WO2018024145A1

WO2018024145A1 - Process for preparing boscalid

Info

Publication number: WO2018024145A1
Application number: PCT/CN2017/094624
Authority: WO
Inventors: James Timothy BRISTOW
Original assignee: Jiangsu Rotam Chemical Co Ltd
Current assignee: Jiangsu Rotam Chemical Co Ltd
Priority date: 2016-08-04
Filing date: 2017-07-27
Publication date: 2018-02-08
Anticipated expiration: 2019-02-04
Also published as: CN109476603A; TWI733869B; GB2552699A; GB2552699B; TW201808904A

Abstract

A process for preparing the crystalline modification II of the anhydrate of boscalid is provided, the process comprising providing a solution of boscalid in an organic solvent system, heating the solution to an elevated temperature, and precipitating solid boscalid from the solution, the elevated temperature being sufficient to preferentially form the crystalline modification II of the anhydrate of boscalid.

Description

PROCESS FOR PREPARING BOSCALID

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to GB Patent Application No. 1613462.9, titled “PROCESS FOR PREPARING BOSCALID” , filed with GB Intellectual Property Office on August 4, 2016, the entire contents of which are incorporated herein by reference.

FIELD

The present invention relates to a process for preparing boscalid, in particular to a process for preparing a specific crystalline form of boscalid.

BACKGROUND

The compound 2-chloro-N- (4’chloro [1, 1’biphenyl] -2-yl) -3-pyridine carboxamide, having the common name boscalid, has the structural formula I:

Boscalid is a fungicide of the carboxamide group and acts as a succinate dehydrogenase inhibitor (SDHI) , a respiratory inhibitor of mitochondria. This class of carboximide compounds and the activity of the compounds was first described in US 4,001,416 and US 5,330,995.

Boscalid is active as a fungicide and is now commercially available in a range of formulations for the treatment of fungal infestations and the resulting disorders.

US 7,087,239 concerns the crystalline hydrates of either nicotinic acid anilide and/or benzoyl anilide derivatives. The synthesis and recovery of the hydrate of boscalid is specifically exemplified in US 7,087,239. The hydrate is obtained by first preparing the anhydrate of boscalid, which is obtained at the end of the synthesis procedure as a solution in hot xylene. Upon cooling, boscalid crystallized from the solution and was dried under vacuum in an oven. The anhydrate is indicated to have the following physical properties:

US 7,087,239 discloses that the hydrate can be formed by dissolving the anhydrate in tetrahydrofuran (THF) at 40℃ in a solvent and adding the resulting solution into water. The precipitate was isolated from the resulting mixture by filtration and dried, to yield the monohydrate of boscalid. The crystalline modification of the anhydrate of boscalid disclosed in US 7,087,239 is referred to herein as the crystalline modification I of boscalid.

US 7,241,896 concerns a process for producing 2-halogen-pyridine-carboxylic acid amides. The preparation of boscalid is disclosed and exemplified. In the examples, boscalid is synthesized by the reaction of 2-chloro-3-nicotinyl chloride II with 2- (4-chlorophenyl) aniline in a solvent system, in particular xylene. Boscalid was crystallized by steady cooling of the organic solution, after extraction with sodium carbonate solution.

We have found that it is hard to mill the crystalline modification of the anhydrate of boscalid disclosed in US 7,087,239 in water. As a consequence, it is not a straightforward task to directly formulate the crystalline modification of boscalid into desired formulations which require grinding and/or milling processes. Such formulations are, for example, granules, encapsulated granules, tablets, water-dispersible granules, water-dispersible tablets, water-dispersible powders or water dispersible powders for seed treatment, dust formulations, and formulations in which the active compound is present in dispersed form, such as, for example, suspension concentrates, oil-based suspension concentrates, suspoemulsions, or suspension concentrates for seed treatment. Hydration of the crystalline modification of boscalid is needed prior to formulating into a suspension concentrate.

US 7,501,384 discloses an alleged novel crystalline modification of the anhydrate of boscalid. The crystalline modification disclosed in US 7,501,384 is referred to herein as the crystalline modification II of boscalid. It is suggested in US 7,501,384 that the crystalline modification II of boscalid is more suitable for making various formulations, which otherwise require prolonged grinding/milling processes.

US 7,501,384 describes that the crystalline modification II of boscalid may be prepared by a process comprising:

a) dissolving the anhydrate of the crystalline modification I of boscalid in a polar organic solvent or an aromatic hydrocarbon； and

b) precipitation of the anhydrate of the crystalline modification II of boscalid by cooling the solvent.

An alternative process for the preparation of the crystalline modification II of boscalid disclosed in US 7,501,384 comprises:

a) heating the crystalline modification I of boscalid to above 150℃ until melted； and

b) cooling the melt with the addition of seed crystals of the crystalline modification II of boscalid.

US 7,501,384 describes the crystalline modification II of boscalid as having the following properties:

The key parameters and the cell matrix obtained from the crystallographic investigations of the crystalline modification II of boscalid using a single crystal diffractometer from Siemens are given in US 7,501,384 as follows:

The parameters indicated above have the following meanings:

a, b, c ＝ edge lengths of the unit cell；

α, β, γ ＝ corresponding angles； and

Z ＝ number of molecules in the unit cell.

It would be of significant advantage if an improved process for the preparation of the crystalline modification II of the anhydrate of boscalid could be provided, in particular a process that is suitable for applying on a commercial scale, with reproducible, high yields of the modification II product. Preferably, the process would be simple to operate and easy to control.

Surprisingly, it has now been found that the formation of crystalline modification II of the anhydrate of boscalid in high yields occurs at elevated temperatures. In contrast, lower temperatures result in the crystalline modification I of the anhydrate of boscalid being preferentially formed. In particular, when precipitating boscalid from a solvent system, surprisingly it has been found that precipitation of boscalid from the solvent system at low temperatures yields predominantly or exclusively the crystalline modification I of the anhydrate of boscalid, while increasing the temperature of the solvent system and precipitating solid boscalid preferentially yields the crystalline II modification of the anhydrate of boscalid.

SUMMARY

In a first aspect, the present invention provides a process for preparing the crystalline modification II of the anhydrate of boscalid, the process comprising providing a solution of boscalid in an organic solvent system, heating the solution to an elevated temperature, and precipitating solid boscalid from the solution, the elevated temperature being sufficient to preferentially form the crystalline modification II of the anhydrate of boscalid.

In the present invention, an elevated temperature is used to form the crystalline modification II of the anhydrate of boscalid. As noted above, such elevated temperatures result in the crystalline modification II of the anhydrate of boscalid being preferentially formed, compared with lower temperatures.

The process of the present invention employs a boscalid starting material. The boscalid starting material is a solution of boscalid in an organic solvent system. Any suitable organic solvent system for boscalid may be used to form the boscalid starting material of this embodiment. The solvent system may be a single organic solvent or a mixture of two or more solvents. Suitable solvents include polar organic solvents and aromatic hydrocarbons. Preferred polar organic solvents are alcohols, including polyols, such as glycols, ketones, ethers, esters, amides and mixtures thereof.

Examples of suitable alcohols are C₁ to C₈ alcohols, preferably C₁ to C₅ alcohols. The alcohol may be a straight chain or branched aliphatic alcohol, more preferably ethanol, propanol and butanol. The alcohol may be an alicyclic alcohol, for example cyclohexanol. The solvent may comprise a polyol, such as a glycol. Examples of suitable glycols are mono-and polyethylene glycols, preferably ethylene glycol and diethylene glycol.

Examples of suitable ketones are C₃ to C₈ ketones, preferably C₃ to C₆ ketones, more preferably propanone, butanone, pentanone and hexanone. The ketones may be straight chain, branched chain or cyclic, for example alkyl propanones and cyclohexanone.

Examples of suitable ethers are C₃ to C₈ ethers, preferably C₃ to C₆ ethers. The ethers may be straight chain, branched chain or cyclic, for example dioxane and tetrahydrofuran.

Examples of suitable esters are C₃ to C₈ esters, preferably C₃ to C₆ esters, more preferably ethyl acetate and methyl acetate.

Examples of suitable amides are C₃ to C₈ amides, preferably C₃ to C₆ amides, more preferably dimethylformamide.

Suitable aromatic solvents are benzene, toluene and xylene. Xylene is one preferred solvent.

Suitable solvents are known in the art and are commercially available.

A mixture of solvents may be employed as the solvent system. For example, the organic solvent may comprise a combination of an aromatic solvent, such as benzene, xylene or toluene, or a cyclic alkane, such as cyclohexene, with one or more aliphatic or alicyclic alcohols, such as cyclohexanol, one or more ketones, one or more ethers, such as a cyclic ether, for example tetrahydrofuran, or one or more amides.

The organic solvent employed in the process of the present invention is preferably substantially free from water, to ensure the maximum yield of the anhydrate of boscalid. The organic solvent may comprise up to 0.4％by weight of water, which may be absorbed by the solvent from the atmosphere. Most preferably, the organic solvent contains no water.

The solution of boscalid may be formed in any suitable manner. For example, the solution may be formed by dissolving a form of boscalid other than solid crystalline modification II of boscalid in the organic solvent system. Alternatively, boscalid may be synthesized in the presence of the organic solvent. Suitable methods for synthesizing boscalid in solution in an organic solvent are known in the art. US 7,087,239 discloses a suitable synthesis route for preparing boscalid.

The process of the present invention comprises precipitating solid boscalid from the solution of boscalid in the organic solvent. The solution is heated to an elevated temperature. The elevated temperature is above ambient temperature or room temperature and is a temperature at which the precipitation preferentially yields the crystalline modification II of the anhydrate of boscalid. Any suitable elevated temperature may be employed. Preferably, the elevated temperature is below the boiling point of the solution of boscalid.

Suitable elevated temperatures may be determined by analysis of the precipitated boscalid material, in particular to determine whether the temperature is sufficiently high for the modification II of the anhydrate of boscalid to be precipitated.

The elevated temperature is preferably at least 35℃, more preferably at least 40℃, still more preferably at least 45℃. In experiments, it has been found that the precipitation of boscalid from solution in an organic solvent after heating to a temperature of 45℃ results in a solid boscalid material comprising the crystalline modification II in an amount of 30％by weight.

More preferably, the boscalid is precipitated from the solution after heating to a temperature of at least 50℃, still more preferably at least 55℃, more preferably still at least 60℃. In experiments, it has been found that precipitation of solid boscalid from solution in an organic solvent after heating to a temperature of 65℃ results in the formation of 100％by weight of the crystalline modification II of the anhydrate of boscalid.

As noted above, the elevated temperature is preferably below the boiling point of the organic solvents and the solution of the boscalid starting material. The elevated temperature is also below the melting point of the crystalline modification II of the anhydrate of boscalid.

The upper limit of the elevated temperature will depend upon the particular solvent or solvent system employed. The elevated temperature is preferably below 140℃, more preferably below 130℃, still more preferably below 120℃, more preferably still below 110℃. In preferred embodiments, the solid boscalid starting material is heated to an elevated temperature below 100℃, more preferably below 90℃, still more preferably below 85℃, more preferably still below 80℃.

Elevated temperatures in the range of from 30 to 130℃ are preferably employed, more preferably from 35 to 120℃, still more preferably from 40 to 110℃, more preferably still from 45 to 100℃, with temperatures in the range of from 50 to 90℃ being preferred, more preferably from 55 to 85℃, still more preferably from 60 to 80℃. A temperature of from 60 to 70℃ is particularly preferred, with a temperature of about 65℃ resulting in the formation of substantially 100％by weight of the modification II of the anhydrate of boscalid.

The precipitation of the boscalid material from the organic solvent may be effected using any suitable technique. The precipitation of boscalid from the solution may be carried out at the elevated temperature. For example, precipitation may be effected by removing the organic solvent at the elevated temperature, for example by evaporation, such as under reduced pressure.

Alternatively, precipitation of boscalid from the solution may be carried out at a temperature below the elevated temperature, after heating the solution to the elevated temperature. In particular, precipitation of the boscalid material from the organic solvent may be effected by cooling a saturated solution of boscalid in the solvent from the elevated temperature to a lower temperature at which precipitation of solid boscalid occurs.

As a further alternative, the process may employ a combination of the aforementioned techniques, that is precipitation of the solid boscalid material may be commenced at the elevated temperature and the solution thereafter cooled, for example to allow further solid to precipitate.

Cooling may be carried out continuously, stepwise, or a combination thereof.

Precipitation of the boscalid product may be carried out in the presence of seed crystals of boscalid, preferably seed crystals of the crystalline modification II of the anhydrate of boscalid in the organic solvent.

The process of the present invention may be carried out batchwise or in a continuous manner.

Any suitable apparatus may be employed to carry out the precipitation of the crystalline modification II of boscalid. Suitable apparatus is known in the art and is commercially available.

In a further aspect, the present invention provides a fungicidal formulation comprising the crystalline modification II of the anhydrate of boscalid prepared by a process as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

FTIR spectrometry may be used to record IR spectra.

Figure 1 is the IR spectrum of the crystalline modification II of the anhydrate of boscalid；

Figure 2 is the IR spectrum of the crystalline modification I of the anhydrate of boscalid.

DETAILED DESCRIPTION OF EMBODIMENTS

Embodiments of the present invention will be described, for illustrative purposes only, by way of the following specific examples.

In the following examples, percentages are weight percent, unless otherwise indicated.

EXAMPLES

Example 1

Boscalid was prepared according to the following general reaction scheme:

A solution of boscalid in xylene was prepared as follows:

A reaction vessel was charged with 396g (1.944 mol) of 2-amino-4'-chlorobiphenyl in 311g of xylene and the mixture was stirred until a homogenous solution was obtained. A solution of 349g (1.984 mol) of 2-chloro-3-nicotinyl chloride in 233g of xylene was added to the reaction vessel and the resultant mixture allowed to heat up to 30℃.

The resultant mixture was heated to an elevated temperature of 95℃ over a period of 4 to 5 hours. Hydrogen chloride (HCl) produced by the reactions was removed using an external scrubber and absorption by a spray tower using water and an alkali solution. The reaction mixture was further maintained for a period of 30 minutes with stirring at the same elevated temperature to remove all traces of all HCL. Thereafter, the reaction mixture was allowed to cool to 30℃ during the period of 5 to 7 hours with slow stirring.

Finally the solution was cooled to room temperature, resulting in the precipitation of a solid boscalid material, which was removed by filtration. Traces of xylene were removed from the precipitate by vacuum drying in an oven.

The boscalid material recovered was analyzed using infrared (IR) spectrometry using a Bruker model No. Tensor 37 spectrometer, with a recording wavelength of 550 to 4000 cm^-1, having 16 scans with a highest resolution of 4 cm^-1. The analysis showed the solid product to be the crystalline modification II of the anhydrate of boscalid.

Example 2

750g of toluene were charged to a reaction vessel under a nitrogen atmosphere. 335g of 2-chloronicotinic acid were added with stirring at room temperature. 35g of dimethyl formamide (DMF) was added to the mixture and the resulting reaction mixture slowly heated to 40℃ with stirring. 300g of thionyl chloride was added over a period of one hour. Hydrogen chloride (HCl) and sulphur dioxide (SO₂) gases liberated by the reaction were removed by scrubbing. Thereafter, the reaction mass was kept under a nitrogen atmosphere and maintained at 60℃ for 4 to 5 hours until complete reaction of the acid had taken place (as monitored using HPLC) . Thereafter, excess thionyl chloride was removed at 60 to 75℃ under reduced pressure. The resulting mixture was cooled to room temperature.

The cooled mixture was diluted with 500g of toulene and 200g of triethyl amine (TEA) with stirring. To this homogeneous mixture, 400g of 4’-chlorobiphenyl-2-amine was added over a period of 30 to 45 minutes at 45℃ and the mixture stirred for an additional 4 to 5 hours to allow the reaction to complete. The mixture was quenched by adding water and stirring for a further 2 to 3 hours.

The organic layer was separated and maintained at an elevated temperature of 60℃. The mixture was filtered to remove insoluble impurities. The mixture was finally cooled to 10 to 15℃ under slow stirring. The solid was isolated by filtration and drying to give 450 to 480g of boscalid.

The solid was analysed by IR spectroscopy, as in Example 1, which showed the solid product to be the crystalline modification II of the anhydrate of boscalid.

Example 3

A reaction vessel was charged with 792g (3.888 mol) of 2-amino-4'-chlorobiphenyl in 622g of xylene and the mixture was stirred until a homogenous solution was obtained. A solution of 698g (3.968 mol) of 2-chloro-3-nicotinyl chloride in 466g of xylene was added to the reaction vessel and the resultant mixture allowed to heat up to a temperature of 30℃.

The resultant mixture was heated to an elevated temperature of 95℃ over a period of 4 to 5 hours. Hydrogen chloride (HCl) produced by the reactions was removed using an external scrubber and absorption by a spray tower using water and an alkali solution. The reaction mixture was further maintained for a period of from 2 to 3 hours with stirring at the same elevated temperature to remove all traces of all HCl.

The resulting mixture was seeded with seed crystals of the crystalline modification II of the anhydrate of boscalid, resulting in the precipitation of a solid material, which was collected by filtration. Traces of xylene were removed from the precipitate by vacuum drying in an oven.

The solid material collected was analyzed using infrared (IR) spectrometry using a Bruker model No. Tensor 37 spectrometer, with a recording wavelength of 550 to 4000 cm^-1, having 16 scans with a highest resolution of 4 cm^-1. The analysis showed the solid product to be the crystalline modification II of the anhydrate of boscalid.

Example 4

375g of the carbonyl intermediate of chloronicotinic acid was prepared following the procedure described in Example 2 and reacted with 400g of 4’-chlorobiphenyl-2-amine to obtain a crude boscalid product. This product was repeatedly washed with tetrahydrofuran (THF) and diluted with 850g of isopropyl alcohol. The resulting solution was heated to 60℃and maintained at this temperature for 2 to 3 hours.

The resulting mixture was cooled to obtain a solid precipitate. The solid was isolated by filtration and drying.

To investigate the effects of temperature on the solid boscalid material obtained in the process, the procedure of Example 1 was repeated with precipitating solid boscalid from the xylene solution held at a range of different elevated temperatures before cooling.

The results are summarized in the following table.

As can be seen from the results summarized in the above table, the form of the boscalid anhydrate precipitated from the organic solvent is dependent upon the temperature of the solution of boscalid from which the precipitation is carried out. In particular, precipitation from xylene heated to a temperature of 65℃ yielded 100％of the crystalline modification II of the anhydrate of boscalid. In contrast, precipitation from the xylenic solution heated to just 30℃ yielded only 10 to 20％of the crystalline modification II of the anhydrate of boscalid, with predominantly crystalline modification I of boscalid being formed at this temperature.

Claims

A process for preparing the crystalline modification II of the anhydrate of boscalid, the process comprising providing a solution of boscalid in an organic solvent system, heating the solution to an elevated temperature, and precipitating solid boscalid from the solution, the elevated temperature being sufficient to preferentially form the crystalline modification II of the anhydrate of boscalid.
The process according to claim 1, wherein the solvent system comprises a polar organic solvent, an aromatic hydrocarbon, or a mixture thereof.
The process according to claim 2, wherein the polar organic solvent is selected from an alcohol, a ketone, an ether, an ester, an amide, and mixtures thereof.
The process according to claim 3, wherein the alcohol is a straight chain or branched aliphatic alcohol or an alicyclic alcohol.
The process according to claim 4, wherein the alcohol is selected from ethanol, propanol, butanol, cyclohexanol, ethylene glycol and diethylene glycol.
The process according to claim 3, wherein the ketone is a selected from propanone, butanone, pentanone and hexanone.
The process according to claim 3, wherein the ether is selected from dioxane and tetrahydrofuran.
The process according to claim 3, wherein the ester is selected from ethyl acetate and methyl acetate.
The process according to claim 3, wherein the amide is dimethylformamide.
The process according to claim 2, wherein the aromatic solvent is selected from benzene, toluene and xylene.
The process according to any preceding claim, wherein the solvent system is substantially free of water.
The process according to any preceding claim, wherein the solution is formed by dissolving a form of boscalid other than solid crystalline modification II of boscalid in the organic solvent system.
The process according to any of claims 1 to 11, wherein the solution is formed by synthesizing boscalid in the presence of the organic solvent system.
The process according to any preceding claim, wherein the elevated temperature is below the boiling point of the solution.
The process according to any preceding claim, wherein the elevated temperature is at least 45℃.
The process according to claim 15, wherein the elevated temperature is at least 55℃.
The process according to claim 16, wherein the elevated temperature is at least 65℃.
The process according to any preceding claim, wherein the elevated temperature is below 100℃.
The process according to claim 18, wherein the elevated temperature is below 85℃.
The process according to claim 19, wherein the elevated temperature is from 55 to 85℃.
The process according to any preceding claim, wherein precipitation of solid boscalid takes place at the elevated temperature.
The process according to any preceding claim, wherein precipitation of solid boscalid takes place at a temperature below the elevated temperature.
The process according to any preceding claim, wherein precipitation is aided by the addition of seed crystals to the solution.
The process according to claim 23, wherein the seed crystals are crystals of the crystalline modification II of the anhydrate of boscalid.
The process according to any preceding claim, wherein the process is conducted in a batchwise or a continuous manner.
A process for preparing the crystalline modification II of the anhydrate of boscalid substantially as hereinbefore described.
A fungicidal formulation comprising the crystalline modification II of the anhydrate of boscalid prepared by a process according to any preceding claim.