Methods and intermediates for preparing compounds

Abstract

This disclosure relates to a method for preparing intermediates useful for preparing compounds that inhibit the function of human immunodeficiency virus (HIV) during the viral replication cycle, such as by disrupting the function of the HIV capsid shell. [Formula 1] JPEG2026524821000058.jpg39145

Description

[Technical Field]

[0001] The present invention relates to a method for preparing intermediates useful for preparing compounds that inhibit the function of human immunodeficiency virus (HIV) during the viral replication cycle, such as by disrupting the function of the HIV capsid shell. [Background technology]

[0002] Acquired immunodeficiency syndrome (AIDS) results from HIV infection. HIV and AIDS remain major global public health problems. In 2021, an estimated 38.4 million people were living with HIV (including 1.7 million children), and the global HIV prevalence was 0.8%. The majority of these figures live in low- and middle-income countries. In the same year, 650,000 people died from AIDS-related illnesses.

[0003] Current treatment for individuals infected with HIV consists of combinations of approved antiretroviral agents. Approximately 50 drugs are currently approved for HIV infection as monotherapy, fixed-dose combinations, or single-tablet regimens, the latter two of which contain 2 to 4 approved drugs. These drugs belong to several different classes that target either the function of viral enzymes or viral proteins during the viral replication cycle. Thus, drugs are classified as either nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase chain transfer inhibitors (INSTIs), or entry inhibitors (one being maraviroc, which targets the host CCR5 protein, and the other being enfuvirtide, a peptide that targets the gp41 region of the viral gp160 protein). In addition, pharmacokinetic enhancers (cobicistat or ritonavir) may be used in combination with antiretroviral agents (ARVs) that require additional immunization.

[0004] Despite the availability of drug and combination therapy options, there remains a medical need for novel antiretroviral agents. High viral diversity, drug-related toxicity, tolerability issues, and poor adherence can all lead to treatment failure and potentially result in the selection of viruses with mutations that confer resistance to one or more antiretroviral agents, or even multiple agents from across the entire class. (Beyrer, C., Pozniak A. "HIV drug resistance - an emerging threat to epidemic control." N.Engl.J.Med.2017, 377, 1605~1607; Gupta, RK, Gregson J et al. "HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis." Lancet Infect.Dis.2017, 18, 346~355; Zazzi, M., Hu, H., Prosperi, M. "The global burden of HIV-1 drug resistance in the past 20 years." PeerJ.201, DOI 10.7717 / peerj.4848). As a result, new drugs are required to be easier to administer, have a high genetic barrier to the emergence of resistance, and have improved safety compared to current drugs. Within this suite of options, novel mechanisms of action (MOAs) that can be used as part of preferred antiretroviral therapy (ART) can still play a major role, as they should be effective against viral resistance to current drugs. Improvements to create drugs that are easier to take over long periods or throughout a lifetime include all or some of the following: reduced side effects, reduced drug interactions, increased duration of medication, or alternative routes of administration that suit the individual patient's preferences.Improved safety objectives may include a high therapeutic index for any toxicity leading to drug discontinuation, and may also include reduced side effects or drug interactions. The potential for lower overall drug dosage in combination regimens would also result in improved adherence and safety. Enhanced antiviral effects, if maintained, particularly in the presence of human plasma and serum albumin, could also lead to dose reductions, directly positively impacting the duration of treatment and the therapeutic index for side effects and toxicity. In summary, the discovery of an anti-HIV drug with a novel mechanism of action and the other advantages mentioned above that promote long-term adherence and safety would bring the greatest benefit to HIV-infected patients.

[0005] A potential therapeutic compound that appears to disrupt the normal function of the HIV capsid has been described in the art. Compounds acting through this mechanism may be a useful additional option for the treatment of HIV infection. Compounds that appear to target the HIV capsid have been the subject of recent reviews describing many of the most important studies to date. These reviews include: "HIV-1 Capsid Inhibitors as Antiretroviral Agents" Thenin-Houssier, Suzie; Valente, Susana T. Current HIV Research, 2016, 14, 270; "Inhibitors of the HIV-1 capsid, a target of opportunity" Carnes, Stephanie K.; Sheehan, Jonathan H.; Aiken, Christopher, Current Opinion in HIV & AIDS 2018, 13, 359-365; "HIV Capsid Inhibitors Beyond PF74" McArthur, Carole, Diseases, 2019, 7, 22; and "Insights into HIV-1 capsid inhibitors in preclinical and early clinical development as antiretroviral agents" Cevik, Muge; Orkin, Chloe Expert Opin Inv.Drugs, 2019, 28, 1021; and PCT patent applications with the following publication numbers: WO2012065062, WO2013006738, WO2013006792, WO2014110296, WO2014110297, WO2014110298, WO2014134566, WO20150 61518, WO2015130964, WO2015130966, WO2016040084, WO2016033243, WO20161724 24, WO2016172425, WO2018035359, WO2018203235, WO2019035904, WO2019035973, W O2019161017, WO2019161280, WO2019198024, WO2020018459, WO2020053811, WO20 20058844, WO2020084480, WO2020084491, WO2020084492, WO2020089778, WO202009 5176, WO2020095177, WO2020157692, WO2020222108, WO2020254985, WO2021064570, WO2021064571, WO2021064677, WO2021070054, WO2021176366, and WO2021176367.

[0006] What is currently needed in this field is further novel and / or useful compounds for the treatment of HIV. There is also a need for the development of such compounds into active ingredients (APIs) suitable for use in drug manufacturing. Compound properties such as solubility, hygroscopicity, and chemical / physical stability are non-limiting factors used in drug development to obtain safe and effective drugs. Synthetic drug chemical routes for novel compounds often focus on diversity, enabling the rapid acquisition of different analogues on a small scale. In contrast, process chemical routes for the production of APIs on an industrial scale need to consider factors such as scalability, overall yield, safety, environmental risk, economics, and the overall feasibility of the route.

[0007] Thus, in another aspect, the present invention addresses the problem of providing an efficient method (e.g., improved enantiomeric excess) for the production of intermediate compounds that can be used in, for example, chemical pathways for generating HIV capsid inhibitors. Summary of the Invention

[0008] The present invention relates to a method for preparing intermediates useful for preparing compounds that inhibit the function of HIV during its replication cycle, such as by disrupting the function of the HIV capsid shell.

[0009] In one aspect, the present invention provides a compound of formula (I-a) [Chemical formula] and a compound of formula (I-b) [Chemical formula] [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1~6 "Alkyl" or "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, sec-butyl, isobutyl and tert-butyl), pentyl, and hexyl.

[0012] The term "alkyl" is used in "halo(C) 1~4 )alkyl and hydroxy(C 1~4 When used in combination with other substituents such as "alkyl," the term "alkyl" is intended to encompass divalent linear or branched hydrocarbon groups whose bonding sites pass through the alkyl moiety.

[0013] The term "cycloalkyl" refers to a non-aromatic saturated monocyclic hydrocarbon ring containing a specific number of carbon atoms. For example, a "cycloalkyl" contains 3 to 8 carbon atoms, i.e., C 3~8 It may be a cycloalkyl group. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0014] The terms "halogen" and "halo" refer to chloro, fluoro, bromo, or iodo substituents.

[0015] The term "cyano" refers to the -CN group.

[0016] The term "chiral amine" refers to an amine covalently bonded to a carbon atom, where the carbon atom has three distinct substituents and is chiral. The term "chiral amine" is used interchangeably to describe the free base or ammonium salt form of a chiral amine. The chiral amine ammonium salt form refers to the ammonium species formed by a combination of a chiral amine free base and an acid.

[0017] The term "alkoxy" refers to an alkyl group bonded via an oxygen-linked atom, i.e., an -O-alkyl group, and "alkyl" is defined above. For example, the term "C 1~6 "Alkoxy" refers to an alkoxy group having 1 to 6 carbon atoms. Exemplary groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

[0018] The term "cycloalkoxy" has the same meaning as the definition above, meaning that a cycloalkyl group having the listed number of carbon atoms is bonded to an extra-ring oxygen atom via a ring carbon atom. For example, "cycloalkoxy" contains 3 to 6 carbon atoms bonded to an extra-ring oxygen atom via a ring carbon atom, i.e., C 3~6 They may be cycloalkoxys. Exemplary groups include, but are not limited to, cyclopropoxyl, cyclobutoxyl, cyclopentoxyl, and cyclohexoxyl.

[0019] The term "allyle" refers to the structural formula H2C=CH-CH2- * This refers to the part that has, * The symbol indicates the bond point of the part to the rest of the molecule, and the bond point is a heteroatom or aromatic part.

[0020] The term "aryl" refers to a monocyclic or bicyclic hydrocarbon aromatic group. Examples of aryls include phenyl and naphthyl. Aryl groups can contain 6 to 14 carbon atoms.

[0021] The term "heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic group containing 5 to 10 ring atoms and at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. This term also encompasses bicyclic heterocyclic aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, which contains 5 to 10 ring atoms and at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Exemplary groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxynyl, benzothienyl, indolidine, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobe Examples include zuimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, sinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthilidinyl, 1,6-naphthilidinyl, 1,7-naphthilidinyl, 1,8-naphthilidinyl, and pteridinyl. Examples of five-membered heteroaryl groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl. Examples of six-membered heteroaryl groups include oxopyridyl, pyridinyl, pyridadinyl, pyrazinyl, and pyrimidinyl.Examples of 6,6-condensed heteroaryl groups include quinolinyl, isoquinolinyl, quinoxalinyl, synnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthilidinyl, 1,6-naphthilidinyl, 1,7-naphthilidinyl, 1,8-naphthilidinyl, and pteridinyl. Examples of 6,5-condensed heteroaryl groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolidinyl, indolyl, isoindolyl, and indazolyl.

[0022] The term "chemical purity" refers to the overall level of the desired product or compound in the composition produced by the preparation. If the compound exists in the form of enantiomers, "chemical purity" as used herein includes both enantiomers in the calculation of the overall level of the desired product. Components of the composition other than the desired product or compound are "impurities." Purity can be measured by a variety of techniques, including but not limited to HPLC analysis.

[0023] The terms “enantiomer purity” or “chiral purity” refer to the overall level of one enantiomer in a composition compared to the other enantiomer in the composition. Components of the composition other than enantiomers are not considered in the calculation of “enantiomer purity” or “chiral purity.” Enantiomer purity or chiral purity can be measured by a variety of techniques, including but not limited to chiral SFC analysis and / or chiral HPLC analysis.

[0024] The term "enantiomer excess," or "ee," refers to the percentage of a mixture in which one enantiomer exceeds the enantiomer of the other. For example, in a mixture containing 60% enantiomer A and 40% enantiomer B, the enantiomer excess of enantiomer A is 20% (60% enantiomer A - 40% enantiomer B = 20%ee).

[0025] The term "may be substituted" indicates a group that is unsubstituted or may be substituted with one or more substituents, as defined herein. In reference to a group, the term "substituted" indicates that one or more hydrogen atoms bonded to the constituent atoms within the group are independently replaced by one or more defined substituents. If a group can be selected from several alternative groups, the selected groups may be identical or different.

[0026] The term "independently selected" means that two or more substituents are selected from several possible substituents, and these substituents may be identical or different. Therefore, each substituent is selected separately from the entire group of enumerated possible substituents.

[0027] The term "leaving group" generally refers to a group that can be readily substituted by a nucleophile such as an amine, thiolate, alkoxide, or enolate. Examples of leaving groups, though not limited to them, include halides, imidazoles, and pyridinium species.

[0028] The term "constituent atom" refers to the atom(s) that form a chain or ring. When two or more constituent atoms are present in a chain or ring, each constituent atom is covalently bonded to an adjacent constituent atom within the chain or ring. Atoms that constitute a substituent bonded to a chain or ring are not considered constituent atoms within the chain or ring.

[0029] The term "aprotic solvent" refers to a solvent molecule that neither accepts nor donates protons.

[0030] Embodiments of the present invention In one embodiment, the present invention relates to the compound of formula (Ia). [ka] and compounds of formula (Ib) [ka] A method for preparing a mixture comprising, (a) Compound of formula (II), [ka] (b) Compound of formula (III), [ka] (wherein X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group), and (c) Chiral amine The present invention relates to a method comprising combining to obtain the mixture.

[0031] In embodiments, the present invention relates to the compound of formula (Ia). [ka] and compounds of formula (Ib) [ka] A method for preparing a mixture comprising, (a) Compound of formula (II), [ka] (b) Compound of formula (III), [ka] (wherein X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group) (c) Chiral amine, (d) Lithium base, (e) Lithium salt, and, if desired (f) aprotic solvents The present invention relates to a method comprising combining to obtain the mixture.

[0032] In an embodiment of the present invention, the compound of formula (III) [ka] In formula (III), X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group. As previously stated, the term “leaving group” generally refers to a group that can be readily substituted by a nucleophile such as an amine, thiolate, alkoxide, or enolate. Such leaving groups are well known in the art, and those skilled in the art will understand that many possible leaving groups can be used. Examples of such leaving groups include, but are not limited to, halides, imidazoles, and pyridinium species. The leaving group can also be described by referring to the chemical substance released when Y of the compound of formula (III) is substituted by a nucleophile. For example, following substitution with a nucleophile, Y can take the form of an alcohol, phenol, carboxylic acid, N-hydroxysuccinimide, N-hydroxybenzotriazole, or their conjugate base.

[0033] In embodiments of the present invention, the compound of formula (III) is a product obtained by reacting a carboxylic acid with an "activator" according to the following formula.

[0034] [ka] In the formula, X is cyclopropyl, difluoromethyl, or trifluoromethyl, and the “activator” is one of many reagents known in the art that can produce a leaving group (Y) in this conversion. Those skilled in the art will understand that many activators can be used. Examples of such activators include, but are not limited to, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 2-propanephosphonic anhydride (T3P), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholinomethylene)]methanaminonium hexafluorophosphate (COMU), and benzotriazol-1-yloxytri(pyrrolidino)phosphonium hexafluorophosphate (PyBOP). Several possible activators are also described in Chem. Rev, 2011, 111(11), 6557-6602.

[0035] In another embodiment of the present invention, Y is selected from -F, -Cl, -Br, -I, -CN, C1-C6 alkoxy, C3-C6 cycloalkoxy, -O(CO)C1-C6 alkyl, -O(CO)C3-C6 cycloalkyl, -O-aryl, or -O-heteroaryl, where -O(CO)C1-C6 alkyl or -O(CO)C3-C6 cycloalkyl may be substituted with 1, 2, or 3 fluorine atoms, and O-aryl and O-heteroaryl may be substituted 1, 2, or 3 times with halogen atoms or substituents independently selected from C1-C3 alkyl.

[0036] In embodiments of the present invention, Y is chloro, methoxy, or ethoxy. In another embodiment of the present invention, Y is methoxy or ethoxy.

[0037] In this embodiment of the present invention, a lithium amide base is formed by combining a chiral amine, a lithium base, and optionally a lithium salt in the presence of a solvent.

[0038] In an embodiment, the lithium base is Li-C1~C6-alkyl, Li-C5~C6-cycloalkyl, Li(aryl), LiH, LiNH2, or lithium metal (Li 0 ) is selected from. In another embodiment, the lithium base is selected from n-butyllithium (n-BuLi), sec-butyllithium (sec-BuLi), isopropyllithium (i-PrLi), or tert-butyllithium (t-BuLi). In another embodiment, the lithium base is n-BuLi.

[0039] In an embodiment, the solvent is any solvent that can coordinate with any of the combined components but does not cause a chemical reaction. One of ordinary skill in the art will understand that many solvents can be used alone or in combination with each other. In an embodiment, the solvent is an aprotic or non-protogenic solvent. Non-limiting examples of such solvents include tetrahydrofuran (THF), 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether (MTBE), and cyclopentyl methyl ether (CPME). In an embodiment, the solvent is selected from THF, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, MTBE, or CPME. In another embodiment, the solvent is selected from THF, 1,4-dioxane, 2-methyltetrahydrofuran, MTBE, or CPME. In another embodiment, the solvent is THF.

[0040] In an embodiment, a lithium salt is present. In another embodiment, the lithium salt is LiCl or LiBr. In an embodiment, no lithium salt is present.

[0041] As mentioned above, the term "chiral amine" refers to an amine covalently bonded to a carbon atom, where the carbon atom has three distinct substituents and is chiral. The term "chiral amine" is used interchangeably to describe the chiral amine free base or ammonium salt form. The chiral amine ammonium salt form refers to the ammonium species formed by a combination of a chiral amine free base and an acid.

[0042] In an embodiment of the present invention, a lithium amide base is formed by combining a chiral amine, a lithium base, and optionally a lithium salt in the presence of a solvent. In the embodiment, a lithium salt is present. In another embodiment, the molar ratio of the chiral amine to the lithium salt is in the range of about 4:1 to about 2:5. In yet another embodiment, the molar ratio of the chiral amine to the lithium salt is in the range of about 6:5 to about 1:1.

[0043] In some embodiments, a lithium amide base is formed by combining a free chiral amine base, a lithium base, and optionally a lithium salt in the presence of a solvent. In another embodiment, the molar ratio of the free chiral amine base to the lithium base is in the range of about 9:10 to about 5:6. In yet another embodiment, the molar ratio of the free chiral amine base to the lithium base is in the range of about 1.0:1.0 to about 1.0:1.1.

[0044] In another embodiment, a lithium amide base is formed by combining a chiral amine ammonium salt, a lithium base, and optionally a lithium salt in the presence of a solvent. In this embodiment, the molar ratio of the chiral amine ammonium salt to the lithium base is in the range of about 1.0:1.8 to about 1.0:1.0:2.4. In another embodiment, the molar ratio of the chiral amine ammonium salt to the lithium base is in the range of about 1.0:2.0 to about 1.0:2.2.

[0045] In one embodiment of the present invention, the lithium base is n-BuLi, the lithium salt is present and is LiCl, and the solvent is THF.

[0046] In one embodiment of the present invention, the chiral amine is a product of formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), or (IV-f):

[0047] [ka] (In the formula, G1 is an unsubstituted phenyl, or a phenyl substituted with one, two, or three substituents independently selected from halogens, cyano, substituted C1-C4 alkyl, unsubstituted C1-C4 alkyl, -O(cyclopropyl), -O(allyl), allyl, -O(R1), or -C(O)(R1). G2 is an unsubstituted phenyl, or a phenyl substituted with one, two, or three substituents independently selected from halogens, cyano, substituted C1-C4 alkyl, unsubstituted C1-C4 alkyl, -O(cyclopropyl), -O(allyl), allyl, -O(R1), or -C(O)(R1). G3 is an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one, two, or three halogen atoms. G4 is an unsubstituted C1-C3 alkyl group, or a C1-C3 alkyl group substituted with one, two, or three halogen atoms. G5 is selected from azetidine, pyrrolidine, morpholine, piperidine, or quinuclidine, each of which may be substituted with one or two substituents independently selected from methyl or halogen. G6 is selected from allyl, cyclopropyl, unsubstituted C1-C5 alkyl, or C1-C5 alkyl substituted with one phenyl or one, two, or three halogen atoms. R1 is an unsubstituted C1-C4 alkyl group, or a C1-C4 alkyl group substituted with one, two, or three halogen atoms. It is a compound selected from among them.

[0048] In one embodiment of the present invention, the chiral amine is (R)-bis((R)-1-phenylethyl)amine, [ka] or (R)-bis((R)-1-phenylethyl)amine hydrochloride [ka] That is the case.

[0049] In one embodiment of the present invention, a lithium amide base formed by combining a chiral amine, a lithium base, and optionally a lithium salt in a solvent ("solvent A") is then combined with bicyclo[3.1.0]hexane-3-one in a solvent ("solvent B"). "Solvent A" and "solvent B" are any solvents that do not chemically react with any of the components being combined. Those skilled in the art will understand that many solvents can be used, and that "solvent A" and "solvent B" may be the same or different. Examples of such solvents, but not limited to, include THF, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, MTBE, and CPME. Those skilled in the art will understand that, prior to stopping and work-up of the reaction mixture, the solvent(s) used and the environment in which the solvent(s) are used should contain little to no water. In the embodiment, the solvent(s) used prior to stopping and work-up of the reaction mixture contain less than 500 ppm of water. In another embodiment, the solvent(s) used before stopping and working up the reaction mixture contain less than 300 ppm of water. In yet another embodiment, the solvent(s) used before stopping and working up the reaction mixture contain less than 150 ppm of water.

[0050] In embodiments of the present invention, the compound of formula (Ia) in the mixture produced by the method described herein is present in an enantiomer excess of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, or 85% or more relative to the compound of formula (Ib).

[0051] In one embodiment of the present invention, the difference in solubility of two compounds present in a mixture is used to selectively concentrate one compound over the other. When the mixture is treated with a solvent in such a way that some solid material is dissolved and some solid material remains, the ratio of the two components to the liquid phase becomes different. This method is known as "trituration".

[0052] In another embodiment, if two compounds are present in the mixture, grinding may be used to selectively concentrate the amount of one compound in the solid phase relative to the other, and the solid is then isolated by filtration.

[0053] In a further embodiment, if two positional isomers are present in the mixture, grinding may be used to selectively concentrate the amount of one positional isomer in the solid phase relative to the other, and the solid is then isolated by filtration.

[0054] In another embodiment, if two positional isomers present in the mixture contain carboxylic acid groups, the carboxylic acid groups are converted to the corresponding lithium acetate groups before grinding.

[0055] In a further embodiment, if two lithium acetate positional isomers are present in the mixture, grinding may be used to selectively concentrate the amount of one positional isomer in the solid phase relative to the other, and the solid is then isolated by filtration.

[0056] In another embodiment, grinding is used to concentrate the amount of one compound in the solid phase relative to the other, and if the solid is then isolated by filtration, the filtrate may also be isolated separately and further processed in a subsequent step to yield additional substances.

[0057] In one embodiment of the present invention, a mixture of the positional isomer 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate and 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-2-yl)lithium acetate

[0058] [ka] The mixture is subjected to a grinding process, and as a result, one positional isomer becomes more concentrated in the solid phase than the other.

[0059] In another embodiment of the present invention, a mixture of the positional isomer 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate and 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-2-yl)lithium acetate [ka] (Here, lithium 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate is present as the main positional isomer (>50% wt)) It is subjected to a grinding process, resulting in 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate. [ka] This can be obtained with a chemical purity of >90%.

[0060] In one embodiment of the present invention, the grinding process used to separate two positional isomers uses water as one component of the solvent.

[0061] In another embodiment of the present invention, the grinding process used to separate two positional isomers uses an aqueous acid solution as one component of the solvent.

[0062] In another embodiment of the present invention, the grinding process used to separate the two positional isomers uses an aqueous acidic solution as the solvent.

[0063] In another embodiment of the present invention, the grinding process used to separate the two positional isomers uses an aqueous HCl solution as the solvent.

[0064] In another embodiment of the present invention, the grinding process used to separate the two positional isomers uses a 1N HCl aqueous solution as the solvent.

[0065] In another embodiment of the present invention, a compound containing a lithium acetate group retains the lithium acetate group when treated with an aqueous acid solution.

[0066] In another embodiment of the present invention, a solid compound containing lithium acetate groups retains the lithium acetate groups when treated with an aqueous acid solution.

[0067] In another embodiment of the present invention, a solid mixture of the positional isomers 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate and 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-2-yl)lithium acetate [ka] (Here, lithium 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate is present as the main positional isomer (>50% wt)) However, it is subjected to a grinding process using an aqueous HCl solution, resulting in 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate. [ka] This can be obtained with a chemical purity of >90%.

[0068] Additional methods As can be understood by those skilled in the art, the compounds of formulas (Ia) and (Ib) are intermediates, and one or both may be useful in additional methods. For example, WO2020 / 054492, which deals with novel capsid inhibitors, mentions, among other things, the intermediate 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one [ka] The preparation is described.

[0069] The methods described herein may be used to prepare a mixture of enantiomers of 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one, corresponding to the compounds of the present invention of formula (Ia) and (Ib), where X is difluoromethyl. Thus, the methods described herein are useful in the method described in WO2020 / 054492 by providing a mixture having a desired enantiomer excess, thereby reducing the resources required for the production of the desired intermediate.

[0070] Similarly, U.S. Patent No. 10,696,657, which covers antiretroviral compounds and methods for producing them, includes, among other things, 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid [ka] A method for preparing is described herein, which is an intermediate used in the synthesis method further described in U.S. Patent No. 10,696,657. The method described herein is, for example, for 2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one [ka] It can also be used to prepare a mixture of enantiomers, corresponding to the compounds of the present invention of formulas (Ia) and (Ib), where X is trifluoromethyl. One or both enantiomers from this mixture can then be used in a method to prepare 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid. Thus, the method described herein is useful in the method described in U.S. Patent No. 10,696,657 by providing a mixture having a desired enantiomer excess, thereby reducing the resources required to produce the desired intermediate.

[0071] Common synthesis routes One embodiment of the method of the present invention can be summarized by the following reaction scheme, where W, X, Y, and Z are as defined above. [ka] [ka]

[0072] The method of the present invention is further illustrated by the following examples. Examples 1, 2, and 3 are outlined in the following three schemes. [ka] [ka] [ka] [Examples]

[0073] Abbreviation ACN Acetonitrile Acetic acid (ACOH) CDCl3 chloroform CPME Cyclopentyl Methyl Ether CUNO Filtration Cartridge DBDMH 1,3-dibromo-5,5-dimethylhydantoin DCM Dichloromethane HCl ethyl acetate EtOH Ethanol HCl (hydrochloric acid) HOPht N-hydroxyphthalimide HPLC (High-Performance Liquid Chromatography) IPA Isopropanol MCH methylcyclohexane 2-MeTHF 2-methyltetrahydrofuran MTBE methyl tert-butyl ether SFC Supercritical Fluid Chromatography (using carbon dioxide) TEA.3HF Triethylamine Hydrofluoride TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) [Example 1]

[0074] Note: 1 wt is defined in grams as the weight of bicyclo[3.1.0]hexane-3-one (1) (Step 1) and the title compound of each preceding step (Steps 2-6) into the reaction vessel. All other weights, volumes, and equivalents are calculated against this value.

[0075] Step 1: Synthesis of intermediate (4) of formula (I-a1)((1S,5S)-2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one): [ka] (R)-bis((R)-1-phenylethyl)amine hydrochloride (2) (1.2 eq.) was placed in a reaction vessel equipped with a stirrer and an internal thermometer. THF (6.3 vol) was added, followed by LiCl (1.0 eq.), then the reaction vessel was degassed and purged three times with nitrogen. The vessel was cooled in an acetone / dry ice bath until the internal reading reached -65 to -75°C. n-BuLi (2.3 eq., 2.5 M) was added dropwise while maintaining the internal temperature at <-60°C. The contents were stirred at -65 to -75°C for 10 minutes, then warmed to 20°C over 1 hour. The contents were then cooled again to -65 to -75°C. In a separate container, a solution of bicyclo[3.1.0]hexane-3-one (1) (55 g, 1 wt, 1.0 eq.) was prepared in THF (1.3 vol), and the container was purged with nitrogen for 10-15 minutes. The freshly prepared ketone solution was added dropwise to a lithium amide base solution at -65 to -75°C while maintaining the internal temperature at <-65°C. The contents were stirred at -65 to -75°C for 20 minutes. Next, ethyl 2,2-difluoroacetic acid (3) (1.5 eq.) was added dropwise to THF (1.3 vol) at -65 to -75°C while maintaining the internal temperature at <-65°C. The contents were stirred at -65 to -75°C for 1-2 hours. The reaction was stopped by rapidly adding HCl (15.9 vol%, 3 M solution in CPME) to the cold mixture. The mixture was then warmed to 0°C while stirring. Water (12.5 vol) and MTBE (12.5 vol) were added, and the solution was stirred for 10 minutes. The phases were separated, and the aqueous phase was drained. The organic phase was washed with 2 M HCl (3 × 8 vol), and then with water (2 × 8 vol). The organic phase was dried over Na₂SO₄, filtered, and the solvent was evaporated under vacuum to obtain crude ((1S,5S)-2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one)(4) as an oily substance (93.5 g, chemical purity 94.1%, chiral purity 85.4%, analytical yield 70.4%). 1H NMR (400 MHz, CDCl3-d) δ ppm 5.90 - 6.47 (m, 1 H), 2.80 (dd, J = 19.93, 6.89 Hz, 1 H), 2.46 (d, J = 19.93 Hz, 1 H), 2.22 - 2.36 (m, 1 H), 1.64 - 1.81 (m, 1 H), 1.12 - 1.22 (m, 2 H), 0.33 (q, J = 4.35 Hz, 1 H).

[0076] Step 2: Synthesis of intermediate (6) of formula (VI-a1)(ethyl 2-((3bS,4aS)-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate): [ka] Aminoglycine hydrochloride (5) (1.2 eq.) was added to the reaction vessel. 2-MeTHF (15 vol) was added, and the vessel was purged with nitrogen for 10-15 minutes. The contents were cooled to 10°C. In a separate container, a solution of ((1S,5S)-2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one(4) (99.6 g, 1 wt., 1.0 eq.) in EtOH (15 vol) was prepared. The freshly prepared solution of ((1S,5S)-2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one(4) was added to a reaction vessel containing hydrazine at 10-15°C. The mixture was heated to 10-20°C until it was observed (by GC) that the starting material had been completely consumed. The mixture was added to a 5% NaHCO3 aqueous solution (15 wt.) at 0-10°C, followed by the addition of SiO (25 vol). The phases were separated. The aqueous phase was drained. The organic phase was... The mixture was washed with water (10 vol), then concentrated to approximately 8-10 vol, 2-MeTHF (10 vol) was added, then the solvent was replaced with IPA (2 × 3 vol), and the mixture was concentrated to 2 vol. MCH (4 vol) was added dropwise at 20°C, the contents were cooled to 0°C, and stirred for 1 hour. The mixture was filtered, the cake was washed with MCH (1 vol), and dried under vacuum at 35°C to obtain (ethyl 2-((3bS,4aS)-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate) (6) as a pale yellow solid (57.2 g, chemical purity 99.9%, chiral purity 99.5%, analytical yield 39.5%). 1H NMR (400 MHz, CDCl3-d) δ ppm 6.38 - 6.84 (m, 1 H), 4.72 (d, J = 8.37 Hz, 2 H), , 4.24 (q, J = 7.14 Hz, 2 H), 2.83 - 3.00 (m, 1 H), 2.64 -2.79 (m, 1 H), 2.06 - 2.24 (m, 2 H), 1.30 (t, J = 7.14 Hz, 3 H), 1.12 (td, J = 7.75, 4.92 Hz, 1 H), 0.33 (q, J = 4.35 Hz, 1 H).

[0077] Step 3: Synthesis of intermediate (7) of formula (IX-1) (ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate): [ka] Ethyl 2-((3bS,4aS)-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (6) (51.2 g, 1 vol, 1.0 eq.) and N-hydroxyphthalimide (HOPht, 0.1 eq.) were placed in a reaction vessel. ACN (7 vol) was added, and the mixture was heated to 60°C. NaClO2 (1.8 eq.) solution in water (4.3 vol) was added dropwise over 3 hours at 55°C-65°C, and the mixture was stirred for 2-6 hours until the reaction was complete. The mixture was cooled to 20-30°C, and 20% NaHSO3 aqueous solution (3 vol) was added for at least 30 minutes while maintaining the temperature below 30°C (potassium iodide starch paper test was performed. Result: negative). 4 vol of pharmaceutically acceptable phosphate (siRNA) was added, followed by phase separation, and the aqueous phase was extracted with 5 vol of siRNA. The combined organic phase was washed with saturated NaHCO3 aqueous solution (6 × 5 vol), followed by saturated Na2SO4 aqueous solution (5 vol). The solvent was evaporated under vacuum to obtain a yellow residue. 0.5 vol of IPA was added to the residue, and the contents were heated to 50°C. 7 vol of MCH was added at 45-55°C, and the contents were stirred for 1-3 hours. The mixture was filtered at 50°C. The filtrate was evaporated under vacuum to obtain a yellow residue. 1 vol of IPA was added to the residue, and the contents were heated to 50°C. 7 vol of MCH was added, and the contents were stirred for 1-3 hours. The contents were cooled to 0°C and stirred for 1-10 hours. The mixture was filtered at 0°C, the cake was washed with MCH (1.5 vol), and then vacuum-dried to obtain (ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate) (7) as a white solid (43.9 g, chemical purity 98.1%, yield 81.8%). 1 H NMR (400 MHz, CDCl3-d) δ ppm 6.51 - 6.87 (m, 1 H), 4.96 (s, 2 H), 3.63 (t, J = 6.64 Hz, 1 H) 2.81 (dt, J = 6.58, 4.21 Hz, 1 H), 2.59 (dt, J = 8.55, 4.21 Hz, 1 H), 1.49 - 1.77 (m, 2 H), 1.30 (t, J=7.14 Hz, 3 H), 0.96 (t, J = 7.38 Hz, 1 H).

[0078] Step 4: Synthesis of intermediate (9) of formula (VII-1) (ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolan]-1(3bH)-yl)acetate: [ka] In a solution of (ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate) (7) (43.6 g, 1 wt., 1.0 eq.) and ethane-1,2-dithiol (8) (1.2 eq.), BF3·2AcOH (3.0 eq.) was added at -5 to 5°C. The mixture was stirred at 0 to 10°C for 40 hours until the reaction was complete. An aqueous solution of KHCO3 (15.3 wt) was added, and the two-phase mixture was filtered through diatomaceous earth. The filter cake was washed with DCM (2.0 wt.). The filtrate was separated, the organic phase was concentrated and replaced with EtOH (2 × 3 vol), and then further diluted with EtOH (3 vol). Water (9 vol) was added, the mixture was cooled and stirred, then filtered, and the wet cake was vacuum dried to obtain ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolan]-1(3bH)-yl)acetate)(9) as a solid (52.4 g, chemical purity 98.0%, analytical yield 93.6%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.75 - 7.14 (m, 1 H), 4.84 - 5.13 (m, 2 H), 4.14 (qd, J = 7.17, 0.98 Hz, 2 H), 3.38 - 3.67 (m, 4 H), 2.66 (ddd, J = 8.31, 5.62, 4.16 Hz, 1 H), 2.28 - 2.45 (m, 1 H), 1.09 - 1.39 (m, 4 H), 0.30 - 0.46 (m, 1 H)

[0079] Step 5: Synthesis of intermediate (11) of formula (IV-b1)(ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate): [ka] To a suspension of DBDMH(10)(3.1eq.) in DCM(7 vol), TEA.3HF(13.3eq.) was added dropwise at -15 to -5°C. Then, a solution of ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolan]-1(3bH)-yl)acetate)(9)(51.9 g, 1 wt., 1.0 eq.) was added to the mixture in DCM(3 vol) at -15 to -5°C. The mixture was stirred at -5 to 5°C until the reaction was complete. A 15% Na2SO3 aqueous solution (7 wt.) was added at -5 to 5°C, the mixture was filtered through diatomaceous earth, and washed with DCM. The combined filtrate was separated. The aqueous phase was extracted with DCM(3 vol). The combined organic phases were basicized with a 20% KHCO3 aqueous solution (2.7 wt.). The two-phase mixture was separated, and the organic phase was washed with water (2 vol). The organic phase was concentrated under vacuum, and the solvent was replaced with THF to obtain ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate (11) in THF solution (51.9 g, 166.7 g in THF solution after workup, chemical purity 89.3%, analytical value 23.8%, analytical yield 90.5%). 1 H NMR (400 MHz, CDCl3-d) δ ppm 6.47 - 6.89 (m, 1 H), 4.85 (s, 2 H), 4.26 (q, J = 7.14 Hz, 2 H), 2.32 - 2.61 (m, 2 H), 1.33 - 1.47 (m, 1 H), 1.29 (t, J = 7.14 Hz, 3 H), 1.15 (dtd, J = 5.94, 3.92, 3.92, 2.46 Hz, 1 H). 19 F NMR (376 MHz, CDCl3-d) δ ppm -112.27, -104.11, -81.28.

[0080] Step 6: Synthesis of intermediate (12) of formula (VI-b1)(2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid): [ka] To a solution of (ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate) (11) (95.4 g, 1 wt., 1.0 eq.) in THF, a solution of LiOH.H2O (1.6 eq.) in water (3.5 vol) was added at 0-10°C. HCl was added at 10-20°C to adjust the pH to 5.5-6.5. The mixture was vacuum concentrated below 35°C to remove THF. Water (6 vol) was added at 15-20°C to completely dissolve the residue, and then 2N HCl was added at 10-20°C to adjust the pH to 1-2. After stirring for 1 hour, the reaction mixture was filtered and the cake was washed with water (2 × 2 vol). The wet cake was dissolved in ACN (8-10 vol) at 15-25°C, then filtered, and the cake was washed with ACN (1-1.5 vol). After circulating through CUNO containing activated carbon, it was washed with ACN (2-3 vol), the filtrate was vacuum concentrated, and the solvent was replaced with water. After stirring at 2-7°C for 2-3 hours, the mixture was filtered, and the cake was washed with water (0.5-1 vol). The wet cake was vacuum dried at 45-50°C to obtain (2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid)(12) as a yellow solid. Re-purification: The solid was dissolved in ELISA, circulated through CUNO containing activated carbon, and washed with ELISA again. The solvent was replaced with ACN, then circulated through CUNO containing activated carbon, and washed with ACN. The filtrate was concentrated under vacuum, and the solvent was replaced with water and filtered. The cake was washed with water and further vacuum-dried to obtain (2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid)(12) as a yellow solid (66.6 g, chemical purity 99.6%, chiral purity 99.9%, analytical yield 77.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 - 13.60 (m, 1 H), 6.79 - 7.27 (m, 1 H), 4.76 - 5.04 (m, 2 H), 2.50 - 2.71 (m, 2 H), 1.44 (qd, J = 6.93, 1.11 Hz, 1 H), 0.89 - 1.02 (m, 1 H). [Example 2]

[0081] Step A: Preparation of intermediate (A) of formula (I-a2)((1S,5S)-2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one): [ka] (R)-bis((R)-1-phenylethyl)amine hydrochloride (2) (1.1 eq.) was placed in a reaction vessel equipped with a stirring bar and an internal thermometer. THF (31 mL) was added, followed by the addition of LiCl (57.2 mL, 1.1 eq.) in THF (0.5 M). The reaction vessel was then degassed and purged three times with nitrogen. The vessel was cooled in an acetone / dry ice bath until the internal reading reached -65 to -75°C. n-BuLi (11.4 mL, 2.2 eq., 2.5 M) was added dropwise while maintaining the internal temperature <-60°C. The contents were stirred at -65 to -75°C for 10 minutes, then warmed to 20°C over 1 hour. The contents were then cooled again to -65 to -75°C. In a separate container, a solution of bicyclo[3.1.0]hexane-3-one(1) (2.5 g, 1 wt., 1.0 eq.) in THF (12.0 mL) was prepared, and the container was purged with nitrogen for 10-15 minutes. The freshly prepared ketone solution was added dropwise to the lithium amide base solution at -65 to -75°C while maintaining the internal temperature <-65°C. The contents were stirred at -65 to -75°C for 20 minutes. Next, ethyl 2,2,2-trifluoroacetic acid(X) (3.71 mL, 1.2 eq.) was added dropwise at -65 to -75°C while maintaining the internal temperature <-65°C. The contents were stirred at -65 to -75°C for 1-4 hours. The reaction was stopped by rapidly adding HCl (19.07 mL, 3 M solution in CPME) to the cold mixture. The mixture was then warmed to 20°C while stirring. Water (60 mL) and MTBE (60 mL) were added, and the solution was stirred for 10 minutes. The phases were separated, and the aqueous phase was drained. The organic phase was washed with 2 M HCl (2 × 60 mL), then water (2 × 60 mL), and then brine (60 mL). The solution was concentrated under vacuum to obtain crude ((1S,5S)-2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one)(A) as an oily substance (6.57 g), which was then subjected directly to step B.

[0082] Step B: Preparation of intermediate (B) of formula (VI-a2)((ethyl 2-((3bS,4aS)-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate): [ka] Aminoglycine hydrochloride (5) (4.83 g, 1.2 eq.) was added to the reaction vessel. 2-MeTHF (75 mL) was added, and the vessel was purged with nitrogen for 10-15 minutes. Sulfuric acid (6.94 mL) was added dropwise at -10-0°C. In a separate vessel, a solution of 2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one (A) (5 g, 1 wt., 1.0 eq.) was prepared in EtOH (75 mL). The freshly prepared 2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one (A) solution was added to the reaction vessel containing hydrazine at 0°C. The mixture was heated to 20°C until it was observed (by GC) that the starting materials had been completely consumed. Water (150 mL) and SiO (200 mL) were added. The phases were separated. The aqueous phase was washed with ethyl acetate (3 × 50 mL), and the combined organic phase was washed with brine (2 × 50 mL). The mixture was concentrated to obtain a brown crude oil (positional isomer ratio 3.2:1, B: positional isomer B). The crude oil was purified by column chromatography to obtain ethyl 2-((3bS,4aS)-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (B) as a white solid (2.65 g, chiral purity 90.1%, ee 79%, preferred enantiomer unknown, yield 37.1% for steps A and B). 1 H NMR (400 MHz, CDCl3-d) δ ppm 4.63 - 4.84 (m, 2 H), 4.23 (q, J=7.14 Hz, 2 H), 2.81 - 2.99 (m, 1 H), 2.66 - 2.79 (m, 1 H), 2.05 - 2.22 (m, 2 H), 1.28 (t, J=7.14 Hz, 3 H), 1.12 (td, J=7.75, 5.17 Hz, 1 H), 0.26 - 0.40 (m, 1 H). 13C NMR (101 MHz, CDCl3-d) δ ppm 166.8, 151.3, 13.9, 134.8 - 136.4 (m, 1 C), 129.8, 121.4 (q, J=268.55 Hz, 1 C), 62.1, 52.2, 27.3, 21.8, 17.40, 14.1. 19 F NMR (376 MHz, CDCl3-d) δ ppm -61.63. MS (ESI): m / z [M + H+] C 12 H 14 Calculated value of F3N2O2: 275.0929; Measured value: 275.1020.

[0083] Step C: Preparation of intermediate (C) of formula (I-a3)((1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one): [ka] (R)-bis((R)-1-phenylethyl)amine hydrochloride (2) (1.1 eq.) was placed in a reaction vessel equipped with a stirring bar and an internal thermometer. THF (25 mL) was added, followed by the addition of LiCl (45.8 mL, 1.1 eq.) in THF (0.5 M). The reaction vessel was then degassed and purged three times with nitrogen. The vessel was cooled in an acetone / dry ice bath until the internal reading reached -65 to -75°C. n-BuLi (9.15 mL, 2.2 eq., 2.5 M) was added dropwise while maintaining the internal temperature at <-60°C. The contents were stirred at -65 to -75°C for 10 minutes, and then warmed to 20°C over 1 hour. The contents were then cooled again to -65 to -75°C. In a separate container, a solution of bicyclo[3.1.0]hexane-3-one (1) (10.4 mL, 1 wt., 1.0 eq.) in THF (10.0 mL) was prepared, and the container was purged with nitrogen for 10-15 minutes. The freshly prepared ketone solution was added dropwise to the lithium amide base solution at -65 to -75°C while maintaining the internal temperature <-65°C. The contents were stirred at -65 to -75°C for 20 minutes. Next, cyclopropane carbonyl chloride (Y) (2.7 mL) was added dropwise at -65 to -75°C while maintaining the internal temperature <-65°C. The contents were stirred at -65 to -75°C for 1-4 hours. The reaction was stopped by rapidly adding HCl (15.3 mL, 3 M solution in CPME) to the cold mixture. The mixture was then warmed to 20°C while stirring. 50 mL of 2 M HCl aqueous solution and 50 mL of MTBE aqueous solution were added, and the solution was stirred for 10 minutes. The phases were separated, and the aqueous phase was then drained. The organic phase was washed with 2 M HCl (2 × 50 mL), then water (2 × 50 mL), and then brine (30 mL), filtered through hydrophobic frit, and the solvent was evaporated under vacuum to obtain crude ((1S,5S)-2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one)(C) as an oily substance (4.00 g), which was then subjected directly to step D.

[0084] Step D: Preparation of intermediate (D) of formula (VI-a3) (ethyl 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate): [ka] Aminoglycine hydrochloride (5) (3.86 g, 1.2 eq.) was added to the reaction vessel. 2-MeTHF (50 mL) was added, and the vessel was purged with nitrogen for 10-15 minutes. The mixture was cooled to -10-0°C. Sulfuric acid (5.55 mL) was added dropwise. In a separate vessel, a solution of 2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one (3.42 g, 1 wt., 1.0 eq.) was prepared in EtOH (50 mL). The freshly prepared solution of 2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one was added to the reaction vessel containing hydrazine at 0°C. The mixture was heated to 20°C until it was observed (by GC) that the starting material had been completely consumed. Water (100 mL) and HCl (150 mL) were added. The phases were separated. The aqueous phase was washed with ethyl acetate (3 × 30 mL), the combined organic phase was washed with brine (2 × 30 mL), and the mixture was vacuum concentrated to obtain a brown oily substance. The oily substance was dissolved in ethyl acetate (100 mL) and washed with water (15 mL), saturated NaHCO3 aqueous solution (40 mL), water (40 mL), and brine (20 mL). The organic phase was vacuum concentrated to obtain 2.18 g of crude oil (crude yield 42.5% relative to steps A and B, purity 60.7%, positional isomer ratio 2.5:1, D: positional isomer D). A portion of the crude oily substance (0.1 g) was purified by mass spectrometry-oriented automated purification (MDAP; water / ACN, formic acid additive), followed by aqueous post-treatment with ethyl acetate (50 mL) and saturated NaHCO3 aqueous solution (10 mL). By vacuum evaporation, (ethyl 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate)(D) was obtained as a white solid (0.03 g, chiral purity 87.5%, ee 75%, preferred enantiomer unknown). 1H NMR (400 MHz, CDCl3-d) δ ppm 4.54 - 4.70 (m, 2H, CH2), 4.18 - 4.28 (m, 2H, CH2CH3), 2.79 - 2.87 (m, 1H, CH2CH), 2.57 - 2.67 (m, 1H, CH2CH), 1.95 - 2.03 (m, 1H, CHa), 1.83 - 1.95 (m, 2H, CH2CHCH2& CHb), 1.23 - 1.32 (m, 3H, CH2CH3), 0.97 - 1.05 (m, 1H, CHCH2CH), 0.75 - 1.04 (m, 4H, CH2CH2), 0.17 - 0.26 (m, 1H, CHCH2CH). 13 C NMR (101 MHz, CDCl3-d) δ ppm 168.0, 150.3, 148.8, 126.8, 61.6, 51.4, 26.7, 21.3, 17.5, 14.1, 13.8, 9.1, 7.3, 6.8. MS (ESI): m / z [M + H+]C 14 H 19 Calculated value of N2O2: 247.1368; Measured value: 247.1450. [Example 3]

[0085] Preparation of 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid Synthesis scheme: [ka]

[0086] Step 1: Preparation of the intermediate of formula (I-a3)(1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one: [ka] In a stirred solution of (R)-bis((R)-1-phenylethyl)amine HCl (1263 mg, 5.61 mmol) in tetrahydrofuran (THF) (2 mL), anhydrous lithium chloride (238 mg, 5.61 mmol) was added under a nitrogen atmosphere. The reaction mixture was cooled to -78°C, and then n-butyllithium (2.5 M in hexane, 4.49 mL, 11.21 mmol) was added dropwise at -78°C. The solution was stirred for 10 minutes, and then warmed to 20°C. The mixture was stirred for 1 hour. The reaction mixture was cooled again to -78°C, and then a solution of bicyclo[3.1.0]hexane-3-one (0.437 mL, 5.10 mmol) in tetrahydrofuran (THF) (2 mL) was added to the mixture. The mixture was stirred for 20 minutes. Cyclopropane carbonyl chloride (0.510 mL, 5.61 mmol) was added dropwise to the mixture at -78°C, and the mixture was then stirred at the same temperature for 4 hours. The progress of the reaction was monitored by TLC (SiO2, 10% HCl / petroleum ether, Rf=0.4, PMA activity). Once complete, the reaction mixture was stopped with 4M HCl in ethyl acetate (4 mL), 2N aqueous HCl (5 mL), and MTBE (10 mL), and the resulting mixture was stirred for 20 minutes. The mixture was filtered, and the filtrate was partitioned. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with 2N aqueous HCl (2 × 5 mL) and water (2 × 5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain crude (1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one (870 mg) as a pale yellow liquid. The product was used directly in the next step. LCMS method: Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1 × 50 mm; Mobile phase C: 0.05% formic acid in water, Mobile phase D: 0.05% formic acid in MeCN; Gradient (min / %D): 0 / 3, 0.4 / 3, 2.5 / 98, 3.4 / 98, 3.5 / 3, 4.5 / 3; Flow rate: 0.6 mL / min; Temperature: 40 °C. LCMS results: Retention time = 2.31 min, Observed ions = 165.06 (M + H).

[0087] Step 2: Preparation of the intermediate of formula (VI-a3)(ethyl 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate): [ka] To a stirred solution of 2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one (870 mg, 3.97 mmol, see previous step), 2-methyltetrahydrofuran (2-MeTHF) (10 mL), and sulfuric acid (0.087 mL, 1.641 mmol) in ethanol (10 mL), ethylaminoglycinate hydrochloride (737 mg, 4.77 mmol) was added in small amounts at 10°C under a nitrogen atmosphere. The reaction mixture was stirred at 85°C for 16 hours. The progress of the reaction was monitored by TLC (SiO2, 20% acetone / petroleum ether, Rf=0.3, UV active). Once complete, the reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with ethyl acetate (50 mL), and then washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (1 g) as a brown liquid. The crude product was subjected to silica gel chromatography (12 g, Flashpure-Buchi cartridge) and gradient eluted with 10-20% ELISA in petroleum ether to obtain the concentrated product, ethyl 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (400 mg, LCMS purity 33%), as a pale yellow liquid as a mixture of positional isomers. Next, the substance was adsorbed onto Celite, and the resulting powder was subjected to C18 chromatography using a Combi-Flash system equipped with a RediSep Gold C18 column (40g, Teledyne Isco). Gradient elution was performed with 50-65% MeCN (containing 0.1% TFA) in water (containing 0.1% TFA) at a flow rate of 20 mL / min. The fractions containing the pure product were combined and concentrated under reduced pressure. The pH of the resulting aqueous solution was adjusted to approximately 7 by adding saturated NaHCO3 aqueous solution.The solution was extracted with ethyl (3 × 50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain concentrated ethyl 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate, a mixture of two positional isomers, as a pale yellow, gum-like oil (210 mg, 15% yield for the two steps). This substance was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ = 4.68-4.53 (m, 2H), 4.24 -4.18 (m, 2H), 2.83 -2.76 (m, 1H), 2.67 -2.58 (m, 1H), 1.96 1.83 (m, 3H), 1.29-1.21 (m, 3H), 1.06 - 0.73 (m, 5H), 0.21-0.16 (m, 1H).LCMS method = Column: CORTECS UPLC C18 1.6 μm, 3.0 × 30 mm, mobile phase A: 0.05% formic acid in water, mobile phase B: 0.05% formic acid in MeCN, gradient (min / %B): 0 / 3, 0.1 / 3, 1.2 / 98, 2.0 / 98, 2.05 / 3, 2.50 / 3, flow rate: 0.85 mL / min, temperature: 45 °C. LCMS results: Retention time = 1.10 minutes, observed ions = 247.56 (M+H). LCMS purity = 88%, HPLC: purity: 64.8%, 21.9%, RT = 3.68, 4.15 min.

[0088] Step 3: Preparation of the intermediate of formula (V-a1)(2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid): [ka] To a stirred solution of ethyl 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (210 mg, 0.758 mmol, see previous step) and methanol (1 mL) in tetrahydrofuran (THF) (2 mL), a solution of LiOH.H2O (91 mg, 3.79 mmol) dissolved in water (1 mL) was added at 0 °C. The reaction mixture was heated to 27 °C and then stirred for 2 hours. The progress of the reaction was monitored by TLC (SiO2, 10% MeOH in DCM, Rf=0.1, UV active). Once complete, the organic solvent was evaporated under reduced pressure. The pH of the resulting aqueous layer was adjusted to approximately 2 by adding 1 N HCl aqueous solution (2 mL). The precipitated solid was collected by filtration and then washed with water (5 L). The solid was ground with n-pentane (5 mL) and then vacuum-dried to obtain 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid (120 mg) as a mixture of positional and enantiomers. LCMS method: Column: CORTECS UPLC C18 (30 × 3 mm, 1.6 μm); Mobile phase A: 0.05% formic acid in water; Mobile phase B: 0.05% formic acid in MeCN; Time (min) / %B: 0 / 3, 0.1 / 3, 1.2 / 98, 2 / 98, 2.05 / 3, 2.5 / 3; Column temperature: 45 °C; Flow rate: 0.85 ml / min. LCMS results: Retention time = 0.87 min and 0.92 min, observed ion = 219.16 (M+H), LCMS purity = 54% and 27% (mixture of positional isomers). Chiral SFC method: Column: CHIRALPAK IC (4.6 × 150 mm) 5 μm, Co-solvent: 0.5% triethylamine in methanol, Total flow rate: 3 mL / min, Eluent: 70% CO2, 30% co-solvent, ABPR: 1500 psi, Column temperature: 30 °C, Detection: Spectrum PDA 237.0 nm. Note: To confirm the identity of the desired product peak, a true homochiral sample of 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid was co-injected.Chiral SFC results: Purity % (Retention time; Identity): 9.37% (2.82 min; 2-((3bR,4aR)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid), 29.41% (3.31 min; 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-2-yl) Acetic acid (stereochemistry not specified), 56.32% (4.25 min, 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid), 4.9% (6.02 min, 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-2-yl)acetic acid, stereochemistry not specified). Summary: The ratio of positional isomers is 2:1, and the main component is the title compound. The enantiomeric excess is 71%, and the main component is the title compound (S,S stereochemistry). [Example 4]

[0089] Preparation of 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid Synthesis scheme: [ka]

[0090] Step 1: Preparation of the intermediate of formula (I-a3)((1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one): [ka] Under a nitrogen atmosphere, anhydrous lithium chloride (47.5 g, 1.12 mol) was added to a stirred solution of (R,R)-bis(α-methylbenzyl)amine hydrochloride (CAS: 82398-30-9) (294 g, 1.12 mol, 1.1 eq) in tetrahydrofuran (THF) (1 L). The reaction mixture was cooled to -78°C. At -78°C, n-butyllithium (2.5 M solution in hexane, 897 mL, 2.24 mol) was slowly added to the mixture. The mixture was then stirred at 20°C for 1 hour. The reaction mixture was cooled to -78°C, and a solution of bicyclo[3.1.0]hexane-3-one (100 g, 1.019 mol) in tetrahydrofuran (100 mL) was added to the mixture over 20 minutes. At -78°C, cyclopropane carbonyl chloride (101.8 mL, 1.121 mol) was added dropwise to the mixture. The mixture was stirred for 3 hours, and the reaction was stopped by adding 500 mL of 2N aqueous HCl solution. The mixture was stirred for 20 minutes. The mixture was filtered, and the filter pad was extracted with petroleum ether (2 × 500 mL). The filtrate was partitioned, and the isolated organic layer was washed with water (2 × 500 mL) and then with brine (2 × 500 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and then concentrated under reduced pressure to obtain crude (1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one (160 g) as a gray liquid. This crude compound was used directly in the next step. LC-MS method: Column = ACQUITY UPLC BEH C18 1.7 μm (2.1 × 50 mm), Mobile phase A = 0.05% formic acid in water, Mobile phase B = 0.05% formic acid in acetonitrile, Gradient (min / %B) = 0 / 3, 0.4 / 3, 2.5 / 98, 3.4 / 98, 3.5 / 3, 4.5 / 3, Flow rate = 0.6 mL / min, Column temperature = 40°C. LC-MS results: Retention time = 2.13 min, Observed ions = 164.99 [M+H] + , LCMS purity=56.7%.

[0091] Step 2: Preparation of the intermediate of formula (VI-a3)(ethyl 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate): [ka] To a stirred solution of (1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one (160 g, 56% wt, 546 mmol, from the previous step) in methanol (2.4 L), ethylaminoglycinate hydrochloride (122 g, 789 mmol) and sodium acetate (163 g, 1.99 mol) were added under an N2 atmosphere at -15°C. The mixture was stirred at -15°C to -10°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (2 L) and then extracted with ethyl acetate (2 × 1 L). The combined organic matter was washed with brine (1 L), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (200 g) as a brown gum-like substance. The crude compound was adsorbed onto silica gel, and the resulting powder was subjected to silica gel chromatography (100-200 mesh). Gradient elution with 13-40% ethyl acetate in petroleum ether was performed to obtain ethyl 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate, a mixture of positional and enantiomers, as a brown gum-like substance (85 g, yield = 33%). 1H NMR (400 MHz, DMSO-d6) δ = 4.94 - 4.81 (m, 2H (secondary)), 4.70 (s, 2H (main)), 4.21 - 4.11 (m, 2H (main)), 4.11-4.02 (m, 2H (secondary)), 2.75-2.65 (m, 1H (main+sub)), 2.61-2.51 (m, 1H (main+sub)), 2.01 - 1.82 (m, 2H (main+sub)), 1.81 - 1.71 (m, 1H (main+sub)), 1.23 - 1.16 (m, 3H (main+sub)), 1.02 - 0.75 (m, 3H (primary + secondary)), 0.72 - 0.59 (m, 2H (main + secondary)), 0.08 - -0.03 (m, 1H (main + secondary)). LCMS method: Column = ACQUITY UPLC BEH C18 1.7μm (2.1×50mm); Mobile phase A = 0.05% formic acid in water; Mobile phase B = 0.05% formic acid in acetonitrile; Gradient (min / %B) = 0 / 3, 0.4 / 3, 7.5 / 98, 9.5 / 98, 9.6 / 3, 10 / 3; Flow rate = 0.6mL / min; Column temperature = 40℃. LCMS results: Retention time = 3.92, 4.05 min; Observed ions = 247.02 [M+H] + LC-MS purity = 51.9% and 27.8%. HPLC: Retention time = 3.07 and 3.48 minutes, HPLC purity = 77.2% and 16.5%.

[0092] Step 3: Preparation of the lithium salt intermediate of formula (V-a1)(2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate): [ka] A stirring solution of ethyl 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (160 g, 65% Wt, 422 mmol) and methanol (300 mL) in tetrahydrofuran (700 mL) was mixed with a solution of lithium hydroxide monohydrate (62.0 g, 1.48 mol) in water (150 mL) at 0°C. The reaction mixture was stirred at 0°C to 10°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue was acidified to approximately pH 5 to 6 with 1N HCl aqueous solution (200 mL), and the mixture was stirred for 10 minutes. The solid precipitate was collected by filtration, washed with water (100 mL) and n-pentane (200 mL), and then vacuum-dried to obtain the title compound, 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate, as an off-white solid (68 g, HPLC: purity 98%, chiral SFC: purity 88.7%). 1 H NMR (400 MHz, DMSO-d6) δ = 4.02 (q, 2H, J=10.4 Hz), 2.75-2.65 (m, 1H), 2.54-2.50 (m, 1H), 1.89 - 1.86 (m, 1H), 1.82 - 1.79 (m, 1H), 1.73 - 1.69 (m, 1H), 0.92 - 0.88 (m, 1H), 0.79 - 0.74 (m, 2H), 0.65 - 0.62 (m, 2H), 0.11 - 0.08 (m, 1H).LCMS method: Column = ACQUITY UPLC BEH C18 1.7 μm (2.1 × 50 mm); Mobile phase A = 0.05% formic acid in water; Mobile phase B = 0.05% formic acid in acetonitrile; Gradient (min / %B) = 0 / 3, 0.4 / 3, 7.5 / 98, 9.5 / 98, 9.6 / 3, 10 / 3; Flow rate = 0.6 mL / min; Column temperature = 40°C. LC-MS results: Retention time = 2.66 min; Observed ions = 218.97 [M+H] +HPLC method: XSelect CSH C18 3.5μm (4.6×150mm); Mobile phase A = 0.05% trifluoroacetic acid in water; Mobile phase B = 100% in acetonitrile, gradient (min / %B) = 0 / 5, 1 / 5, 3 / 15, 7 / 55, 11 / 98, 16 / 98, 16.1 / 5, 20 / 5, flow rate = 1.0 mL / min, column temperature = room temperature, HPLC results: retention time = 7.57 min, purity = 98%, Chiral SFC method: Column = CHIRALPAK IC 5μm (2.1×50mm), eluate = 0.5% triethylamine in CO2:MeOH (70:30), back pressure = 1500 psi, flow rate = 4 mL / min, column temperature = 30℃. Chiral SFC results: Main peak 88.7%, retention time of main peak = 2.96 mins, retention time of secondary peak = 2.13 mins. Li content = 3.60% w / w (1.2 eq.). Note: Analysis of the filtrate confirmed a mixture of positional isomers (70 g, LCMS: title compound 63%, positional isomers of the title compound 25%).

[0093] Step 4: SFC purification of the lithium salt intermediate of formula (V-a1)(2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)lithium acetate): [ka] Chiral concentrated lithium 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate (70 g) was purified by SFC chromatography according to the following method: Column = Chiralpak IC 5 μ (250 × 30 mm); Elutate = 0.5% triethylamine (70:30) in CO2:MeOH; Flow rate = 100 g / min; Back pressure = 100 bar; Detection = 240 nm (UV); Stack time = 6.7 min; Single injection volume = 1.50 g. The pure main peak (peak 2) fraction was collected and concentrated under reduced pressure to obtain lithium 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate as an off-white solid (45 g, LCMS: purity 98%, chiral SFC: purity 99.9%). The obtained compound was further treated with 150 mL of 1N HCl aqueous solution at 0°C and stirred for 10 minutes. The solid was collected by filtration and then washed with water (20 mL) and n-pentane (100 mL). The solid was vacuum-dried to obtain lithium 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate as an off-white solid (30.08 g). 1H NMR (400 MHz, DMSO-d6) δ = 4.02 (q, 2H, J=10.4 Hz), 2.75-2.65 (m, 1H), 2.54-2.50 (m, 1H), 1.89 - 1.86 (m, 1H), 1.82 - 1.79 (m, 1H), 1.73 - 1.69 (m, 1H), 0.92 - 0.88 (m, 1H), 0.79 - 0.74 (m, 2H), 0.65 - 0.62 (m, 2H), 0.11 - 0.08 (m, 1H).LCMS method: Column = X Bridge C18 3.5 μm (4.6 × 150 mm); Mobile phase A = 10 mM ammonium bicarbonate in water; Mobile phase B = 100% acetonitrile; Gradient (min / %B): 0 / 5, 1 / 5, 3 / 15, 7 / 55, 11 / 98, 16 / 98, 16.01 / 5, 20 / 5; Column temperature = room temperature; Flow rate = 1.0 mL / min. LCMS results: Retention time = 6.68 mins; Observed ions = 219.15 [M + H] + LCMS purity = 99%. HPLC: Retention time = 6.83 min; HPLC purity = 98%. Chiral SFC method: Column = CHIRALPAK IC 5 μm (4.6 × 150 mm); Eluent = CO2: 0.5% diethylamine in methanol (65:35); Total flow rate = 3 mL / min; Back pressure = 1500 psi; Temperature = 30°C. Chiral SFC result: Retention time = 1.78 min; Purity: 99.8%. Specific rotation [α] 25 D (0.34% in methanol) = -11.824°. Lithium content = 3.60% w / w (1.15 eq.). Water content = 1.33%.

Claims

1. Compound of formula (I-a) 【Chemistry 1】 and compounds of formula (I-b) 【Chemistry 2】 A method for preparing a mixture comprising, (a) Compound of formula (II), 【Transformation 3】 (b) Compound of formula (III), 【Chemistry 4】 (wherein X is cyclopropyl, difluoromethyl, or trifluoromethyl, Y is a leaving group.) (c) Chiral amines, (d) Lithium base, (e) Lithium salt, and, if desired (f) aprotic solvent, A method for preparing the mixture, comprising combining the following to obtain the aforementioned mixture.

2. The chiral amine (c) is a compound selected from formulas (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), or (IV-f): 【Transformation 5】 During the ceremony, G １ This is an unsubstituted phenyl, or halogen, cyano, or substituted C １ ~C ４ Alkyl, unsubstituted C １ ~C ４ Alkyl, -O (cyclopropyl), -O (allyl), allyl, -O (R １ ), or -C(O)(R １ A phenyl compound substituted with one, two, or three substituents independently selected from ) G ２ is phenyl which is unsubstituted, or phenyl substituted by one, two or three substituents independently selected from halogen, cyano, substituted C １ ~C ４ alkyl, unsubstituted C １ ~C ４ alkyl, -O(cyclopropyl), -O(allyl), allyl, -O(R １ ), or -C(O)(R １ ). G ３ is an unsubstituted C １ ~C ３ C substituted with alkyl or 1, 2, or 3 halogen atoms １ ~C ３ It is alkyl, G ４ is an unsubstituted C １ ~C ３ C substituted with alkyl or 1, 2, or 3 halogen atoms １ ~C ３ It is alkyl, G ５ This may be selected from azetidine, pyrrolidine, morpholine, piperidine, or quinuclidine, each of which may be substituted with one or two substituents independently selected from methyl or halogen. G ６ C is allyl; cyclopropyl; unsubstituted １ ~C ５ Alkyl; or C substituted with one phenyl, or one, two, or three halogen atoms. １ ~C ５ Selected from alkyl groups, R １ is an unsubstituted C １ ~C ４ C substituted with alkyl or 1, 2, or 3 halogen atoms １ ~C ４ The method according to claim 1.

3. G １ However, it is an unsubstituted phenyl, G ２ However, it is an unsubstituted phenyl, G ３ However, it is methyl, G ４ However, it is methyl, G ５ However, each of these may be selected from azetidine, pyrrolidine, morpholine, piperidine, or quinuclidine, and each may be substituted with one or two substituents independently selected from methyl or fluorine. G ６ However, allyl; cyclopropyl; unsubstituted C １ ~C ５ Alkyl; or C substituted with one phenyl atom or one, two, or three fluorine atoms. １ ~C ５ Selected from alkyl, and R １ However, non-substituted C １ ~C ４ Alkyl or C substituted with 1, 2, or 3 fluorine atoms １ ~C ４ The method according to claim 2, wherein the alkyl group is alkyl.

4. The chiral amine (c) is of formula (IV-a), 【Transformation 6】 (In the formula: G １ and G ２ These are unsubstituted phenyl compounds, G ３ and G ４ (Each of these is methyl.) The method according to claim 2 or claim 3, wherein the compound is [the compound].

5. The method according to any one of claims 1 to 4, wherein the compound of formula (I-a) in the mixture is present in an enantiomer excess of 10% or more relative to the compound of formula (I-b).

6. The method according to any one of claims 1 to 5, wherein the compound of formula (I-a) in the mixture is present in an enantiomer excess of 80% or more relative to the compound of formula (I-b).

7. The lithium base (d) is Li-C １ ~C ６ -Alkyl, Li-C ５ ~C ６ -Cycloalkyl, Li(aryl), LiH, LiNH ２ , or lithium metal (Li ０ The method according to any one of claims 1 to 6, selected from )

8. The method according to any one of claims 1 to 7, wherein the lithium base (d) is selected from n-BuLi, sec-BuLi, i-PrLi, or t-BuLi.

9. The method according to any one of claims 1 to 8, wherein the aprotic solvent (f) is selected from THF, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, MTBE, or CPME.

10. The method according to any one of claims 1 to 9, wherein the aprotic solvent (f) is THF.

11. The method according to any one of claims 1 to 10, wherein the lithium salt (e) is present.

12. The method according to claim 11, wherein the lithium salt (e) is LiCl or LiBr.

13. The method according to any one of claims 1 to 12, wherein X is cyclopropyl.

14. The method according to any one of claims 1 to 12, wherein X is difluoromethyl.

15. The method according to any one of claims 1 to 12, wherein X is trifluoromethyl.

16. Y is -F, -Cl, -Br, -I, -CN, -OC １ ~C ６ Alkyl, -O-C ３ ~C ６ Cycloalkyl, -O(CO)C １ ~C ６ Alkyl, -O(CO)C ３ ~C ６ Selected from cycloalkyl, -O-aryl, or -O-heteroaryl, where -O(CO)C １ ~C ６ Alkyl, -O(CO)C ３ ~C ６ The cycloalkyl group may be substituted with one, two, or three fluorine atoms, and furthermore, the -O-aryl or -O-heteroaryl group may be a halogen atom or C １ ~C ３ The alkyl group may be substituted one, two, or three times with substituents independently selected from the alkyl group. The method according to any one of claims 1 to 15.

17. The method according to any one of claims 1 to 16, wherein Y is selected from -Cl, -OMe, or -OEt.

18. The method according to any one of claims 1 to 17, further comprising separating the compound of formula (I-a) from the mixture.

19. The method according to claim 18, wherein the compound of formula (I-a) is separated from the mixture by grinding.

20. Compound of formula (I-a) 【Transformation 7】 (wherein X is as defined by any one of claims 1 to 19), And, A compound produced by the method described in any one of claims 1 to 19.

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