from a range of, for example, 0.01% or more (e.g., 0.05% or more), 0.1% or more (e.g., 0.3% or more), preferably 0.5% or more (e.g., 0.7% or more), more preferably 1% or more (e.g., 1.2% or more), and particularly 1.5% or more (e.g., , 1.8% or more, 2% or more, 2.2% or more, 2.5% or more, 2.8% or more, 3% or more, 3.2% or more, 3.5% or more, 3.8% or more, 4% or more, 4.2% or more, 4.5% or more, 4.8% or more, 5% or more, 5.2% or more, 5.5% or more), or 50% or less (for example, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 22% or less, 20% or less, 18% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5.5% or less), etc.

When a mixture (reaction mixture, etc.) contains Δ9-THC, the ratio of Δ9-THC to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the mixture (e.g., the ratio based on HPLC area) can be selected from a range of, for example, 0.01% or more (e.g., 0.03% or more), 0.05% or more (e.g., 0.1% or more), preferably 0.2% or more (e.g., 0.3% or more), and more preferably 0.5% or more (e.g., It may be 0.7% or more), particularly 0.8% or more (e.g., 1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, 2% or more), or it may be 20% or less (e.g., 18% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4.5% or less, 4% or less, 3.5% or less, 3% or less, 2.8% or less, 2.5% or less, 2.2% or less), etc.

When a mixture (such as a reaction mixture) contains Δ8-THC, the ratio of Δ8-THC to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the mixture (e.g., the ratio based on HPLC area) can be selected from a range of, for example, 0.001% or more (e.g., 0.005% or more), 0.01% or more (e.g., 0.03% or more), preferably 0.05% or more (e.g., 0.07% or more). , more preferably 0.1% or more (e.g., 0.12% or more), particularly 0.15% or more (e.g., 0.18% or more, 0.2% or more, 0.22% or more, 0.25% or more), or may be 10% or less (e.g., 5% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.55% or less, 0.5% or less, 0.45% or less, 0.4% or less, 0.35% or less, 0.3% or less), etc.

When a mixture (reaction mixture, etc.) contains Δ9-THC and Δ8-THC, the ratio of Δ9-THC and Δ8-THC to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the mixture (e.g., the ratio based on HPLC area) can be selected from a range of, for example, 0.01% or more (e.g., 0.03% or more), 0.05% or more (e.g., 0.1% or more), preferably 0.2% or more (e.g., 0.3% or more), and more preferably 0.5% or more (e.g., , 0.7% or more), particularly 0.8% or more (e.g., 1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, 2% or more, 2.1% or more, 2.2% or more), or 20% or less (e.g., 18% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4.5% or less, 4% or less, 3.5% or less, 3.2% or less, 3% or less, 2.8% or less, 2.5% or less), etc.

When a mixture (reaction mixture, etc.) contains olivetol, the ratio of olivetol to CBD in the mixture (i.e., olivetol ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, about 10 or less (e.g., 8 or less), and can be 5 or less (e.g., 4 or less), preferably 3 or less (e.g., 2.8 or less), more preferably 2.5 or less (e.g., 2.2 or less), particularly 2 or less (e.g., 1.8 or less, 1.5 or less, 1. 2 or less, 1 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, 0.32 or less, 0.3 or less, 0.28 or less, 0.25 or less, 0.22 or less), or 0.001 or more (e.g., 0.005 or more, 0.01 or more, 0.03 or more, 0.05 or more, 0.07 or more, 0.08 or more, 0.1 or more, 0.12 or more, 0.15 or more, 0.18 or more, 0.2 or more), etc.

When a mixture (reaction mixture, etc.) contains abn-CBD, the ratio of abn-CBD to CBD in the mixture (i.e., abn-CBD ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, about 10 or less (e.g., 8 or less), and is preferably 5 or less (e.g., 4 or less), preferably 3 or less (e.g., 2.8 or less), more preferably 2.5 or less (e.g., 2.2 or less), particularly 2 or less (e.g., 1.8 or less, 1.5 or less, It may be 1.2 or less, 1 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, 0.32 or less, 0.3 or less, 0.28 or less, 0.25 or less, 0.22 or less, 0.2 or less), or it may be 0.001 or more (e.g., 0.005 or more, 0.01 or more, 0.03 or more, 0.05 or more, 0.07 or more, 0.08 or more, 0.1 or more, 0.12 or more, 0.15 or more, 0.18 or more), etc.

When a mixture (such as a reaction mixture) contains olivetol and abn-CBD, the ratio of olivetol and abn-CBD to CBD in the mixture (i.e., the sum of (the ratio of olivetol and the ratio of abn-CBD)/the ratio of CBD) (e.g., the ratio based on HPLC area) can be selected from a range of, for example, about 20 or less (e.g., 15 or less), and is preferably 10 or less (e.g., 8 or less), preferably 6 or less (e.g., 5.5 or less), and more preferably 5 or less (e.g., 4 0.5 or less), particularly 4 or less (e.g., 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.8 or less, 1.6 or less, 1.5 or less, 1.2 or less, 1 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less), or 0.002 or more (e.g., 0.01 or more, 0.02 or more, 0.05 or more, 0.1 or more, 0.15 or more, 0.18 or more, 0.2 or more, 0.25 or more, 0.3 or more, 0.35 or more, 0.4 or more), etc.

When a mixture (such as a reaction mixture) contains a 2:1 adduct, the ratio of the 2:1 adduct to CBD in the mixture (i.e., the ratio of 2:1 adduct/the ratio of CBD) (e.g., the ratio on an HPLC area basis) can be selected from a range of, for example, about 3 or less (e.g., 2.5 or less), and may be 2 or less (e.g., 1.5 or less), preferably 1 or less (e.g., 0.8 or less), more preferably 0.5 or less (e.g., 0.3 or less), particularly 0.2 or less (e.g., 0.18 or less, 0.15 or less, 0.12 or less, 0.1 or less, 0.09 or less), or may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more), etc.

When a mixture (reaction mixture, etc.) contains abn-CBD and 2:1 adducts, the ratio of abn-CBD and 2:1 adducts to CBD in the mixture (i.e., (the sum of the ratio of abn-CBD and the ratio of 2:1 adducts)/CBD ratio) (e.g., the ratio based on HPLC area) can be selected from a range of, for example, about 15 or less (e.g., 12 or less), and is preferably 10 or less (e.g., 8 or less), preferably 5 or less (e.g., 4 or less), more preferably 3 or less (e.g., 2.8 or less), and particularly preferably 2.5 or less (e.g., 2. .1 or less, 2 or less, 1.8 or less, 1.5 or less, 1.2 or less, 1 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, 0.32 or less, 0.3 or less), or 0.001 or more (e.g., 0.005 or more, 0.01 or more, 0.03 or more, 0.05 or more, 0.07 or more, 0.08 or more, 0.1 or more, 0.12 or more, 0.15 or more, 0.18 or more, 0.2 or more, 0.22 or more, 0.25 or more, 0.28 or more), etc.

When a mixture (reaction mixture, etc.) contains Δ9-THC, the ratio of Δ9-THC to CBD in the mixture (i.e., Δ9-THC ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, about 1 or less (e.g., 0.8 or less), and can be 0.5 or less (e.g., 0.4 or less), preferably 0.3 or less (e.g., 0.28 or less), more preferably 0.25 or less (e.g., 0.22 or less), and particularly 0.2 or less (e.g., 0.18 or less, 0.15 or less, 0.12 or less). or less, 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.055 or less, 0.05 or less, 0.045 or less, 0.04 or less, 0.035 or less), or it may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.003 or more, 0.005 or more, 0.007 or more, 0.008 or more, 0.01 or more, 0.012 or more, 0.015 or more, 0.018 or more, 0.02 or more, 0.022 or more, 0.025 or more, 0.028 or more, 0.03 or more), etc.

When a mixture (reaction mixture, etc.) contains Δ8-THC, the ratio of Δ8-THC to CBD in the mixture (i.e., Δ8-THC ratio/CBD ratio) (e.g., ratio on an HPLC area basis) can be selected from a range of, for example, about 0.1 or less (e.g., 0.08 or less), and can be 0.05 or less (e.g., 0.04 or less), preferably 0.03 or less (e.g., 0.028 or less), more preferably 0.025 or less (e.g., 0.022 or less), particularly 0.02 or less (e.g., 0.018 or less, 0.015 or less, 0.012 or less, It may be 0.01 or less, 0.009 or less, 0.008 or less, 0.007 or less, 0.006 or less, 0.0055 or less, 0.005 or less, 0.0045 or less, 0.004 or less), or it may be 0.00001 or more (e.g., 0.00005 or more, 0.0001 or more, 0.0003 or more, 0.0005 or more, 0.0007 or more, 0.0008 or more, 0.001 or more, 0.0012 or more, 0.0015 or more, 0.0018 or more, 0.002 or more, 0.0022 or more, 0.0025 or more, 0.0028 or more, 0.003 or more), etc.

When a mixture (reaction mixture, etc.) contains Δ9-THC and Δ8-THC, the ratio of Δ9-THC and Δ8-THC to CBD in the mixture [i.e., (total ratio of Δ9-THC and Δ8-THC)/CBD ratio] (e.g., ratio on an HPLC area basis) can be selected, for example, from a range of about 1 or less (e.g., 0.8 or less), and is preferably 0.5 or less (e.g., 0.4 or less), preferably 0.3 or less (e.g., 0.28 or less), more preferably 0.25 or less (e.g., 0.22 or less), and particularly preferably 0.2 or less (e.g., 0.18 or less, It may be 0.15 or less, 0.12 or less, 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.055 or less, 0.05 or less, 0.045 or less, 0.04 or less), or it may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.003 or more, 0.005 or more, 0.007 or more, 0.008 or more, 0.01 or more, 0.012 or more, 0.015 or more, 0.018 or more, 0.02 or more, 0.022 or more, 0.025 or more, 0.028 or more, 0.03 or more, 0.032 or more, 0.035 or more), etc.

In a mixture (reaction mixture, etc.), the ratio of olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of (olivetol ratio, abn-CBD ratio, 2:1 adduct ratio, Δ9-THC ratio, and Δ8-THC ratio)/CBD ratio] (e.g., ratio based on HPLC area) can be selected from a range of, for example, about 30 or less (e.g., 25 or less), and is preferably 20 or less (e.g., 15 or less), preferably 10 or less (e.g., 8 or less), more preferably 5 or less (e.g., 4 or less), and particularly preferably 3 or less (e.g., It may be 2.8 or less, 2.5 or less, 2.2 or less, 2 or less, 1.9 or less, 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1 or less, less than 1, 0.95 or less, 0.9 or less, 0.85 or less, 0.8 or less, 0.75 or less), or it may be 0.001 or more (e.g., 0.01 or more, 0.03 or more, 0.05 or more, 0.1 or more, 0.15 or more, 0.2 or more, 0.25 or more, 0.3 or more, 0.35 or more, 0.4 or more, 0.45 or more, 0.5 or more, 0.55 or more, 0.6 or more, 0.65 or more, 0.7 or more), etc.

In a mixture (reaction mixture, etc.), the ratio of abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of (the ratio of abn-CBD, the ratio of 2:1 adducts, the ratio of Δ9-THC, and the ratio of Δ8-THC)/the ratio of CBD] (e.g., the ratio based on HPLC area) can be selected, for example, from a range of approximately 20 or less (e.g., 15 or less), and is preferably 10 or less (e.g., 8 or less), preferably 5 or less (e.g., 4 or less), more preferably 3 or less (e.g., 2.5 or less), and particularly preferably 2 or less (e.g., 1. 9 or less, 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1 or less, less than 1, 0.95 or less, 0.9 or less, 0.85 or less, 0.8 or less, 0.75 or less, 0.7 or less, 0.65 or less, 0.6 or less, 0.55 or less), or 0.001 or more (e.g., 0.005 or more, 0.01 or more, 0.02 or more, 0.05 or more, 0.1 or more, 0.15 or more, 0.2 or more, 0.25 or more, 0.3 or more, 0.35 or more, 0.4 or more, 0.45 or more, 0.5 or more), etc.

(First purified product (crude CBD))
As mentioned above, the reaction mixture (the mixture after the reaction) typically contains other components in addition to CBD.

Therefore, such mixtures may be further purified (CBD may be purified from the reaction mixture (components other than CBD (e.g., at least by-products) may be separated)).

The purification method (CBD purification (separation) method, purification technology, purification technique) is not particularly limited, and conventional methods (e.g., extraction, crystallization, recrystallization, distillation, chromatography, filtration, concentration) may be used.

In this regard, with the above-described mixture (reaction mixture), it is possible to relatively suppress the production of by-products (and thus obtain a mixture with relatively few by-products (low in relation to CBD)). Therefore, by using such a mixture (for example, the reaction mixture obtained by the method of the present invention), efficient purification is possible, as described above, in combination with the formation of solvates.

The inventors have discovered a method that allows for more efficient purification even when using such mixtures (mixtures in which the production of by-products is relatively suppressed, or mixtures in which the by-products are relatively low (relative to CBD)). This method is described in detail below.

(Adsorption step (first purification step))
First, the mixture is subjected to an adsorption treatment, if necessary.

Such adsorption treatment appears to make it relatively easy to separate (selectively separate (by adsorption)) by-products, particularly olivetol and abn-CBD, relatively efficiently. Therefore, such adsorption treatment is particularly effective for mixtures containing (especially containing relatively large amounts of) olivetol and abn-CBD (components that are at least one selected from olivetol and abn-CBD).

In particular, according to the inventors' research, olivetol is a highly polar component and tends to interfere with the crystallization of CBD, making the purification of CBD difficult and cumbersome. Therefore, it is preferable to separate olivetol to a high degree (as much as possible). This type of adsorption treatment is particularly suitable for mixtures that contain at least olivetol (especially those that contain a relatively large amount of olivetol).

The mixture (the mixture to be subjected to the adsorption treatment) may be a mixture containing a solvent (it may be a solvent mixture), such as the reaction mixture obtained by the method described above.

Solvents include, for example, hydrocarbons [e.g., aliphatic hydrocarbons (e.g., pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, ethylbenzene, etc.)], halogenated solvents (e.g., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), esters (e.g., aliphatic esters such as methyl acetate, ethyl acetate, butyl acetate, etc.), carbonates (e.g., ethylene carbonate, propylene carbonate, etc.), ethers [e.g., chain ethers (e.g., diethyl ether, methyl t-butyl ether, etc.), cyclic ethers (e.g., tetrahydrofuran, dioxane, etc.)], etc. , glycol ethers (e.g., ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, propylene glycol monomethyl ether, diethylene glycol monoethyl ether, etc.), glycol ether esters (e.g., ethylene glycol monomethyl ether acetate, etc.), nitrogen-containing solvents (e.g., amides [e.g., N-substituted linear amides (e.g., N-alkyl-substituted alkanamides such as N,N-dimethylformamide), cyclic amides (e.g., 2-pyrrolidone, etc.], etc.]), nitriles (e.g., acetonitrile, etc.), sulfur-containing solvents (e.g., sulfoxides such as dimethyl sulfoxide; sulfones such as dimethyl sulfone and sulfolane), alcohols [e.g., alkanols (e.g., methanol, ethanol, isopropanol), etc.], polyols (e.g., alkanediols such as ethylene glycol and propylene glycol; glycerin, etc.), etc.], water, etc.

Solvents may be used alone or in combination of two or more.

Among these solvents, from the perspective of efficient separation (separation by adsorption treatment) of by-products (e.g., olivetol, abn-CBD, etc., particularly olivetol), aprotic solvents (e.g., aprotic solvents with low polarity) may be preferably used, and hydrocarbons (especially aliphatic hydrocarbons) may be particularly preferably used.

Therefore, the solvent may contain at least an aprotic solvent or a hydrocarbon, and in particular may contain at least an aliphatic hydrocarbon (for example, pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, etc. [for example, aliphatic hydrocarbons having 5 or more carbon atoms (for example, 5 to 18 carbon atoms, 6 to 12 carbon atoms, 6 to 10 carbon atoms, etc.) (for example, linear or cyclic aliphatic hydrocarbons, saturated or unsaturated hydrocarbons, linear or cyclic saturated aliphatic hydrocarbons), etc.]).

When the solvent contains an aliphatic hydrocarbon, the proportion of the aliphatic hydrocarbon (e.g., heptane, etc.) relative to the total solvent may be selected from a range of, for example, 1 vol.% or more (e.g., 3 vol.% or more), preferably 5 vol.% or more (e.g., 10 vol.% or more), and more preferably 15 vol.% or more (e.g., 20 vol.% or more), and may be 25 vol.% or more [e.g., 30 vol.% or more, 35 vol.% or more, 40 vol.% or more, 50 vol.% or more, more than 50 vol.%, 60 vol.% or more, 70 vol.% or more, 80 vol.% or more, 85 vol.% or more, 90 vol.% or more, 95 vol.% or more, or (substantially) 100 vol.% (almost) only aliphatic hydrocarbons].

Aliphatic hydrocarbons may be used in combination with other solvents (solvents other than aliphatic hydrocarbons, for example, aromatic hydrocarbons such as toluene). In such cases, the proportion of the other solvent in the total solvent may be, for example, 99% by volume or less (e.g., 97% by volume or less), preferably 95% by volume or less (e.g., 90% by volume or less), and more preferably 85% by volume or less (e.g., 80% by volume or less, 75% by volume or less, 70% by volume or less, 65% by volume or less), or may be 1% by volume or more (e.g., 3% by volume or more, 5% by volume or more, 10% by volume or more, 15% by volume or more, 20% by volume or more, 25% by volume or more, 30% by volume or more, 35% by volume or more), etc.

The solvent may or may not contain a protic solvent (e.g., water, alcohols, etc.). However, from the perspective of efficient separation (separation by adsorption treatment) of by-products (e.g., olivetol, abn-CBD, etc., particularly at least olivetol), it is preferable that the solvent not contain any protic solvent, or contain only a small amount of water [e.g., 10% by volume or less of the solvent (e.g., 5% by volume or less, 3% by volume or less, 1% by volume or less, 0.5% by volume or less, 0.1% by volume or less)]. In particular, the solvent may not contain any water, or contain only a small amount of water [e.g., 10% by volume or less of the solvent (e.g., 5% by volume or less, 3% by volume or less, 1% by volume or less, 0.5% by volume or less, 0.1% by volume or less)].

In a mixture containing a solvent, the proportion (concentration) of components other than the solvent (solids) relative to the total amount of the solvent and components other than the solvent may be, for example, about 0.1% by mass or more (e.g., 0.5% by mass or more, 1% by mass or more, 3% by mass or more, 5% by mass or more), or may be 99% by mass or less (e.g., 95% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 45% by mass or less, 40% by mass or less, 35% by mass or less, 30% by mass or less, 25% by mass or less, 20% by mass or less, 15% by mass or less, 12% by mass or less, 10% by mass or less), etc.

In a mixture containing a solvent, the ratio of solvent to CBD1 may be approximately 0.01 or more (e.g., 0.05 or more, 0.1 or more, 0.3 or more, 0.5 or more) by volume, or may be 1000 or less (e.g., 800 or less, 500 or less, 300 or less, 200 or less, 150 or less, 120 or less, 100 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less), etc.

The mixture containing the solvent can be prepared by an appropriate method depending on the reaction mixture used, the type and amount of solvent, etc. For example, if the reaction mixture used is one from which the reaction solvent (the solvent used in the reaction) has been separated (removed), the mixture can be prepared by mixing the solvents. Additionally, if the reaction mixture used contains a reaction solvent, and the reaction solvent and the adsorption solvent (the solvent used in the adsorption treatment) are different, the reaction solvent can be separated (for example, by concentration) and then mixed with the solvent used in the adsorption treatment; if the reaction solvent is the same, the reaction solvent can be used as the adsorption solvent as is; and if the amount (ratio) of the solvent is different even when the solvent is the same, the amount of solvent can be adjusted appropriately (for example, by concentration or mixing).

The adsorption treatment method is not particularly limited, but a typical method involves contacting an adsorbent (adsorption means) with a mixture (especially a mixture containing a solvent).

Examples of adsorbents include silica (silica gel), alumina (activated alumina), zeolite, celite, diatomaceous earth, clay, activated clay, activated carbon, synthetic adsorbents, and ion exchange resins (such as activated alumina ion exchange resins).

Among these, silica may be preferably used from the viewpoint of efficient separation (selective separation) of by-products (e.g., olivetol, abn-CBD, etc., particularly at least olivetol).

The shape of the adsorbent (silica, etc.) is not particularly limited, but examples include granular shapes, which also include spherical shapes.

If the adsorbent is granular, the particle size is not particularly limited, but may be, for example, an average particle size of 1 to 500 μm (e.g., 3 to 300 μm, 5 to 100 μm), etc.

The adsorbents may be used alone or in combination of two or more types.

The amount of adsorbent (amount used) may be selected depending on the adsorption treatment method (mode of adsorption treatment), the type of adsorbent (adsorption capacity), the amount of by-products, etc., and is not particularly limited. For example, it may be selected from a range of approximately 0.01 parts by mass or more (e.g., 0.05 parts by mass or more, 0.1 parts by mass or more, 0.15 parts by mass or more) per 1 part by mass of CBD (or solids content (components other than solvent) contained in the mixture), or may be 0.2 parts by mass or more (e.g., 0.25 parts by mass or more), preferably 0.3 parts by mass or more (e.g., 0.35 parts by mass or more), and more preferably 0.4 parts by mass or more (e.g., 0.45 parts by mass or more, 0.5 parts by mass or more).

The amount (upper limit) of adsorbent is not particularly limited, but may be selected from a range of approximately 300 parts by mass or less (e.g., 100 parts by mass or less) per part by mass of CBD (or solids (components other than the solvent) contained in the mixture), and may be 80 parts by mass or less (e.g., 50 parts by mass or less), preferably 30 parts by mass or less (e.g., 20 parts by mass or less), and more preferably 10 parts by mass or less (e.g., 8 parts by mass or less, 5 parts by mass or less, 3 parts by mass or less, 2 parts by mass or less, 1 part by mass or less).

The adsorption treatment method (method of contacting the adsorbent with the mixture) is not particularly limited and can be selected appropriately depending on the form of the adsorbent, etc. For example, it may be a method of mixing the adsorbent with the mixture, a method of passing the mixture through an adsorbent (for example, a method of passing the mixture through an adsorbent fixed by appropriate means (for example, a column packed with adsorbent)), or a combination of these methods.

Among these, a method of mixing the adsorbent with the mixture may be preferably used from the viewpoint of efficient separation of by-products (e.g., olivetol, abn-CBD, etc., particularly at least olivetol).

Mixing may be carried out under stirring.

Mixing may also be carried out in an inert atmosphere (e.g., under nitrogen or argon).

There are no particular restrictions on the container used for mixing, and any conventional container can be used.

The adsorption treatment conditions are not particularly limited and can be appropriately selected depending on the amount, type, etc. of the adsorbent.
For example, adsorption may be carried out at room temperature (or normal temperature), under heating, or under cooling. Specific adsorption temperatures include, for example, −30° C. to 80° C. (e.g., 0 to 60° C., 5 to 50° C., 10 to 40° C.). The adsorption treatment time (e.g., the time for contacting the adsorbent with the mixture) can be selected depending on the type of adsorbent, the mode of the adsorption method, and the like, and is not particularly limited. For example, the adsorption treatment time may be 1 minute or more (e.g., 3 minutes or more), preferably 5 minutes or more (e.g., 10 minutes or less), more preferably 20 minutes or more (e.g., 30 minutes or more), or may be 24 hours or less (e.g., 12 hours or less, 6 hours or less, 3 hours or less), etc.

After the adsorption treatment, depending on the adsorption treatment (method), the adsorbent may be separated (for example, the adsorbent may be separated from a mixture containing the adsorbent). The separation method can be selected appropriately depending on the adsorbent and the type of adsorption treatment, and examples include filtration and decantation.

The adsorbent may be washed (washed) as needed, and the washing liquid [or solids (at least CBD, etc.) recovered from the washing liquid (e.g., recovered by concentration, etc.)] may be mixed with the adsorbed mixture. This method (washing process) can also recover CBD, etc. from the adsorbent [e.g., CBD that has adhered to the adsorbent (not adsorbed)]. Therefore, after the adsorption process, a further washing process [a process of washing the adsorbent (washing to recover CBD, etc.)] may be carried out.

The cleaning solvent is not particularly limited, and the solvents exemplified above may be used. The preferred embodiments of the solvent are the same as those described above. For example, hydrocarbons (particularly aliphatic hydrocarbons), preferably solvents containing at least aliphatic hydrocarbons (e.g., aliphatic hydrocarbons, or aliphatic and aromatic hydrocarbons), may be used.

The amount of cleaning solvent used can be selected appropriately depending on the amount of adsorbent, etc.

After the adsorption process (and further washing process), if necessary, the solvent (or solvent components, such as the adsorption solvent, washing solvent, etc.) may be separated (by concentration, etc.).

Through the above-described steps [adsorption treatment (adsorption treatment step), and, if necessary, washing step, etc.], a purified product containing CBD [sometimes referred to as a first purified product, crude product, etc. (in relation to the purified product described below)] is obtained {the mixture can be purified [components other than CBD (particularly, at least one component selected from olivetol and abn-CBD) can be separated (selectively separated)] from the mixture}.

Furthermore, even after undergoing adsorption treatment, etc., CBD can be almost completely recovered. For example, when the mass of CBD in the mixture (the mixture to be subjected to adsorption treatment) is A1 and the mass of CBD in the first purified product is A2, the value of A2/A1 can be selected from a range of, for example, approximately 0.5 or more (e.g., 0.6 or more), and may be approximately 0.7 or more (e.g., 0.75 or more, 0.8 or more, 0.85 or more, 0.88 or more, 0.9 or more, 0.92 or more, 0.95 or more, 0.96 or more, 0.97 or more, 0.98 or more, 0.99 or more, or substantially 1).

In the first purified product, the ratio of CBD (e.g., the ratio based on HPLC area (peak area)) to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC can be selected from a range of, for example, 40% or more (e.g., 45% or more), 50% or more (e.g., 52% or more), preferably 55% or more (e.g., 58% or more), more preferably 60% or more (e.g., 62% or more), and particularly preferably 65% or more. or higher (e.g., 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more), or 99.9% or less (e.g., 99.5% or less, 99% or less, 98% or less, 97% or less, 95% or less, 92% or less, 90% or less, 88% or less, 85% or less, 82% or less, 80% or less), etc.

When the ratio of CBD (e.g., the ratio based on the HPLC area (peak area)) to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC in the mixture is defined as M1, and the ratio of CBD (e.g., the ratio based on the HPLC area (peak area)) to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC in the first purified product is defined as M2, the value of M2-M1 may be greater than 0%, or may be selected from a range of approximately 0.1% or more (e.g., 0.5% or more), or may be 1% or more (e.g., 1.5% or more), preferably 2% or more (e.g., 2.5% or more), more preferably 3% or more (e.g., 4% or more), and particularly 5% or more (e.g., 7% or more, 8% or more, 10% or more, 12% or more, 15% or more).

The first purified product may or may not contain olivetol, but even if it does, it will often contain small amounts. For example, in the first purified product, the ratio of olivetol to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 20% or less (e.g., 15% or less, 12% or less, 10% or less, 8% or less, 5% or less, 3% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less), etc.

In addition, when the first purified product contains olivetol, the ratio of olivetol to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC in the first purified product (lower limit of the ratio, for example, the ratio based on HPLC area) may be 0.0001%, 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, etc.

In the mixture (mixture to be subjected to adsorption treatment, reaction mixture, etc.), the ratio of olivetol to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area (peak area)) is designated M1, and in the first purified product, the ratio of olivetol to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., HPLC area (peak area)) is designated M2. When the ratio based on the LC area (peak area) is taken as M2, the value of M1-M2 may be greater than 0%, or may be selected from a range of approximately 0.01% or more (e.g., 0.1% or more, 0.3% or more, 0.5% or more), or may be 1% or more (e.g., 1.5% or more), preferably 2% or more (e.g., 2.5% or more), and more preferably 3% or more (e.g., 3.5% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more).

The first purified product may or may not contain abn-CBD, but even if it does contain abn-CBD, it will often contain only small amounts. For example, in the first purified product, the ratio of abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 30% or less (e.g., 25% or less, 20% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less), etc.

In addition, when the first purified product contains abn-CBD, the ratio of abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC in the first purified product (lower limit of the ratio, for example, the ratio based on HPLC area) may be 0.01%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, etc.

In the mixture, the ratio of abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., the ratio based on HPLC area (peak area)) is defined as M1, and in the first purified product, the ratio of abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., the ratio based on HPLC area (peak area)) is defined as M2. The value of M1-M2 may be greater than 0%, or may be selected from a range of about 0.01% or more (e.g., 0.05% or more), and may be 0.1% or more (e.g., 0.2% or more), preferably 0.3% or more (e.g., 0.5% or more), more preferably 1% or more (e.g., 1.5% or more), and particularly 2% or more (e.g., 3% or more, 3.5% or more, 4% or more, 4.5% or more, 5% or more, 5.5% or more, 6% or more, 6.5% or more, 7% or more, 7.5% or more).

The first purified product may or may not contain olivetol and abn-CBD, but even if it does, it will often contain small amounts. For example, in the first purified product, the ratio of olivetol and abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 40% or less (e.g., 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5.5% or less), etc.

In addition, when the first purified product contains olivetol and abn-CBD, the ratio of olivetol and abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC in the first purified product (lower limit of the ratio, for example, the ratio based on HPLC area) may be 0.01%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, etc.

In the mixture, the ratio of olivetol and abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., the ratio based on the HPLC area (peak area)) is designated M1, and in the first purified product, the ratio of olivetol and abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., the ratio based on the HPLC area (peak area)) is designated M2. When M1 is 2, the value of M1-M2 may be greater than 0%, or may be selected from a range of approximately 0.05% or more (e.g., 0.1% or more), and may be 0.5% or more (e.g., 1% or more), preferably 2% or more (e.g., 3% or more), more preferably 5% or more (e.g., 7% or more), and particularly 8% or more (e.g., 9% or more, 10% or more, 11% or more, 12% or more, 13% or more, 14% or more, 15% or more, 16% or more, 17% or more, 18% or more, 19% or more, 20% or more).

The first purified product may also contain other components (e.g., by-products).

For example, if the first purified product contains a 2:1 adduct, the ratio of the 2:1 adduct to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the first purified product (e.g., the ratio based on HPLC area) can be selected from a range of, for example, 0.01% or more (e.g., 0.05% or more), 0.1% or more (e.g., 0.3% or more), preferably 0.5% or more (e.g., 0.7% or more), more preferably 1% or more (e.g., 1.2% or more), and particularly preferably 1.5% or more (e.g., 1.8% or more). or more, 2% or more, 2.2% or more, 2.5% or more, 2.8% or more, 3% or more, 3.2% or more, 3.5% or more, 3.8% or more, 4% or more, 4.2% or more, 4.5% or more, 4.8% or more, 5% or more, 5.2% or more, 5.5% or more, 5.8 or more, 6 or more, 7.2 or more, 7.5 or more), or 50% or less (for example, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 22% or less, 20% or less, 18% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less), etc.

If the first purified product contains Δ9-THC, the ratio of Δ9-THC (e.g., the ratio based on HPLC area) to the total amount of CBD, olivetol, abn-CBD, the 2:1 adduct, Δ9-THC, and Δ8-THC in the first purified product can be selected from a range of, for example, 0.01% or more (e.g., 0.03% or more), 0.05% or more (e.g., 0.1% or more), preferably 0.2% or more (e.g., 0.3% or more), more preferably 0.5% or more (e.g., 0.7% or more), and particularly 0.8% or more (e.g., For example, it may be 1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, 2% or more, 2.1% or more, 2.2% or more, 2.3% or more, 2.4% or more, 2.5% or more, 2.6% or more, 2.7% or more, 2.8% or more), or it may be 20% or less (for example, 18% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4.5% or less, 4% or less, 3.5% or less, 3% or less), etc.

When the first purified product contains Δ8-THC, the ratio of Δ8-THC to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC in the first purified product (e.g., the ratio based on HPLC area) can be selected from a range of, for example, 0.001% or more (e.g., 0.005% or more), 0.01% or more (e.g., 0.03% or more), preferably 0.05% or more (e.g., 0.07% or more), and even more preferably It may be 0.1% or more (e.g., 0.12% or more), particularly 0.15% or more (e.g., 0.2% or more, 0.25% or more, 0.3% or more, 0.35% or more, 0.4% or more, 0.45% or more, 0.5% or more, 0.55% or more, 0.6% or more, 0.65% or more, 0.7% or more), or it may be 10% or less (e.g., 8% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, 0.9% or less, 0.8% or less), etc.

When the first purified product contains Δ9-THC and Δ8-THC, the ratio of Δ9-THC and Δ8-THC to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC in the first purified product (e.g., ratio based on HPLC area) can be selected from a range of, for example, 0.01% or more (e.g., 0.03% or more), 0.05% or more (e.g., 0.1% or more), preferably 0.2% or more (e.g., 0.3% or more), more preferably 0.5% or more (e.g., 0.7% or more), and particularly 0.8% or more (e.g., 1% or more, 1.2% or more, 1.3% or more). %, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, 2% or more, 2.1% or more, 2.2% or more, 2.3% or more, 2.4% or more, 2.5% or more, 2.6% or more, 2.7% or more, 2.8% or more, 2.9% or more, 3% or more, 3.1% or more, 3.2% or more, 3.3% or more, 3.4% or more, 3.5% or more, 3.6% or more), or it may be 20% or less (for example, 18% or less, 15% or less, 12% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5.5% or less, 5% or less, 4.5% or less, 4% or less), etc.

When the first purified product contains olivetol, the ratio of olivetol to CBD in the first purified product (i.e., the olivetol ratio/CBD ratio) (e.g., the ratio based on HPLC area) can be selected from a range of, for example, about 1 or less (e.g., 0.5 or less), and may be 0.3 or less (e.g., 0.25 or less), preferably 0.2 or less (e.g., 0.15 or less), more preferably 0.1 or less (e.g., 0.05 or less), particularly 0.03 or less (e.g., 0.02 or less, 0.01 or less, 0.009 or less, 0.008 or less, 0.007 or less, 0.006 or less), or may be 0.00001 or more (e.g., 0.00005 or more, 0.0001 or more, 0.0005 or more, 0.001 or more, 0.002 or more, 0.003 or more, 0.004 or more, 0.005 or more), etc.

When the ratio of olivetol to CBD in the mixture (i.e., the ratio of olivetol/CBD) (e.g., the ratio based on the HPLC area (peak area)) is N1, and the ratio of olivetol to CBD in the first purified product (i.e., the ratio of olivetol/CBD) (e.g., the ratio based on the HPLC area (peak area)) is N2, the value of N1-N2 may be greater than 0, may be selected from a range of approximately 0.01 or more (e.g., 0.02 or more), may be 0.03 or more (e.g., 0.05 or more), preferably 0.07 or more (e.g., 0.08 or more), and more preferably 0.1 or more (e.g., 0.12 or more, 0.15 or more).

When the first purified product contains abn-CBD, the ratio of abn-CBD to CBD in the first purified product (i.e., abn-CBD ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, about 10 or less (e.g., 5 or less), and may be 3 or less (e.g., 2.5 or less), preferably 2 or less (e.g., 1.5 or less), more preferably 1 or less (e.g., 0.5 or less), particularly 0.3 or less (e.g., 0.2 or less, 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less), or may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more), etc.

If the ratio of abn-CBD to CBD in the mixture (i.e., the ratio of abn-CBD/the ratio of CBD) (e.g., the ratio based on the HPLC area (peak area)) is N1, and the ratio of abn-CBD to CBD in the first purified product (i.e., the ratio based on the HPLC area (peak area)) is N2, the value of N1-N2 may be greater than 0, or may be selected from a range of approximately 0.01 or more (e.g., 0.02 or more), and may be 0.03 or more (e.g., 0.05 or more), preferably 0.07 or more (e.g., 0.08 or more), and more preferably 0.1 or more (e.g., 0.12 or more, 0.15 or more).

When the first purified product contains olivetol and abn-CBD, the ratio of olivetol and abn-CBD to CBD in the first purified product [i.e., (ratio of olivetol and abn-CBD)/CBD ratio] (e.g., ratio based on HPLC area) can be selected from a range of, for example, about 10 or less (e.g., 7 or less), and is preferably 5 or less (e.g., 3 or less), and preferably 2.5 or less (e.g., 2 or less). ), more preferably 1.5 or less (e.g., 1 or less), particularly 0.5 or less (e.g., 0.4 or less, 0.3 or less, 0.2 or less, 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less), or may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more), etc.

When the ratio of olivetol and abn-CBD to CBD in the mixture (i.e., the sum of the olivetol ratio and the abn-CBD ratio)/the CBD ratio (e.g., the ratio based on the HPLC area (peak area)) is N1, and the ratio of olivetol and abn-CBD to CBD in the first purified product (i.e., the sum of the olivetol ratio and the abn-CBD ratio)/the CBD ratio (e.g., the ratio based on the HPLC area (peak area)) is N2, the value of N1-N2 may be greater than 0, may be selected from a range of approximately 0.01 or greater (e.g., 0.03 or greater), may be 0.05 or greater (e.g., 0.07 or greater), preferably 0.1 or greater (e.g., 0.15 or greater), and more preferably 0.2 or greater (e.g., 0.25 or greater, 0.3 or greater).

When the first purified product contains a 2:1 adduct, the ratio of the 2:1 adduct to CBD in the first purified product (i.e., the ratio of 2:1 adduct/the ratio of CBD) (e.g., the ratio on an HPLC area basis) can be selected from a range of, for example, about 3 or less (e.g., 2.5 or less), and may be 2 or less (e.g., 1.5 or less), preferably 1 or less (e.g., 0.8 or less), more preferably 0.5 or less (e.g., 0.3 or less), particularly 0.2 or less (e.g., 0.18 or less, 0.15 or less, 0.12 or less, 0.1 or less), or may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more), etc.

When the first purified product contains abn-CBD and 2:1 adducts, the ratio of abn-CBD and 2:1 adducts to CBD in the first purified product (i.e., the sum of the ratio of abn-CBD and the ratio of 2:1 adducts)/the ratio of CBD) (e.g., the ratio on an HPLC area basis) can be selected from a range of, for example, about 10 or less (e.g., 8 or less), and may be 5 or less (e.g., 4 or less), preferably 3 or less (e.g., 2 or less), more preferably 1 or less (e.g., 0.8 or less), particularly 0.5 or less (e.g., 0.4 or less, 0.3 or less, 0.2 or less, 0.15 or less), or may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.01 or more, 0.05 or more, 0.07 or more, 0.08 or more, 0.1 or more, 0.12 or more), etc.

If the first purified product contains Δ9-THC, the ratio of Δ9-THC to CBD in the first purified product (i.e., the ratio of Δ9-THC/CBD) (e.g., the ratio based on HPLC area) can be selected from a range of, for example, about 1 or less (e.g., 0.8 or less), and can be 0.5 or less (e.g., 0.4 or less), preferably 0.3 or less (e.g., 0.28 or less), more preferably 0.25 or less (e.g., 0.22 or less), and particularly 0.2 or less (e.g., 0.18 or less, 0.15 or less, 0.1 2 or less, 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.055 or less, 0.05 or less, 0.045 or less, 0.04 or less), or 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.003 or more, 0.005 or more, 0.007 or more, 0.008 or more, 0.01 or more, 0.012 or more, 0.015 or more, 0.018 or more, 0.02 or more, 0.022 or more, 0.025 or more, 0.028 or more, 0.03 or more), etc.

If the first purified product contains Δ8-THC, the ratio of Δ8-THC to CBD in the first purified product (i.e., the ratio of Δ8-THC/CBD) (e.g., the ratio based on HPLC area) can be selected from a range of, for example, about 0.1 or less (e.g., 0.08 or less), and can be 0.05 or less (e.g., 0.04 or less), preferably 0.03 or less (e.g., 0.028 or less), more preferably 0.025 or less (e.g., 0.022 or less), and particularly preferably 0.02 or less (e.g., 0.03 or less). It may be 0.018 or less, 0.015 or less, 0.012 or less, 0.01 or less), or 0.00001 or more (e.g., 0.00005 or more, 0.0001 or more, 0.0003 or more, 0.0005 or more, 0.0007 or more, 0.0008 or more, 0.001 or more, 0.0012 or more, 0.0015 or more, 0.0018 or more, 0.002 or more, 0.0022 or more, 0.0025 or more, 0.0028 or more, 0.003 or more, 0.005 or more, 0.007 or more), etc.

When the first purified product contains Δ9-THC and Δ8-THC, the ratio of Δ9-THC and Δ8-THC to CBD in the first purified product [i.e., (the sum of the ratio of Δ9-THC and the ratio of Δ8-THC)/the ratio of CBD] (e.g., the ratio on an HPLC area basis) can be selected, for example, from a range of about 1 or less (e.g., 0.8 or less), and can be 0.5 or less (e.g., 0.4 or less), preferably 0.3 or less (e.g., 0.28 or less), more preferably 0.25 or less (e.g., 0.22 or less), and particularly 0.2 or less (e.g., 0.18 or less, 0. It may be 0.15 or less, 0.12 or less, 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.055 or less, 0.05 or less, 0.045 or less, 0.04 or less), or it may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.003 or more, 0.005 or more, 0.007 or more, 0.008 or more, 0.01 or more, 0.012 or more, 0.015 or more, 0.018 or more, 0.02 or more, 0.022 or more, 0.025 or more, 0.028 or more, 0.03 or more, 0.032 or more, 0.035 or more), etc.

In the first purified product, the ratio of olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of (olivetol ratio, abn-CBD ratio, 2:1 adduct ratio, Δ9-THC ratio, and Δ8-THC ratio)/CBD ratio] (e.g., ratio based on HPLC area) can be selected from a range of, for example, approximately 20 or less (e.g., 10 or less), preferably 5 or less (e.g., 4 or less), preferably 3 or less (e.g., 2 or less), and more preferably may be 1.5 or less (e.g., 1.2 or less), particularly 1 or less (e.g., less than 1, 0.95 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, 0.3 or less, 0.25 or less), or may be 0.0001 or more (e.g., 0.0005 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.05 or more, 0.08 or more, 0.1 or more, 0.12 or more, 0.15 or more, 0.18 or more, 0.2 or more), etc.

In the mixture, the ratio of olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of (the ratio of olivetol, the ratio of abn-CBD, the ratio of 2:1 adducts, the ratio of Δ9-THC, and the ratio of Δ8-THC)/CBD] (e.g., the ratio on an HPLC area basis) is designated N1, and in the first purified product, the ratio of olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of (the ratio of olivetol, the ratio of abn-CBD, the ratio of 2:1 adducts, the ratio of Δ9-THC, and the ratio of Δ8-THC]/CBD] (e.g., the ratio on an HPLC area basis) is designated N2. When N2 is the ratio of CBD to total CBD, Δ9-THC, and Δ8-THC (sum of the ratio of CBD to total CBD, Δ9-THC, and Δ8-THC) / CBD ratio (e.g., the ratio based on HPLC area), the value of N1 - N2 may be greater than 0, and may be selected from a range of approximately 0.01 or more (e.g., 0.02 or more), and may be 0.03 or more (e.g., 0.05 or more), preferably 0.07 or more (e.g., 0.08 or more), and more preferably 0.1 or more (e.g., 0.12 or more, 0.15 or more, 0.18 or more, 0.2 or more, 0.22 or more, 0.25 or more, 0.28 or more, 0.3 or more).

In the first purified product, the ratio of abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of (the ratio of abn-CBD, the ratio of 2:1 adducts, the ratio of Δ9-THC, and the ratio of Δ8-THC)/the ratio of CBD] (e.g., the ratio based on HPLC area) can be selected, for example, from a range of about 15 or less (e.g., 10 or less), and is preferably 5 or less (e.g., 4 or less), preferably 3 or less (e.g., 2 or less), and more preferably 1.5 or less (e.g., It may be 1.2 or less), particularly 1 or less (for example, less than 1, 0.95 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.55 or less, 0.5 or less, 0.45 or less, 0.4 or less, 0.35 or less, 0.3 or less, 0.25 or less), or 0.0001 or more (for example, 0.0005 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.05 or more, 0.08 or more, 0.1 or more, 0.12 or more, 0.15 or more, 0.18 or more, 0.2 or more), etc.

In the mixture, the ratio of abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of the ratio of abn-CBD, the ratio of 2:1 adducts, the ratio of Δ9-THC, and the ratio of Δ8-THC]/CBD (e.g., the ratio on an HPLC area basis) is designated N1, and in the first purified product, the ratio of abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD [i.e., the sum of the ratio of abn-CBD, the ratio of 2:1 adducts, the ratio of Δ9-THC, and the ratio of Δ8-THC]/CBD (e.g., the ratio on an HPLC area basis) is designated N2. When the ratio (based on the area of LC) is N2, the value of N1 - N2 may be greater than 0, and may be selected from a range of about 0.01 or more (e.g., 0.02 or more), and may be 0.03 or more (e.g., 0.05 or more), preferably 0.07 or more (e.g., 0.08 or more), and more preferably 0.1 or more (e.g., 0.12 or more, 0.15 or more, 0.18 or more, 0.2 or more, 0.22 or more, 0.25 or more, 0.28 or more, 0.3 or more, 0.32 or more, 0.35 or more, 0.38 or more, 0.4 or more, 0.42 or more, 0.45 or more, 0.48 or more, 0.5 or more).

<CBD production from solvates>
CBD can be produced (manufactured, regenerated) from a solvate of CBD [e.g., a solvate obtained via naturally-derived CBD (crude CBD), a second purified product, or a crystal or crystallized product (obtained from naturally-derived CBD (crude CBD) or a second purification step (e.g., a step of obtaining a second purified product via a first purified product)].

The method for producing CBD is not particularly limited as long as it can release (desolvate) the solvent (e.g., DMA) from the solvate of CBD to produce CBD, and can be selected appropriately depending on the characteristics of the solvate of CBD, etc.

Specific methods include desolvation of the CBD solvate by heating, and desolvation of the CBD solvate by dissolving it in a solvent.

Typically, a solvate of CBD (such as a DMA solvate of CBD) may be brought into contact with water (dissolved or dispersed in water) to produce CBD through desolvation.

The resulting CBD can be separated (recovered) using conventional methods, particularly extraction.

For example, by coexisting a solvent that is a poor solvent for water (a solvent that undergoes phase separation or liquid-liquid separation with water, a hydrophobic solvent) and that can dissolve CBD (a good solvent for CBD, an extraction solvent, for example, an aliphatic hydrocarbon such as heptane) (a hydrophobic solvent that can dissolve CBD and is used as an extraction solvent), the (produced) CBD can be migrated (separated, extracted) into the hydrophobic solvent layer (hydrophobic solvent layer, liquid-liquid separation layer).
Such hydrophobic solvents include the solvents exemplified above, such as hydrocarbons.
In particular, the hydrophobic solvent may contain at least an aliphatic hydrocarbon {for example, an aliphatic hydrocarbon such as pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, or methylcyclohexane [for example, an aliphatic hydrocarbon having 5 or more carbon atoms (for example, 5 to 18 carbon atoms, 6 to 12 carbon atoms, 6 to 10 carbon atoms, etc.) (for example, a linear or cyclic aliphatic hydrocarbon, a saturated or unsaturated hydrocarbon, or a linear or cyclic saturated aliphatic hydrocarbon)], etc.}.

This type of extraction may result in the CBD solvate containing other components (e.g., by-products) (even if they are present in trace amounts), and may allow for further purification (leading to even higher CBD purity).

For example, by-products such as olivetol and abn-CBD are often present in trace amounts in solvates, but it is possible to further separate and remove these trace amounts of olivetol and by-products from CBD to obtain CBD of higher purity.

Then, CBD can be obtained from the separated layer (e.g., the hydrophobic solvent layer).

The separation layer (e.g., the hydrophobic solvent layer) may be further washed with a solvent (washing solvent) such as water.

The cleaning may be repeated once or more times.

The ratio (amount used, total amount) of the washing solvent may be, for example, 0.1 or more (e.g., 0.5 or more, 1 or more, 2 or more, 3 or more, 5 or more) or 30 or less (e.g., 20 or less, 15 or less, 10 or less, 8 or less) on a volume basis relative to 1 of the separation layer (e.g., the hydrophobic solvent layer).
When washing is performed two or more times, the ratio of the washing solvent per washing (amount used, total amount) may be, for example, 0.01 or more (e.g., 0.05 or more, 0.1 or more, 0.2 or more, 0.3 or more, 0.5 or more) or 30 or less (e.g., 20 or less, 10 or less, 5 or less, 3 or less, 2 or less, 1.5 or less) on a volume basis relative to 1 of the separation layer (e.g., the hydrophobic solvent layer).

CBD may be obtained by removing the solvent component from the separation layer (e.g., the hydrophobic solvent layer), or by crystallizing the CBD. As described above, crystallization may allow for further purification (leading to even higher CBD purity).

CBD can be crystallized using conventional methods, including, but not limited to, crystallization (recrystallization).

The solvent used for crystallization (recrystallization) is not particularly limited, and the solvents mentioned above can be used, but examples include hydrocarbons [e.g., aliphatic hydrocarbons (e.g., pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, ethylbenzene, etc.)], ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), ethers [e.g., chain ethers (e.g., diethyl ether, methyl t-butyl ether, etc.), cyclic ethers (e.g., tetrahydrofuran, dioxane, etc.)].

Among these, aliphatic hydrocarbons (e.g., aliphatic hydrocarbons such as pentane, hexane, isohexane, heptane, 2-methylhexane, 2,2-dimethylpentane, octane, isooctane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and methylcyclohexane [e.g., aliphatic hydrocarbons having 5 or more carbon atoms (e.g., 5 to 18 carbon atoms, 6 to 12 carbon atoms, 6 to 10 carbon atoms, etc.) (e.g., linear or cyclic aliphatic hydrocarbons, saturated or unsaturated hydrocarbons, linear or cyclic saturated aliphatic hydrocarbons)]) may be particularly used.

In crystallization (recrystallization), the proportion (amount) of solvent used can be selected depending on the crystallization conditions, etc., but may be, for example, a proportion (concentration) that results in a solids concentration of 1% by mass or more (e.g., 5% by mass or more, 10% by mass or more, 20% by mass or more, 30% by mass or more) or 90% by mass or less (e.g., 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less).

The reaction (crystallization) may also be carried out in the presence of seed crystals.

Crystallization (recrystallization) can be carried out at room temperature (or normal temperature), under heating, or under cooling.

Specific crystallization (recrystallization) temperatures include, for example, -100°C or higher (e.g., -80°C or higher, -60°C or higher, -40°C or higher, -20°C or higher, -10°C or higher, 0°C or higher, 10°C or higher, 20°C or higher, 30°C or higher, 35°C or higher, 40°C or higher), and 150°C or lower (e.g., 140°C or lower, 130°C or lower, 120°C or lower, 110°C or lower, 100°C or lower, 90°C or lower, 80°C or lower, 70°C or lower, 60°C or lower, 50°C or lower).

In particular, the crystallization (recrystallization) temperature may be relatively low or not too high (e.g., 40°C or less, 35°C or less, 30°C or less, 25°C or less, 20°C or less, 15°C or less, 10°C or less, 5°C or less). The crystallization (recrystallization) temperature may also be decreased in stages.

The crystallization (recrystallization) time can be selected appropriately depending on the degree of progress of crystallization (recrystallization), various crystallization (recrystallization) conditions, etc., and is not particularly limited, but may be, for example, 30 seconds or more (e.g., 1 minute or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 20 minutes or more, 25 minutes or more, 30 minutes or more, 40 minutes or more, 60 minutes or more, 1.5 hours or more, 2 hours or more), etc., or 48 hours or less (e.g., 36 hours or less, 24 hours or less, 18 hours or less, 12 hours or less, 6 hours or less), etc.

Crystallization (recrystallization) may be carried out with stirring or by leaving the mixture to stand.

Crystallization (recrystallization) may also be carried out under an inert atmosphere (e.g., under nitrogen or argon).

There are no particular restrictions on the container used for crystallization (recrystallization), and conventional containers can be used.

Through the above reaction (crystallization), CBD is produced (manufactured, recovered, and recycled).

Furthermore, when the CBD is almost completely recovered, for example, when the mass of CBD in the CBD solvate is A1 and the mass of CBD (regenerated CBD) is A2, the value of A2/A1 can be selected, for example, from a range of approximately 0.7 or more, and may be approximately 0.8 or more (e.g., 0.85 or more, 0.88 or more, 0.9 or more, 0.92 or more, 0.93 or more, 0.94 or more, 0.95 or more, 0.96 or more, 0.97 or more, 0.98 or more, 0.99 or more, or substantially 1).

Furthermore, CBD may or may not contain components other than CBD (olivetol, by-products, other cannabinoids, etc.), but even if it does contain them, they will be in extremely small amounts (highly purified).

For example, in CBD (regenerated CBD), the proportion of CBD (e.g., the proportion based on HPLC area (peak area)) relative to the total amount of CBD and other cannabinoids [or CBG, CBN, CBC, CBDV, and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN, and THC (e.g., Δ9-THC, Δ8-THC)] can be selected from a range of, for example, 88% or more (e.g., 90% or more), and may be 92% or more (e.g., 93% or more), preferably 95% or more (e.g., 96% or more), more preferably 97% or more (e.g., 97.5% or more), particularly 98% or more, 98.5% or more, 99% or more, 99.2% or more, 99.5% or more, 99.9% or more, 99.95% or more, or substantially 100%.

Furthermore, in CBD (regenerated CBD), the proportion of CBD (e.g., the proportion based on HPLC area (peak area)) relative to the total amount of CBD, olivetol, abn-CBD, 2:1 adduct, Δ9-THC, and Δ8-THC can be selected from a range of, for example, 88% or more (e.g., 90% or more), and may be 92% or more (e.g., 93% or more), preferably 95% or more (e.g., 96% or more), more preferably 97% or more (e.g., 97.5% or more), particularly 98% or more, 98.5% or more, 99% or more, 99.2% or more, 99.5% or more, 99.9% or more, 99.95% or more, or substantially 100%.

CBD (regenerated CBD) may or may not contain olivetol, but even if it does, it often contains small amounts. For example, in CBD (regenerated CBD), the ratio of olivetol to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 8% or less (e.g., 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.01% or less, 0.001% or less), etc.

CBD (regenerated CBD) may or may not contain abn-CBD, but even if it does, it will often contain small amounts. For example, in CBD (regenerated CBD), the ratio of abn-CBD to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 8% or less (e.g., 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.01% or less, 0.001% or less), etc.

CBD (regenerated CBD) may or may not contain 2:1 adducts, but even if it does, it will often contain small amounts. For example, in CBD (regenerated CBD), the ratio of 2:1 adducts to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 3% or less (e.g., 2.5% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.001% or less, 0.0001% or less), etc.

CBD (regenerated CBD) may or may not contain other cannabinoids, but even if it does contain other cannabinoids, it often does so in small amounts. For example, in CBD (regenerated CBD), the ratio of other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] [or CBG, CBN and THC (e.g., Δ9-THC, Δ8-THC)] to the total amount of CBD and other cannabinoids [or CBG, CBN, CBC, CBDV and THC (e.g., Δ9-THC, Δ8-THC)] is For example, the proportion of each of the Δ9-THC and Δ8-THC (e.g., proportion based on HPLC area) may be, for example, 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1.2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.001% or less, 0.0001% or less, or the like.

CBD (regenerated CBD) may or may not contain Δ9-THC, but even if it does, it will often contain small amounts. For example, in CBD (regenerated CBD), the ratio of Δ9-THC to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 1% or less (e.g., 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.001% or less, 0.0001% or less, etc.).

CBD (regenerated CBD) may or may not contain Δ8-THC, but even if it does, it often contains small amounts. For example, in CBD (regenerated CBD), the ratio of Δ8-THC to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 1% or less (e.g., 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.001% or less, 0.0001% or less), etc.

CBD (regenerated CBD) may or may not contain Δ9-THC and Δ8-THC, but even if it does, it often contains small amounts. For example, in CBD (regenerated CBD), the ratio of Δ9-THC and Δ8-THC to the total amount of CBD, olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC (e.g., ratio based on HPLC area) may be, for example, 1% or less (e.g., 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.05% or less, 0.01% or less, 0.001% or less, 0.0001% or less), etc.

When CBD (regenerated CBD) contains olivetol, the ratio of olivetol to CBD in the CBD (regenerated CBD) (i.e., olivetol ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0001 or less), etc.

When CBD (regenerated CBD) contains abn-CBD, the ratio of abn-CBD to CBD in the CBD (regenerated CBD) (i.e., abn-CBD ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, approximately 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0001 or less, etc.).

When CBD (regenerated CBD) contains 2:1 adducts, the ratio of the 2:1 adducts to CBD in the CBD (regenerated CBD) (i.e., the ratio of 2:1 adducts/CBD) (e.g., the ratio on an HPLC area basis) can be selected from a range of, for example, about 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

When CBD (regenerated CBD) contains Δ9-THC, the ratio of Δ9-THC to CBD in the CBD (regenerated CBD) (i.e., Δ9-THC ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, approximately 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

When CBD (regenerated CBD) contains Δ8-THC, the ratio of Δ8-THC to CBD in the CBD (regenerated CBD) (i.e., Δ8-THC ratio/CBD ratio) (e.g., ratio based on HPLC area) can be selected from a range of, for example, approximately 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

When CBD (regenerated CBD) contains Δ9-THC and Δ8-THC, the ratio of Δ9-THC and Δ8-THC to CBD in the CBD (regenerated CBD) [i.e., (total of Δ9-THC ratio and Δ8-THC ratio)/CBD ratio] (e.g., ratio on an HPLC area basis) can be selected from a range of, for example, approximately 0.1 or less (e.g., 0.05 or less), and may be 0.03 or less (e.g., 0.025 or less), preferably 0.02 or less (e.g., 0.015 or less), more preferably 0.01 or less (e.g., 0.008 or less), and particularly 0.005 or less (e.g., 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

When the CBD (regenerated CBD) contains at least one selected from olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC, the ratio of olivetol, abn-CBD, 2:1 adducts, Δ9-THC, and Δ8-THC to CBD in the CBD (regenerated CBD) [i.e., (the sum of the olivetol ratio, the abn-CBD ratio, the 2:1 adduct ratio, the Δ9-THC ratio, and the Δ8-THC ratio)/the CBD ratio] (e.g., For example, the ratio based on the HPLC area can be selected from a range of about 0.5 or less (e.g., 0.3 or less), and may be 0.1 or less (e.g., 0.08 or less), preferably 0.05 or less (e.g., 0.03 or less), more preferably 0.02 or less (e.g., 0.015 or less), and particularly 0.01 or less (e.g., 0.008 or less, 0.006 or less, 0.004 or less, 0.003 or less, 0.002 or less, 0.001 or less, 0.0005 or less, 0.0001 or less), etc.

CBD (regenerated CBD) typically does not contain (or the amount is below the detection limit of) a solvent [residual solvent, for example, a solvent derived from a solvate (a solvent that constitutes a solvate, for example, dimethylacetamide), a solvent used during regeneration (for example, an aliphatic hydrocarbon such as heptane)], or even if it contains a solvent, the amount may be very small.
For example, when CBD (regenerated CBD) contains a solvent (solvent component), the ratio of the solvent to the entire CBD (CBD including residual solvent) may be, for example, 5% by mass or less (e.g., 4% by mass or less, 3.5% by mass or less, 3% by mass or less, 2.5% by mass or less, 2% by mass or less, 1.5% by mass or less, 1.2% by mass or less, 1% by mass or less, 0.8% by mass or less, 0.7% by mass or less, 0.6% by mass or less, 0.5% by mass or less, 0.3% by mass or less, 0.2% by mass or less, 0.1% by mass or less), etc.
More specifically, the proportion (upper limit) of the solvent derived from the solvate (the solvent that constitutes the solvate, for example, dimethylacetamide) relative to the total CBD may be 5% by mass or less, 4.5% by mass or less, 4% by mass or less, 3.5% by mass or less, 3% by mass or less, 2.5% by mass or less, 2% by mass or less, 1.5% by mass or less, 1.2% by mass or less, 1% by mass or less, 0.8% by mass or less, 0.5% by mass or less, 0.3% by mass or less, 0.2% by mass or less, 0.1% by mass or less, etc.
In addition, the proportion (upper limit) of hydrocarbons (e.g., aliphatic hydrocarbons such as heptane) relative to the total CBD may be 3% by mass or less, 2.5% by mass or less, 2% by mass or less, 1.5% by mass or less, 1.2% by mass or less, 1% by mass or less, 0.8% by mass or less, 0.5% by mass or less, 0.3% by mass or less, 0.2% by mass or less, 0.1% by mass or less, 0.08% by mass or less, 0.05% by mass or less, etc.

Furthermore, when CBD (regenerated CBD) contains a solvent (solvent component), the ratio of the solvent to the entire CBD (CBD including residual solvent) may be above the detection limit, for example, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.02% by mass or more, 0.03% by mass or more, 0.05% by mass or more, 0.06% by mass or more, 0.07% by mass or more, 0.08% by mass or more, 0.09% by mass or more, 0.1% by mass or more, etc.
More specifically, the proportion (lower limit) of the solvent derived from the solvate (the solvent that constitutes the solvate, for example, dimethylacetamide) relative to the total CBD may be 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.5% by mass or more, 1% by mass or more, etc.
In addition, the proportion (lower limit) of hydrocarbons (e.g., aliphatic hydrocarbons such as heptane) relative to the total CBD may be 0.0001% by mass or more, 0.0005% by mass or more, 0.0001% by mass or more, 0.001% by mass or more, 0.005% by mass or more, 0.01% by mass or more, 0.05% by mass or more, 0.1% by mass or more, 0.5% by mass or more, etc.

The solvent ratio may be measured, for example, by gas chromatography.

CBD (reconstituted CBD) may in particular be in the form of crystals (crystalline form).

The present invention will be explained in detail below using examples, but the present invention is not limited to these.

Various analyses and measurements (calculations) were performed as follows:

[HPLC]
Measurement was performed using the following equipment and conditions.
Equipment: Shimadzu Corporation LC-2010HT
Measurement wavelength: 210nm
Column: Waters Corporation, Xselect CSH C18, 4.6 mm x 150 mm (particle size: 3.5 μm)
Column temperature: 35°C
Mobile phase A: 0.1% formic acid aqueous solution Mobile phase B: 0.1% formic acid acetonitrile solution Flow rate: 1.0 mL/min
Gradient:

The "%" in the composition indicates that the total peak area from 0.0 to 18.0 minutes is 100%.

[Powder X-ray (2θ)]
Measurement was performed using the following equipment and conditions.
Device: Rigaku SmartLab
Measurement method: Reflection method Light source type: Cu tube Wavelength used: CuKβ rays Tube current: 200mA
Tube voltage: 45Kv
Sample plate: Circular anti-reflective sample holder X-ray incident angle: 4 to 40°

[ ^1H -NMR]
Measurement was carried out using an Ascend ^™ 400 manufactured by Bruker.

[Melting point]
The endothermic peak temperature was measured in DSC using the following equipment and conditions, and was taken as the melting point.
Apparatus: DSC 3+ manufactured by Mettler Toledo Co., Ltd.
Conditions: Approximately 1.2 mg of sample was weighed and placed in an aluminum pan, and the measurement was carried out at a temperature range of 60°C to 70°C and a temperature rise rate of 0.5°C/min.

[Gas Chromatography]
Measurement was performed under the following conditions.
Detector: FID
Column: DB-624 (30 m x 0.320 mm, 1.80 μm)
Column temperature: 35°C (0 min) - 3°C/min - 70°C (0 min) - 9°C/min - 130°C (5 min) - 15°C/min - 230°C (0 min)
Inlet temperature: 200℃
Detector temperature: 230°C
Carrier gas: _N2
Flow control mode: Constant flow Split ratio: 40:1
Injection volume: 1.0μL
Area measurement range: 30 minutes Sample dilution solvent: N-methylpyrrolidone The retention times of the residual solvents were MTBE (8.0 minutes), heptane (13.0 minutes), toluene (16.5 minutes), DMA (21.6 minutes), etc.

[Example 1]
Cannabidiol (CBD) was dissolved in DMA [1.6 V (1.6 times the volume of DMA relative to CBD)], 0.3 V of water was added, and the mixture was rapidly cooled to 5°C. After confirming the precipitation of a solid (crystal), the slurry was filtered to obtain the solid (crystal).

Separately, heptane (10 V), DMA (3 eq.), and toluene (0.3 V) were added to cannabidiol and rapidly cooled to 5°C to obtain a solid (crystals).

Analysis of the resulting solids (crystals) revealed that they were all compounds in which 2 moles of DMA were added (solvated) to 1 mole of cannabidiol (CBD-2DMA).

The analysis results are as follows:

・Powder X-ray (2θ):
It was confirmed that the characteristic peaks shown in (C) above (i.e., the following approximately 20 peaks) were present.
8.3±0.2°, 8.5±0.2°, 10.6±0.2°, 11.8±0.2°, 13.4±0.2°, 15.4±0.2°, 15.8±0.2°, 16.4±0.2°, 17.0±0.2°, 18.9±0.2°, 19.9±0.2°, 21.4±0.2°, 22.7±0.2°, 22.9±0.2°, 23.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.5±0.2°, 27.1±0.2°, 27.7±0.2°

^1H -NMR
δppm: 0.88 (t, J=7.2Hz, 3H), 1.22-1.36 (m, 2H), 1.52-1.60 (m, 2H), 1.64-1.6 7 (m, 3H), 1.75-1.85 (m, 2H), 1.78-1.80 (m, 3H), 2.07-2.13 (m, 2H), 2.08 (s, 6H) ), 2.18-2.28 (m, 3H), 2.37-2.46 (m, 3H), 2.94 (s, 6H), 3.01 (s, 6H), 3.82-3.87 (m, 1H), 4.56 (s, 1H), 4.65-4.67 (m, 1H), 5.56-5.58 (m, 1H), 6.13-6.30 (m, 1H)

Melting point: 52-55°C [using the above-mentioned equipment and conditions (DSC)]

Furthermore, the resulting solid (crystal, CBD-2DMA) had lower solubility in various solvents, such as heptane, than CBD.

[Synthesis Example 1]
21.63 parts by mass of Olivetol containing 9.3% by mass of water [i.e., 19.62 parts by mass of Olivetol (1.09 eq. relative to menthadienol) and 2.01 parts by mass of water] was subjected to azeotropic dehydration treatment three times with 171.52 parts by mass of toluene [13 V (13 times the volume of menthadienol)], and the weight was adjusted so that the toluene in the reaction vessel became 20 V.

To this was added 3.19 parts by mass (0.1 eq. relative to menthadienol) of zinc iodide (ZnI ₂ ), and the temperature was adjusted to 110°C.
A solution of 15.22 parts by mass of menthadienol in 171.54 parts by mass of toluene (13 V) was added dropwise over 30 minutes [i.e., the total amount of solvent (toluene) was 33 V], and the mixture was allowed to react for 5 minutes after the dropwise addition, and then allowed to return to room temperature over 1 hour to obtain a reaction mixture (reaction liquid).

The proportion of water in the reaction vessel (reaction system) was 0.04% by mass when menthadienol was added (at the start of the reaction, immediately before addition).

The composition of the reaction solution was confirmed by HPLC to be 62.96% CBD, 13.26% olivetol, 12.17% abn-CBD, 2.20% Δ9-THC, 0.28% Δ8-THC, and 5.46% 2:1 adduct. The quantitative value was calculated to be 63.40%.
The quantitative value is the yield (calculated value) obtained by using a standard (CBD standard) to calculate the amount of CBD in the liquid by HPLC (the same applies below).

[Synthesis Example 2]
Tetrahydrofuran (20V) and 85.3 mg (1.8 eq. relative to menthadienol) of boron trifluoride diethyl etherate (BF ₃ OEt ₂ ) were added to the reaction vessel, and the temperature was adjusted to −10° C. using the jacket.

To this, 21.63 parts by mass of olivetol containing 9.3% by mass of water [i.e., 19.62 parts by mass of olivetol (1.09 eq. relative to menthadienol), 2.01 parts by mass of water] and a solution of 15.22 parts by mass of menthadienol in 171.54 parts by mass of toluene (13V) were added (flowed in) [i.e., the total amount of solvent (toluene) was 33V], and the mixture was allowed to react for 3.5 hours after addition (flowing in), and then returned to room temperature over 1 hour to obtain a reaction mixture (reaction liquid).

The composition of the reaction solution was confirmed by HPLC, and was found to be 13.97% CBD, 31.365% olivetol, and 45.02% abn-CBD, with Δ9-THC and Δ8-THC below the detection limit.

As is clear from the composition of each reaction solution, the method used in Synthesis Example 1 was able to reduce this relatively compared to Synthesis Example 2 by selecting a different synthesis method, but unreacted components (olivetol) and by-products were still present in the reaction mixture.

[Example 2]
(Crude product preparation process)
In the crude product preparation step, the mass of menthadienol used in the reaction was used as the basis for wt (mass) and V (volume).
The reaction liquid obtained in Synthesis Example 1 was concentrated under reduced pressure to 2.9 wt, and 104.10 parts by mass of heptane (10V) was added, followed by concentration under reduced pressure again, and the solvent was replaced with heptane.

343.64 parts by mass of heptane (33V) and 45.66 parts by mass (3 wt) of silica gel (particle size 40-50 μm, neutral, spherical) were added to the concentrated liquid and stirred at room temperature for 30 minutes.

The silica gel was filtered and washed with 103.42 parts by mass of a 3% by volume toluene-heptane solution (10V). The filtrate was then concentrated under reduced pressure to 1.6 wt. to obtain a crude product (mixture, first purified product).

The composition of the crude product was confirmed by HPLC, and was found to be 79.91% CBD, 0.41% olivetol, 4.63% abn-CBD, 2.95% Δ9-THC, 0.72% Δ8-THC, and 7.9% 2:1 adducts. The quantitative value was calculated to be 55.7%.

(purification process)
In the purification process, the quantitative values of cannabidiol in the crude product (mixture, first purified product) were used as the basis for wt (mass), V (volume), and eq. (equivalent).
To the obtained crude product, 107.85 parts by mass of heptane (9V) and 12.96 parts by mass of methyl t-butyl ether (MTBE) (1V) were added, and after confirming that the solution had become one layer, the mixture was cooled to 10°C.

To this, 4.58 parts by mass (1 eq.) of DMA was added dropwise, and 0.0127 parts by mass (0.07 wt% based on the quantitative value of CBD in the crude composition) of crystals (seed crystals) obtained from the CBD-2DMA crystals obtained in Example 1 were added.

After confirming the precipitation of crystals, 9.70 parts by mass (2 eq.) of DMA was added dropwise and the mixture was cooled to 0-5°C. After aging the mixture at 0-5°C for 2 hours, the crystals were filtered, washed with 43.17 parts by mass (3.5V) of a washing solvent [heptane:MTBE:DMA = 9:1:0.3 (volume ratio)], and dried by blowing nitrogen for 20 minutes.

The resulting crystals (solid) were confirmed to be CBD-2DMA (containing CBD-2DMA) using the same method as above.

71.90 parts by mass of heptane (6V) and 105.12 parts by mass of tap water (6V) were added to the crystals (solid), and after stirring, it was confirmed that all of the solid had dissolved.

After separation, the organic layer was washed three times with 105.12 parts by mass (6V) of tap water, and the washed organic layer was dried over 35.04 parts by mass (2 wt) of sodium sulfate.
The sodium sulfate was filtered off, and the solution was concentrated under reduced pressure to 1.0 wt.

When the composition of the organic layer after washing was confirmed by HPLC, it was found to be 99.63% CBD, 0.1% olivetol, and 0.27% abn-CBD, with no detectable Δ9-THC, Δ8-THC, or 2:1 adducts. The quantitative value was calculated to be 51.8%.

In the subsequent purification steps, the quantitative values of cannabidiol in the organic layer after washing were used as the basis for wt (mass) and V (volume).
22.28 parts by mass of heptane (2 V relative to the quantitative value of CBD) was added to the concentrated solution, and after heating to 30°C, 0.1722 parts by mass of CBD seed crystals (1 wt% relative to the quantitative value of CBD) were added. After confirming the precipitation of crystals, the solution was crystallized and aged at 25°C for 1 hour.

Then, it was cooled to 0-5°C over 20 minutes, crystallized and aged for 45 minutes, and then cooled to -15°C over 15 minutes. After crystallization and aging for 2 hours, the crystals (solid) were filtered and washed with 12.07 parts by mass (1.1 V) of heptane that had been cooled to the same temperature. The crystals (solid) were aerated and dried for 25 minutes, and then dried under reduced pressure at 40°C for 1 hour, yielding 14.92 parts by mass of solid (crystal).

The obtained solid (crystal) was confirmed to be CBD as a result of ¹ H-NMR analysis.
In other words, it was found that the obtained solid (crystal, CBD-2DMA) releases DMA when exposed to water (in water) and becomes CBD (regenerates CBD).

The composition of the solid (CBD crystals) was confirmed by HPLC, and was found to be 100.00% CBD, with no detectable olivetol, abn-CBD, Δ9-THC, Δ8-THC, or 2:1 adducts. The CBD yield (assuming 100% of menthadienol had reacted) was calculated to be 46.9% (calculated by subtracting the mass of the seed crystals).

In addition, the obtained solid (CBD crystals) contained very small amounts of residual solvent (heptane: 176 ppm by mass, DMA: 251 ppm by mass).
Therefore, various additions and changes were made to the purification process, which allowed the amount of residual solvent to be reduced. For example, when the aforementioned procedure of washing the organic layer three times with 105.12 parts by mass (6V) of tap water was changed to a procedure of washing the organic layer three times with 105.12 parts by mass (6V) of tap water and four times with 122.64 parts by mass (7V) of tap water, the proportion of DMA in the resulting solid (CBD) was below the detection limit (undetectable).

In the above method, CBD-2DMA is used as a seed crystal, but it has been confirmed that crystals can be obtained (crystallization or precipitation occurs) even without seed crystals.

[Example 3]
(Crude product preparation process)
In the crude product preparation step, the mass of menthadienol used in the reaction was used as the basis for wt (mass) and V (volume).
A reaction solution was obtained in the same manner as in Synthesis Example 1.
The composition of the reaction solution was confirmed by HPLC to be 62.897% CBD, 13.764% olivetol, 10.695% abn-CBD, 3.067% Δ9-THC, 0.412% Δ8-THC, and 4.642% 2:1 adduct. The quantitative value was calculated to be 64.77%.

This reaction solution was concentrated under reduced pressure to 2.49 wt, and then 6.6 V of heptane was added and concentrated under reduced pressure twice to replace the solvent with heptane.

To the concentrate, 33V of heptane and 45.6 parts by mass (3 wt) of silica gel (particle size 40-50 μm, neutral, spherical) were added, and the mixture was stirred at room temperature for 1 hour.
The silica gel was filtered off and washed with 10 V of a 3% by volume toluene-heptane solution, and the filtrate was concentrated under reduced pressure to 1.7 wt to obtain a crude product.

The composition of the crude product was confirmed by HPLC, revealing 76.47% CBD, 0.28% olivetol, 3.7% abn-CBD, 4.32% Δ9-THC, 1.25% Δ8-THC, and 11.65% 2:1 adducts. The quantitative value was calculated to be 52.5%.

(purification process)
In the purification process, the quantitative values of cannabidiol in the crude product (mixture, first purified product) were used as the basis for wt (mass), V (volume), and eq. (equivalent).
To the crude product, 9 V of heptane and 1 V of methyl t-butyl ether (MTBE) were added, and after confirming that the solution had become a single layer, the mixture was cooled to 10°C.

1 eq. of DMA was added dropwise to the mixture, and seed crystals obtained from the CBD-2DMA crystals obtained in Example 1 were added.

After confirming the precipitation of crystals, 2 eq. of DMA was added dropwise and the mixture was cooled to 0-5°C. After aging the crystals at 0-5°C for 1 hour, the crystals were filtered, washed with 1.8 V of washing solvent [heptane:MTBE:DMA = 9:1:0.3 (volume ratio)], and dried by blowing nitrogen for 30 minutes.

5.7V of heptane and 5.7V of tap water were added to the crystals (solid), and after stirring, it was confirmed that all of the solid had dissolved.

After separation, the organic layer was washed three times with 5.7 V of tap water, and the washed organic layer was dried over 7.05 parts by mass (4.3 wt) of sodium sulfate.
The sodium sulfate was filtered off, and the solution was concentrated under reduced pressure to 1.0 wt, after which 3.0 V of heptane was added.

When the composition of the organic layer after washing was confirmed by HPLC, it was found to be 99.06% CBD, 0.03% olivetol, and 0.91% abn-CBD, with no detectable Δ9-THC, Δ8-THC, or 2:1 adducts. The quantitative value was calculated to be 49.41%.

In the subsequent purification steps, the quantitative values of cannabidiol in the organic layer after washing were used as the basis for wt (mass) and V (volume).
Heptane 3V was added to the concentrated solution, and the temperature was raised to 25°C. 0.0009 parts by mass (0.06 wt%) of CBD seed crystals was added. After confirming the precipitation of crystals, the solution was crystallized and aged at 25°C for 1 hour. The solution was then cooled to -10°C and crystallized and aged for 1 hour. The crystals (solid) were filtered and washed with heptane cooled to the same temperature. The crystals (solid) were aerated and dried for 15 minutes, then dried under reduced pressure at 40°C for 1 hour, yielding 1.25 parts by mass of solid (crystal).

The composition of the solid (CBD crystals) was confirmed by HPLC, revealing that it was 100.00% CBD, with no detectable olivetol, abn-CBD, Δ9-THC, Δ8-THC, or 2:1 adducts. The CBD yield (assuming 100% of menthadienol had reacted) was calculated to be 40.3% (calculated by subtracting the mass of the seed crystals).

[Example 4]
(Crude product preparation process)
In the crude product preparation step, the mass of menthadienol used in the reaction was used as the basis for wt (mass) and V (volume).
A reaction solution was obtained in the same manner as in Synthesis Example 1.
The composition of the reaction solution was confirmed by HPLC to be 62.897% CBD, 13.764% olivetol, 10.695% abn-CBD, 3.067% Δ9-THC, 0.412% Δ8-THC, and 4.642% 2:1 adduct. The quantitative value was calculated to be 64.77%.

The reaction mixture was concentrated and used in the next purification step.

(purification process)
In the purification process, the quantitative values of cannabidiol in the concentrate were determined on the basis of wt (mass), V (volume), and eq. (equivalent).
To the concentrated reaction mixture were added 4.5 V of heptane and 0.5 V of methyl t-butyl ether (MTBE), and after confirming that the solution had become a single layer, the mixture was cooled to 0°C.
2 eq. of DMA was added dropwise thereto, and the crystals obtained based on the CBD·2DMA crystals obtained in Example 1 were added as seed crystals.

After confirming the precipitation of crystals, 1 eq. of DMA was added dropwise, and the mixture was allowed to crystallize and mature for 90 minutes at 0-5°C. The crystals were then filtered, washed with a washing solvent [heptane:MTBE:DMA = 9:1:0.3 (volume ratio)], and dried by blowing nitrogen for 30 minutes.

The resulting crystals (solid) were confirmed to be CBD-2DMA (containing CBD-2DMA) using the same method as above.

4V of heptane and 4V of tap water were added to the crystals (solid), and after stirring, it was confirmed that all of the solid had dissolved.

After separation, the organic layer was washed with 4V of tap water, and the washed organic layer was dried over 1 wt of sodium sulfate. The sodium sulfate was filtered off, washed with heptane, and the solution was concentrated under reduced pressure.

When the composition of the organic layer after washing was confirmed by HPLC, it was found to be 94.37% CBD, 3.55% olivetol, and 2.07% abn-CBD, with no detectable Δ9-THC, Δ8-THC, or 2:1 adducts. The quantitative value was calculated to be 45.13%.

In the subsequent purification steps, the quantitative values of cannabidiol in the organic layer after washing were used as the basis for wt (mass) and V (volume).
4.8V of heptane was added to the concentrated solution, and after adjusting the temperature to 10°C, CBD seed crystals were added and crystal precipitation was confirmed. The solution was then cooled to 0°C and crystallized and aged at the same temperature. The crystals (solid) were filtered and washed with heptane cooled to the same temperature to obtain 0.7896 parts by mass of solid (crystal).

The composition of the solid (CBD crystals) was confirmed by HPLC to be 94.51% CBD, 4.80% olivetol, and 0.69% abn-CBD, with no detectable Δ9-THC, Δ8-THC, or 2:1 adducts. The CBD yield (assuming 100% menthadienol had reacted) was calculated to be 25.6% (calculated after subtracting the mass of the seed crystals).

Furthermore, an oily substance was slightly exuded onto the surface of the solid. This substance is thought to be olivetol.

Furthermore, while the above method uses CBD-2DMA as seed crystals, it has been confirmed that crystals can be obtained (crystallization or precipitation occurs) even without seed crystals.

[Example 5]
(Crude product preparation process)
In the crude product preparation step, the mass of menthadienol used in the reaction was used as the basis for wt (mass) and V (volume).
A reaction solution was obtained in the same manner as in Synthesis Example 1.
The composition of the reaction solution was confirmed by HPLC to be 62.897% CBD, 13.764% olivetol, 10.695% abn-CBD, 3.067% Δ9-THC, 0.412% Δ8-THC, and 4.642% 2:1 adduct. The quantitative value was calculated to be 64.77%.

This reaction solution was concentrated under reduced pressure to 2.49 wt, and then 6.6 V of heptane was added and concentrated under reduced pressure twice to replace the solvent with heptane.

33V of toluene and 2 wt of silica gel (particle size 40-50 μm, neutral, spherical) were added to the concentrated liquid and stirred at room temperature for 1 hour.

The silica gel was filtered and washed with 16V of heptane, and the filtrate was concentrated under reduced pressure to 2.0 wt to obtain the crude product.

The composition of the crude product was confirmed by HPLC, and was found to be 70.99% CBD, 5.14% olivetol, 9.56% abn-CBD, 4.26% Δ9-THC, 0.97% Δ8-THC, and 6.37% 2:1 adducts. The quantitative value was calculated to be 62.2%.

(purification process)
In the purification process, the quantitative values of cannabidiol in the crude product were used as the basis for wt (mass), V (volume), and eq. (equivalent).
To the crude product, 9 V of heptane and 1 V of methyl t-butyl ether (MTBE) were added, and after confirming that the solution had become a single layer, the solution was cooled to 0° C. 3 eq. of DMA was added dropwise thereto, and precipitation of crystals was confirmed.

After aging for 1 hour at 0-5°C, the crystals were filtered, washed with a washing solvent [heptane:MTBE:DMA = 9:1:0.3 (volume ratio)] (1.5V), and dried by blowing nitrogen for 15 minutes.

7V heptane and 7V tap water were added to the crystals (solid), and after stirring, it was confirmed that all of the solid had dissolved.

After separation, the organic layer was washed with 6V of 10% DMA water and 12V of tap water (twice at 6V). After drying the washed organic layer with 1.1 wt. of sodium sulfate, the solids were filtered off and the solution was concentrated under reduced pressure.

The composition of the organic layer after washing was confirmed by HPLC, and was found to be 93.55% CBD, 1.59% olivetol, 3.97% abn-CBD, and 0.89% Δ9-THC. No Δ8-THC or 2:1 adducts were detected. The quantitative value was calculated to be 56.27%.

[Example 6]
We used commercially available CBD.
According to the COA (Certificate of Analysis), the CBD obtained contains impurities derived from hemp, a natural product (crude CBD, crude product).

Specifically, the CBD purity was 87.940%, and the main impurities (cannabinoids other than CBD) were 1.573% CBG (cannabigerol), 1.891% CBN (cannabinol), 1.055% CBC (cannabichromene), and 0.345% CBDV (cannabidivarin).

(purification process)
In the purification process, the CBD obtained was measured in wt (mass), V (volume), and eq. (equivalent).

Heptane was added to the obtained CBD (crude CBD) to adjust the weight to 7.2 wt (CBD 1 wt, heptane 6.2 wt) (equivalent to 9V of heptane), and MTBE (2V) was added and cooled to 10°C.

Furthermore, DMA (3.0 eq.) was added dropwise, cooled to -10°C, and after confirming crystallization, the mixture was aged for 2 hours (crystallization aging).

The aged slurry was filtered, and the crystals were washed with a washing solvent [a mixture of heptane (3.1V), MTBE (0.35V), and DMA (0.1V)] cooled to -10°C, and then dried with nitrogen blower for at least 15 minutes to obtain crystals (solid).

Furthermore, when the filtrate from the slurry was analyzed by HPLC, impurities (such as CBN) were detected.

Heptane (7V) and purified water (7V) were added to the resulting solid (crystals), and after stirring, it was confirmed that all of the solid had dissolved.

After separation, the organic layer was washed six times with purified water (7V). The washed organic layer was then dried over sodium sulfate (1.5 wt). The sodium sulfate was then filtered off, and the solution was concentrated under reduced pressure to 1.3 wt.

Furthermore, when the composition of the organic layer after washing was confirmed by HPLC, it was found to be 99.2% CBD, with the quantitative value calculated to be 80.6%.

In subsequent purification steps, the quantitative values of cannabidiol in the organic layer after washing were used as the basis for wt (mass) and V (volume).

Heptane was added to the concentrate to adjust the weight to 2.5 wt (CBD 1 wt, heptane 1.5 wt) (equivalent to 2V heptane), and the temperature was adjusted to 28°C.

After confirming the precipitation of crystals, the slurry was cooled to -15°C over 1 hour. After crystallization and aging at -15°C for at least 1 hour, the crystals (solid) were filtered and washed with heptane (1V) cooled to the same temperature. After further drying under aeration, the crystals were dried under reduced pressure at 40°C to obtain the crystals (solid).

The composition of the resulting crystals (solid) was confirmed by HPLC to be 99.5% CBD, with no detectable traces of CBG, CBN, Δ9-THC, Δ8-THC, etc.

As is clear from the results of the examples, according to the present invention, solvates of cannabidiol can be obtained. Such solvates can also be obtained via mixtures containing olivetol or other cannabinoids.

Furthermore, by utilizing (forming or passing through) such solvates of cannabidiol, it was possible to efficiently purify (recover) cannabidiol.

In particular, according to the present invention, as described above, cannabidiol can be efficiently purified (recovered) even through a mixture containing olivetol and other cannabinoids.
In particular, as in Examples 2 and 3, by using (passing through) a mixture from which olivetol and the like have been relatively separated (removed), cannabidiol could be purified (recovered) more efficiently.
Additionally, as is clear from Example 6, cannabidiol could be efficiently purified (recovered) from a mixture regardless of its origin (e.g., chemically synthesized, naturally occurring, etc.).

The present invention provides solvates of cannabidiol, etc.

Claims (29)

A solvate of cannabidiol, in which solvent S1 of the solvate contains an aprotic polar solvent. The solvate according to claim 1, wherein solvent S1 comprises an amide solvent. The solvate according to claim 1, wherein solvent S1 comprises dimethylacetamide. The solvate according to claim 1, which is a solvate in which dimethylacetamide is solvated in a ratio of 2 moles per mole of cannabidiol. The solvate of claim 1, which is crystalline. A method for producing a solvate of cannabidiol, in which solvent S1 of the solvate contains an aprotic polar solvent, by forming the solvate in a mixture containing cannabidiol and solvent S1. The method of claim 6, wherein solvent S1 comprises an amide solvent. The method of claim 6, wherein solvent S1 contains dimethylacetamide, and the solvate is a solvate in which dimethylacetamide is solvated in a ratio of 2 moles per mole of cannabidiol. The method of claim 6, wherein the mixture further comprises a solvent S2 different from solvent S1. The method of claim 6, wherein the mixture further comprises an aliphatic hydrocarbon. The method of claim 6, wherein the mixture contains dimethylacetamide and an aliphatic hydrocarbon, and a solvate is precipitated in which dimethylacetamide is solvated in a ratio of 2 moles per mole of cannabidiol. The method of claim 6, wherein the mixture further contains other cannabinoids. The method of claim 6, wherein the mixture contains at least one other cannabinoid selected from cannabigerol, cannabinol, cannabichromene, cannabidivarin, and tetrahydrocannabinol. the mixture further comprises at least one other cannabinoid selected from cannabigerol, cannabinol, delta-9-tetrahydrocannabinol and delta-8-tetrahydrocannabinol;
7. The method according to claim 6, wherein the ratio of cannabigerol, cannabinol, Δ-9-tetrahydrocannabinol and Δ-8-tetrahydrocannabinol to the total amount of cannabidiol, cannabigerol, cannabinol, Δ-9-tetrahydrocannabinol and Δ-8-tetrahydrocannabinol is 0.1% or more based on HPLC area. The method of claim 6, wherein the mixture is derived from hemp. The method of claim 6, wherein the mixture further contains at least one selected from olivetol, a positional isomer of cannabidiol, an adduct of 2 moles of menthadienol per 1 mole of olivetol, Δ-9-tetrahydrocannabinol, and Δ-8-tetrahydrocannabinol. The mixture comprises cannabidiol and an adduct of 2 moles of menthadienol to 1 mole of olivetol,
the ratio of cannabidiol to the total amount of cannabidiol, olivetol, positional isomers of cannabidiol, an adduct in which 2 moles of menthadienol are added to 1 mole of olivetol, Δ-9-tetrahydrocannabinol, and Δ-8-tetrahydrocannabinol is 60% or more based on the area of HPLC;
Olivetol is not contained or is contained in a ratio of 0.03 or less based on the area of HPLC relative to cannabidiol,
The composition is free of positional isomers of cannabidiol or contains them in a ratio of 0.3 or less based on the area of cannabidiol by HPLC;
The method according to claim 6, wherein the adduct in which 2 moles of menthadienol are added to 1 mole of olivetol is contained in a ratio of 0.0001 to 0.5 based on the area of HPLC relative to cannabidiol. The method further comprises a step of subjecting a mixture containing cannabidiol and at least one selected from olivetol and positional isomers of cannabidiol to an adsorption treatment to produce a purified product containing cannabidiol,
The method according to claim 6, wherein a solvate is formed in a mixture containing the purified product obtained through this step and solvent S1. moreover,
Menthadienol and olivetol,
in the presence of at least one catalyst selected from non-boron Lewis acids and Bronsted acids;
At temperatures above 40°C,
A step of reacting at a water content of 5% by mass or less in the reaction system at the start of the reaction to produce a reaction mixture containing cannabidiol;
The reaction mixture obtained through this step is subjected to an adsorption treatment to produce a purified product containing cannabidiol,
The method according to claim 6, wherein a solvate is formed in a mixture containing the purified product obtained through this step and solvent S1. A method for producing cannabidiol by desolvating the solvate described in any one of claims 1 to 5. A method for producing cannabidiol by mixing the solvate described in any one of claims 1 to 5 with water. A method for extracting (liquid-separating) cannabidiol into a layer of the hydrophobic solvent by mixing the solvate described in any one of claims 1 to 5 with water and a hydrophobic solvent capable of dissolving cannabidiol. An extraction step of mixing the solvate according to any one of claims 1 to 5, water, and a hydrophobic solvent capable of dissolving cannabidiol, and extracting cannabidiol into a layer of the hydrophobic solvent;
A method for producing cannabidiol, comprising: a crystallization step of crystallizing the cannabidiol obtained through the extraction step. Cannabidiol obtained by the method of any one of claims 20 to 23. The cannabidiol according to claim 24, wherein the proportion of cannabidiol relative to the total amount of cannabidiol, cannabigerol, cannabinol, Δ-9-tetrahydrocannabinol, and Δ-8-tetrahydrocannabinol is 97% or more based on HPLC area. The cannabidiol according to claim 24, wherein the proportion of cannabidiol relative to the total amount of cannabidiol, olivetol, positional isomers of cannabidiol, an adduct in which 2 moles of menthadienol are added to 1 mole of olivetol, Δ-9-tetrahydrocannabinol, and Δ-8-tetrahydrocannabinol is 97% or more based on the area of HPLC. Cannabidiol according to claim 24, which does not contain solvent S1 of the solvate or the proportion of solvent S1 of the solvate is 3% by mass or less. Cannabidiol according to claim 24, containing 0.001% by mass or more of solvent S1 of the solvate. Cannabidiol according to claim 24, containing 0.001% by mass or more of solvent S1 of the solvate and 0.001% by mass or more of an aliphatic hydrocarbon.