Method for producing 4,5-dihydro-1H-pyrazole and intermediates

Abstract

Methods for making compounds comprising a (S)-4,5-dihydro-1H-pyrazole ring are described. These methods include a chiral resolution step performed on an intermediate using a selected chiral resolution agent. For example, the chiral resolution agent can be selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-cytisine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R,2S)-(+)-cis-1-amino-2-indanol. #imgabs0#

Description

[0001] Related Applications

[0002] Under applicable law, this application claims priority to U.S. Provisional Application No. 63 / 006,311, filed on April 7, 2020, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure generally relates to methods for producing enantiomerically enriched substituted 4,5-dihydro-1H-pyrazoles and intermediates thereof. Background Art

[0004] It is generally known that activation of the cannabinoid CB1 receptor increases appetite, increases lipid biosynthesis and storage, inhibits the activation of insulin and leptin, and promotes inflammation and fibrosis. Therefore, research has focused on the development of CB1 receptor inhibitors for the potential treatment of obesity and the metabolic disorder associated therewith, known as metabolic syndrome. Rimonabant has been shown to be effective in treating metabolic syndrome, but causes neuropsychiatric (i.e., CNS-related) side effects, which has led to its withdrawal from the market.

[0005] George Kunos et al. disclosed in U.S. Pat. No. 9,765,031 that compounds preferentially target CB1 receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic β cells, and gastrointestinal tract) without interacting with CB1 receptors in brain tissue, thereby avoiding or reducing CNS-related side effects.

[0006] The compounds described by Kunos et al. all have at least one chiral center. The separation of enantiomers of the final compound or synthetic intermediate is usually carried out by chiral chromatography (HPLC or SFC). For large-scale production, such methods will be impractical or too expensive. Summary of the invention

[0007] According to a first aspect, the present technology relates to a method for preparing an enantiomerically enriched compound, the method comprising the steps of:

[0008] (a) providing a compound of formula I or a tautomer thereof:

[0009]

[0010] in,

[0011] R 1 , R 2 and R 3each independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted borate, optionally substituted silanyl, and imino; and a, b, and c are each independently 0, 1, 2, 3, 4, or 5;

[0012] wherein the compound of Formula I comprises a mixture of R and S isomers at the (*) carbon atom (C*), and wherein the fourth atom attached to C* is hydrogen or an isotope thereof (e.g., deuterium);

[0013] (b) dissolving the compound of formula I in a solvent to obtain a solution;

[0014] (c) dissolving a chiral resolving agent in the solution to form a precipitate and a supernatant, wherein the chiral resolving agent is selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-spartein, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R,2S)-(+)-cis-1-amino-2-indanol; and

[0015] (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant comprises the enantiomerically enriched compound, the enantiomerically enriched compound comprising a higher concentration of the S-enantiomer than the R-enantiomer of the compound of Formula I;

[0016] Wherein steps (b) and (c) are performed simultaneously or sequentially.

[0017] In one embodiment, the solvent is an aprotic organic solvent, such as acetonitrile. In an alternative embodiment, the solvent comprises an alcohol having 1 to 4 carbon atoms or a combination thereof, for example, the alcohol is selected from ethanol, isopropanol and a combination thereof (e.g., isopropanol). In one embodiment, the solvent further comprises water at a concentration of 10% or less, or 5% or less, or the solvent is anhydrous.

[0018] In other embodiments, in step (b), the concentration of the compound of Formula I is from about 50 g to about 150 g, or from about 75 g to about 120 g, or from about 85 g to about 115 g per liter of solvent.

[0019] In other embodiments, step (c) comprises about 0.5 to about 1 or about 0.55 to about 0.75 or about 0.6 to about 0.7 or about 0.65 molar equivalents of said chiral resolving agent relative to said compound of Formula I.

[0020] In some embodiments, the chiral resolving agent is selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine and (R)-(-)-2-amino-3-methyl-1-butanol, preferably (-)-quinine. In these embodiments, the method may further include a step of treating the supernatant to obtain a solid rich in the (S) isomer of the compound of Formula I. In one embodiment, the treating step includes concentrating the supernatant by at least partially evaporating the solvent. In other embodiments, the treating step includes adding an acidic aqueous solution to the supernatant, for example, the acidic aqueous solution has a pH included in the range of 0 to 1, preferably about 0. In a preferred embodiment, the volume ratio of the acidic aqueous solution to the total volume of the solution is 4% to 20%. In one embodiment, the acidic aqueous solution has a pH of about 0, and the volume ratio of the acidic aqueous solution to the total volume of the solution is 10% to 16%, or 12% to 14%.

[0013] In any of the preceding embodiments, the method typically further comprises the step of separating the solids from the supernatant after the treating step.

[0021] In other embodiments, the chiral resolving agent is selected from (-)-cinchonidine, (-)-cytisine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R,2S)-(+)-cis-1-amino-2-indanol, for example, (-)-cytisine. In these embodiments, the method may further include recrystallizing the precipitate.

[0022] In another embodiment, the method further comprises the step of separating the (S) isomer of the compound of Formula I from the chiral resolving agent, for example, by adding an acid (eg, hydrochloric acid).

[0023] In yet other embodiments, the method further comprises recovering the (R) isomer of the compound of formula I, at least partially racemizing the (R) isomer to obtain the compound of formula I, and further processing the compound through steps (a) to (d).

[0024] In another embodiment of the present method, the compound has Formula I, wherein a is zero, R 1 does not exist, and R 2 and R 3Each is independently selected from haloalkyl and halogen, preferably b and c are each 1. In one embodiment, the compound has formula I(a) or I(b):

[0025]

[0026] or a tautomer thereof.

[0027] According to other aspects, the present technology relates to methods for preparing compounds of formula III or tautomers thereof:

[0028]

[0029] in,

[0030] R 1 , R 2 , R 3 , a, b and c are defined herein;

[0031] R 4 is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted borate, optionally substituted silanyl, and imino; and

[0032] R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkyl C(O)NH, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted borate, optionally substituted silanyl, and imino;

[0033] wherein the fourth atom attached to the chiral carbon is hydrogen or an isotope thereof (e.g., deuterium);

[0034] The method comprises the following steps:

[0035] (i) preparing a compound of formula II according to the method defined above:

[0036]

[0037] as well as

[0038] (ii) converting the compound of formula II into the compound of formula III.

[0039] In one embodiment, step (ii) comprises the following steps:

[0040] (ii-a) reacting the compound of formula II with a chlorinating agent (e.g. POCl3) to produce a compound of formula IV:

[0041]

[0042] (ii-b) reacting the compound of formula IV with a compound of formula V or a salt thereof:

[0043]

[0044] To produce the compound of formula III.

[0045] In one embodiment, the step (ii-a) further comprises a base (e.g., 2,6-lutidine). In other embodiments, the step (ii-b) further comprises a base (e.g., DBU, K2HPO4). In another embodiment, a is zero and R 1 Does not exist, R 2 and R 3 Each is independently selected from haloalkyl and halogen, preferably b and c are each 1. In a preferred embodiment, the compound of formula III is selected from compounds 1 to 26 as defined herein, or tautomers thereof.

[0046] Additional objects and features of the present compounds, compositions, methods and uses will become more apparent upon reading the non-limiting description of the following illustrative embodiments and examples, which should not be construed as limiting the scope of the invention. DETAILED DESCRIPTION

[0047] All technical and scientific terms and expressions used herein have the same definitions as those terms and expressions commonly understood by those skilled in the art. However, the definitions of some terms and expressions used are provided below. To the extent that the definitions of the terms in the publications, patents and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification will prevail. The section headings used herein are only for organizational purposes and should not be construed as limiting the disclosed subject matter.

[0048] The chemical structures described herein are drawn according to conventional standards. In addition, when an atom such as a carbon atom as drawn appears to include an incomplete valence, it is assumed that the valence is satisfied by one or more hydrogen atoms, even if these hydrogen atoms are not necessarily explicitly drawn. It should be inferred that the hydrogen atom is part of the compound.

[0049] The terms used herein are only for the purpose of describing specific embodiments and are not intended to be limiting. It should be noted that the singular forms "a", "an", and "the" also include plural forms unless the content clearly stipulates otherwise. Thus, for example, a composition comprising a "compound" is also covered by a mixture of two or more compounds. It should also be noted that, unless the context clearly stipulates otherwise, the term "or" is generally used in its sense, including "and / or". In addition, to the extent that the terms "including", "includes", "having", "has", "with" or variations thereof are used in detailed descriptions and / or claims, such terms are intended to be included in a manner similar to the term "comprising".

[0050] As determined by one of ordinary skill in the art, the term "about" means within an acceptable error range for a particular value, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to the practice in the art, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or methods, the term can mean within the order of magnitude of a value, preferably within 5 times and more preferably within 2 times. Where specific values ​​are described in the present application and claims, the meaning of the term "about" within an acceptable error range for a specific value should be assumed unless otherwise stated.

[0051] As used herein, the terms "compound", "active ingredient" and equivalent expressions refer to compounds described in the present application and in U.S. Patent No. 9,765,031 and PCT Patent Application Nos. WO2009 / 059264 and WO2014 / 018695, including those covered by Structural Formula I, optionally with reference to any applicable embodiment, and also including exemplary compounds, such as compounds 1 to 26, and pharmaceutically acceptable salts, tautomeric forms, solvates, esters and prodrugs thereof when applicable. When a zwitterionic form is possible, for practical purposes, the compound can be drawn as its neutral form, but the compound is understood to also include its zwitterionic form. The embodiments herein may also exclude one or more of the compounds. The compound can be identified by its chemical structure or its chemical name. In the case where the chemical structure and the chemical name are inconsistent, the chemical structure shall prevail.

[0052] Unless otherwise indicated, the present compounds also encompass all possible tautomeric forms of the indicated compounds, if any. The term also includes isotopically labeled compounds in which one or more atoms have an atomic mass different from the most abundant atomic mass found in nature. Examples of isotopes that may be incorporated into the present compounds include, but are not limited to 2 H(D), 3 H(T), 11 C. 13 C. 14 C. 15 N. 18 O. 17 O, any of the isotopes of sulfur, etc. The compounds may also exist in unsolvated forms as well as solvated forms, including hydrated forms. These compounds may exist in a variety of crystalline or amorphous forms. However, for the formulations contemplated herein, amorphous or substantially amorphous forms are preferred.

[0053] The chiral compounds and intermediates prepared by this method can be substantially free of the corresponding enantiomer and can be enantiomer-enriched. "Enantiomer-enriched" means that the compound is composed of a significantly larger proportion of one enantiomer. In some embodiments, the compound is composed of at least about 60% by weight, or at least about 70% by weight, or at least about 80% by weight, or at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98% or 99% by weight of the preferred enantiomer. Preferred enantiomers can be separated from racemic mixtures by any method known to those skilled in the art, including high pressure liquid chromatography (HPLC) on chiral carriers and the formation and crystallization of chiral salts, or prepared by asymmetric synthesis.

[0054] As used herein, the terms "ee", "%ee" and "enantiomeric excess" refer to the excess of one enantiomer for a chiral substance. For example, a racemic mixture has 0%ee, a pure enantiomer has 100%ee, and a sample with 90% S-isomer and 10% R-isomer has 80%ee with respect to the S-isomer.

[0055] The expression "pharmaceutically acceptable salt" refers to those salts of the compounds described herein, which are suitable for use in contact with the tissues of humans and lower animals within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction, etc., and commensurately have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Salts can be prepared in situ during the final separation and purification of the compounds described herein, or prepared separately by reacting the free base functional group of the compound with a suitable organic or inorganic acid (acid addition salt) or by reacting the acidic functional group of the compound with a suitable organic or inorganic base (base addition salt).

[0056] The term "solvate" refers to a physical association of one or more solvent molecules (including water and non-aqueous solvent molecules) in the present compound. This physical association may include hydrogen bonds. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The term "solvate" covers both solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, hemihydrates, alcoholates (e.g., ethanolates, hemiethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, etc.), and other physiologically acceptable solvents such as International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (2017) The solvate of the solvent of category 3 described. Therefore, the compound as described herein also includes each of its solvates and its mixture.

[0057] As used herein, the expression "pharmaceutically acceptable prodrug" refers to those prodrugs of the compounds formed by the methods described herein that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, have excessive toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to provide any compound depicted by the formula described herein.

[0058] Abbreviations may also be used throughout the application, unless otherwise indicated, such abbreviations are intended to have the meanings generally understood in the art. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (isobutyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (benzyloxycarbonyl), Boc or BOC (tert-butoxycarbonyl), Su or Suc (succinimide), EtOH (ethanol), iPrOH or i-PrOH or IPA (isopropanol), MeCN (acetonitrile), EtOAc (ethyl acetate), DME (dimethoxyethane), MTBE (methyl tert-butyl ether), TFA (trifluoroacetic acid) and DBU (1,8-diazabicyclo [5.4.0] undec-7-ene).

[0059] The number of carbon atoms in a hydrocarbon substituent can be determined by the prefix "C x -C y ” or “C x-y ” indicates that x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms. However, when the prefix “C x -C y ” or “C x -C y When the definition is related to a group incorporating one or more heteroatoms (e.g., heterocycloalkyl, heteroaryl, etc.), then x and y define the minimum and maximum number of atoms in the ring, respectively, including carbon atoms and one or more heteroatoms.

[0060] As used herein, the term "alkyl" refers to a saturated, straight or branched hydrocarbon group typically containing 1 to 20 carbon atoms. For example, a "C1-C8 alkyl" contains one to eight carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl groups, etc.

[0061] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and typically 2 to 20 carbon atoms. For example, "C 2-8 The term "alkenyl" refers to a group consisting of two to eight carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0062] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and typically 2 to 20 carbon atoms. 2-8"Alkynyl" contains two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0063] The terms "cycloalkyl", "alicyclic", "carbocycle" and equivalent expressions refer to groups including saturated or partially unsaturated (non-aromatic) carbocycles in monocyclic or polycyclic ring systems, including spirocyclic (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems having three to fifteen ring members. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, etc. The term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups. The term "C3-C n "Cycloalkyl" refers to cycloalkyl groups having from 3 to the indicated "n" number of carbon atoms in the ring structure. Unless the number of carbons is otherwise indicated, "lower cycloalkyl" groups as used herein have at least 3 and equal to or less than 8 carbon atoms in their ring structure.

[0064] As used herein, the terms "heterocycle", "heterocycloalkyl", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a saturated or partially unsaturated chemically stable 3- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety and, in addition to carbon atoms, have one or more, preferably one to four heteroatoms as defined above. When used with respect to the ring atoms of the heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl). The heterocycle may be attached to its side group at any heteroatom or carbon atom that produces a chemically stable structure, and any one of the ring atoms may be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, 1,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, 4,5-dihydropyrazolyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothiophenyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine oxazepinyl, diazepine Thiazepine 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolizinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, etc. Heterocyclic groups also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as dihydroindolinyl, 3H-indolyl, chromanyl, benzopyranyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclic ring. The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted. 3-n "Heterocycloalkyl" refers to a heterocycloalkyl group having from 3 to the indicated "n" number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0065] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties as defined herein.

[0066] The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkyloxy", "aryloxy" or "aryloxyalkyl", refers to an aromatic group having 4n+2 conjugated π (pi) electrons, wherein n is an integer from 1 to 3 in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of six to 15 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present description, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracenyl, etc., which may carry one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyl include, but are not limited to, benzyl, phenethyl, etc. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthimidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl, and the like. 6-n"Aryl" refers to an aromatic group having from 6 to the indicated "n" number of atoms in the ring structure.

[0067] The term "heteroaryl", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refers to an aromatic group having 4n+2 conjugated π (pi) electrons, where n is an integer from 1 to 3 (e.g., having 5 to 18 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons in common in the ring array); and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" includes, but is not limited to, nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. A heteroaryl group can be a single ring, or two or more fused rings. As used herein, the term "heteroaryl" also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g., pyrrolo[3,2-b]pyridinyl or pyrrolo[3,2-c]pyridinyl), pyrazolopyridinyl The heteroaryl groups may be monocyclic or bicyclic. The heteroaryl groups include phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinylcarbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl groups may be monocyclic or bicyclic. The heteroaryl groups include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted. Examples include, but are not limited to, pyridylmethyl, pyrimidylethyl, and the like. For example, the term "C 5-n"Heteroaryl" refers to heteroaryl groups having from 5 to the indicated "n" number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0068] The term "halogen" refers to a halogen atom, ie a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0069] As described herein, the compounds of the present description may include "optionally substituted" parts. Generally, whether or not there is the term "optionally" in front, the term "substituted" means that one or more hydrogens of the specified part are replaced by suitable substituents. Unless otherwise indicated, the "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituent can be the same or different at each position. The combination of substituents envisioned in this description is preferably those that lead to the formation of chemically stable or chemically feasible compounds. As used herein, the term "chemically stable" refers to a compound that does not change substantially when subjected to conditions that allow its production, detection, and in some embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0070] The term "optionally substituted" therefore refers to groups that are substituted or unsubstituted by independently replacing one, two or three or more hydrogen atoms on the group with substituents, including but not limited to F, CI, Br, I, OH, CO2H, alkoxy, oxo, thiooxo, NO2, CN, CF3, NH2, NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl, NHheterocycle, dialkylamino, diarylamino, diheteroarylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocycle, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(O)cycloalkyl , C(O)aryl, C(O)heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OCO2aryl, OCO2heteroaryl, OCO2 heterocycloalkyl, OC(O)NH2, OC(O)NH alkyl, OC(O)NH alkenyl, OC(O)NH alkynyl, OC(O)NH cycloalkyl, OC(O)NH aryl, OC(O)NH heteroaryl, OC(O)NH heterocycloalkyl, NHC(O) alkyl, NHC(O) alkenyl, NHC(O) alkynyl, NHC(O) cycloalkyl, NHC(O) aryl, NHC(O) heteroaryl, NHC(O) heterocycloalkyl, NHCO2 alkyl, NHCO2 alkenyl, NHCO2 alkynyl, NHCO2 cycloalkyl, NHCO2 aryl, NHCO2 heteroaryl, NHCO2 heterocycloalkyl, NHC(O)NH2, NHC(O)NH alkyl, NHC(O)NH alkenyl , NHC(O)NH alkenyl, NHC(O)NH cycloalkyl, NHC(O)NH aryl, NHC(O)NH heteroaryl, NHC(O)NH heterocycloalkyl, NHC(S)NH2, NHC(S)NH alkyl, NHC(S)NH alkenyl, NHC(S)NH alkynyl, NHC(S)NH cycloalkyl, NHC(S)NH aryl, NHC(S)NH heteroaryl, NHC(S)NH heterocycloalkyl, NHC(NH)NH2, NHC(NH)NH alkyl, NHC(NH)NH alkenyl, NHC(NH)NH alkenyl, NHC(NH)NH cycloalkyl, NHC(NH)NH aryl, NHC(NH)NH heteroaryl, NHC(NH)NH heterocycloalkyl,NHC(NH)alkyl, NHC(NH)alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl, NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl, C(NH)NHalkenyl, C(NH)NHalkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl, C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)2alkyl, S(O)2alkenyl, S(O)2alkynyl, S(O)2cycloalkyl, S(O)2aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO 2NH alkyl, SO2NH alkenyl, SO2NH alkynyl, SO2NH cycloalkyl, SO2NH aryl, SO2NH heteroaryl, SO2NH heterocycloalkyl, NHSO2 alkyl, NHSO2 alkenyl, NHSO2 alkynyl, NHSO2 cycloalkyl, NHSO2 aryl, NHSO2 heteroaryl, NHSO2 heterocycloalkyl, CH2NH2, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocyclic, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl or methylthiomethyl. ,

[0071] The present compound is an intermediate for the synthesis of peripherally restricted CB1 antagonists. These compounds include a chiral center on the dihydropyrazole ring. The S isomer is more commonly determined to be more effective than the R counterpart. Therefore, efforts are directed to determining a scalable method for isomer separation of the final product or its intermediates. However, attempts to perform enantiomeric separation by crystallizing diastereoisomeric salts of the final product (e.g., Compound 1 below) have not been successful.

[0072] Examples of final compounds that can be produced using this method are as defined in U.S. Patent No. 9,765,031 and PCT Patent Application No. WO2009 / 059264 and No. WO2014 / 018695, all of which are incorporated herein by reference in their entirety for all purposes, and include those defined herein in the following paragraphs. When referring to chemical moieties, the narration of a list of chemical groups in any definition of a variable includes the definition of the variable as any single group or a combination of listed groups. Similarly, the narration of the embodiments herein includes the embodiment as any single embodiment or in combination with any other embodiment or part thereof. Therefore, the following embodiments exist individually or in combination, if applicable.

[0073] More particularly, the present document relates to a method for preparing an enantiomerically enriched compound comprising a dihydropyrazole ring. For example, the method comprises the following steps:

[0074] (a) providing a compound of formula I or a tautomer thereof:

[0075]

[0076] in,

[0077] R 1 , R 2 and R 3 each independently selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted borate, optionally substituted silanyl, and imino; and a, b, and c are each independently 0, 1, 2, 3, 4, or 5;

[0078] wherein the compound of Formula I comprises a mixture of R and S isomers at the (*) carbon atom (C*), and wherein the fourth atom attached to C* is hydrogen or an isotope thereof (e.g., deuterium);

[0079] (b) dissolving the compound of formula I in a solvent to obtain a solution;

[0080] (c) dissolving a chiral resolving agent in the solution to form a precipitate and a supernatant, wherein the chiral resolving agent is selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-cytisine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R,2S)-(+)-cis-1-amino-2-indanol; and

[0081] (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant comprises the enantiomerically enriched compound, the enantiomerically enriched compound comprising a higher concentration of the S-enantiomer than the R-enantiomer of the compound of Formula I;

[0082] Wherein steps (b) and (c) are performed simultaneously or sequentially.

[0083] The solvent used is an organic solvent, which can be protic or aprotic and can further include water. The solvent preferably includes at least one lower alcohol, for example selected from alcohols with 1 to 4 carbon atoms (e.g., ethanol and isopropanol), or a combination thereof. Other solvents include aprotic organic solvents, such as acetonitrile. The solvent can also further include water (e.g., less than 10% v / v, or 5% v / v or lower) or can be used without adding water.

[0084] According to the chiral resolving agent used, the compound rich in S-enantiomer can be present in the supernatant. The example of such chiral resolving agent includes (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine and (R)-(-)-2-amino-3-methyl-1-butanol, preferably (-)-quinine. When using one of these, the supernatant is further treated to obtain a solid of (S) isomer of the compound of rich formula I, which is further separated from the supernatant. Such processing can include by the following concentration of the supernatant: at least partially evaporate (e.g., by heating and / or vacuum) solvent, add an acidic aqueous solution to the supernatant, such as having a pH in the range of 0 to 1, preferably about 0, or a combination of partial evaporation and acidic treatment.

[0085] When an acidic treatment is used, the volume ratio of the acidic aqueous solution to the total volume of the solution is 4% to 20%. For example, the acidic aqueous solution has a pH of about 0, and the volume ratio of the acidic aqueous solution to the total volume of the solution is 10% to 16%, or 12% to 14%.

[0086] In other cases, the compound rich in the S-enantiomer may be present in the precipitate of step (c). Examples of such chiral resolving agents include (-)-cinchonidine, (-)-cytisine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R, 2S)-(+)-cis-1-amino-2-indanol, preferably (-)-cytisine. The precipitate may then be further treated after separation to increase its S-enantiomer content, for example by recrystallization.

[0087] Said method also further comprises the step of separating the compound of the rich enantiomer of formula I from the chiral resolving agent for separation. Acidification is generally used for such separation. For example, acid, such as hydrochloric acid, can be used for forming salt with chiral resolving agent, and it preferably stays in solution, and the free rich enantiomer compound precipitates.

[0088] The resulting enantiomerically enriched compound consists of at least about 60% by weight, or at least about 70% by weight, or at least about 80% by weight, or at least about 90% by weight of the S-enantiomer. Preferably, the compound consists of at least about 95%, 98% or 99% by weight of the S-enantiomer.

[0089] The method may further include recovering the (R) isomer of the compound of formula I, at least partially racemizing the (R) isomer to obtain the compound of formula I, and further treating the compound through steps (a) to (d) above to provide another isomer (S) of the compound of formula I. For example, such racemization can be carried out in the presence of an organic base such as DBU.

[0090] It is understood that the S-enantiomer of the compound of Formula I is the compound of Formula II or a tautomer thereof:

[0091]

[0092] In some cases of Formula I or II, a is 0 and R 1 is absent, i.e. all five free carbon atoms of the aryl group are connected to hydrogen atoms. Preferably, b is 1 and R 2 is halogen and / or c is 1 and R 3 is halogen (e.g., chlorine) or halogenated C 1-6 Alkyl, such as trifluoromethyl. For example, a is zero, R 1 does not exist, and R 2 and R 3 Each is independently selected from haloalkyl and halogen, preferably b and c are each 1.

[0093] According to one embodiment, the compound of formula I is a compound of formula I(a) or I(b), or a tautomer thereof:

[0094]

[0095] According to other examples, the compound of formula II is a compound of formula II(a) or II(b), or a tautomer thereof:

[0096]

[0097] Although this document describes the separation of (S)-enantiomers of compounds of Formula I, it is understood that (R)-enantiomers will be separated using the procedures described herein with chiral separation agents of the opposite chirality of the disclosed chirality. Examples of chiral separation agents of opposite chirality include (+)-quinine, (R)-1-naphthylethylamine, (R)-phenylethylamine, (S)-phenylethylamine, (S)-(-)-2-amino-3-methyl-1-butanol, (+)-cinconidine, (+)-cytisine, (S)-1-naphthylethylamine, L-arginine, D-lysine, (R)-(-)-2-pyrrolidinemethanol, (1S, 2R)-(-)-cis-1-amino-2-indanol, etc. For example, the synthesis of (+)-quinine has been described previously (see, for example, S. Shiomi et al., Chem. Sci., 2019, 10, 9433).

[0098] The compounds of formula I can generally be prepared by: 3 ) c ArSO2NH2 compound (A) reacts with ClC(O)OMe under alkaline conditions to provide (R 3 ) c ArSO2NHC(O)OMe intermediate (B) is then coupled with a free amine (C) of the formula:

[0099]

[0100] The present technology further relates to methods for making compounds containing an S-dihydropyrazole ring, such as CB1 receptor inhibitors as defined above, such as compound (S)-Ibipinabant or a compound of Formula III below.

[0101] For example, the method comprises (i) preparing a compound of formula II according to the above method, and (ii) converting the compound of formula II into a compound of formula III or a tautomer thereof:

[0102]

[0103] in,

[0104] R 1 , R 2 , R 3 , a, b and c are as defined above;

[0105] R 4is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted borate, optionally substituted silanyl, and imino; and

[0106] R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkyl C(O)NH, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted borate, optionally substituted silanyl and imino.

[0107] Step (ii) may include the following steps:

[0108] (ii-a) reacting a compound of formula II with a chlorinating agent to produce a compound of formula IV:

[0109]

[0110] (ii-b) reacting a compound of formula IV with a compound of formula V or a salt thereof:

[0111]

[0112] to produce the compound of formula III.

[0113] An example of a chlorinating agent is POCl3 and step (ii-a) preferably further comprises an organic base such as 2,6-lutidine. Step (ii-b) also preferably further comprises a base, for example an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or an inorganic base such as K2HPO4.

[0114] In some instances, R 4 is H. In other instances, R 5 It is C 1-6 Alkyl (such as methyl) or C 1-6 Alkyl C(O)NH (eg CH3C(O)NH).

[0115] Alternatively, the compound of formula IV is 4 The amine of NH2 is reacted to produce a compound as defined in PCT Patent Application No. WO2009 / 059264 or No. WO2014 / 018695.

[0116] Non-limiting examples of compounds of Formula III include the following compounds 1 to 26:

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0126] Example

[0127] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention.These examples will be better understood with reference to the accompanying drawings.

[0128] Unless otherwise stated, all numerals used in the specification and claims to represent component amounts, reaction conditions, concentrations, characteristics, stability, etc. should be understood to be modified by the term "about" in all cases. At least, each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying common rounding techniques. Therefore, unless otherwise indicated, the numerical parameters set forth in this specification and the appended claims are approximate values ​​that can vary according to the characteristics sought to be obtained. Although the numerical ranges and parameters of the wide range of embodiments set forth are approximate values, the numerical values ​​set forth in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors caused by changes in experiments, test measurements, statistical analysis, etc.

[0129] Example 1 - Enantiomeric resolution using various chiral resolving agents (Formula I(a))

[0130] A racemic mixture or substantially racemic mixture of a compound of Formula I(a):

[0131]

[0132] The chiral base compound was dissolved in three different solvents (isopropanol, isopropanol: water 95:5 v / v, and ethanol: water 95:5 v / v) together with the resolving agent. The resolving agent is commercially available, and the compound of formula I (a) is prepared by known methods.

[0133] Micro-scale screening experiments were carried out in 4mL glass vials by adding a compound (0.5mmol, 1 equivalent) and a resolving agent (0.5mmol, 1 equivalent) of equimolar amounts of formula I (a). Then, the calculated amount of solvent was added to each vial to obtain a solution of 23% w / w based on the theoretical weight of the formed diastereoisomer salt, and the resulting suspension was heated until a clear solution or a moderately clear mixture was obtained. The vial was then shaken at room temperature in an orbital oscillator at 95rpm for two days to induce crystallization.

[0134] Nearly 30 different resolving agents were tested. In experiments where no crystal formation was observed, up to 4 different treatments (if necessary) (i.e., cooling to -20 ° C, ultrasonic treatment at room temperature, slow evaporation of solvent at room temperature, solvent evaporation under vacuum at 50 ° C) were applied to trigger crystal formation. The results of the resolving agents showing the presence of solid and rich S-enantiomers (in solid or supernatant) are shown in Table 1.

[0135] Table 1. Selected screening results

[0136]

[0137] a. Solvent A: 95% EtOH / water; B: 95% i-PrOH / water; C: iPrOH; D: MeCN;

[0138] bn / a: Data not available due to no solid formation (or oil formation).

[0139] Among those tested, (-)-quinine and (-)-cytisine showed some potential as resolving agents in the 3 different solvents tested (liquid composition ≠ 50:50). In all 3 solvents, (-)-quinine showed medium-high enantiomeric enrichment of the S-enantiomer in the liquid, while the R-enantiomer was present in the solid. (-)-Cytisine in IPA and IPA / water 95:5 v / v showed low-moderate enantiomeric enrichment of the S-enantiomer in the crystal. Some other chiral resolving agents were also shown to be rich in the desired S isomer in the crystal or mother liquor.

[0140] Example 2 - Optical Resolution in Isopropanol (Formula I(a))

[0141] Additional testing was performed using (-)-quinine to determine the optimal amount of solvent and scale conditions to use during the resolution.

[0142] The screening experiment was repeated with the compound of formula I(a) and (-)-quinine in IPA on a 17.7 mmol scale (9.0 g of formula I(a)). For crystallization, the reaction mixture was subjected to several heating-cooling cycles in the range of 40-70°C and after the last cycle, gradually cooled to ambient temperature under stirring, seeded with diastereoisomer salt crystals with 85% ee of the R-enantiomer. The reaction mixture was stirred at room temperature for about 18 hours.

[0143] A sample was then taken from the reaction mixture and the composition of the mother liquor and solid was determined by chiral HPLC (Phenomenex LuxTM i-amylose-1 column, 40°C, isocratic elution with IPA / hexane / TFA 99:1:0.1 v / v / v). The %ee in the mother liquor showed 34.4%ee for (S). Since the calculated cocrystal 77.5%ee (S) was not reached in the liquid (34.4%ee was determined by chiral HPLC), the slurry was vacuum filtered to provide 2.17g of diastereomeric salt (87.4%ee solid; determined by chiral HPLC). The mother liquor was evaporated to 1 / 3 of the initial volume (54g of IPA solution) and then seeded with the R-diastereomeric salt (85%ee for the R-enantiomer) at 40°C. The reaction was stirred at room temperature overnight. After stirring for 14 hours, a sample was taken from the reaction mixture to determine the composition of the mother liquor and solid by chiral HPLC (42.2% ee of S in the mother liquor). The reaction mixture was vacuum filtered again, and the resulting mother liquor was concentrated to about 60% of the initial volume (34 g) and then seeded with the R-diastereoisomer salt (85% ee for the R-enantiomer) at 40°C. The reaction was stirred at room temperature over the weekend (76 hours). The composition of the mother liquor and solid was determined by chiral HPLC (45.7% ee in the mother liquor).

[0144] After stirring overnight at room temperature, the reaction was repeated on a 4 g scale to give 49.3% ee of the S-enantiomer in the mother liquor. After vacuum filtration of the reaction mixture, the mother liquor was evaporated to half of the initial volume (39.9 g of IPA solution) and the resulting mixture was seeded with the R-diastereoisomer salt (85% ee for the R-enantiomer) at 40°C. The reaction was stirred at room temperature for 76 hours. The composition of the mother liquor and solid was determined by chiral HPLC (61.5% ee in the mother liquor).

[0145] The subsequent reaction was carried out on a 2g scale, with slightly changed reaction conditions. The initial stage of the reaction was carried out at 70°C until a clear solution was observed (approximately 10min). The solution was then cooled to room temperature (precipitate began to appear) and stirred for another 1 hour and 20 minutes. The reaction was diluted with 20mL IPA and refluxed at 70°C for 10min, then additional IPA (20mL) was added. The suspension was cooled to room temperature again, then 20mL IPA was added. The suspension was stirred for 15min, and then filtered through an S3 sinter funnel. After IPA washing, HPLC analysis showed that the crystals had ee 85.3% (R), and the liquid %ee was 72.4 (S). The reaction of the 2g scale was repeated according to the above procedure and the suspension was stirred overnight (18h). HPLC analysis showed that the crystals had ee 64.8% (R); the solution was 85.6% ee (S). The diastereomeric salts were decomposed by addition of 2M aqueous HCl (85.6% ee) and the resulting precipitate was filtered on a sinter funnel (porosity 3) to afford the S-enantiomer (99.4% ee).

[0146] Example 3 - Optical resolution and further enrichment in acetonitrile (Formula I(a))

[0147] (a) Chiral separation

[0148] The reaction of 50 g scale was carried out in a reactor using a compound of formula I (a) and (-)-quinine. More particularly, 50 g of the compound of formula I (a), 20.76 g of (-)-quinine (0.65 equivalent) and 443 g of HPLC grade acetonitrile (MeCN, about 564 mL) were mixed in a reactor and the temperature was raised to 65 ° C for 30 minutes. The mixture was then cooled to 20 ° C over a period of 4.5 hours and kept overnight (about 18 hours) at 15 ° C. The slurry was then filtered. The crystals included 95.8% (ee) of the R-isomer, while the mother liquor provided 77.2% (ee) of the S-isomer.

[0149] (b) Enrichment of the S-isomer

[0150] Further process the mother liquor comprising the solution of the rich S-isomer from step (a) to improve the enantiomeric excess (ee) of the S-isomer.The volume of mother liquor is adjusted to 400mL (69.25g / L formula I (a)), and half solution is used for ee improvement determination.Collect ten 20mL parts (fractions), each of them comprising 1.38g pyrazoline.Each 20mL aliquot is treated with the acidic water of pH 1 or 0 of different volumes (referring to Table 2).After stirring overnight in MeCN / water, solid is filtered and analyzed by HPLC and NMR.

[0151] Table 2. HPLC results for %ee improvement determination

[0152]

[0153] As shown in Table 2, both the increase of water and the decrease of pH reduce the solubility of the desired compound. With the starting material having 77.24% ee of the S-isomer, the conditions using 3mL of pH 0 solution provided the best results. In fact, a near-perfect 76.58% yield was obtained, with> 99% ee. It was found that acidification at a lower temperature (10-20°C) was preferred because it resulted in fewer side reactions and increased yields compared to acidification at a warmer temperature (40-55°C). These conditions applied to the remaining mother liquor (200mL) (adding about 15% water pH 0 to a compound solution of 69-70g / L) confirmed the robustness sufficient to provide a good return on a 13.8g scale. In fact, after filtration and further drying (rotary evaporation 5-10 mbar, 45°C, 4h), 8.87g of S-isomer with> 99% ee was obtained. 1 H-NMR showed the presence of 0.52 equivalents of water.

[0154] Steps (a) and (b) were repeated using 500 g of the racemic starting material in step (a), 208 g of (-)-quinine (0.65 equivalents) and 3.48 kg MeCN (about 4.43 L). Step (b) was carried out as above using 270 g of the S-isomer-rich compound (ee: 76.24%), MeCN (total volume 3.9 L) and 1 N HCl (pH 0, 592 mL), and 205 g of 99.5 ee% of the S-isomer (Formula II (a)) was provided. This compound can be used to prepare compounds of Formula III, such as compounds 1, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25.

[0155] Example 4 - R-isomer separation and racemization (Formula I(a))

[0156] The R-isomer-enriched crystals of the (-)-quinine salt comprising the R-isomer (e.g. isolated from step (a) of Example 3) are recycled by first destroying the salt formed and then by racemizing the isolated R-isomer for reuse in the resolution process. Two alternative methods are illustrated below.

[0157] Method 1:

[0158] The first step was carried out by mixing the salts (about 230 g of (R), 140 g of quinine) in 2.3 L of HPLC grade dichloromethane and adding 1.15 L of 1N HCl solution under stirring. The mixture was mixed at 20° C. for 1.5 hours. The organic phase was separated, washed with 0.6 L of water, and dried over MgSO4. Filtration and evaporation under reduced pressure gave the R-isomer-enriched compound (211 g, 92% yield).

[0159] The obtained solid was then dissolved in anhydrous DME (1L) and mixed with DBU (93.5mL, 1.5 equivalents). The solution was stirred at 70-80°C for 6 hours. The mixture was cooled to 10-20°C and water was added. The pH was adjusted to 4-5 by adding HCl. The aqueous phase was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried with MgSO4. All volatiles were removed under reduced pressure, and the residue was ground with MTBE / EtOAc (8 / 1). The slurry was filtered and washed with cold MTBE. The solid was further dried under reduced pressure to obtain the racemic compound (175g, 82% yield) of formula I (a). The racemic compound was then further used in the method of Example 3 to produce the S-isomer.

[0160] Method 2:

[0161] R-isomer quinine salt (79 kg, 1.0 equivalent) was introduced into the reaction vessel. 1N hydrochloric acid solution (3 volumes) was added to the vessel, then 2-methyltetrahydrofuran (2-MeTHF) (2 volumes) was added, and the mixture was stirred until it became clear. The mixture was separated, and the organic phase was washed with water (1 volume) and concentrated to dryness. DME (3 volumes) was added, and the mixture was concentrated to dryness again.

[0162] The obtained solid was then dissolved in anhydrous DME (3 volumes) and mixed with DBU (1.5 equivalents). The solution was stirred at 70-80°C until complete racemization was achieved (monitored by chiral chromatography). The mixture was cooled to 10-20°C and water (3.5 volumes) was added dropwise. The pH was adjusted to 2-3 by slowly adding 1N HCl solution. The mixture was filtered and the filter cake was washed with water (2 volumes). The filter cake was dried at 50-60°C to obtain the racemic compound of formula I (a) (42 g, 95% yield). The racemic compound was then further used in the method of Example 3 to produce the S-isomer.

[0163] Example 5 - Optical Resolution of Compounds of Formula I(b)

[0164] To a mixture of the compound of formula I (b) (96.0 g, 1.00 equiv) in MeCN (960 mL) was added (-)-quinine (50.0 g, 0.76 equiv) at 15-20 ° C, and the mixture was then stirred at 60-70 ° C for 1.5 hours. The mixture was then cooled to 20-30 ° C and stirred for 16 hours. The mixture was filtered and the filter cake was dried to obtain a white solid (96.0 g), which was checked by SFC and HPLC. The mother liquor was checked by SFC and HPLC. The mother liquor was warmed to 40-45 ° C, and HCl (1M, 61.7 mL) and H2O (150 mL) were added to the solution. The mixture was stirred at 15-20 ° C for 4 hours. The mixture was then filtered and a solid was obtained. The solid was ground with MeCN / H2O (150 mL / 15 mL). The S-isomer of formula II (b) was obtained as a light yellow solid (25.0 g, 99.5% purity) by 1 H NMR, LCMS, HPLC and SFC confirmed. The S-isomer can be further used to prepare compounds of formula III, for example, for preparing compounds 2, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26, or for preparing other compounds such as (S)-epinaban and other compounds described in U.S. Patent No. 9,765,031 and PCT Patent Application Nos. WO2009 / 059264 and WO2014 / 018695.

[0165] 1 H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 7.93-8.10 (m, 2H), 7.80 (d, J = 8.8Hz, 2H), 7.67-7.76 (m, 2H), 7.37-7.52 (m, 2H), 7 .26-7.36(m,2H),7.12-7.26(m,3H),4.98(dd,J=11.6,4.8Hz,1H),4.27(t,J=11.6Hz,1H),3.67(dd,J=11.2,4.8Hz,1H).

[0166] LCMS: RT=1.063min, m / z=474(M+H) + .

[0167] Many modifications may be made to any of the embodiments described above without departing from the scope of the invention.Any reference, patent or scientific literature document mentioned in this document is incorporated herein by reference in its entirety for all purposes.

Claims

1. A method for preparing an enantiomerically enriched compound comprising the following steps: (a) providing a compound of formula I: in, a is zero, R 1 does not exist, and R 2 and R 3 are each independently selected from haloalkyl and halogen, and b and c are both 1; Wherein the compound of formula I is selected from the compound of formula I(a) or formula I(b): wherein the compound of Formula I comprises a mixture of R and S isomers at the (*) carbon atom (C*), and wherein the fourth atom attached to C* is hydrogen or an isotope thereof; (b) dissolving the compound of formula I in a solvent to obtain a solution, wherein the solvent is an aprotic organic solvent, or the solvent comprises an alcohol having 1 to 4 carbon atoms or a combination thereof; (c) dissolving a chiral resolving agent in the solution to form a precipitate and a supernatant, wherein the chiral resolving agent is selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-cytisine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R,2S)-(+)-cis-1-amino-2-indanol; and (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant comprises the enantiomerically enriched compound, the enantiomerically enriched compound comprising a higher concentration of the S-enantiomer than the R-enantiomer of the compound of Formula I; Wherein steps (b) and (c) are performed simultaneously or sequentially.

2. The method according to claim 1, wherein: The isotope is deuterium.

3. The method according to claim 1, wherein: The aprotic organic solvent is acetonitrile.

4. The method according to claim 1, wherein: The alcohol is selected from ethanol, isopropanol and combinations thereof.

5. The method according to claim 4, wherein: The alcohol is isopropanol.

6. The method according to any one of claims 1 to 5, wherein: The solvent further comprises water at a concentration of 10% or less, or the solvent is anhydrous.

7. The method according to claim 6, wherein: The solvent further comprises water at a concentration of 5% or less, or the solvent is anhydrous.

8. The method according to any one of claims 1 to 5, wherein: In step (b), the concentration of the compound of formula I is 50 g to 150 g per liter of solvent.

9. The method according to claim 8, wherein: In step (b), the concentration of the compound of formula I is 75 g to 120 g per liter of solvent.

10. The method according to claim 8, wherein: In step (b), the concentration of the compound of formula I is 85 g to 115 g per liter of solvent.

11. The method according to any one of claims 1 to 5, wherein: Step (c) comprises 0.5 to 1 molar equivalent of the chiral resolving agent relative to the compound of formula I.

12. The method according to claim 11, wherein: Step (c) comprises 0.55 to 0.75 molar equivalents of the chiral resolving agent relative to the compound of formula I.

13. The method according to claim 11, wherein: Step (c) comprises 0.6 to 0.7 molar equivalents of the chiral resolving agent relative to the compound of formula I.

14. The method according to claim 11, wherein: Step (c) comprises 0.65 molar equivalent of the chiral resolving agent relative to the compound of formula I.

15. The method according to any one of claims 1 to 5, wherein: The chiral resolving agent is selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine and (R)-(-)-2-amino-3-methyl-1-butanol.

16. The method according to claim 15, wherein: The chiral resolving agent is (-)-quinine.

17. The method according to claim 15, further comprising the step of treating the supernatant to obtain a solid enriched in the (S) isomer of the compound of formula I.

18. The method according to claim 17, wherein: The treating step comprises concentrating the supernatant by at least partially evaporating the solvent.

19. The method according to claim 17, wherein: The treating step comprises adding an acidic aqueous solution to the supernatant.

20. The method according to claim 19, wherein: The acidic aqueous solution has a pH comprised in the range of 0 to 1.

21. The method according to claim 20, wherein: The volume ratio of the acidic aqueous solution to the total volume of the solution is 4% to 20%.

22. The method according to claim 21, wherein: The acidic aqueous solution has a pH of 0, and a volume ratio of the acidic aqueous solution to the total volume of the solution is 10% to 16%.

23. The method according to claim 22, wherein: The volume ratio of the acidic aqueous solution to the total volume of the solution is 12% to 14%.

24. The method of claim 17, further comprising the step of separating the solids from the supernatant.

25. The method according to any one of claims 1 to 5, wherein: The chiral resolving agent is selected from (-)-cinchonidine, (-)-cytisine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol and (1R, 2S)-(+)-cis-1-amino-2-indanol.

26. The method according to claim 25, wherein: The chiral resolving agent is (-)-cytisine.

27. The method of claim 25, further comprising recrystallizing the precipitate.

28. The method according to any one of claims 1 to 5, further comprising the step of separating the (S) isomer of the compound of formula I from the chiral resolving agent.

29. The method according to claim 28, wherein: The separation step comprises adding an acid.

30. The method of claim 29, wherein: The acid is hydrochloric acid.

31. The process according to any one of claims 1 to 5, further comprising recovering the (R) isomer of the compound of formula I, at least partially racemizing the (R) isomer to obtain the compound of formula I, and further treating the compound by steps (a) to (d).

32. A method for preparing a compound of formula III: in, R 1 , R 2 , R 3 , a, b and c are as defined in claim 1; R 4 is selected from H, alkyl, cycloalkyl and piperidinyl; R 5 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, amino, alkylC(O)NH, phenyl and pyridyl; and Wherein the compound of formula III is selected from: wherein the fourth atom attached to the chiral carbon is hydrogen or an isotope thereof; The method comprises the following steps: (i) preparing a compound of formula II(a) or II(b) according to a process as defined in any one of claims 1 to 31: Where R 1 , R 2 , R 3 , a, b and c as defined in claim 1; and (ii) converting the compound of formula II (a) or II (b) into compound 1, 2, Any of 7, 8 and 11-26.

33. The method of claim 32, wherein: Step (ii) comprises the following steps: (ii-a) reacting the compound of formula II with a chlorinating agent to produce a compound of formula IV: Where R 1 , R 2 , R 3 , a, b and c as defined in claim 1; and (ii-b) reacting the compound of formula IV with a compound of formula V or a salt thereof: Where R 4 is H or piperidinyl, and R 5 C 1-6 Alkyl, C 3-15 Cycloalkyl, phenyl, pyridyl, amino or C 1-6 Alkyl C(O)NH to produce any one of compounds 1, 2, 7, 8 and 11-26.

34. The method of claim 33, wherein: The chlorinating agent is POCl3.

35. The method of claim 33, wherein: The step (ii-a) further comprises a base.

36. The method of claim 35, wherein: The base of step (ii-a) is 2,6-lutidine.

37. The method of claim 33, wherein: Step (ii-b) further comprises a base.

38. The method of claim 37, wherein: The base of step (ii-b) is DBU or K2HPO4.

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