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WO2025035069A2 - Processus de production de (3s,6r)-6-(cyanométhyle)-tétrahydro-2h-pyran-3-amine - Google Patents

Processus de production de (3s,6r)-6-(cyanométhyle)-tétrahydro-2h-pyran-3-amine Download PDF

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Publication number
WO2025035069A2
WO2025035069A2 PCT/US2024/041658 US2024041658W WO2025035069A2 WO 2025035069 A2 WO2025035069 A2 WO 2025035069A2 US 2024041658 W US2024041658 W US 2024041658W WO 2025035069 A2 WO2025035069 A2 WO 2025035069A2
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Prior art keywords
amine
protecting group
pyran
tetrahydro
cyanomethyl
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WO2025035069A3 (fr
WO2025035069A9 (fr
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David Leahy
Mahipal BODUGAM
Bal Reddy ANUSUYA
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Biohaven Therapeutics Ltd
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Biohaven Therapeutics Ltd
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Publication of WO2025035069A9 publication Critical patent/WO2025035069A9/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present disclosure relates to the discovery of a dynamic process to synthesize ((3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine) hydrochloride, a critical drug intermediate, in high yield.
  • the compound (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine hydrochloride known as APA, is a chiral intermediate useful for preparing drug compounds such as the TYK2/JAK1 inhibitor BHV-8000 (previously known as TLL-041).
  • existing methods to produce this chiral intermediate, or other useful salts of the compound (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine are inefficient and provide poor yield. Therefore, improved methods to produce this intermediate are necessary.
  • the present disclosure provides for a dynamic synthetic process which achieves a favorable diastereomer ratio, and provides significantly improved yield at industrially-relevant scales.
  • the dynamic process involves conversion of the undesired diastereomer back to starting material as the reaction proceeds to accumulate an excess of the desired diastereomer.
  • the described processes also replace a harmful and costly solvent which is favorable from a green chemistry perspective. Additionally, resource-intensive steps may be avoided to produce the critical APA intermediate more efficiently.
  • the present disclosure relates to an improved process to synthesize ((3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine) hydrochloride, or other useful salts of ((3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine).
  • the following embodiments are illustrative, and further embodiments described herein are contemplated.
  • a process comprising: reacting (2S)-6-cyano-5-hexen-l-ol-2-amine, having a protecting group on the amine, with a base in an alcohol solvent to produce (via a ring-closing reaction) a reaction mixture containing a diastereomeric mixture of (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3- amine, having said protecting group on the amine, and (3S,6S)-6-(cyanomethyl)- tetrahydro- 2H-pyran-3 -amine, having said protecting group on the amine.
  • a conjugate acid of the base has a pKa from about 16 to about 20.
  • the base is a salt of an alkoxide ion.
  • the alkoxide ion is Zc/7-butoxide or isopropoxide.
  • the salt is potassium /c/V-butoxide, sodium /c/7-butoxide, or lithium /c77-butoxide.
  • the salt is potassium tert-butoxide.
  • the alcohol solvent comprises one or more of methanol, ethanol, n- propanol, isopropanol, butanol, 1,2 butanediol, 1,3 butanediol, 1,4 butanediol, 2,3 butanediol, isoamyl alcohol, and tert-amyl alcohol.
  • the alcohol solvent comprises isopropanol. In an embodiment, the alcohol solvent is isopropanol.
  • the protecting group on the amine is selected from the group consisting of benzyl carbamate (Cbz), acetamide (Ac), trifluoroacetamide (TFAc), phthalimide, triphenylmethylamine (Tr), benzylideneamine, and /?-toluenesulfonamide (Ts), and /c77-butyloxy carbonyl.
  • the protecting group on the amine is /c/V-butyloxy carbonyl.
  • the ring-closing reaction is conducted at a temperature ranging from about 10 - 50 °C, optionally at 20 - 30 °C.
  • the ring-closing reaction is performed for about 24 hours, or until the amount of (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, is no longer increasing.
  • the process further comprises quenching the reaction mixture with an acidic solution to neutralize the base after completion of the ring closing reaction.
  • a solid phase comprising (3S,6R)-6-(cyanomethyl)- tetrahydro- 2H-pyran-3 -amine, having said protecting group on the amine, and (3S,6S)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, precipitates from the alcohol solvent.
  • the solid phase comprises a diastereomeric ratio of (3S,6R)-6- (cyanom ethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, to (3 S, 6 S)-6-(cy anomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, of at least about 75:25.
  • the diastereomeric ratio is about 90: 10.
  • the process further comprises filtering the solid phase from the reaction mixture.
  • the process further comprises purifying (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, from the solid phase.
  • (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine is purified from the diastereomeric mixture at a diastereomeric ratio of about 99: 1.
  • the purification comprises contacting the diastereomeric mixture with a purification solvent in which (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, is insoluble and precipitates from solution and (3 S, 6 S)-6-(cy anomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, is soluble and remains in solution, and filtering a resultant, purified precipitate containing (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine.
  • the purification solvent comprises methyl tert-butyl ether. In an embodiment, the purification solvent is methyl tert-butyl ether.
  • the process further comprises reacting the purified (3S,6R)-6- (cyanom ethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, with hydrochloric acid to deprotect the amine and to form ((3S,6R)-6-(cyanomethyl)- tetrahy dro-2H-py ran-3 -y 1 ) hydrochi ori de .
  • the process further comprises isolating the ((3S,6R)-6- (cyanom ethyl)- tetrahydro-2H-pyran-3-yl) hydrochloride.
  • a process comprising: reacting (2S)-6-cyano-5-hexen-l-ol-2-amine, having a protecting group on the amine, with a base in a solvent to produce a reaction mixture containing a solid phase, wherein: the solid phase comprises a diastereomeric mixture of (3S,6R)-6-(cyanomethyl)- tetrahydro- 2H-pyran-3 -amine, having said protecting group on the amine, and (3S,6S)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine; wherein the (3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, is insoluble in the solvent; and wherein the (3S,6S)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group
  • the solvent is miscible with water.
  • the solvent is a weak acid.
  • the solvent has a pKa which is different from the pKa of a conjugate acid of the base by about 25% or less.
  • the solvent has a pKa from about 16 to about 20.
  • the solid phase contains a diastereomeric ratio of (3S,6R)-6- (cyanom ethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, to (3 S, 6 S)-6-(cy anomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine, of at least about 75:25, preferably about 90: 10
  • a process comprising: reacting (2S)-6-cyano-5-hexen-l-ol-2-amine, having a protecting group on the amine, with an alkoxide base in an alcohol solvent to produce a reaction mixture containing a solid phase, wherein: the solid phase comprises a diastereomeric mixture of (3S,6R)-6-(cyanomethyl)- tetrahydro- 2H-pyran-3 -amine, having said protecting group on the amine, and (3S,6S)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine, having said protecting group on the amine; and wherein the solid phase has a diastereomeric ratio of (3S,6R)-6-(cyanomethyl)- tetrahydro- 2H-pyran-3 -amine, having said protecting group on the amine, to (3S,6S)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine
  • the reaction is conducted until at least about 80% of APA-7 is converted to APA-8.
  • the reaction is conducted at a temperature from about 10 - 50 °C, optionally at 20 - 30 °C.
  • the reaction mixture is stirred or agitated while the ring-closing reaction is conducted.
  • FIG. 1 depicts a reference process to produce APA-8
  • FIG. 2 depicts an exemplary process to produce APA-8
  • FIG. 3 depicts crystallization-induced dynamic resolution which can accumulate a diastereomeric excess of the desired APA-8 product
  • FIG. 4 depicts an HPLC chromatogram for produced and purified APA-8
  • FIG. 5 depicts LC-MS data for produced and purified APA-8
  • FIG. 6 depicts a ' H NMR spectrum for produced and purified APA-8
  • FIG. 7 depicts a 13 C NMR spectrum for produced and purified APA-8.
  • FIG. 8 depicts an IR spectrum for produced and purified APA-8.
  • APA The compound ((3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3 -amine) hydrochloride (APA) is a critical intermediate for the synthesis of drug compounds such as BHV-8000.
  • the structure of APA, in a hydrochloride salt form, is shown below.
  • APA may be synthesized according to a synthetic scheme as shown below in Scheme 1, starting from readily-available L-glutamic acid starting material. Alternative synthetic schemes to produce APA-7 are also contemplated.
  • APA-7 a linear alkene ((2S)-6-cyano-5-hexen-l-ol-2-amine) having a protecting group on the amine, is subjected to ring-closing conditions to produce APA-8, which may be deprotected to form APA.
  • APA-8 i.e., tert-butyl ((3S,6R)-6- (cyanomethyl)- tetrahydro-2H-pyran-3-yl)carbamate
  • APA-8 i.e., tert-butyl ((3S,6R)-6- (cyanomethyl)- tetrahydro-2H-pyran-3-yl)carbamate
  • APA-7 The ring closing reaction of APA-7 also tends to produce an undesired cis diastereomer, termed APA-8b (i.e., tert-butyl ((3S,6S)-6- (cyanom ethyl)- tetrahydro-2H-pyran-3-yl)carbamate). While “APA-8” and “APA-8b” refer to specific structures containing a Boc protecting group, it should be appreciated that recitations of these terms can encompass the same compounds having other suitable protecting groups as described herein. APA-8 and APA-8b are shown below.
  • the present disclosure provides for an improved synthetic procedure to produce the required diastereomer APA-8, among other related improvements.
  • Know methods to produce APA-8 provide poor yield and unfavorable stereoisomerism of APA-8 (the desirable stereoisomer) compared to APA-8b (the undesirable stereoisomer).
  • a related, previous process was generally described in Congxin et al., International Application Number PCT/CN2022/129966, filed December 19, 2022 corresponding to WO 2023/125102, published July 6, 2023, which is incorporated by reference herein. An example based on this previous process is shown below. ur cat on wt
  • Scheme 2 Exemplary reference process to produce APA-8 from APA-7.
  • APA-8 corresponds to compound 2-2 of Congxin et al., and the reference reports 42.2% yield of this compound at a scale of 43.2 kg isolated.
  • Congxin et al. do not discuss the ratios of diasteromers produced by the reaction.
  • the diastereomers depicted in Scheme 2 generally result from the ring-closing reaction.
  • aqueous work-up, organic extraction, carbon (charcoal) treatment, and distillation steps are utilized.
  • a version of the Congxin et al. process was performed herein with comparable yield due in part to poor diastereomeric selectivity for APA-8.
  • FIG. 1 depicts a flow chart of an adapted Congxin et al. process (hereinafter the “reference process”) performed as a comparison to the dynamic process described herein.
  • APA-7 was reacted with sodium methoxide (NaOMe) in tetrahydrofuran (THF) solvent.
  • RM reaction mixture
  • the ratio of diastereomers APA-8 to APA-8b was determined to be 60:40, meaning that 40% of the material produced is immediate waste by the reference process.
  • APA-8 was obtained at an isolated yield of approximately 40% based on the amount of APA-7 utilized, with purity >98%.
  • the present invention provides for a solution to these issues by way of an alternative, dynamic synthetic procedure which produces APA-8 from APA-7 with a reaction mixture ratio of diastereomers APA-8 to APA-8b of about 90: 10, and an approximately doubled isolated yield of APA-8 of about 80% based on the amount of APA-7 utilized, at industrially-relevant scales.
  • the process herein also avoids the use of THF, instead using a greener solvent, such as an alcohol (e.g., isopropyl alcohol (IP A) or others).
  • IP A isopropyl alcohol
  • Scheme 3 Exemplary dynamic process to produce APA-8 from APA-7.
  • FIG. 2 depicts an exemplary dynamic process according to the present disclosure.
  • crystallization- induced dynamic resolution This phenomenon is depicted in FIG. 3, and is known as crystallization- induced dynamic resolution.
  • crystallization in this context does not necessarily imply any particular ordered or crystalline structure, but means that the desired material precipitates out from the reaction mixture.
  • APA-8b is more soluble in the reaction mixture, it will undergo the reverse ring-opening reaction to form a linear APA-7 product, which will then undergo the ring-closing reaction again.
  • the statistical amount of APA- 8 formed from each ring closing reaction precipitates or crystallizes from the solvent where it does not readily undergo the reverse reaction, and a diastereomeric excess of the APA-8 product is formed over time.
  • alcohol solvents having from 1 to 5 carbon atoms i.e., from methanol to pentanols having one or more hydroxyl groups
  • THF reference process solvent
  • the present disclosure contemplates other protic organic solvents in which APA-8 has poorer solubility compared to APA-8b.
  • the dynamic process provides several additional improvements to obtain APA-8 in high chiral purity while eliminating several disadvantageous steps utilized in the reference process, including aqueous work-up, extraction, carbon treatment, and distillation. In an aspect, these steps are avoided by use of a water-miscible solvent rather than immiscible THF. On an industrial scale, eliminating these steps can be highly significant.
  • APA-7 is reacted with a strong or relatively strong base in a solvent to produce a favorable diastereomeric distribution of APA-8 and APA-8b.
  • the solvent is a protic organic solvent.
  • the solvent is a weak acid (in this context, meaning that is has a pKa of about 10 or higher, or whose conjugate base is capable of deprotonating APA-7 to initiate the cyclization reaction).
  • the solvent has a pK a ranging from about 16 to about 20.
  • the solvent has a pKa which is different from the pKa of a conjugate acid of the base by about 25% or less, including solvents which have the same pKa as the pKa of the conjugate acid of the base (for example, an isopropyl alcohol solvent and isopropoxide base).
  • the solvent is an organic solvent comprising an alcohol.
  • the solvent is an alcohol.
  • the alcohol contains from 1 to 5 carbon atoms.
  • the alcohol is selected from the group consisting of methanol, ethanol, n- propanol, isopropanol, butanol (including 1 -butanol, 2-butanol, tert-butanol, and isobutanol), and various isomers of butanediols and pentanols (including isoamyl alcohol and tert-amyl alcohol).
  • Other alcohol solvents can include ethylene glycol, propylene glycol, etc.
  • the alcohol is isopropanol.
  • the amount of solvent in a particular reaction may be adjusted as necessary, however in some embodiments approximately 6 mL of solvent per gram of APA-7 is utilized. In further embodiments, about 1 mL of solvent per gram of APA- 7 to about 100 mL of solvent per gram of APA-7 may be utilized.
  • APA-7 generally means the compound (2S)-6-cyano-5- hexen-l-ol-2-amine having a protecting group on the amine. While Boc (tert-butyl carbamate) is a suitable protecting group, other protecting groups may be utilized. As a nonlimiting list of protecting groups, benzyl carbamate (Cbz), acetamide (Ac), trifluoroacetamide (TFAc), phthalimide, triphenylmethylamine (Tr), benzylideneamine, and /?-toluenesulfonamide (Ts), among others, may be utilized in alternative embodiments.
  • a base having suitable basicity is utilized.
  • the base is a strong base or relatively strong base (for example, a base stronger than hydroxide but not as strong as butyllithiums and related bases).
  • the base strength may be defined by the negative log of the acid dissociation constant (pK a ) of its conjugate acid, where a higher pK a indicates poorer acidity of the conjugate acid and thus higher basicity of the base.
  • the base has a pK a of its conjugate acid ranging from about 16 to about 20.
  • a suitable base is an alkoxide, although other bases capable of catalyzing the ring closing reaction are contemplated.
  • the base is an alkoxide base.
  • An alkoxide base is generally introduced as a salt of an alkoxide ion.
  • an ionic complex including a cation such as potassium, sodium, or lithium and an alkoxide anion may be utilized.
  • the cation may be an alkali cation such as potassium (K + ), sodium (Na + ), or lithium (Li + ).
  • other cations may be present.
  • alkaline dications such as Mg 2+ or Ca 2+ or monocations such as (MgCl) + may be utilized.
  • any ionic complex including a useful alkoxide base are contemplated.
  • the salt will generally be soluble in the reaction mixture, meaning that the ionic complex disassociates to provide some amount of accessible base.
  • Alkoxides may be linear (such as methoxide, ethoxide, and w-propoxide, etc.) or branched (such as isopropoxide, tert-butoxide, 2-butanolate, etc.).
  • the amount of base used may vary depending upon reaction conditions and can alter the overall reaction time to completion. In some embodiments, the amount of strong base is about 0.1 molar equivalents of APA-7, however the amount of strong base may vary. For example, in other embodiments, the amount of strong base may be about 0.01 molar equivalents of APA-7, 0.1 molar equivalents of APA-7, 1 molar equivalent of APA-7, or higher. Because the base is catalytic, it may be generally present at lower concentration compared to APA-7.
  • APA-8 is produced from APA-7 in a diastereomeric ratio (defined by APA-8:APA-8b) of at least 70:30, or at least 75:25, or at least 80:20, or at least 85: 15, or at least 90: 10 (where “at least” encompasses APA-8 proportions higher than the recited first number in the ratio and APA-8b proportions lower than the recited number in the ratio).
  • APA-7 is reacted with the base in the solvent for a sufficient time to complete the conversion to APA-8 (and minor product APA-8b) at the given reaction temperature. For example, the reaction may be performed at 25 ⁇ 5°C for approximately 24 hours.
  • the reaction may be performed at lower temperatures which are above the freezing point of the solvent, which make the reaction kinetically feasible, and which do not make the undesired APA-8b product insoluble.
  • the reaction temperature should also not be high enough to render the desired APA-8 product soluble or to prevent its precipitation.
  • the temperature may be from about 10°C to about 50°C.
  • the heterogeneous reaction mixture contains major product APA-8 as a precipitated or crystallized product as well as solubilized minor product APA-8b, residual APA-7, solvent, base, and trace byproducts.
  • the precipitated APA-8 product may also contain a small amount of APA-8b, and other minor impurities, which are removed in a later purification step.
  • the RM may then be quenched, for example, by addition of a sufficient amount of water. An excess of water may be used, such as for example 20 mL of water per gram of APA-7.
  • the water may contain an acid at the same or similar molar equivalent to the base.
  • the water used to quench the reaction may contain ammonium chloride or another acid.
  • the acid may be first added in a smaller aliquot of water (such as about 0.25 mL per g of APA-7) and stirred for several minutes (e.g., 10 - 15 minutes) followed by addition of excess water.
  • the RM may be cooled before, during, or after quenching to maintain or reduce temperature of the RM as a result of quenching exotherms.
  • the RM may be cooled and maintained at a temperature from about 0°C to about 10°C, or as necessary to avoid loss of product.
  • the RM may be cooled for a period of time, such as for about 1 hour, to ensure quenching is complete.
  • the wet product containing APA-8 may be collected by gravity filtration, vacuum filtration, or other means of removing the liquid phase. The wet product may be washed with water during filtration.
  • the wet product obtained from filtration may then be purified.
  • the wet product may be first dried, and then re-wetted with water, although it is generally more efficient to purify the wet product obtained from the reaction.
  • Various purification methods are contemplated, including but not limited to chemical purification, chromatographic purification (column or high-throughout), and any other method. A nonlimiting example of a chemical purification is described below.
  • a recrystallization from methyl tert-butyl ether is utilized to purify the product.
  • the wet material containing APA-8) is mixed with about 3 mL of methyl tert-butyl ether (MTBE) per gram of APA-7 utilized. More or less MTBE may be utilized as would be appreciated by a person of ordinary skill in the art.
  • the MTBE suspension may be stirred for at least about 1 hour at about 25 - 30 °C, which dissolves at least some of the wet material containing APA-8. Then, the mixture is cooled to about 0 - 5°C (where APA-8 forms solid crystals) and mixed for an additional time of at least about 1 hour.
  • the liquid may then be removed by vacuum filtration and the solid may be washed with cooled MTBE.
  • the solid obtained may then be dried to obtain the purified APA- 8 product. While MTBE is generally preferred, any solvent in which APA-8 is relatively insoluble compared to APA-8b may be utilized for purification and crystallization of the APA-8 product.
  • the wet material may be mixed with about 5 mL of n-heptane per gram of APA-7 utilized.
  • the n-heptane suspension may be stirred for at least about 30 minutes at 25 - 30 °C, followed by vacuum filtration and rinsing with n-heptane.
  • the n-heptane wash may assist in removing additional solvent or other impurities from the wet material prior to recrystallization.
  • Other volatile solvents such as hexanes may be utilized.
  • Example 1 Synthesis of tert-butyl ((3S,6R)-6-(cyanomethyl)- tetrahydro-2H-pyran-3- yl)carbamate (APA-8):
  • reaction completion (chemical conversion and desired/undesired isomers ratio was monitored by HPLC)
  • reaction mixture was quenched with 20% ammonium chloride solution (25 mL) at below 30 °C and stirred the mass for 30 minutes at 25-30 °C.
  • Water (1000 mL) was added to the mass at 25-30 °C over a period of 20 minutes and stirred the mass for 30 minutes.
  • the mass was cooled to 0-10 °C and stirred for 1 h.
  • the resultant solids were filtered and washed with water (250 mL) and vacuum dried for 30 minutes. The wet material was collected and subjected to the below purification process.
  • HPLC was performed using a Dura shell C18 (250 x 4.6) mm x 5.0 pm or equivalent (Lot number: 110805) column and UV/PDA detection.
  • the chromatographic conditions are shown in Table 1 below.
  • Table 1 HPLC chromatographic conditions [0074] Under these conditions, it was found that APA-7, APA-8, and APA-8b (listed by elution order) had differing retention times which could be resolved. These retention times, as shown in the exemplary chromatogram of FIG. 4, corresponded to 19.9, 24.7, and 25.7 minutes, respectively.
  • MS Mass spectrometry
  • NMR spectroscopy J H and 13 C was used to characterize and verify the APA-8 structure obtained.
  • One dimensional NMR spectra were acquired on a 300 MHz Bruker NMR spectrometer. Samples were prepared by dissolving a mass (5 mg for 1 H NMR, 20 mg for 13 C NMR) of APA-8 sample in 0.7mL of DMSO-d6 solvent, then transferring the solution into an NMR tube. Exemplary 1 H and 13 C NMR spectra are shown in FIGs. 6 and 7, respectively.
  • FTIR Fourier-Transform Infrared Spectroscopy
  • Desired & undesired isomers ratio in purified product 99.31 :0.68.
  • Mass (ES+): m/z 241.2234 (M++1); Melting range: 166.3 °C to 169.5 °C
  • compositions and methods of the present invention where the term comprises is used with respect to the recited components of the compositions or steps of the methods, it is also contemplated that the compositions and methods consist essentially of, or consist of, the recited steps or components. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • composition can be described as being composed of the components prior to mixing, because upon mixing certain components can further react or be transformed into additional materials.

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Abstract

La présente divulgation concerne des processus de synthèse de chlorhydrate de ([3S,6R]-6-[cyanométhyle]-tétrahydro-2H-pyrane-3-amine) et un intermédiaire de médicament critique. Les processus atteignent approximativement deux fois le pourcentage de rendement de processus connus avec une chimie plus écologique, et éliminent avantageusement des étapes intensives en ressources pour une efficacité industrielle et une applicabilité améliorées.
PCT/US2024/041658 2023-08-10 2024-08-09 Processus de production de (3s,6r)-6-(cyanométhyle)-tétrahydro-2h-pyran-3-amine Pending WO2025035069A2 (fr)

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