Process for preparing 4,5-dihydro-1H-pyrazoles and intermediates

Abstract

Methods for preparing compounds containing an (S)-4,5-dihydro-1H-pyrazole ring are described. These methods include a chiral resolution step of an intermediate using a selected chiral resolving agent. For example, the chiral resolving agent may be selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol. TIFF2023521100000043.tif49158

Description

[Technical field]

[0001] Related Applications This application claims priority under applicable law to U.S. Provisional Application No. 63 / 006,311, filed April 7, 2020, the contents of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure relates generally to methods for making enantiomerically enriched substituted 4,5-dihydro-1H-pyrazoles and intermediates thereof. [Background technology]

[0003] Cannabinoid CB 1 It is generally known that activation of the receptor increases appetite, promotes lipid synthesis and storage, inhibits the action of insulin and leptin, and promotes inflammation and fibrosis. Therefore, CB12 is a potential treatment for obesity and its associated metabolic disorders, known as metabolic syndrome. 1 There has been considerable research into the development of receptor inhibitors. Rimonabant has been shown to be effective in treating metabolic syndrome but has been shown to cause neuropsychiatric (i.e., CNS-related) side effects and has been withdrawn from the market.

[0004] The CBs are expressed in peripheral tissues (e.g., adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic β cells, and the gastrointestinal tract). 1 receptors in brain cells, whereas CB 1 Compounds that do not affect receptors, thereby avoiding or reducing CNS-related side effects, have been disclosed by George Kunos et al. in US Pat. No. 9,765,031. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Pat. No. 9,765,031 [Patent Document 2] International Publication No. 2009 / 059264 [Patent Document 3] International Publication No. 2014 / 018695 [Non-patent literature]

[0006] [Non-Patent Document 1] SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19 (1977) [Non-Patent Document 2] International Conference on Harmonization (ICH), Guidance for Industry, Q3C Impurities: Residual Solvents (2017) [Non-Patent Document 3] S. Shiomi et al., Chem. Sci., 2019, 10, 9433 Summary of the Invention [Problem to be solved by the invention]

[0007] All of the compounds described in the Kunos et al. patent have at least one chiral center. Separation of the enantiomers of the final compounds or synthetic intermediates is usually accomplished by chiral chromatography (HPLC or SFC). Such methods would be impractical or too expensive for large-scale production. [Means for solving the problem]

[0008] According to a first aspect, the present technology provides a method for preparing an enantiomerically enriched compound, comprising the steps of: (a) a compound of Formula I: [ka] (In the formula, R 1 , R 2 , and R 3are 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 boronic ester, optionally substituted silyl, and imino; a, b, and c are each independently 0, 1, 2, 3, 4, or 5; The compound of formula I is * ) attached to the carbon atom (C * ) including a mixture of R and S isomers in C * The fourth atom bonded to is hydrogen or an isotope thereof (e.g., deuterium). or a tautomer thereof; (b) dissolving the compound of formula I in a solvent to obtain a solution; (c) dissolving a chiral resolving agent (optical resolving agent) selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol in the solution to form a precipitate and a supernatant; and (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant contains an enantiomerically enriched compound containing a higher concentration of the S-enantiomer relative to the R-enantiomer of the compound of formula I; The method relates to a method in which steps (b) and (c) are carried out simultaneously or sequentially.

[0009] 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 combinations thereof (e.g., isopropanol). In one embodiment, the solvent further contains water at a concentration of 10% or less, or 5% or less, or the solvent is anhydrous.

[0010] In another embodiment, the compound of formula I is at a concentration of between about 50 g and about 150 g, or between about 75 g and about 120 g, or between about 85 g and about 115 g per liter of solvent in step (b).

[0011] In further embodiments, step (c) comprises between about 0.5 molar equivalents to about 1 molar equivalent, or between about 0.55 molar equivalents to about 0.75 molar equivalents, or between about 0.6 molar equivalents to about 0.7 molar equivalents, or about 0.65 molar equivalents of said chiral resolving agent relative to the compound of formula I above.

[0012] 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 comprise treating the supernatant to obtain a solid enriched in the (S)-isomer of the compound of formula I. In one embodiment, the treating comprises concentrating the supernatant by at least partial evaporation of the solvent. In another embodiment, the treating comprises adding an acidic aqueous solution to the supernatant, for example, the acidic aqueous solution having a pH comprised within 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 between 4% and 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 between 10% and 16%, or between 12% and 14%. In any of the above embodiments, the method also typically further comprises the step of separating the solids from the supernatant after the above treatment steps.

[0013] In other embodiments, the chiral resolving agent is selected from (-)-cinchonidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol, such as (-)-sparteine. In these embodiments, the above method may further comprise the step of recrystallizing the precipitate.

[0014] In a further embodiment, the above method further comprises the step of separating the (S)-isomer of the compound of formula I from the chiral resolving agent, for example, by addition of an acid (eg, hydrochloric acid).

[0015] In yet another embodiment, the above process further comprises recovering the (R)-isomer of the compound of formula I, at least partially racemizing said (R)-isomer to obtain the compound of formula I, and further processing said compound according to steps (a)-(d).

[0016] In a further embodiment of the method, the compound has formula I, where a is 0 and R 1 does not exist and R 2 and R 3 are each independently selected from an alkyl halide and a halogen, preferably b and c are each 1. In one embodiment, the compound is a compound of formula I, wherein b and c are each independently selected from an alkyl halide and a halogen, preferably b and c are each 1. In one embodiment, the compound is a compound of formula I(a) or I(b): [ka] or a tautomer thereof.

[0017] According to another aspect, the present technology provides a compound according to formula III: [ka] (In the formula, R 1 , R 2 , R 3 , a, b, and c are as defined herein; 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 boronic ester, optionally substituted silyl, and imino; and R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkylC(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 boronic ester, optionally substituted silyl, and imino; The fourth atom attached to the chiral carbon is hydrogen or an isotope thereof (e.g., deuterium). or a tautomer thereof, The method is: (i) preparing a compound of formula II: [ka] preparing a compound of formula (I); and (ii) converting the compound of formula II into the compound of formula III.

[0018] In one embodiment, step (ii) comprises: (ii-a) reacting the compound of formula II with a chlorinating agent (e.g., POCl 3 ) to obtain a compound of formula IV: [ka] and (ii-b) reacting a compound of formula IV with a compound of formula V: [ka] or a salt thereof to produce a compound of formula III.

[0019] In one embodiment, step (ii-a) further comprises a base (e.g., 2,6-lutidine). In another embodiment, step (ii-b) further comprises a base (e.g., DBU, K 2 HPO 4 In a further embodiment, a is 0 and R 1 does not exist and R 2 and R 3 are each independently selected from an alkyl halide and a halogen, and preferably b and c are each 1. In a preferred embodiment, the compound of formula III above is selected from compounds 1-26 as defined herein, or a tautomer thereof.

[0020] Further objects and features of the compounds, compositions, methods and uses of the present invention will become more apparent upon reading the following non-limiting illustrative embodiments and examples section, which should not be construed as limiting the scope of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Detailed Description All technical and scientific terms and expressions used herein have the same definitions as commonly understood by those skilled in the art to which this technology pertains. Nevertheless, definitions of some of the terms and expressions used are provided below. To the extent that the definitions of terms in the publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth herein, the definitions in this specification shall control. The section headings used herein are for organizational purposes only and should not be construed as limiting the disclosed subject matter.

[0022] The chemical structures described herein are drawn according to conventional standards.In addition, when an atom, such as a carbon atom, appears to have incomplete valences, it is assumed that the valences are filled with one or more hydrogen atoms, even if they are not necessarily drawn explicitly.Hydrogen atoms should be inferred to be part of the compound.

[0023] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that the singular forms ("a", "an", and "the" in foreign language specifications) also include the plural, unless the context clearly dictates otherwise. Thus, for example, a reference to a composition containing "a compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is typically used in its sense including "and / or" unless the context clearly dictates otherwise. Furthermore, to the extent that the terms "including", "includes", "having", "has", "with", or variations thereof are used in any of the detailed description and / or claims, such terms are intended to be inclusive in a manner similar to the term "comprising".

[0024] The term "about" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on the constraints of the method, i.e., the measurement system, in which the value is measured or determined. For example, "about" may mean within one standard deviation or more than one standard deviation, as is customary in the art. Alternatively, "about" may mean within 20%, preferably within 10%, more preferably within 5%, and even more preferably within 1% of a given value. Alternatively, particularly with respect to biological systems or methods, the term may mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value. When a particular value is described in this application and claims, unless otherwise stated, it should be presumed that the term "about" means within an acceptable error range for the particular value.

[0025] As used herein, the terms "compound", "active ingredient" and equivalent expressions refer to compounds described in this application, U.S. Pat. No. 9,765,031, and WO 2009 / 059264 and WO 2014 / 018695, including those encompassed by structural formula I, optionally with reference to any applicable embodiment, and also including exemplary compounds, such as compounds 1-26, and pharma- ceutically acceptable salts, tautomeric forms, solvates, esters, and prodrugs thereof, where applicable. Where zwitterionic forms are possible, the compounds may be depicted as their neutral forms for practical purposes, but it is understood that the compounds also include their zwitterionic forms. An embodiment herein may also not feature one or more of the compounds. Compounds may be identified by either their chemical structure or their chemical name. In the event that the chemical structures and chemical names appear to be inconsistent, the chemical structures take precedence.

[0026] The compounds of the present invention also include all possible tautomeric forms of the above exemplified compounds, if any, unless otherwise stated. The above term also includes compounds labeled with an isotopically labeled atom in which one or more atoms have an atomic mass different from the atomic mass most abundant in nature. Isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, 2 H(D), 3 H(T), 11 C. 13 C. 14 C. 15 N, 18 O. 17 The compounds may also be present in unsolvated or solvated form, for example hydrated form. The compounds may also be present in various crystalline forms or in amorphous form. However, amorphous or substantially amorphous form is preferred for the formulations contemplated herein.

[0027] The chiral compounds and intermediates prepared by the methods of the invention can be substantially free of the corresponding enantiomer and can be enantiomerically enriched. By "enantiomerically enriched" is meant that the compound is composed of a significantly greater proportion of one enantiomer. In certain 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 a preferred enantiomer. In other embodiments, the compound is composed of at least about 95% by weight, 98% by weight, or 99% by weight of a preferred enantiomer. The preferred enantiomer can be isolated from a racemic mixture by any method known to those skilled in the art, including, for example, high performance liquid chromatography (HPLC) on a chiral support and the formation and crystallization of chiral salts, or can be prepared by asymmetric synthesis.

[0028] 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 of the S-isomer.

[0029] The expression "pharmaceutical acceptable salt" refers to a salt of the compound of the present invention that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts may be prepared in situ during the final isolation and purification of the compounds of the present invention, or may be prepared separately by reacting a free basic functional group of the compound with a suitable organic or inorganic acid (acid addition salts) or an acidic functional group of the compound with a suitable organic or inorganic base (base addition salts).

[0030] The term "solvate" refers to a physical association of one of the compounds of the present invention with one or more solvent molecules, such as water molecules and non-water solvent molecules. This physical association may include hydrogen bonds. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" encompasses both solution-phase and isolatable solvates. Examples of solvates include, but are not limited to, hydrates, hemihydrates, alcoholates (e.g., ethanolate, hemiethanolate, n-propanolate, iso-propanolate, 1-butanolate, 2-butanolate, etc.), and other physiologically acceptable solvents, such as solvates of Class 3 solvents as described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvent (2017). Thus, the compounds described herein also encompass each of their solvates and mixtures thereof.

[0031] As used herein, the phrase "pharmaceutically acceptable prodrug" refers to a prodrug of a compound formed by a process herein that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio and is effective for their intended use. As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to provide any of the compounds depicted by the formulas herein.

[0032] Abbreviations are also used throughout this application, and unless otherwise stated, such abbreviations are intended to have the meaning commonly understood by the art. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), 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).

[0033] The number of carbon atoms in a hydrocarbon substituent is indicated by the prefix "C x ~C y " or "C x~y " where x is the minimum number of carbon atoms in the substituent and y is the maximum number. However, the prefix "C x ~C y " or "C x~y " is linked to a group that by definition incorporates 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 heteroatoms.

[0034] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group that typically contains from 1 to 20 carbon atoms. For example, "C 1 ~C 8 Alkyl" contains 1 to 8 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, and the like.

[0035] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and typically containing 2 to 20 carbon atoms. For example, "C 2~8 Alkenyl" contains 2 to 8 carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.

[0036] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds and typically containing 2 to 20 carbon atoms. For example, 2~8 Alkynyl" contains 2 to 8 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0037] The terms "cycloalkyl", "alicyclic", "carbocyclic" and equivalent expressions refer to groups containing saturated or partially unsaturated (non-aromatic) carbocyclic rings in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond), or bridged (sharing two or more bonds) carbocyclic ring systems, of 3 to 15 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]nonanyl, norbornyl, and the like. The term cycloalkyl includes both unsubstituted and substituted cycloalkyl groups. The term "cycloalkyl" includes both unsubstituted and substituted cycloalkyl groups. 3 ~C n"Cycloalkyl" refers to cycloalkyl groups having three up to the designated "n" carbon atoms in their ring structure. Unless the number of carbons is specifically specified, "lower cycloalkyl" groups used herein have at least three, and no more than eight, carbon atoms in their ring structure.

[0038] 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- to 10-membered bicyclic heterocyclic moiety having one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having one to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure, and any 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, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thiamine ... Examples of such aryl groups include ethanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, 3-azabicyclo[3,1,0]hexanyl, 3-azabicyclo[4,1,0]heptanyl, quinolidinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, and the like.Heterocyclic groups also include groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the linking group or point of attachment is on the heterocyclyl ring. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl portions independently may be optionally substituted. The term "C. 3~n "Heterocycloalkyl" refers to a heterocycloalkyl group having from three to the indicated "n" atoms in a ring structure that includes carbon atoms and heteroatoms.

[0039] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond between ring atoms, but is not aromatic. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0040] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", "aryloxy", or "aryloxyalkyl" refers to an aromatic group having 4n+2 conjugated π (pi) electrons, where n is an integer from 1 to 3, in a single ring moiety or in a bicyclic or tricyclic fused ring system having 6 to 15 rings in total, where at least one ring in the system is aromatic and each ring in the system is 3 to 7 rings. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments herein, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, azulenyl, anthracyl, and the like, which may bear 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, and the like. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthomimidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl. 6~n "Aryl" refers to an aryl group having six to the indicated "n" atoms in the ring structure.

[0041] 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, with 6, 10, or 14 π electrons shared in the cyclic arrangement), and having 1 to 5 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 a basic nitrogen. A heteroaryl may be a single ring or two or more fused rings. The term "heteroaryl", as used herein, also includes groups in which an aromatic heterocycle is fused to one or more aryl, alicyclic, or heterocycles, and the binding group or point of attachment is on the aromatic heterocycle.Non-limiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, 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 Heteroaryl groups include, for example, pyrazolo[1,5-a]pyridinyl), pyrazolopyridinyl (e.g., pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g., imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinyl, carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic or bicyclic. Heteroaryl groups include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like. For example, the term "C. 5~n "Heteroaryl" refers to heteroaryl groups having from five to the indicated "n" atoms in the ring structure that includes carbon atoms and heteroatoms.

[0042] The term "halogen" refers to a halogen atom, ie, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine or chlorine.

[0043] As described herein, the compounds herein may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be either the same or different at each position. The combinations of substituents envisioned herein are preferably those that result in the formation of chemically stable or chemically feasible compounds. As used herein, the term "chemically stable" refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0044] Thus, the term "optionally substituted" refers to a group that is substituted or unsubstituted by independent replacement of one, two, or more hydrogen atoms in that group with a substituent, which is not particularly limited and can include, for example, F, CI, Br, I, OH, CO 2 H, alkoxy, oxo, thiooxo, NO 2 , C.N., C.F. 3 , N.H. 2 , 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, CO 2 Alkyl, CO 2Alkenyl, CO 2 Alkynyl, CO 2 Cycloalkyl, CO 2 Aryl, CO 2 Heteroaryl, CO 2 Heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH 2 , C(O)NH alkyl, C(O)NH alkenyl, C(O)NH alkynyl, C(O)NH cycloalkyl, C(O)NH aryl, C(O)NH heteroaryl, C(O)NH heterocycloalkyl, OCO 2 Alkyl, OCO 2 Alkenyl, OCO 2 Alkynyl, OCO 2 Cycloalkyl, OCO 2 Aryl, OCO 2 Heteroaryl, OCO 2 Heterocycloalkyl, OC(O)NH 2 , 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, NHCO 2 Alkyl, NHCO 2 Alkenyl, NHCO 2 Alkynyl, NHCO 2 Cycloalkyl, NHCO 2 Aryl, NHCO 2 Heteroaryl, NHCO 2 Heterocycloalkyl, NHC(O)NH 2 , 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)NH 2, 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)NH 2 , 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)NH alkyl, C(NH)NH alkenyl, C(NH)NH alkynyl, C(NH)NH cycloalkyl, C(NH)NH aryl, C(NH)NH heteroaryl, C(NH)NH heterocycloalkyl, S(O) alkyl, S(O) alkenyl, S(O) alkynyl, S(O) cycloalkyl, S(O) aryl, S(O) 2 Alkyl, S(O) 2 Alkenyl, S(O) 2 Alkynyl, S(O) 2 Cycloalkyl, S(O) 2 Aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO 2 NH 2 , S.O. 2 NH alkyl, SO 2 NH Alkenyl, SO 2 NH alkynyl, SO 2 NH Cycloalkyl, SO 2 NHaryl, SO 2 NH Heteroaryl, SO 2 NHHeterocycloalkyl, NHSO 2 Alkyl, NHSO 2 Alkenyl, NHSO 2 Alkynyl, NHSO 2 Cycloalkyl, NHSO 2 Aryl, NHSO 2 Heteroaryl, NHSO 2 Heterocycloalkyl, CH2 NH 2 , C.H. 2 SO 2 CH 3 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocycle, heterocycle, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, or methylthiomethyl.

[0045] The compounds of the present invention are intermediates in the synthesis of peripherally restricted CB1 antagonists. These compounds contain a chiral center on the dihydropyrazole ring. It has been identified that the S-isomer is in most cases more potent than its R counterpart. Therefore, efforts have been directed to identifying scalable methods for separating the isomers of either the final product or its intermediates. However, attempts to separate the enantiomers by crystallization of the diastereomeric salts of the final product, such as compound 1 below, have been unsuccessful.

[0046] Examples of final compounds that may be prepared using the methods of the present invention are as set forth in U.S. Pat. No. 9,765,031, and WO 2009 / 059264 and WO 2014 / 018695, all of which are incorporated herein by reference in their entirety for all purposes, including those set forth herein in the following paragraphs. When referring to chemical moieties, the recitation of a list of chemical groups in a definition of a variable includes the definition of that variable as any single group or combination of the listed groups. Similarly, the recitation of an embodiment herein includes that embodiment as a single embodiment or in combination with any other embodiment or portion thereof. Thus, the following embodiments exist alone or in combination, where applicable.

[0047] More specifically, the present disclosure relates to a method for preparing an enantiomerically enriched compound comprising a dihydropyrazole ring, for example, the method comprising the steps of: (a) Formula I: [ka] (In the formula, R 1 , R 2 , and R 3 are 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 boronic ester, optionally substituted silyl, and imino; and a, b, and c are each independently 0, 1, 2, 3, 4, or 5; The compound of formula I is * ) carbon atom (C * ) containing a mixture of R and S isomers in C * The fourth atom bonded to is hydrogen or an isotope thereof (e.g., deuterium). or a tautomer thereof; (b) dissolving the compound of formula I in a solvent to obtain a solution; (c) dissolving a chiral resolving agent selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol into the solution to form a precipitate and a supernatant; and (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant contains an enantiomerically enriched compound of formula I comprising a higher concentration of the S-enantiomer relative to the R-enantiomer; Step (b) and step (c) are carried out simultaneously or sequentially.

[0048] The solvent used is an organic solvent that may be protic or aprotic and may further contain water. The solvent preferably contains at least one lower alcohol, for example selected from alcohols having 1 to 4 carbon atoms (e.g., ethanol and isopropanol), or a combination thereof. Other solvents include aprotic organic solvents, for example acetonitrile. The solvent may also further contain water (e.g., less than 10% v / v, or 5% v / v or less), or may be used without adding water.

[0049] Depending on the chiral resolving agent used, the compound enriched in the S-enantiomer may be present in the supernatant. Examples of such chiral resolving agents include (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, and (R)-(-)-2-amino-3-methyl-1-butanol, preferably (-)-quinine. When one of these is used, the supernatant is further treated to obtain a solid enriched in the (S)-isomer of the compound of formula I, which is further separated from the supernatant. Such treatment may include concentrating the supernatant by at least partial evaporation of the above-mentioned solvent (e.g., by heating and / or vacuum), by adding to the supernatant an acidic aqueous solution, for example having a pH comprised within the range of 0 to 1, preferably about 0, or by a combination of partial evaporation and acidic treatment.

[0050] When an acid treatment is used, the volume ratio of the aqueous acid solution to the total volume of the solution is between 4% and 20%. For example, the aqueous acid solution has a pH of about 0 and the volume ratio of the aqueous acid solution to the total volume of the solution is between 10% and 16%, or between 12% and 14%.

[0051] In other cases, the S-enantiomer-enriched compound may be present in the precipitate of step (c). Examples of such chiral resolving agents include, for example, (-)-cinchonidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol, preferably (-)-sparteine. The precipitate may then be further treated after isolation, for example by recrystallization, to increase its S-enantiomer content.

[0052] The method may also further comprise a step of separating the enantiomerically enriched compound of formula I from the chiral resolving agent used in the resolution. For such separation, acidification is usually used. For example, an acid, such as hydrochloric acid, can be used to form a salt with the chiral resolving agent, which preferably remains in solution while the free enantiomerically enriched compound precipitates.

[0053] The resulting enantiomerically enriched 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 S-enantiomer. Preferably, the compound is composed of at least about 95%, 98%, or 99% by weight of the S-enantiomer.

[0054] The above method may still further include recovering the (R) isomer of the compound of formula I, at least partially racemizing the (R) isomer to obtain a compound of formula I, and further treating the compound according to steps (a)-(d) above to obtain a further 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.

[0055] The S-enantiomer of the compound of formula I is represented by formula II: [ka] or a tautomer thereof.

[0056] In some examples of Formula I or Formula II, a is 0 and R 1 is absent, i.e., all five free carbon atoms of the aryl group are bonded to a hydrogen atom. 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 For example, a is 0 and R 1 does not exist and R 2 and R 3are each independently selected from alkyl halides and halogens, and preferably b and c are each 1.

[0057] According to one example, the compound of formula I above is a compound of formula I(a) or formula I(b), or a tautomer thereof. [ka]

[0058] According to another example, the compound of formula II above is a compound of formula II(a) or formula II(b), or a tautomer thereof. [ka]

[0059] Although this specification describes the isolation of the (S)-enantiomer of the compound of formula I, it is understood that the (R)-enantiomer will be isolated using the procedures described herein with a chiral resolving agent of opposite chirality to that disclosed. Examples of chiral resolving agents of opposite chirality include, for example, (+)-quinine, (R)-1-naphthylethylamine, (R)-phenethylamine, (S)-phenethylamine, (S)-(-)-2-amino-3-methyl-1-butanol, (+)-cinchonidine, (+)-sparteine, (S)-1-naphthylethylamine, L-arginine, D-lysine, (R)-(-)-2-pyrrolidinemethanol, and (1S,2R)-(-)-cis-1-amino-2-indanol. For example, the synthesis of (+)-quinine has been previously described (see, e.g., S Shiomi et al., Chem. Sci., 2019, 10, 9433).

[0060] The compound of formula I above can be generally reacted under basic conditions with (R 3 ) c ArSO 2 NH 2 The reaction of compound (A) with ClC(O)OMe gives (R 3 ) c ArSO2 An NHC(O)OMe intermediate (B) is obtained, which is then reacted with the compound of the formula: [ka] with the free amine (C).

[0061] The present technology also provides compounds containing an S-dihydropyrazole ring, such as CB 1 The present invention further relates to a method for the preparation of a receptor inhibitor, such as the compound (S)-Ibipinabant or the compound of formula III below.

[0062] For example, the above method includes the steps of: (i) preparing a compound of formula II according to the above method; and (ii) converting the compound of formula II to a compound of formula III, or a tautomer thereof:

[0063] [ka] (In the formula, R 1 , R 2 , R 3 , a, b, and c are as defined above; 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 boronic ester, optionally substituted silyl, and imino; and R 5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkylC(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 boronic ester, optionally substituted silyl, and imino.

[0064] Step (ii) comprises the steps of: (ii-a) reacting the compound of formula II with a chlorinating agent to obtain a compound of formula IV: [ka] and (ii-b) reacting a compound of formula IV with a compound of formula V: [ka] or a salt thereof to produce a compound of formula III above.

[0065] An example of a chlorinating agent is POCl 3 and step (ii-a) preferably further comprises an organic base such as 2,6-lutidine. Step (ii-b) also preferably comprises a base, for example an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or K 2 HPO 4 Further included are inorganic bases such as:

[0066] In some instances, R 4 is H. In other examples, R 5 is C 1~6 Alkyl (e.g., methyl) or C 1~6 AlkylC(O)NH (e.g., CH 3 C(O)NH).

[0067] Alternatively, the compound of formula IV above may be represented by the formula R 4 NH 2 to produce a compound as defined in WO 2009 / 059264 or WO 2014 / 018695.

[0068] Non-limiting examples of compounds of formula III include compounds 1-26 below.

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] The description of an embodiment of a variable part herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. The description of an embodiment herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. EXAMPLES

[0079] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention, which will be better understood with reference to the accompanying drawings.

[0080] Unless otherwise indicated, all numbers expressing amounts of ingredients, reaction conditions, concentrations, properties, stability, and the like used in the specification and claims should be understood to be modified in all instances by the term "about". At the very least, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Thus, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical values, however, inherently contain certain errors resulting from variations in experiments, testing measurements, statistical analyses and the like.

[0081] Example 1 - Enantiomer resolution with various chiral resolving agents (Formula I(a)) Formula I(a): [ka] Racemic or substantially racemic mixtures of compounds of formula I(a) were dissolved in three different solvents (isopropanol, isopropanol:water 95:5 v / v, and ethanol:water 95:5 v / v) with a chiral base compound as a resolving agent. The resolving agents are commercially available, while compounds of formula I(a) were prepared by known methods.

[0082] The screening test was carried out on a microscale in 4 mL glass vials by adding equimolar amounts of the compound of formula I(a) (0.5 mmol, 1 eq.) and the resolving agent (0.5 mmol, 1 eq.). A calculated amount of solvent was then added to each vial to give a 23% w / w solution based on the theoretical mass of the diastereoisomeric salt formed, and the resulting suspension was heated until a clear solution or a somewhat clear mixture was obtained. The vials were then shaken at 95 rpm in an orbital shaker at room temperature for 2 days or more to allow crystallization to occur.

[0083] Nearly 30 different resolving agents were tested. In experiments where crystal formation was not observed, up to four different treatments (if necessary) were applied to induce crystal formation (i.e., cooling to -20°C, sonication at room temperature, slow evaporation of the solvent at room temperature, evaporation of the solvent at 50°C under reduced pressure). For resolving agents showing the presence of solids and enrichment of the S-enantiomer (in the solids or supernatant), the results are shown in Table 1.

[0084] [Table 1]

[0085] Of those tested, (-)-quinine and (-)-sparteine ​​showed considerable potential as resolving agents (liquid composition not 50:50) in the three different solvents tested. In all three solvents, (-)-quinine showed moderate to high enantioenrichment of the S-enantiomer in the solution, while the R-enantiomer was present in the solid. (-)-Sparteine ​​in IPA and IPA / water 95:5 v / v showed low to moderate enantioenrichment of the S-enantiomer in the crystals. Several other chiral resolving agents also showed enrichment of the desired S isomer in the crystals or mother liquor.

[0086] Example 2 - Optical resolution in isopropanol (Formula I(a)) Additional studies were performed with (-)-quinine to determine the optimal amount of solvent and scale conditions to be used in the resolution.

[0087] The screening test with compound of formula I(a) and (-)-quinine in IPA was repeated on a 17.7 mmol scale (9.0 g of formula I(a)). To effect crystallization, the reaction mixture was subjected to several heating and cooling cycles ranging from 40 to 70°C, and after the final cycle, it was gradually cooled to room temperature under stirring while seeding with diastereomeric salt crystals of 85% ee for the R-enantiomer. The reaction mixture was stirred at room temperature for approximately 18 hours.

[0088] A sample was then removed from the reaction mixture and the composition of the mother liquor and solids was determined by chiral HPLC (Phenomenex Lux™ 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). As the calculated eutectic 77.5%ee (S) was not achieved in the solution (34.4%ee determined by chiral HPLC), the slurry was vacuum filtered to give 2.17 g of the diastereoisomeric salt (87.4%ee solids; determined by chiral HPLC). The mother liquor was evaporated to ⅓ of the initial volume (54 g IPA solution) and then seeded with the R-diastereoisomeric salt (85%ee for the R-enantiomer) at 40° C. The reaction was allowed to stir at room temperature overnight. After stirring for 14 hours, a sample was taken from the reaction mixture and the composition of the mother liquor and solids was determined by chiral HPLC (42.2% ee for S in mother liquor). The reaction mixture was again vacuum filtered and the resulting mother liquor was concentrated to about 60% of the initial volume (34 g) and then seeded with the R-diastereoisomeric salt (85% ee for R-enantiomer) at 40° C. The reaction was allowed to stir at room temperature over the weekend (76 hours). The composition of the mother liquor and solids was determined by chiral HPLC (45.7% ee in mother liquor).

[0089] The reaction was repeated on a 4 g scale to give the S-enantiomer in 49.3% ee in the mother liquor after stirring at room temperature overnight. 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-diastereoisomeric salt (85% ee for the R-enantiomer) at 40° C. The reaction was allowed to stir at room temperature for 76 h. The composition of the mother liquor and solids was determined by chiral HPLC (61.5% ee in the mother liquor).

[0090] Subsequent reactions were carried out on a 2 g scale with slight changes to the reaction conditions. The initial reaction was carried out at 70° C. until a clear solution was observed (approximately 10 min). The solution was then cooled to room temperature (precipitation began to occur) and stirred for an additional 1 h 20 min. The reaction was diluted with 20 mL of IPA and refluxed at 70° C. for 10 min, after which additional IPA (20 mL) was added. The suspension was again cooled to room temperature before 20 mL of IPA was added. The suspension was stirred for 15 min and then filtered through a S3 sinter funnel. After an IPA wash, HPLC analysis showed the crystals to have 85.3% ee(R), while the liquid % ee was 72.4(S). The 2 g scale reaction was repeated following the above procedure and the suspension was stirred overnight (18 h). HPLC analysis revealed the crystals to be 64.8% ee(R) and the liquid to be 85.6% ee(S). The diastereoisomeric salt (85.6% ee) was decomposed by addition of 2M aqueous HCl, followed by filtration of the resulting precipitate on a sintered funnel (porosity 3) to give the S-enantiomer (99.4% ee).

[0091] Example 3 - Optical resolution and further concentration in acetonitrile (Formula I(a)) (a) Chiral resolution A 50 g scale reaction was carried out in a reactor using the compound of formula I(a) and (-)-quinine. More specifically, 50 g of the compound of formula I(a), 20.76 g of (-)-quinine (0.65 equivalents) and 443 g of HPLC grade acetonitrile (MeCN, approximately 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 4.5 hours and held at 15° C. overnight (approximately 18 hours). The slurry was then filtered. The crystals contained 95.8% (ee) of the R-isomer, while the mother liquor yielded 77.2% (ee) of the S-isomer.

[0092] (b) Enrichment of S-isomer The mother liquor from step (a), containing the S-isomer enriched solution, was further treated to improve the enantiomeric excess (ee) of the S-isomer. The volume of the mother liquor was adjusted to 400 mL (69.25 g / L of formula I(a)) and half of the solution was used for the ee improvement assay. Ten fractions of 20 mL were collected, each containing 1.38 g of pyrazoline. Each 20 mL aliquot was treated with various volumes of acidified water at pH 1 or pH 0 (see Table 2). After stirring overnight in MeCN / water, the solids were filtered and analyzed by HPLC and NMR.

[0093] [Table 2]

[0094] As shown in Table 2, both increasing water and decreasing pH decreased the solubility of the desired compound. For the starting material with 77.24% ee for the S-isomer, conditions using 3 mL of pH 0 solution gave the best results. In fact, a near perfect 76.58% yield was obtained with >99% ee. It was discovered that acidification at lower temperatures (10-20°C) was preferred because it led to fewer side reactions and improved yield compared to warmer (40-55°C) acidification. These conditions (addition of about 15% pH 0 water to a solution of 69-70 g / L compound) applied to the remaining mother liquor (200 mL) proved robust enough to give good returns on the 13.8 g scale. In fact, after filtration and further drying (rotary evaporator 5-10 mbar, 45°C, 4 h), 8.87 g of S-isomer was obtained with >99% ee. 1 H-NMR indicated the presence of 0.52 equivalents of water.

[0095] Step (a) and step (b) were repeated using 500 g of racemic starting material in step (a), 208 g of (-)-quinine (0.65 equivalents), and 3.48 kg of MeCN (about 4.43 L). Step (b) was carried out as above using 270 g of S-isomer enriched compound (ee: 76.24%), MeCN (total volume 3.9 L), and 1N HCl (pH 0, 592 mL) to obtain 205 g of S-isomer (formula II(a)) with 99.5 ee%, which can be used to prepare compounds of formula III, such as compounds 1, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25.

[0096] Example 4 - Isolation and racemization of the R-isomer (Formula I(a)) For example, the R-isomer-enriched crystals containing the (-)-quinine salt of the R-isomer isolated from step (a) of Example 3 were recycled for reuse in the resolution process by first destroying the formed salt and then racemizing the isolated R-isomer. Two alternative methods are illustrated below.

[0097] Method 1: The first step was carried out by mixing the salt (approximately 230 g (R), 140 g quinine) in 2.3 L of HPLC grade dichloromethane and adding 1.15 L of 1N HCl solution with stirring. The mixture was mixed at 20° C. for 1.5 hours. The organic phase was separated and washed with 0.6 L of water and MgSO 4 Filtration and evaporation under reduced pressure gave the R-isomer enriched compound (211 g, 92% yield).

[0098] The resulting solid was then dissolved in anhydrous DME (1 L) and mixed with DBU (93.5 mL, 1.5 equiv). The solution was stirred at 70-80 °C for 6 h. The mixture was cooled to 10-20 °C and water was added. The pH was adjusted to 4-5 by addition of HCl. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine and diluted with MgSO 4The solid was dried by hexanes. All volatiles were removed under reduced pressure and the residue was triturated with MTBE / EtOAc (8 / 1). The slurry was filtered and washed with cold MTBE. The solid was further dried under reduced pressure to give the racemic compound of formula I(a) (175 g, 82% yield). This racemic compound was then further used in the method of Example 3 to produce the S-isomer.

[0099] Method 2: The quinine salt of the R-isomer (79 kg, 1.0 equiv.) was introduced into the reaction vessel. 1N hydrochloric acid solution (3 volumes) was added to the vessel, followed by 2-methyltetrahydrofuran (2-MeTHF) (2 volumes) 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 again to dryness.

[0100] The resulting solid was then dissolved in anhydrous DME (3 volumes) and mixed with DBU (1.5 equiv). 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 slow dropwise addition of 1N HCl solution. The mixture was filtered and the cake was washed with water (2 volumes). The cake was dried at 50-60° C. to obtain the racemic compound of formula I(a) (42 g, 95% yield). This racemic compound was then further used in the method of Example 3 to prepare the S-isomer.

[0101] Example 5 - Resolution of compounds of formula I(b) To a mixture of 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 h. The mixture was then cooled to 20-30° C. and stirred for 16 h. The mixture was filtered and the cake was dried to a white solid (96.0 g) which was examined by SFC and HPLC. The mother liquor was examined by SFC and HPLC. The mother liquor was warmed to 40-45° C. and the solution was diluted with HCl (1 M, 61.7 mL) and H 2 2H2O (150 mL) was added. The mixture was stirred at 15-20 °C for 4 h. The mixture was then filtered to obtain a solid. The solid was diluted with MeCN / H2O 2 The S-isomer of formula II(b) (25.0 g, 99.5% purity) was obtained as a pale yellow solid, which was 1 Confirmed by H NMR, LCMS, HPLC and SFC. This S-isomer can be further used for the preparation of compounds of formula III, for example, compounds 2, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26, or for the preparation of other compounds such as (S)-ibipinabant and other compounds described in U.S. Pat. No. 9,765,031, and WO 2009 / 059264 and WO 2014 / 018695.

[0102] 1 H NMR (400MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 7.93-8.10 (m, 2H), 7.80 (d, J = 8.8 Hz, 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, 4.8 Hz, 1H), 4.27 (t, J = 11.6 Hz, 1H), 3.67 (dd, J = 11.2, 4.8 Hz, 1H). LCMS: RT = 1.063 min, m / z = 474 (M+H) + .

[0103] It is believed that numerous modifications may be made to any of the above-described embodiments without departing from the scope of the invention. Any references, patents, or scientific literature documents mentioned herein are hereby incorporated by reference in their entirety.

Claims

1. A method for producing an enantiomerically enriched compound comprising the steps of: (a) a compound of formula I(a) or I(b): 【Chemistry 1】 (The compound of formula I(a) or I(b) is ( ＊ ) carbon atom (C ＊ ) in which R and S isomers are included, ＊ The fourth atom bonded to is hydrogen or an isotope thereof (e.g., deuterium). or a tautomer thereof; (b) dissolving the compound of formula I(a) or I(b) in a solvent to obtain a solution, wherein the solvent is acetonitrile or a solvent comprising an alcohol selected from ethanol, isopropanol, and combinations thereof, and wherein the solvent further comprises water at a concentration of 10% or less, or the solvent is anhydrous; (c) dissolving a chiral resolving agent selected from (-)-quinine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinchonidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol in the solution to form a precipitate and a supernatant; and (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant contains an enantiomerically enriched compound containing a higher concentration of S-enantiomer relative to the R-enantiomer of the compound of formula I(a) or I(b); The method, wherein steps (b) and (c) are carried out simultaneously or sequentially.

2. The method of claim 1 , wherein the solvent is acetonitrile.

3. 2. The method of claim 1, wherein the solvent is isopropanol, and the isopropanol further comprises water at a concentration of 10% or less or is anhydrous.

4. The method of any one of claims 1 to 3, wherein the solvent further comprises water at a concentration of 5% or less, or the solvent is anhydrous.

5. 5. The process according to any one of claims 1 to 4, wherein the compound of formula I(a) or I(b) in step (b) is at a concentration of between 50g and 150g, or between 75g and 120g, or between 85g and 115g per litre of solvent.

6. 6. The method of any one of claims 1 to 5, wherein step (c) comprises between 0.5 molar equivalents to 1 molar equivalent, or between 0.55 molar equivalents to 0.75 molar equivalents, or between 0.6 molar equivalents to 0.7 molar equivalents, or 0.65 molar equivalents of said chiral resolving agent relative to said compound of formula I(a) or I(b).

7. 7. The method of any one of claims 1 to 6, wherein the chiral resolving agent is selected from (-)-quinine, (S)-1-naphthylethylamine, and (R)-(-)-2-amino-3-methyl-1-butanol.

8. The method of claim 7, wherein the chiral resolving agent is (-)-quinine.

9. 9. The method of claim 7 or 8, further comprising the step of treating the supernatant to obtain a solid enriched in the (S)-isomer of the compound of formula I(a) or I(b).

10. 10. The method of claim 9, wherein said treating step comprises concentrating said supernatant by at least partial evaporation of said solvent.

11. 11. The method of claim 9 or 10, wherein the treating step comprises adding an acidic aqueous solution to the supernatant.

12. The method of claim 11, wherein the acidic aqueous solution has a pH comprised within the range of 0 to 1.

13. 13. The method of claim 12, wherein the volume ratio of the aqueous acidic solution to the total volume of the solution is between 4% and 20%.

14. 14. The method of claim 13, wherein the acidic aqueous solution has a pH of 0 and the volume ratio of the acidic aqueous solution to the total volume of the solution is between 10% and 16%, or between 12% and 14%.

15. 15. The method of any one of claims 9 to 14, further comprising the step of separating the solids from the supernatant.

16. 7. The method of any one of claims 1 to 6, wherein the chiral resolving agent is selected from (-)-cinchonidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol.

17. The method of claim 16, wherein the chiral resolving agent is (-)-sparteine.

18. 18. The method of claim 16 or 17, further comprising recrystallizing the precipitate.

19. 19. The method of any one of claims 1 to 18, further comprising the step of separating the (S)-isomer of the compound of formula I(a) or I(b) from the chiral resolving agent.

20. 20. The method of claim 19, wherein the separating step comprises adding an acid (e.g., hydrochloric acid).

21. 21. The method of any one of claims 1 to 20, further comprising recovering the (R)-isomer of the compound of formula I(a) or I(b), at least partially racemizing the (R)-isomer to obtain the corresponding compound of formula I(a) or I(b), and further treating said compound according to steps (a)-(d).

22. A compound of the formula: 【Chemistry 2】 (In the formula, 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 boronic ester, optionally substituted silyl, and imino; and R ５ is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkylC(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 boronic ester, optionally substituted silyl, and imino; The fourth atom attached to the chiral carbon is hydrogen or an isotope thereof (e.g., deuterium). or a tautomer thereof, comprising the steps of: (i) obtaining the desired compound of formula III(a) according to the method defined in any one of claims 1 to 21 or III(b) of the following formula II(a) or II(b): 【Chemistry 3】 preparing a compound of formula (I); and (ii) converting said compound of formula II(a) or II(b) into said desired compound of formula III(a) or III(b).

23. Step (ii) comprises the steps of: (ii-a) Reacting the compound of formula II(a) or II(b) with a chlorinating agent (e.g., POCl ３ ) to produce the corresponding compound of formula IV(a) or IV(b): 【Chemistry 4】 and (ii-b) reacting the compound of formula IV(a) or IV(b) with a compound of formula V: 【Chemistry 5】 or a salt thereof to produce the corresponding compound of formula III(a) or III(b).

24. 24. The method of claim 23, wherein step (ii-a) further comprises the use of a base (e.g., 2,6-lutidine).

25. Step (ii-b) is a reaction with a base (e.g., DBU, K ２ H.P.O. ４ 25. The method of claim 23 or 24, further comprising the use of

26. The compound of formula III(a) or III(b) is the following compound: 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 26. The method of any one of claims 22 to 25, wherein said compound is selected from:

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