PROCESS FOR PRODUCING 4,5-DIHYDRO-1H-PYRAZOLES AND INTERMEDIATES

Abstract

Scalable processes for the preparation of compounds containing a (S)-4,5-dihydro-1H-pyrazole ring are described; these processes include a chiral resolution step of an intermediate using selected chiral resolving agents; for example, the chiral resolving agents can be selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-1-naphthylethylamine, (R)-(-)-2-amino-3-methyl-1-butanol, (-)-cinconidine, (-)-sparteine, (R)-1-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-1-amino-2-indanol.

Description

PROCESS FOR PRODUCING 4,5-DIHYDRO-1H-PYRAZOLES AND INTERMEDIATES RELATED APPLICATION This application claims priority under applicable law 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 This disclosure generally refers to processes for producing enantiomerically enriched substituted 4,5-dihydro-1Hpyrazoles and intermediates thereto. BACKGROUND OF THE INVENTION In general, activation of the cannabinoid receptor CBi is known to increase appetite, enhance lipid biosynthesis and storage, inhibit the actions of insulin and leptin, and promote inflammation and fibrosis. Therefore, research focused on developing CBi receptor inhibitors for the potential treatment of obesity and the associated metabolic disorder known as metabolic syndrome. Rimonabant proved effective in treating metabolic syndrome, but it caused neuropsychiatric (i.e., CNS-related) side effects, leading to its withdrawal from the market. Compounds that preferentially target the CBi receptor in peripheral tissue (e.g., adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic beta cells, and gastrointestinal tract), while not interacting with CBi receptors in brain tissue, thereby avoiding or reducing CNS-related side effects, were disclosed by George Kunos et al. in U.S. Patent No. 9,765,031. The compounds described in Kunos et al. all have at least one chiral center. Separation of the enantiomers from the final compound or a synthetic intermediate is generally performed using chiral chromatography (HPLC or SFC). Such methods would be impractical or too expensive for large-scale production. BRIEF DESCRIPTION OF THE INVENTION According to a first aspect, the present technology refers to a process for the preparation of an enantiomerically enriched compound, comprising the following steps: (a) provide a compound of Formula I or a tautomer thereof: Formula I where, R1, R2, and R3 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 boronate, optionally substituted silyl, and amino; a, b, and c are each independently 0, 1, 2, 3, 4, or 5; wherein said compound of Formula I comprises a mixture of R and S isomers at the carbon atom (*) (C*) and wherein the fourth atom bonded to C* is hydrogen or an isotope thereof (for example, deuterium); (b) dissolve the compound of the Formula I in a solvent to obtain a solution; (c) dissolving a chiral resolving agent selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-l-naphthylethylamine, (R)-(-)-2-amino-3-methyl-l-butanol, (-)-cinconidine, (-)-sparteine, (R)-l-naphthylethylamine, D-arginine, lysine, (S)-(+)-2-pyrrolidone methanol, and (1R,2S)-(+)-cis-l-amino-2-indannol in solution to form a precipitate and a supernatant; and (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant comprises the enantiomerically enriched compound comprising a higher concentration in the S enantiomer compared to the R enantiomer of the compound of Formula I; where steps (b) and (c) are carried out simultaneously or sequentially. In one embodiment, the solvent is an aprotic organic solvent, for example, acetonitrile. In an alternative embodiment, the solvent comprises an alcohol having from 1 to 4 carbon atoms, or a combination thereof, for example, the alcohol is selected from ethanol, isopropanol, and a combination thereof (for example, 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. In another embodiment, the compound of Formula I is at a concentration of between approximately 50 g and approximately 150 g, or between approximately 75 g and approximately 120 g, or between approximately 85 g and approximately 115 g per liter of solvent in step (b). In a further embodiment, step (c) comprises between approximately 0.5 and approximately 1, or between approximately 0.55 and approximately 0.75, or between approximately 0.6 and approximately 0.7, or approximately 0.65 molar equivalents of said chiral resolving agent with respect to the compound of Formula I. In some embodiments, the chiral resolving agent is selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-l-naphthylethylamine, and (R)-(-)-2-amino-3-methyl-l-butanol, preferably (-)-quinine. In these embodiments, the process may further comprise a supernatant treatment step to obtain a solid enriched in the (S) isomer of the compound of Formula I. In one embodiment, the treatment step comprises concentrating the supernatant by at least partial evaporation of the solvent. In another embodiment, the treatment step comprises adding an acidic aqueous solution to the supernatant; for example, the acidic aqueous solution has a pH within the range of 0 to 1, preferably around 0. In a preferred embodiment, the volume ratio of the acidic aqueous solution to the total volume of solution is between 4% and 20%.In one embodiment, the acidic aqueous solution has a pH of approximately 0, and the volume ratio of the acidic aqueous solution to the total solution volume is between 10% and 16%, or between 12% and 14%. In either embodiment, the process generally also includes a step of separating the solid from the supernatant after the treatment step. In other embodiments, the chiral resolving agent is selected from (-)-cinconidine, (-)-sparteine, (R)-l-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (lR,2S)-(+)cis-l-amino-2-indanol, for example, (-)-sparteine. In these embodiments, the process may further comprise recrystallization of the precipitate. In an additional embodiment, the process further comprises a step of separating the isomer (S) of the compound of Formula I from the chiral resolving agent, for example, by adding an acid (for example, hydrochloric acid). In yet another embodiment, the process further comprises recovering the isomer (R) of the compound of Formula I, racemizing at least partially said isomer (R) to obtain the compound of Formula I, and further treating said compound by steps (a) to (d). In a further embodiment of the present process, the compound has Formula I where a is zero, R1 is absent, and R2 and R3 are each independently selected from halogenated alkyl and halogen, preferably b and c each being 1. In one embodiment, the compound is of Formula I(a) or I(b): C7 iΠ / 77Ω7 / Β / YILI Formula I(b); or a tautomer of the same. According to another aspect, the present technology refers to a process for preparing a compound of Formula III, or a tautomer thereof: Formula III where, R1, R2, R3, a, b, and c are as defined herein; R4 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 boronate, optionally substituted silyl, and amino; and R5 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 boronate, optionally substituted silyl, and mino; where the fourth atom bonded to the chiral carbon is hydrogen or an isotope thereof (for example, deuterium); The process includes the following steps: (i) prepare a compound of the Formula II: Formula II according to the process as defined above; and (ii) converting said compound of Formula II into the compound of Formula III. In one modality, step (ii) comprises the steps of: (ii-a) reacting the compound of Formula II with a chlorinating agent (for example, POCh) to produce a compound of Formula IV: Formula IV; and (ii-b) reacting the compound of Formula IV with a compound of Formula V: NR4 R5NH2 Formula V or a salt thereof, to produce the compound of Formula III. In one embodiment, said step (ii-a) further comprises a base (for example, 2,6-lutidine). In another embodiment, step (ii-b) further comprises a base (for example, DBU, K2HPO4). In a further embodiment, a is zero and R1 is absent, and R2 and R3 are each independently selected from halogenated alkyl and halogen, preferably b and c each being 1. In a preferred embodiment, the compound of Formula III is selected from Compounds 1 to 26 as defined herein, or a tautomer thereof. Objectives and additional features of the present compound, compositions, methods and uses will become more evident by reading the following non-restrictive description of the illustrative embodiments and the examples section, which should not be interpreted as limiting the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION All technical and scientific terms and expressions used herein have the same definitions as those commonly understood by a person skilled in the art to which this technology belongs. However, definitions of some terms and expressions are provided below. To the extent that the definitions of terms in publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification shall prevail. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter disclosed. The chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a carbon atom, as drawn appears to have an incomplete valency, it is assumed that the valency is satisfied by one or more hydrogen atoms, even if these are not necessarily drawn explicitly. It should be inferred that the hydrogen atoms are part of the compound. The terminology used herein is for the purpose of describing particular forms only and is not intended to be exhaustive. As used herein, the singular forms a, an, and the include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a composition containing one compound also includes a mixture of two or more compounds. It should also be noted that the term or is generally used in its inclusive sense unless the context clearly dictates otherwise. Additionally, to the extent that the terms including, has, possesses, or variants thereof are used in the detailed description and / or in the claims, such terms are intended to be inclusive in a manner similar to the term comprising. The term "approximately" means within an acceptable range of error for the particular value determined by a person skilled in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, "approximately" may mean within one or more standard deviations, depending on the practice in the art. Alternatively, "approximately" may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with regard to biological systems or procedures, the term may mean within an order of magnitude, preferably within five times, and most preferably within two times of a value.When particular values ​​are described in the application and claims, unless otherwise stated, it should be assumed that the term approximately means within an acceptable range of error for the particular value. As used herein, the terms compounds, active ingredient, and equivalent expressions refer to the compounds described in this application and in U.S. Patent No. 9,765,031 and PCT Patent Applications Nos. WO2009 / 059264 and WO2014 / 018695, including those covered by Structural Formula I, optionally with reference to any of the applicable embodiments, and also include illustrative compounds, such as Compounds 1 through 26, as well as their pharmaceutically acceptable salts, tautomeric forms, solvates, esters, and prodrugs, where applicable. Where a zwitterionic form is possible, the compound may be represented as its neutral form for practical purposes, but it is understood that the compound also includes its zwitterionic form. Embodiments herein may also exclude one or more of the compounds. The compounds may be identified by either their chemical structure or their chemical name.In a case where the chemical structure and the chemical name conflict, the chemical structure will prevail. Unless otherwise stated, the present compounds also encompass all possible tautomeric forms of the illustrated compound, if any. The term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature. Examples of isotopes that may be incorporated into the present compounds include, but are not limited to, 2H (D), 3H (T), 1C, 13C, 14C, 15N, 18O, 17O, any of the sulfur isotopes, etc. The compounds may exist in unsolvated as well as solvated forms, including hydrated forms. The compounds may exist in multiple crystalline or amorphous forms. However, amorphous or substantially amorphous forms are preferred for the formulations contemplated herein.Chiral compounds and intermediates prepared by this process may be substantially free of the corresponding enantiomer and may be enantiomerically enriched. Enantiomerically enriched means that the compound is formed from a significantly higher proportion of one enantiomer. In certain embodiments, the compound is made of at least approximately 60% by weight, or at least approximately 70% by weight, or at least approximately 80% by weight, or at least approximately 90% by weight of a preferred enantiomer. In other embodiments, the compound is composed of at least approximately 95%, 98%, or 99% by weight of a preferred enantiomer.The preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high-performance liquid chromatography (HPLC) on chiral support and the formation and crystallization of chiral salts, or prepared by asymmetric synthesis. The terms ee, % ee, and enantiomeric excess, as used herein, refer to the excess of one enantiomer in a chiral substance. For example, a racemic mixture has 0% ee, a pure enantiomer has 100% ee, and a sample containing 90% S isomer and 10% R isomer has 80% ee in the S isomer. The term "pharmaceutically acceptable salt" refers to those salts of the compounds described herein that are, to the best 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 are appropriate with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences. R / C7 I Π / 77Π7 / Β / YILI 66:1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acid function of the compound with a suitable organic or inorganic base (base addition salts). The term solvate refers to a physical association of one of the compounds present with one or more solvent molecules, including water molecules and non-aqueous solvents. This physical association may include hydrogen bonding. In certain cases, 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 solvates in both solution and isolable forms. Illustrative solvates include, but are not limited to, hydrates, hemihydrates, alcoholates (e.g., ethanolates, hemiethanolates, n-propanolates, isopropanolates, 1-butanolates, 2-butanolates, etc.), and solvates of other physiologically acceptable solvents, such as the Class 3 solvents described in the International Conference on Harmonisation (ICH) Guide for Industry, Q3C Impurities: Residual Solvents (2017).Accordingly, the compound as described herein also includes each of its solvates and mixtures thereof. The term "pharmaceutically acceptable prodrugs," as used herein, refers to those prodrugs of the compounds formed by the process described herein that are, to the best of medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, proportionate to a reasonable benefit-risk ratio, and effective for their intended use. "Prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to yield any compound delineated by the formulas described herein. Abbreviations may also be used throughout the application, unless otherwise stated; such abbreviations have the meaning generally understood in the field. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (terebutyl), i-Bu (sobutyl), 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), ¡PrOH or i-PrOH or IPA (isopropanol), MeCN (acetonitrile), EtOAc (ethyl acetate), DME (dimethoxyethane), MTBE (methyl tert-butyl ether), TFA (trifluoroacetic acid), and DBU (1,8diazabicyclo[5.4.0]undec-7-ene). The number of carbon atoms in a hydrocarbon substituent can be indicated by the prefix Cx-Cyo or Cx-y, where x is the minimum number and y is the maximum number of carbon atoms in the substituent. However, when the prefix Cx-Cyo or Cx-y is associated with a group that incorporates one or more heteroatoms by definition (e.g., heterocycloalkyl, heteroaryl, etc.), then x and y define, respectively, the minimum and maximum number of atoms in the ring, including both the carbon atoms and the heteroatoms. The term alkyl, as used herein, refers to a saturated hydrocarbon radical, either linear or branched, typically containing 1 to 20 carbon atoms. For example, the alkyl group of Ci-Cs contains one to eight carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl, and similar groups. The term alkenyl, as used herein, denotes a linear or branched hydrocarbon radical containing one or more double bonds and typically 2 to 20 carbon atoms. For example, a C2-8 alkenyl contains two to eight carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, l-methyl-2-butenyl, heptenyl, octenyl, and the like. The term alkynyl, as used herein, denotes a linear or branched hydrocarbon radical containing one or more triple bonds and typically 2 to 20 carbon atoms. For example, C2-8 alkynyl contains two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octinyl, and the like. The terms cycloalkyl, alicyclic, carbocyclic, and equivalent expressions refer to a group comprising a saturated or partially unsaturated (nonaromatic) carbocyclic ring 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, having from three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, 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 Cs-Cn cycloalkyl refers to a cycloalkyl group having from 3 to the indicated number of carbon atoms in the ring structure. Unless otherwise specified, lower cycloalkyl groups, as used herein, have at least 3 and equal to or fewer than 8 carbon atoms in their ring structure. As used herein, the terms heterocycle, heterocycloalkyl, heterocyclyl, heterocyclic radical, and heterocyclic ring are used interchangeably and refer to a chemically stable 3- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is either saturated or partially unsaturated and that has, in addition to atoms of C7 iP / 77Ω7 / B / YILI carbon, one or more, preferably from one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term nitrogen includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1 to 3 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 resulting 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, morpholinol, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepaniyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2Hpyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, 3azabicyclo[3,l,0]hexanyl, 3-azabicyclo[4,l,0]heptanyl, quinolizinyl, 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 cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenantridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the radical or attachment point is on the heterocyclic ring. A heterocyclic group may be mono- or bicyclic. The term heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl group, where the alkyl and heterocyclyl portions are independently or optionally substituted. The term C3-n heterocycloalkyl refers to a heterocycloalkyl group having from 3 to the indicated number n of atoms in the ring structure, including carbon atoms and heteroatoms. As used herein, the term partially unsaturated refers to a ring portion 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 having multiple sites of unsaturation but is not intended to include aryl or heteroaryl portions, as defined herein. The term aryl, used alone or as part of a larger portion as in aralkyl, aralkoxy, aryloxy, or aryloxyalkyl, refers to aromatic groups having 4n+2 conjugated n(p) electrons, where n is an integer from 1 to 3, in a monocyclic portion or in 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 where each ring in the system contains three to seven ring members. The term aryl may be used interchangeably with the term aryl ring. In certain embodiments of the present description, aryl refers to an aromatic ring system that includes, but is not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracite, and the like, which may have 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, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naftimidyl, fluorenyl, phenantridinyl, or tetrahydronaphthyl, and the like. The term naryl Ce-n refers to an aryl group having from 6 to the indicated number n atoms in the ring structure. The term heteroaryl, used alone or as part of a larger portion, e.g., heteroaralkyl or heteroaralkoxy, refers to aromatic groups having 4n+2 conjugated n(pi) electrons, where n is an integer from 1 to 3 (e.g., having 5 to 18 atoms in the ring, preferably 5, 6, or 9 atoms in the ring; having 6, 10, or 14 shared n electrons in a cyclic array); and having, in addition to the carbon atoms, one to five heteroatoms. 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 may be a single ring or two or more fused rings. The term heteroaryl, as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, aliphatic, or heterocyclic rings,where the radical or point of union is in the heteroaromatic ring. No limitantes de grupos heteroarilo include tienilo, furanilo (furilo), pirrolilo, imidazolilo, pirazolilo, triazolilo, tetrazolilo, oxazolilo, isoxazolilo, oxadiazolilo, tiazolilo, isotiazolilo, tiadiazolilo, piridilo, piridazinilo, pyrimidinilo, pirazinilo, triazinilo, indolilo, 3Hindolilo, isoindolilo, indolizinilo, benzotienilo (benzotiofenilo), benzofuranilo, dibenzofuranilo, indazolilo, bencimidazolilo, benzoxazolilo, benzotiazolilo, benzotriazolilo, pirrolopiridinilo (por ejemplo, pirrolo[3,2b]piridinilo o pirrolo[3,2-c]p¡r¡d¡nilo), pyrazolopiridinilo (for example, p¡razolo[l,5-a]piridinilo), furopiridinilo, purinilo, imidazopirazinilo (for example, ¡midazo[4,5-b]pirazinilo), quinolilo (quinolinilo), isoquinolinilo (isoquinolinilo), quinolonilo, isoquinolonilo, quinoxalinilo, 4H-quinol·z·n·lo, naftiridinilo, y pteridinilo carbazolilo, acridinilo, phenantridinilo,Phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group can be mono- 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 are independently or optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like. For example, the term Cs-n heteroaryl refers to a heteroaryl group having from 5 to the indicated number n of atoms in the ring structure, including the carbon atoms and the heteroatoms. The term halogen designates a halogen atom, that is, an atom of fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. As described herein, the compounds in this description may contain optionally substituted portions. In general, the term "substituted," whether preceded by "optionally" or not, means that one or more hydrogens of the designated portion are replaced with a suitable substituent. Unless otherwise stated, an optionally substituted group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specific group, the substituent may be the same or different at each position. Combinations of substituents contemplated under this description are preferably those that result in the formation of chemically stable or chemically workable compounds.The term chemically stable, as used herein, refers to compounds that are not substantially altered when subjected to conditions that permit their production, detection, and, in certain modalities, their recovery, purification, and use for one or more of the purposes disclosed herein. Therefore, the term optionally substituted refers to groups that are substituted or unsubstituted by the independent replacement of one, two, or three or more of the hydrogen atoms therein with substituents that include, but are not limited to, F, Cl, Br, I, OH, CO2H, alkoxy, oxo, thiooxo, NO2, CN, CF3, NH2, NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl, NHheterocyclic, dialkylamino, diarylamino, diheteroarylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocyclic, 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, COiheteroaryl, 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)NHalconyl, C(O)NHakynyl, C(O)NHcycloalkyl, C(O)NHaryl,C(O)NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2C¡chloalkyl, OCO2aryl, OCO2heteroaryl, OCO2heterocycloalkyl, OC(O)NH OC(O)Nhaquinyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O)NHheteroaryl, OC(O)NHheterocycloalkyl, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl, NHC(O)cyclo, NH(HCO) NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO2alkyl, NHCO2alkenyl, NHCO2alkynyl, NHCO2C¡chloalkyl, NHCO2aryl, NHCO2heteroaryl, NHCO2heterocycloalkyl, NHC(O)NH2, NH NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl, NHC(O) NHheteroaryl, NHC(O)NHheterocycloalkyl, NHC(S)NH2, NHC(S)NHalkyl, NHC(S)NH,N NHC(S)NHalquinyl, NHC(S)NHcycloalkyl, NHC(S)Haryl, NHC(S)NHheteroaryl, NHC(S)NHheterocycloalkyl, NHC(NH)NH2, NHC(NH)NHalkyl, C7 ίΠ / 77Ω7 / Β / ΥΙΛΙ NHC(NH)NHalquenyl, NHC(NH)NHalkenyl, NHC(NH)NHcycloalkyl, NHC(NH)NHaryl, NHC(NH)NHheteroaryl, NHC(NH)NHheterocycloalkyl, 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)NHalquinyl, 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)2C¡cloalkyl, S(O)2aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO2NHalkyl, SO2NHalkenyl, SO2NHalkynyl, SO2NHcycloalkyl, SO2NHaryl, SO2NH heteroaryl, SO2NHheterocycloalkyl, NHSChalkyl, NHSO2alkenyl, NHSO2alkynyl, NHSChcycloalkyl, NHSOzaryl, NHSO2heteroaryl, NHSO2heteroc!cloalkyl, CH2NH2, CHzSOzCHs, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocyclic, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, Salkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, or methylthiomethyl. The compounds presented here are intermediates in the synthesis of peripherally restricted CB1 antagonists. These compounds include a chiral center in the dihydropyrazole ring. The S isomers have been identified as the most potent compared to their R counterparts. Therefore, efforts have been directed toward identifying a scalable process for separating the isomers from the final product or an intermediate thereof. However, attempts at enantiomeric resolution by crystallization of diastereomeric salts of the final product, such as Compound 1 below, have not been successful. Examples of end compounds that could be produced using the present process are those defined in U.S. Patent No. 9,765,031 and PCT Patent Applications No. WO2009 / 059264 and No. WO2014 / 018695, all incorporated herein by reference in their entirety for all purposes, and including those defined herein in the following paragraphs. When chemical portions are referenced, the recitation of a list of chemical groups in any definition of a variable includes definitions of that variable as any single group or combination of groups listed. Similarly, the recitation of a modality herein includes that modality as any single modality or in combination with any other modality or portions thereof. As such, the following modalities are present either alone or in combination, if applicable. More specifically, this document relates to a process for preparing enantiomerically enriched compounds comprising a dihydropyrazole ring. For example, the process comprises the following steps: (a) provide a compound of Formula I or a tautomer thereof: Formula I wherein, R1, R2, and R3 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 boronate, optionally substituted silyl, and amino; a, b, and c are each independently 0, 1, 2, 3, 4, or 5; wherein said compound of Formula I comprises a mixture of R and S isomers at the carbon atom (*) (C*) and wherein the fourth atom bonded to C* is hydrogen or an isotope thereof (for example, deuterium); (b) dissolve the compound of the Formula I in a solvent to obtain a solution; (c) dissolving a chiral resolving agent selected from (-)-quinine, (R)-phenethylamine, (S)-phenethylamine, (S)-l-naphthylethylamine, (R)-(-)-2-amino-3-methyl-l-butanol, (-)-cinconidine, (-)-sparteine, (R)-l-naphthylethylamine, D-arginine, lysine, (S)-(+)-2-pyrrolidonemethanol, and (1R,2S)-(+)-cis-l-amino-2-indanol in solution to form a precipitate and a supernatant; and (d) separating the precipitate from the supernatant, wherein one of the precipitate or the supernatant comprises the enantiomerically enriched compound comprising a higher concentration in the S enantiomer compared to the R enantiomer of the compound of Formula I; where steps (b) and (c) are carried out simultaneously or sequentially. The solvent used is an organic solvent that may be protic or aprotic and may also include water. The solvent preferably comprises 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 such as acetonitrile. The solvent may also comprise water (e.g., less than 10% v / v, or 5% v / v less) or may be used without the addition of water. 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)-l-naphthylethylamine, and (R)-(-)-2-amino-3-methyl-l-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 then separated from the supernatant. Such treatment may include concentrating the supernatant by at least partial evaporation of the solvent (e.g., by heating and / or vacuum), by adding an acidic aqueous solution to the supernatant, for example, having a pH within the range of 0 to 1, preferably around 0, or by a combination of partial evaporation and acid treatment. Where acid treatment is used, the volume ratio of the aqueous acid solution to the total solution volume is between 4% and 20%. For example, if the aqueous acid solution has a pH of approximately 0, the volume ratio of the aqueous acid solution to the total solution volume is between 10% and 16%, or between 12% and 14%. In other cases, the S-enantiomer-enriched compound may be present in the precipitate from step (c). Examples of such chiral resolving agents include (-)-cinconidine, (-)-sparteine, (R)-l-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (IR, 25)-(+)cis-l-amino-2-indanol, preferably (-)-sparteine. The precipitate may then be further treated after isolation to increase its S-enantiomeric content, for example, by recrystallization. The process described above also includes a step of separating the enantiomerically enriched compound of Formula I from the chiral resolving agent used for resolution. Acidification is generally used for such separation. 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 is precipitated. The resulting enantiomerically enriched compound is made of at least approximately 60% by weight, or at least approximately 70% by weight, or at least approximately 80% by weight, or at least approximately 90% by weight of an S enantiomer. Preferably, the compound is composed of at least approximately 95%, 98%, or 99% by weight of an S enantiomer. The process may also further comprise 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 treating said compound by steps (a) to (d) above to enable the additional (S) isomer of the compound of Formula I. For example, such racemization may be carried out in the presence of an organic base such as DBU. The S-enantiomer of the compound in Formula I is understood to be a compound of Formula II, or a tautomer thereof: Formula II In some cases of Formula I or II, a is 0 and R1 is absent, meaning all five free carbon atoms of the aryl group are bonded to a hydrogen atom. Preferably, b is 1 and R2 is a halogen and / or c is 1 and R3 is a halogen (e.g., chlorine) or a halogenated Cl-6 alkyl, e.g., trifluoromethyl. For example, a is zero, R1 is absent, and R2 and R3 are each independently selected from halogenated alkyl and halogen, preferably b and c each being 1. According to one example, the compound of Formula I is a compound of Formula I(a) or I(b), or a tautomer thereof: Formula I(b). According to another example, the compound in Formula II is a compound of the Formula II(a) or II(b), or a tautomer thereof: Formula II(b). While this document describes the isolation of the (S) enantiomer of a compound of Formula I, it is understood that the (R) enantiomer would be isolated using the procedure described herein with a chiral resolving agent having the reverse chirality of that disclosed. Examples of chiral resolving agents of reverse chirality include (+)-quinine, (R)-1-naphthylethylamine, (R)-phenethylamine, (S)-phenethylamine, (S)-(-)-2-amino-3-methylbutanol, (+)-cinconidine, (+)-sparteine, (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 previously described (see, for example, S. Shiomi et al., Chem. Sci., 2019, 10, 9433). The compounds of Formula I can generally be prepared by reacting a compound (R3)cArSO2NH2 (A) with CIC(O)OMe under basic conditions to allow an intermediate (R3)cArSO2NHC(O)OMe (B), which is then coupled with a free amine (C) of Formula: The present technology also relates to a process for manufacturing a compound containing an S-dihydropyrazole ring, such as CBi receptor inhibitors as defined above, such as the compound (S)-Ibipinabant or a compound of Formula III below. For example, the process comprises (i) preparing a compound of Formula II according to the above process, and (ii) converting the compound of Formula II into a compound of Formula III, or a tautomer thereof: Formula III where, R1, R2, R3, a, b, and c are as previously defined; R4 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 boronate, optionally substituted silyl, and imine; and R5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkyl(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 boronate, optionally substituted silyl, and amino. Step (i) may include the steps of: (ii-a) reacting the compound of Formula II with a chlorinating agent to produce a compound of Formula IV: Formula IV; and (ii-b) reacting the compound of Formula IV with a compound of Formula V: NR4 R5NH2 Formula V or a salt thereof, to produce the compound of Formula III. An example of a chlorinating agent is POCh, 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. In some examples, R4 is H. In other examples, R5 is C1-6 alkyl (e.g., methyl) or Ci-6C(O)NH alkyl (e.g., CH3C(O)NH). Alternatively, the compound of Formula IV is reacted with an amine of Formula R4NH2 to produce a compound as defined in PCT Patent Application No. WO2009 / 059264 or No. WO2014 / 018695. Non-limiting examples of Formula III compounds include the following Compounds 1 to 26: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 C7 iΠ / 77Ω7 / Β / YILI Compound 7 R / C7Ln / 77n7 / E / YIAI Compound 9 SMe Compound 10 Compound 11 Compound 12 Compound 16 C7 iΠ / 77Ω7 / Β / YILI R / C7Ln / 77n7 / E / YIAI Compound 19 Adamantyl Compound 20 Compound 21 Compound 22 R / C7Ln / 77n7 / E / YIAI Compound 25 Compound 26. The enumeration of a modality for a variable herein includes that modality either as a single modality or in combination with any other modality or portions thereof. The recitation of a modality herein includes that modality either as a single modality or in combination with any other modality or portions thereof. EXAMPLES The following non-limiting examples are illustrative 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 figures. Unless otherwise stated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, stabilities, and other properties used in this specification and claims shall be understood as being modified in all cases by the term "approximately." At a minimum, each numerical parameter shall be interpreted in light of the number of significant digits reported and by applying ordinary rounding techniques. Consequently, unless otherwise stated, the numerical parameters presented in this specification and in the appended claims are approximations that may vary depending on the properties sought. Although the ranges and numerical parameters that define the broad scope of the formulations are approximations, the numerical values ​​presented in specific examples are reported as precisely as possible.Any numerical value, however, inherently contains certain errors resulting from variations in experiments, test measurements, statistical analyses, and the like. EXAMPLE 1 Enantiomeric resolution with several chiral resolution agents (Formula lia) A racemic mixture or a substantially racemic mixture of the compound of the Formula I(a): It was dissolved in three different solvents (isopropanol, isopropanol water 95:5 v / v, and ethane water 95:5 v / v) along with a chiral base compound as a resolving agent. The resolving agents are commercially available, while the compound of Formula I(a) was prepared by known methods. Screening experiments were 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 equiv.) and resolving agent (0.5 mmol, 1 equiv.). The calculated amount of solvent was then added to each vial to give a 23% w / w solution based on the theoretical weight of the diastereomeric salt formed, and the resulting suspension was heated to a clear solution or a reasonably clear mixture. The vials were then shaken at room temperature on an orbital shaker at 95 rpm for two days to induce crystallization. Nearly 30 different resolving agents were tested. In experiments where no crystal formation was observed, up to four different treatments (if necessary) (i.e., cooling to -20°C, sonication at room temperature, slow solvent evaporation at room temperature, and vacuum solvent evaporation at 50°C) were applied to stimulate crystal formation. The results for resolving agents that showed the presence of a solid and enrichment in the S-enantiomer (in the solid or supernatant) are shown in Table 1. TABLE 1 Selected screening results Resolving agent Solvent3 % of supernatant ee % of ee solid (-)-quinine A 72.2(5) 83.4(R) (-)-quinine B 40.2(S) 41.2(R) (-)-quinine C 94.6(5) 26.7(R) (-)-quinine C 94.6(5) 26.7(R) (-)-quinine 92(S) 92(S) (-)-c¡ncon¡d¡na B 0 9.8(S) (-)-sparteine ​​B 44.2(R) 32.8(S) (-)-spartane C 85.4(R) 17.0(S) (R)-phenethylamine B 16.6(S) n / abyl (S)-phenethylamine B 16.4(S) n. (R)-l-naphthylethylamine B 6.4(R) 11.8(S) (S)-l-napht¡let¡lam¡na B 4.2(S) 6.2(R) D-arginine B 0 3.9(5) L-lysine B 0 6.3(S) (R)-(-)-amino-l-butane B 23.8(5) 18.8(R) (S)-(+)-2-pyrrolide¡nmethanol B 0 16.0(S) (lR,2S)-(+)-cis-l-amino-2indanol C 4.8(R) 2.7(S) to. Solvent A: 95% EtOH / water; B: 95% ¡-PrOH / water; C: PrOH; D: MeCN; b. n / a: data not available due to no formation of solids (or oil formation). Among those tested, (-)-quinine and (-)-sparteine ​​showed some potential as resolving agents (liquor composition * 50:50) in all three different solvents tested. In all three solvents, (-)-quinine showed moderate to high enantiomerization of the S enantiomer in the liquors, while the test enantiomer was present in the solid. (-)-sparteine ​​in IPA and 95:5 v / v IPA / water showed low to moderate enantiomerization of the S enantiomer in the crystals. Some other chiral resolving agents also showed enrichment of the desired S isomer in the crystal or mother liquor. EXAMPLE 2 Optical resolution in isoDropanol (Formula I(aB Additional tests were carried out using (-)-quinine to determine the optimum amount of solvent and scaling conditions to be used during resolution. The repeat screening experiment with the compound of Formula I(a) and (-)quinine in IPA was carried out at a scale of 17.7 mmol (9.0 g of Formula I(a)). To carry out the crystallization, the reaction mixture was subjected to several heating and cooling cycles in the range of 40–70°C, and after the last cycle it was gradually cooled to room temperature under stirring with seeding using 85% ee diastereomeric salt crystals in the R enantiomer. The reaction mixture was stirred for approximately 18 hours at room temperature. A sample of the reaction mixture was then taken, and the composition of the mother liquors 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 liquors showed 34.4% ee in (S). Since the calculated 77.5% eutectic ee (S) was not achieved in the liquors (34.4% ee was determined by chiral HPLC), the suspension was vacuum filtered to provide 2.17 g of diastereomeric salt (87.4% solid ee; determined by chiral HPLC). The mother liquor was evaporated to 1 / 3 of the initial volume (54 g of IPA solution) followed by plating with diastereomeric salt R (85% ee in R enantiomer) at 40°C. The reaction was stirred overnight at room temperature. After 14 hours of stirring, a sample of the reaction mixture was taken 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 filtered again under vacuum, and the resulting mother liquor was concentrated to approximately 60% of the initial volume (34 g), followed by seeding with diastereomeric R salt (85% ee in the R enantiomer) at 40°C. The reaction was allowed to continue stirring 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). The reaction was repeated on a 4 g scale, yielding 49.3% ee of the S enantiomer in the mother liquor after overnight stirring at room temperature. After vacuum filtration of the reaction mixture, the mother liquor was evaporated to half its initial volume (39.9 g of IPA solution), and the resulting mixture was seeded with diastereomeric R salt (85% ee in the R enantiomer) at 40°C. The reaction was allowed to proceed with stirring for 76 hours at room temperature. The composition of the mother liquor and solid was determined by chiral HPLC (61.5% ee in the mother liquor). A subsequent reaction was carried out on a 2 g scale with a slight alteration of the reaction conditions. The initial phase of the reaction was conducted at 70°C until a clear solution was observed (approximately 10 min). The solution was then cooled to room temperature (a precipitate began to appear) and stirred for a further 1 hour and 20 minutes. The reaction was diluted with 20 mL of IPA and refluxed for 10 min at 70°C, followed by the addition of an additional 20 mL of IPA. A suspension was cooled again to room temperature, followed by the addition of 20 mL of IPA. The suspension was stirred for 15 min and then filtered through an S3 sintered funnel. After washing with IPA, HPLC analysis showed that the crystals had an ee of 85.3% (R), while the %ee of the liquor was 72.4% (S). The reaction was repeated on a 2 g scale following the above procedure and the suspension was left to stir overnight (18 h).HPLC analysis revealed crystals with 64.8% ee (R); the liquor was 85.6% ee (S). The diastereomeric salt (85.6% ee) was decomposed by the addition of 2M aq. HCl followed by filtration of the resulting precipitate in a sintered funnel (porosity 3) to allow the S enantiomer (99.4% ee). EXAMPLE 3 Optical resolution and additional enrichment in acetonitrile (Formula lia)) (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 eq.), and 443 g of HPLC-grade acetonitrile (MeCN, approximately 564 mL) were mixed in the reactor, and the temperature was raised to 65°C for 30 minutes. The mixture was then cooled to 20°C for 4.5 hours and maintained at 15°C overnight (approximately 18 hours). The suspension was then filtered. The crystals contained 95.8% (ee) of the R isomer, while the mother liquor provided 77.2% (ee) of the S isomer. (b) Enrichment of the S isomer The mother liquor from step (a), comprising the S-isomer-enriched solution, was further treated to enhance the enantiomeric excess (ee) of the S-isomer. The mother liquor volume was adjusted to 400 mL (69.25 g / L Formula I(a)), and half of the solution was used for an ee enhancement assay. Ten 20 mL aliquots, each containing 1.38 g of pyrazoline, were collected. Each 20 mL aliquot was treated with various volumes of acidic water at pH 1 or 0 (see Table 2). After overnight stirring in MeCN / water, the solids were filtered and analyzed by HPLC and NMR. Α / ΟΖίΠ / ΖΖηΖ / Ε / ΥΙΛΙ TABLE 2 HPLC results for % improvement assays of ee pH 1 water added (mL) pH 0 water added (mL) Total volume (mL) S-ee crystals (%) Crystal yield (%) 3 - 23 99.82 65.38 4 - 24 99.76 73.06 5 - 25 99.68 79.10 6 - 26 90.99 86.96 7 - 27 85.88 92.36 - 1 21 99.89 59.85 - 2 22 99.79 72.25 - 3 23 99.70 76.58 - 4 24 96.71 81.84 - 5 25 91.67 85.54 C7 ΙΠ / 77Ω7 / Β / ΥΙΙΛΙ As shown in Table 2, both an increase in water and a decrease in pH reduced the solubility of the desired compound. With a starting material containing 77.24% ee in the S isomer, conditions using 3 mL of a pH 0 solution yielded the best results. In fact, a near-perfect yield of 76.58% with >99% ee was obtained. Acidification at a lower temperature (10–20°C) was found to be preferable as it led to fewer side reactions and better yields compared to warmer acidification (40–55°C). These conditions (addition of approximately 15% pH 0 water to a 69–70 g / L compound solution) applied to the remaining mother liquors (200 mL) proved robust enough to provide good yields on a 13.8 g scale. In fact, 8.87 g of S isomer with > 99% ee were obtained after filtration and subsequent drying (rotavap 5-10 mbar, 45°C, 4 h). XH-NMR showed the presence of 0.52 eq of water. Steps (a) and (b) were repeated using 500 g of racemic starting material, 208 g of (-)-quinine (0.65 eq.), and 3.48 kg of MeCN (approximately 4.43 L) in step (a). Step (b) was performed as before using 270 g of compound enriched with the S isomer (ee: 76.24%), MeCN (total volume 3.9 L), and 1 N HCl (pH 0, 592 mL), and yielded 205 g of the S isomer (Formula II(a)) at 99.5% ee. The compound can be used in the preparation of compounds of Formula III, for example, compounds 1, 7, 9, 11, 13, 15, 17, 19, 21, 23, and 25. EXAMPLE 4 Isolation and racemization of the R isomer (Formula I(aB The R-isomer-rich crystals, for example, isolated from step (a) of Example 3, comprising the (-)-quinine salt of the R-isomer, were recycled by first breaking down the salt formed and then racemizing the isolated R-isomer for reuse in the resolution process. Two alternative processes are illustrated below. Process 1 The first step involved mixing the salt (approximately 230 g (R), 140 g of quinine) in 2.3 L of HPLC-grade dichloromethane and adding 1.15 L of a 1 N HCl solution under stirring. The mixture was stirred 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 yielded the R-isomer-rich compound (211 g, 92% yield). The resulting solid was then dissolved in anhydrous DME (1 L) and mixed with DBU (93.5 mL, 1.5 eq.). 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 layers were washed with saline solution and dried with MgSO₄. All volatiles were removed under reduced pressure, and the residue was ground with MTBE / EtOAc (8:1). The suspension was filtered and washed with cold MTBE. The solid was further dried under reduced pressure to yield the racemic compound of Formula I(a) (175 g, 82% yield). This racemic compound is then further used in the process of Example 3 to produce the S-isomer. Process 2 The quinine salt of the R isomer (79 kg, 1.0 eq.) is introduced into the reaction vessel. A 1 N hydrochloric acid solution (3 volumes) is added to the vessel, followed by 2-methyltetrahydrofuran (2-MeTHF) (2 volumes), and the mixture is stirred until it becomes clear. The mixture is separated, and the organic phase is washed with water (1 volume) and concentrated to dryness. DME (3 volumes) is added, and the mixture is concentrated again to dryness. The resulting solid was then dissolved in anhydrous DME (3 L) and mixed with DBU (1.5 eq.). 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 the slow, dropwise addition of HCl solution to IN. The mixture was filtered, and the cake was washed with water (2 volumes). The cake was dried at 50–60°C to yield the racemic compound of Formula I(a) (42 g, 95% yield). This racemic compound was then further used in the process of Example 3 to produce the S isomer. EXAMPLE 5 Optical resolution of the compound of Formula Ifb) To a mixture of the Compound of Formula I(b) (96.0 g, 1.00 eq.) in MeCN (960 mL) was added (-)-Quinine (50.0 g, 0.76 eq.) at 15–20°C, and then the mixture was 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 cake was dried to give a white solid (96.0 g), which was verified by SFC and HPLC. The mother liquor was also verified by SFC and HPLC. The mother liquor was heated to 40–45°C, and HCl (1 M, 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 the solid was obtained. The solid was ground with MeCN / HzO (150 mL / 15 mL). The S isomer (25.0 g, 99.5% purity) of Formula II(b) was obtained as a light yellow solid, which was confirmed by Ή NMR, LCMS, HPLC and SFC.The S isomer can also be used in the preparation of compounds of Formula III, for example, in the preparation of 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. Patent No. 9,765,031 and PCT Patent Applications No. WO2009 / 059264 and No. WO2014 / 018695. Ή NMR (400MHz, DMSO-íA) 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)+. Numerous modifications could be made to any of the modalities described above without departing from the scope of the present invention. Any references, patents, or scientific literature documents mentioned herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A process for preparing an enantiomerically enriched compound, characterized in that it comprises the steps of: (a) providing a compound of Formula I or a tautomer thereof: Formula I wherein, R1, R2, and R3 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 boronate, optionally substituted silyl, and amino; (a), (b), and (c) are each independently O, 1, 2, 3, 4, or 5;wherein said compound of Formula I comprises a mixture of R and S isomers at the carbon atom (*) (C*) and wherein the fourth atom bonded to C* is hydrogen or an isotope thereof (for example, deuterium); (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)-l-naphthylethylamine, (R)-(-)-2-amino-3-methylbutanol, (-)-cinconidine, (-)-sparteine, (R)-l-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (1R,2S)-(+)-cis-l-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 comprises the enantiomerically enriched compound comprising a higher concentration of the S enantiomer compared to the R enantiomer of the compound of Formula I;where steps (b) and (c) are carried out simultaneously or sequentially.; 2. The process in accordance with claim 1, further characterized in that said solvent is an aprotic organic solvent.

3. The process in accordance with claim 2, further characterized in that the aprotic organic solvent is acetonitrile.

4. The process according to claim 1, further characterized in that said solvent comprises an alcohol having from 1 to 4 carbon atoms, or a combination thereof.

5. The process according to claim 4, further characterized in that said alcohol is selected from ethanol, isopropanol, and a combination thereof, preferably the alcohol being isopropanol.

6. The process in accordance with any of claims 2 to 5, further characterized in that the solvent additionally comprises water at a concentration of 10% or less, or 5% or less, or the solvent is anhydrous.

7. The process in accordance with any of claims 1 to 6, further characterized in that the compound of Formula I is at a concentration of between approximately 50 g and approximately 150 g, or between approximately 75 g and approximately 120 g, or between approximately 85 g and approximately 115 g, per liter of solvent in step (b).

8. The process in accordance with any of claims 1 to 7, further characterized in that step (c) comprises between approximately 0.5 and approximately 1, or between approximately 0.55 and approximately 0.75, or between approximately 0.6 and approximately 0.7, or approximately 0.65 molar equivalents of said chiral resolving agent with respect to the compound of Formula I. 9.- The process according to any of claims 1 to 8, further characterized in that the chiral resolving agent is selected from (-)-quinine, (R)phenethylamine, (S)-phenethylamine, (S)-l-naphthylethylamine, and (R)-(-)-2-amino-3-methyl-l-butanol.

10. The process according to claim 9, further characterized in that said chiral resolving agent is (-)-quinine.

11. The process according to claim 9 or 10, further characterized in that it additionally comprises a step of treating the supernatant to obtain a solid enriched in the isomer (S) of the compound of Formula I. 12.- The process according to claim 11, further characterized in that said treatment step comprises concentrating the supernatant by at least partial evaporation of the solvent.

13. The process according to claim 11 or 12, further characterized in that said treatment step comprises adding an acidic aqueous solution to the supernatant.

14. The process according to claim 13, further characterized in that the acidic aqueous solution has a pH within the range of 0 to 1, preferably around 0.

15. The process according to claim 14, further characterized in that the volume ratio of the acidic aqueous solution to the total volume of solution is between 4% and 20%.

16. The process according to claim 15, further characterized in that the acidic aqueous solution has a pH of approximately 0, and the volume ratio of the acidic aqueous solution to the total volume of solution is between 10% and 16%, or between 12% and 14%.

17. The process in accordance with any of claims 11 to 16, further characterized in that it additionally comprises a step of separating the solid from the supernatant.

18. The process according to any of claims 1 to 8, further characterized in that said chiral resolving agent is selected from (-)-cynconidine, (-)sparteine, (R)-l-naphthylethylamine, D-arginine, L-lysine, (S)-(+)-2-pyrrolidinemethanol, and (lR,2S)-(+)-cis-lamino-2-indanol. 19.- The process in accordance with claim 18, further characterized in that said chiral resolving agent is (-)-sparteine.

20. The process according to claim 18 or 19, further characterized in that it additionally comprises recrystallizing the precipitate.

21. The process in accordance with any of claims 1 to 20, further characterized in that it additionally comprises a step of separating the isomer (S) of the compound of Formula I from the chiral resolving agent. 22.- The process according to claim 21, further characterized in that said separation step comprises adding an acid (for example, hydrochloric acid).

23. The process according to any of claims 1 to 22, further characterized in that it further comprises recovering the isomer (R) of the compound of Formula I, racemizing at least partially said isomer (R) to obtain the compound of Formula I, and further treating said compound by steps (a) to (d).

24. The process according to any of claims 1 to 23, further characterized in that a is zero, R1 is absent, and R2 and R3 are each independently selected from halogenated alkyl and halogen, preferably b and c each being 1. 25.- The process according to claim 24, further characterized in that said compound is of Formula I(a) I(b): Formula I(b); 5 or a tautomer thereof.

26. A process for preparing a compound of Formula III, or a tautomer thereof: Formula III 10 wherein, R1, R2, R3, a, b, and c are as defined in claim 1; R4 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 boronate, optionally substituted silyl, and imine;and R5 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkyl(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 boronate, optionally substituted silyl, and amino; wherein the fourth atom attached to the chiral carbon is hydrogen or an isotope thereof (for example, deuterium); the process comprises the steps of: (i) preparing a compound of Formula II: R / czLn / zznz / E / YiAi Formula II according to the process as defined in any one of claims 1 to 23;and (ii) converting said compound of Formula II into the compound of Formula III.; 27. The process according to claim 26, further characterized in that step (i) comprises the steps of: (ii-a) reacting the compound of Formula II with a chlorinating agent (for example, POCb) to produce a compound of Formula IV: Formula IV; and (ii-b) reacting the compound of Formula IV with a compound of Formula V or a salt thereof, to produce the compound of Formula III.

28. The process according to claim 27, further characterized in that said step (ii-a) additionally comprises a base (for example, 2,6-lutidine).

29. The process according to claim 27 or 28, further characterized in that step (ii-b) additionally comprises a base (for example, DBU, K2HPO4).

30. The process in accordance with any of claims 26 to 29, further characterized in that a is zero and R1 is absent, R2 and R3 are each independently selected from halogenated alkyl and halogen, preferably b and c each being 1.

31. The process according to any of claims 26 to 30, further characterized in that said compound of Formula III is selected from: R / C7Ln / 77n7 / E / YIAI R / C7Ln / 77n7 / E / YIAI C7 ίΠ / 77Ω7 / Β / YΙΛΙ R / C7Ln / 77n7 / E / YIAI