Process and intermediates for preparing compounds

Abstract

The present invention relates to processes for preparing intermediates useful in the preparation of compounds that inhibit human immunodeficiency virus (HIV) function (e.g., disrupt HIV capsid function) during the viral replication cycle.

Description

Invention Field

[0001] This invention relates to a method for preparing intermediates that can be used to prepare compounds that inhibit the function of human immunodeficiency virus (HIV) during the viral replication cycle (e.g., disrupt the function of the HIV capsid). Background Technology

[0002] Acquired Immunodeficiency Syndrome (AIDS) is caused by HIV infection. HIV and AIDS remain major public health problems worldwide. It is estimated that approximately 38.4 million people worldwide (including 1.7 million children) lived with HIV in 2021 – a global HIV infection rate of 0.8%. The vast majority of these people live in low- and middle-income countries. In the same year, 650,000 people died from AIDS-related illnesses.

[0003] Currently, treatment regimens for HIV infection consist of combinations of approved antiretroviral agents. Nearly 40 drugs are currently approved for HIV infection, including monotherapy, fixed-dose combination regimens, and single-tablet regimens; the latter two typically contain 2-4 approved agents. These agents belong to several different categories, targeting the function of viral enzymes or proteins in the viral replication cycle. Therefore, these agents can be categorized as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and entry inhibitors (one of which (maravirol) targets the host CCR5 protein, while another (enfuvirdi) targets a peptide in the gp41 region of the viral gp160 protein). Furthermore, pharmacokinetic enhancers (cobistat or ritonavir) can be used in combination with antiretroviral agents (ARVs) requiring enhanced efficacy.

[0004] Despite the availability of numerous drugs and drug combinations, new antiretroviral agents are still needed in medicine. High viral heterogeneity, drug-related toxicity, tolerability issues, and poor adherence can all lead to treatment failure and may result in the selection of mutated viruses that confer resistance to one or more antiretroviral agents, or even to multiple drugs across the entire class (Beyrer, C., Pozniak A. “HIV drug resistance – anemerging threat to epidemic control.” N. Engl. J. Med. 2017, 377, 1605-1607; Gupta, RK, Gregson J., et al. “HIV-1 drug resistance before initiation orre-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.”). Peer J. 2018, DOI 10.7717 / peerj.4848). Therefore, there is a need for new drugs that are more convenient to administer, have a higher genetic barrier to resistance, and offer a higher safety profile than existing agents. Among the many options, novel mechanisms of action (MOAs) that can be part of preferred antiretroviral therapy (ART) continue to play an important role, as they should be effective against viruses resistant to existing drugs. Improvements that make drugs easier to administer long-term or even lifelong may include all or some of the following: reduced side effects, reduced drug interactions, extended dosing intervals, or alternative routes of administration that conform to individual patient preferences. Targets for improved safety include a high therapeutic index against any toxicities that could lead to discontinuation, and may also include reduced side effects or reduced drug interactions. The potential for a smaller total number of drugs in combination therapy regimens can also improve patient adherence and safety. Enhancing the potency of antiviral targets, especially in the presence of human plasma and serum albumin, can also reduce the dose and may directly and positively influence the duration of dosing and the therapeutic index in terms of side effects and toxicity.In conclusion, if an anti-HIV drug with a novel mechanism of action can be discovered that also offers the aforementioned advantages of improved long-term adherence and safety, it could benefit people living with HIV to the greatest extent possible.

[0005] Several potential therapeutic compounds have been described in the prior art, which appear to work by interfering with the normal function of the HIV capsid. Compounds that function through this mechanism would be a valuable addition to existing HIV infection treatment options. It appears that compounds targeting the HIV capsid have been the subject of several recent review articles describing the most significant research findings to date. These review articles include: "HIV-1 Capsid Inhibitors as Antiretroviral Agents" Thenin-Houssier, Suzie; Valente, Susana T. Current HIVResearch, 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 BeyondPF74" McArthur, Carole, Diseases, 2019, 7, 22; and "Insights into HIV-1 capsidinhibitors in preclinical and early clinical development as antiretroviralagents" Cevik, Muge; Orkin, Chloe Expert Opin Inv.Drugs, 2019, 28, 1021; and PCT patent applications with the following publication numbers: WO2012065062, WO2013006738, WO 2013006792, WO2014110296, WO2014110297, WO2014110298, WO2014134566, WO2015061518, WO2015130964, WO2015130966, WO201604008 4. WO2016033243, WO2016172424, WO2016172425, WO2018035359, WO2018203235, WO2019035904, WO2019035973, WO2019161017, WO201916 1280, WO2019198024, WO2020018459, WO2020053811, WO2020058844, WO2020084480, WO2020084491, WO2020084492, WO2020089778, WO202 0095176, WO2020095177, WO2020157692, WO2020222108, WO2020254985, WO2021064570, WO2021064571, WO2021064677, WO2021070054, WO 2021176366 and WO2021176367. .

[0006] Currently, there is a need in the field for more novel and / or effective compounds for treating HIV. Furthermore, these compounds need to be developed into active pharmaceutical ingredients (APIs) suitable for drug production. The properties of compounds, such as solubility, hygroscopicity, and chemical / physical stability, are not limiting factors in obtaining safe and effective drugs during drug development. Medicinal chemistry routes for synthesizing new compounds typically focus on diversity to rapidly obtain different analogs on a small scale. In contrast, process chemistry routes for industrial-scale API production need to consider factors such as scalability, overall yield, safety, environmental hazards, economics, and the overall feasibility of the route.

[0007] Therefore, from another perspective, the present invention addresses the problem of providing an efficient process for manufacturing intermediate compounds (e.g., increasing enantiomeric excess) that can be used, for example, in the production of HIV capsid inhibitors in chemical routes. Summary of the Invention

[0008] This invention relates to a method for preparing intermediates that can be used to prepare compounds that inhibit HIV function (e.g., disrupt the function of the HIV capsid) during the viral replication cycle.

[0009] On one hand, the present invention relates to a method for preparing a mixture comprising: a compound of formula (Ia)

[0010] (Ia),

[0011] and compound of formula (Ib)

[0012] (Ib),

[0013] This method includes combinations:

[0014] (a) Compound of formula (II),

[0015] (II);

[0016] (b) Compound of formula (III),

[0017] (III),

[0018] Where X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group; and

[0019] (c) Chiral amines;

[0020] To provide a mixture.

[0021] On the other hand, the present invention relates to compounds prepared by the above method. Detailed Implementation

[0022] definition

[0023] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having a specified number of carbon atoms. For example, the terms "C1-6 alkyl" or "C1-C6 alkyl" refer to alkyl groups 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.

[0024] When the term "alkyl" is used in combination with other substituents, such as "halogenated (C1-4)alkyl" and "hydroxyl (C1-4)alkyl", the term "alkyl" is intended to cover divalent straight-chain or branched hydrocarbon groups, where the connecting point is through the alkyl moiety.

[0025] The term "cycloalkyl" refers to a non-aromatic, saturated, monocyclic hydrocarbon ring containing a specified number of carbon atoms. For example, a "cycloalkyl" may contain 3 to 8 carbon atoms, i.e., a C3-8 cycloalkyl group. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0026] The terms “halogen” and “halogenated” refer to chlorine, fluorine, bromine, or iodine substituents.

[0027] The term "cyano" refers to the -CN group.

[0028] The term "chiral amine" refers to an amine covalently bonded to a carbon atom, which has three distinct substituents that make it chiral. The term "chiral amine" is used interchangeably to describe either the free base or ammonium salt form of a chiral amine. The ammonium salt form of a chiral amine refers to the ammonium compound formed by the combination of the free base of the chiral amine with an acid.

[0029] The term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group linked by an oxygen atom, where "alkyl" is as 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, sec-butoxy, isobutoxy, and tert-butoxy.

[0030] The term "cycloalkoxy" means a cycloalkyl group having the same number of carbon atoms as previously defined, connected via a ring carbon atom to an external oxygen atom. For example, a "cycloalkoxy" may contain 3-6 carbon atoms connected via a ring carbon atom to an external oxygen atom, i.e., a C3-6 cycloalkoxy group. Exemplary groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0031] The term "allyl" refers to a compound with the structural formula H2C=CH-CH2- Part of which This indicates the connection point between this part and the rest of the molecule, and the connection point is the connection point with a heteroatom or aromatic part.

[0032] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group. Aryl groups include, for example, phenyl and naphthyl groups. Aryl groups can contain 6 to 14 carbon atoms.

[0033] The term "heteroaryl" refers to a group or portion comprising an aromatic monovalent monocyclic or bicyclic group containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The term also covers bicyclic heterocyclic-aryl compounds containing an aryl ring portion fused with a heterocyclic alkyl ring portion containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Exemplary functional groups include, but are not limited to, furanyl, thiophene, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxacyclopentenyl, dihydrobenzodioxacyclohexene, benzothiophene, inazinyl, indoleyl, isoindoleyl, and dihydroindoleyl. Examples of 5-membered "heteroaryl" compounds include furanyl, thiophenyl, pyrroleyl, imidazoleyl, pyrazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazoleyl, imidazole-pyridyl, pyrazolyl, benzotriazolyl, triazolyl-pyridyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, terpineyl, phthalazinyl, quinazolinyl, 1,5-naphthodinyl, 1,6-naphthodinyl, 1,7-naphthodinyl, 1,8-naphthodinyl, and pteridinyl. Examples of 6-membered "heteroaryl" compounds include oxopyridyl, pyridyl, pyridinyl, pyrazinyl, and pyrimidinyl. Examples of 6,6-fused "heteroaryl" compounds include quinolinyl, isoquinolinyl, quinoxalinyl, cyclolinyl, phthalazinyl, quinazolinyl, 1,5-naphthodinyl, 1,6-naphthodinyl, 1,7-naphthodinyl, 1,8-naphthodinyl, and pteridinyl. Examples of 6,5-fused "heteroaryl" compounds include benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, indazinyl, indoleyl, isoyindoleyl, and indazoleyl.

[0034] The term "chemical purity" refers to the overall level of the desired product or compound in a composition produced through preparation. When the compound exists in enantiomeric form, "chemical purity" as used herein includes both enantiomeric forms 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 using various techniques, including but not limited to HPLC analysis.

[0035] The terms "enantiomer purity" or "chiral purity" refer to the overall level of one enantiomer in a composition compared to another enantiomer in the composition. Components in the composition other than any enantiomer are not considered in the calculation of "enantiomer purity" or "chiral purity". Enantiomer or chiral purity can be measured by various techniques, including but not limited to chiral SFC analysis and / or chiral HPLC analysis.

[0036] The term "enantiomer excess" or "ee" refers to the percentage composition in which one enantiomer exceeds the other in a mixture of two enantiomers. 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).

[0037] The term "optionally substituted" means that the group may be unsubstituted or substituted with one or more substituents as defined herein. The term "substituted" with respect to a group means that one or more hydrogen atoms bonded to member atoms within the group are independently replaced by one or more defined substituents. Where the group can be selected from a number of alternative groups, the selected groups may be the same or different.

[0038] The term "independently selected" means that when more than one substituent is selected from a large number of possible substituents, those substituents may be the same or different. Therefore, each substituent is selected from the entire group of the listed possible substituents.

[0039] The term "leaving group" generally refers to a group that is readily replaced by nucleophiles such as amines, thiolates, alcohols, or enols. Examples of leaving groups include, but are not limited to, halides, imidazoles, and pyridinium compounds.

[0040] The term "member atom" refers to one or more atoms that form a chain or ring. When more than one member atom is present in a chain or ring, each member atom is covalently bonded to its adjacent member atom in the chain or ring. Atoms that constitute substituents attached to the chain or ring are not member atoms in the chain or ring.

[0041] The term "nonprotic solvent" refers to solvent molecules that neither accept nor donate protons.

[0042] Embodiments of the present invention

[0043] On one hand, the present invention relates to a method for preparing a mixture comprising: a compound of formula (Ia)

[0044] (Ia),

[0045] and compound of formula (Ib)

[0046] (Ib),

[0047] This method includes combinations:

[0048] (a) Compound of formula (II),

[0049] (II);

[0050] (b) Compound of formula (III),

[0051] (III),

[0052] Where X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group; and

[0053] (c) Chiral amines;

[0054] To provide a mixture.

[0055] In an embodiment, the present invention relates to a method for preparing a mixture comprising: a compound of formula (Ia)

[0056] (Ia),

[0057] and compound of formula (Ib)

[0058] (Ib),

[0059] This method includes combinations:

[0060] (a) Compound of formula (II),

[0061] (II);

[0062] (b) Compound of formula (III),

[0063] (III),

[0064] Where X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group;

[0065] (c) Chiral amines;

[0066] (d) Lithium alkali;

[0067] (e) Optionally, lithium salts; and

[0068] (f) Aprotic solvents;

[0069] To provide a mixture.

[0070] In one aspect of the invention, the compound of formula (III) is

[0071] (III),

[0072] Where X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group. As previously mentioned, the term "leaving group" generally refers to a group that is readily replaced by a nucleophile such as an amine, thiolate, alcohol, or enol. 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 compounds. The leaving group can also be described with reference to the chemical substance released when Y of a compound of formula (III) is replaced by a nucleophile. For example, after replacement by a nucleophile, Y can take the form of an alcohol, phenol, carboxylic acid, N-hydroxysuccinimide, N-hydroxybenzotriazole, or its conjugate base.

[0073] In one embodiment of the invention, the compound of formula (III) is the product of the reaction of a carboxylic acid of the following formula with an "activator":

[0074]

[0075] Wherein X is cyclopropyl, difluoromethyl, or trifluoromethyl, and the “activator” is one of many agents known in the art capable of generating a leaving group (Y) in this transformation. 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-tetramethylureon hexafluorophosphate (HATU), 2-propanephosphonic anhydride (T3P), 1-[(1-(cyano-2-ethoxy-2-oxoethylaminooxy)-dimethylamino-morpholinomethyl)]methylammonium hexafluorophosphate (COMU), and benzotriazol-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP). Some possible activators are also described in Chem. Rev. 2011, 111 (11), 6557-6602.

[0076] In another embodiment of the 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; wherein -O(CO)C1-C6 alkyl or -O(CO)C3-C6 cycloalkyl may optionally be substituted with 1, 2, or 3 fluorine atoms, and wherein O-aryl and O-heteroaryl may optionally be substituted 1, 2, or 3 times by substituents independently selected from halogen atoms or C1-C3 alkyl.

[0077] In one embodiment of the invention, Y is chlorine, methoxy, or ethoxy. In another embodiment of the invention, Y is methoxy or ethoxy.

[0078] In one aspect of the invention, a combination of a chiral amine, a lithium base, and optionally a lithium salt forms an aminolithium base in the presence of a solvent.

[0079] In one embodiment, the lithium base is selected from Li-C1-C6-alkyl, Li-C5-C6-cycloalkyl, Li (aryl), LiH, LiNH2, or lithium metal (Li). 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 yet another embodiment, the lithium base is n-BuLi.

[0080] In one embodiment, the solvent is any solvent that can cooperate with any of its components without undergoing a chemical reaction. Those skilled in the art will understand that many solvents can be used alone or in combination with each other. In one 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 cyclopentylmethyl ether (CPME). In one 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 yet another embodiment, the solvent is THF.

[0081] In one embodiment, a lithium salt is present. In another embodiment, the lithium salt is LiCl or LiBr. In one embodiment, no lithium salt is present.

[0082] As previously stated, the term "chiral amine" refers to an amine covalently bonded to a carbon atom, which has three distinct substituents that make it chiral. The term "chiral amine" is used interchangeably to describe either the free base or ammonium salt form of a chiral amine. The ammonium salt form of a chiral amine refers to the ammonium substance formed by the combination of the free base of the chiral amine with an acid.

[0083] In one aspect of the invention, a combination of a chiral amine, a lithium base, and optionally a lithium salt is used to form an aminolithium base in the presence of a solvent. In one 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.

[0084] In one embodiment, a combination of a chiral amine free base, a lithium base, and optionally a lithium salt forms an aminolithium base in the presence of a solvent. In another embodiment, the molar ratio of the chiral amine free 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 chiral amine free base to the lithium base is in the range of about 1.0:1.0 to about 1.0:1.1.

[0085] In another embodiment, a combination of a chiral ammonium amine salt, a lithium base, and optionally a lithium salt forms an aminolithium base in the presence of a solvent. In one embodiment, the molar ratio of the chiral ammonium amine 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 ammonium amine salt to the lithium base is in the range of about 1.0:2.0 to about 1.0:2.2.

[0086] In one embodiment of the invention, the lithium base is n-BuLi, the lithium salt is present and is LiCl, and the solvent is THF.

[0087] In one embodiment of the invention, the chiral amine is a compound selected from formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), or (IV-f):

[0088]

[0089] in

[0090] G1 is an unsubstituted phenyl or a phenyl substituted by one, two or three substituents independently selected from the following: halogen, cyano, substituted C1-C4 alkyl, unsubstituted C1-C4 alkyl, -O (cyclopropyl), -O (allyl), allyl, -O (R1) or -C(O)(R1).

[0091] G2 is an unsubstituted phenyl or a phenyl substituted by one, two or three substituents independently selected from the following: halogen, cyano, substituted C1-C4 alkyl, unsubstituted C1-C4 alkyl, -O (cyclopropyl), -O (allyl), allyl, -O (R1) or -C(O)(R1).

[0092] G3 is an unsubstituted C1-C3 alkyl group or a C1-C3 alkyl group substituted with one, two or three halogen atoms;

[0093] G4 is an unsubstituted C1-C3 alkyl group or a C1-C3 alkyl group substituted with one, two or three halogen atoms;

[0094] G5 is selected from aziridine, pyrrolidine, morpholine, piperidine or quinine ring, each of which is optionally substituted by one or two independent substituents selected from methyl or halogen;

[0095] 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;

[0096] R1 is an unsubstituted C1-C4 alkyl group or a C1-C4 alkyl group substituted with one, two or three halogen atoms.

[0097] In one embodiment of the invention, the chiral amine is (R)-bis((R)-1-phenylethyl)amine.

[0098] ,

[0099] Or (R)-bis((R)-1-phenylethyl)amine hydrochloride,

[0100] .

[0101] In one embodiment of the invention, an aminolithium base formed by combining a chiral amine, a lithium base, and optionally a lithium salt in a solvent (“solvent A”) is then combined with a 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 they are combined with. Those skilled in the art will understand that many solvents can be used, and that “solvent A” and “solvent B” can be the same or different. Examples of such solvents include, but are not limited to, THF, 1,4-dioxane, 2-methyltetrahydrofuran, diethyl ether, MTBE, and CPME. Those skilled in the art will recognize that the solvent used and the environment in which it is used must be substantially anhydrous prior to quenching and post-treatment of the reaction mixture. In one embodiment, the solvent used prior to quenching and post-treatment of the reaction mixture contains less than 500 ppm of water. In another embodiment, the solvent used prior to quenching and post-treatment of the reaction mixture contains less than 300 ppm of water. In yet another embodiment, the solvent used prior to quenching and post-treatment of the reaction mixture contains less than 150 ppm of water.

[0102] In one embodiment of the invention, the compound of formula (Ia) in the mixture prepared by the method described herein is present in excess of the enantiomeric compound of formula (Ib) at an amount equal to or greater than 5%, equal to or greater than 10%, equal to or greater than 15%, equal to or greater than 20%, equal to or greater than 25%, equal to or greater than 30%, equal to or greater than 35%, equal to or greater than 40%, equal to or greater than 45%, equal to or greater than 50%, equal to or greater than 55%, equal to or greater than 60%, equal to or greater than 65%, equal to or greater than 70%, equal to or greater than 75%, equal to or greater than 80%, or equal to or greater than 85%.

[0103] In one embodiment of the invention, the different solubilities of two compounds present in the mixture are used to selectively enrich one compound relative to the other. When the mixture is treated with a solvent, causing some solid material to dissolve and some solid material to remain, the ratio of the two components in the solid phase to the liquid phase becomes different. This process is referred to as "trituration".

[0104] In another embodiment, when two compounds are present in a mixture, grinding can be used to selectively enrich the amount of one compound relative to the other in the solid phase, and then the solid can be separated by filtration.

[0105] In another embodiment, when two regioisomers are present in the mixture, grinding can be used to selectively enrich the amount of one regioisomer relative to the other in the solid phase, and then the solid can be separated by filtration.

[0106] In another embodiment, when the two regioisomers present in the mixture contain carboxylic acid groups, the carboxylic acid groups are converted into the corresponding lithium acetate groups prior to grinding.

[0107] In another embodiment, when two lithium acetate regioisomers are present in the mixture, grinding can be used to selectively enrich the amount of one regioisomer relative to the other in the solid phase, and then the solid can be separated by filtration.

[0108] In another embodiment, when grinding is used to enrich the amount of one compound relative to another in the solid phase and then the solid is separated by filtration, the filtrate can also be separated separately and further processed in subsequent steps to provide additional material.

[0109] In one embodiment of the invention, a mixture of regioisomers 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate and 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-2-yl)lithium acetate,

[0110]

[0111] The grinding process leads to the enrichment of one regioisomer relative to another regioisomer in the solid phase.

[0112] In another embodiment of the invention, a mixture of the regioisomers 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate and 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-2-yl)lithium acetate,

[0113] ,

[0114] Among them, 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate is the predominant (>50%wt) regioisomer. A grinding process was performed to obtain 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate.

[0115] ,

[0116] Chemical purity >90%.

[0117] In one embodiment of the invention, the grinding method for separating two regional isomers uses water as a component of the solvent.

[0118] In another embodiment of the invention, the grinding method for separating two regional isomers uses an aqueous acid solution as a component of the solvent.

[0119] In another embodiment of the invention, the grinding method for separating two regional isomers uses an aqueous acid solution as a solvent.

[0120] In another embodiment of the invention, the grinding method for separating two regional isomers uses an aqueous HCl solution as a solvent.

[0121] In another embodiment of the invention, the grinding method for separating two regional isomers uses a 1N HCl aqueous solution as a solvent.

[0122] In another embodiment of the invention, when treated with an acidic aqueous solution, the compound containing the lithium acetate group retains the lithium acetate group.

[0123] In another embodiment of the invention, when treated with an acidic aqueous solution, the solid compound containing lithium acetate groups retains the lithium acetate groups.

[0124] In another embodiment of the invention, a solid mixture of the regioisomer 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate and 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-2-yl)lithium acetate, wherein

[0125] ,

[0126] 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate was the predominant (>50% wt) regioisomer, which was obtained by grinding with aqueous HCl solution to give 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate.

[0127] ,

[0128] Chemical purity >90%.

[0129] Another method

[0130] As will be understood by those skilled in the art, the compounds of formulas (Ia) and (Ib) are intermediates, one or both of which can be used in other methods. For example, WO 2020 / 054492 for novel capsid inhibitors specifically describes the preparation of the intermediate 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one.

[0131] .

[0132] The methods described herein can be used to prepare mixtures of enantiomers of 2-(2,2-difluoroacetyl)bicyclo[3.1.0]hex-3-one, corresponding to the compounds of the present invention of formulas (Ia) and (Ib), wherein X is a difluoromethyl group. Therefore, the methods described herein can be used in accordance with the methods described in WO 2020 / 054492, thereby reducing the resources required to produce the desired intermediate by providing a mixture having an excess of the desired enantiomer.

[0133] Similarly, U.S. Patent No. 10,696,657, which relates to antiretroviral compounds and methods for their preparation, specifically describes a method for preparing 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid.

[0134] ,

[0135] It is an intermediate used in the synthetic method further described in U.S. Patent No. 10,696,657. The method described herein can also be used, for example, to prepare mixtures of enantiomers of 2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hex-3-one.

[0136] ,

[0137] The compounds of the present invention correspond to formulas (Ia) and (Ib), wherein X is trifluoromethyl. Any one or both enantiomers from this mixture can be used on their own in the preparation of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid. Therefore, the methods described herein can be used in accordance with the methods described in U.S. Patent No. 10,696,657, thereby reducing the resources required to produce the desired intermediate by providing a mixture with an excess of the desired enantiomer.

[0138] General synthetic route

[0139] One embodiment of the method of the present invention can be summarized by the following reaction scheme, wherein W, X, Y and Z are as defined above.

[0140] Option 1

[0141]

[0142] Option 2

[0143]

[0144] The method of the present invention is further illustrated by the following embodiments. Embodiments 1, 2, and 3 are summarized in the following three schemes:

[0145] Option 3 (Example 1):

[0146]

[0147] Option 4 (Example 2):

[0148]

[0149] Option 5 (Example 3):

[0150]

[0151] Example

[0152] abbreviation:

[0153] ACN Acetonitrile

[0154] AcOH (acetic acid)

[0155] CDCl3 Chloroform

[0156] CPME cyclopentylmethyl ether

[0157] CUNO filter cartridge

[0158] DBDMH 1,3-Dibromo-5,5-Dimethylhydantoin

[0159] DCM dichloromethane

[0160] EtOAc (ethyl acetate)

[0161] EtOH (ethanol)

[0162] HCl hydrochloric acid

[0163] HOPht N-hydroxyphthalimide

[0164] HPLC (High Performance Liquid Chromatography)

[0165] IPA isopropanol

[0166] MCH methylcyclohexane

[0167] 2-MeTHF 2-Methyltetrahydrofuran

[0168] MTBE (methyl tert-butyl ether)

[0169] SFC (Supercritical Fluid Chromatography) using carbon dioxide

[0170] TEA.3HF Triethylamine Trihydrofluoride

[0171] TFA (trifluoroacetic acid)

[0172] THF Tetrahydrofuran

[0173] Example 1

[0174] Note: 1 wt is defined as the weight in grams of the bicyclo[3.1.0]hexane-3-one (1) (step 1) and the respective title compounds from the preceding steps (steps 2-6) added to the reaction vessel. All other weights, volumes, and equivalents given are calculated relative to this figure.

[0175] Step 1: Synthesize the intermediate of formula (I-a1) ((1S,5S)-2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one) (4):

[0176]

[0177] (R)-bis((R)-1-phenylethyl)amine hydrochloride (2) (1.2 equivalents) was added to a reaction vessel equipped with a stirrer and an internal thermometer. THF (6.3 volumes) was added, followed by LiCl (1.0 equivalents), and 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 (2.3 equivalents, 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 heated to 20°C over 1 hour. The contents were then cooled back to -65 to -75°C. A solution of bicyclo[3.1.0]hexane-3-one (1) (55 g, 1 wt., 1.0 equivalents) in THF (1.3 volumes) was prepared in a separate vessel, and the vessel was purged with nitrogen for 10–15 minutes. Freshly prepared ketone solution was added dropwise to an aminolithium base solution at -65 to -75°C while maintaining an internal temperature < -65°C. The contents were stirred at -65 to -75°C for 20 minutes. Next, a solution of ethyl 2,2-difluoroacetate (3) (1.5 equivalents) in THF (1.3 volumes) was added dropwise at -65 to -75°C while maintaining an internal temperature < -65°C. The contents were stirred at -65 to -75°C for 1–2 hours. The reaction was quenched by rapidly adding HCl (15.9 volumes, 3M solution in CPME) to the cold mixture. The mixture was then heated to 0°C while stirring. Water (12.5 volumes) and MTBE (12.5 volumes) 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 2M HCl (3 × 8 volumes) and then with water (2 × 8 volumes). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under vacuum to obtain a crude product ((1S,5S)-2-(2,2-difluoroacetyl)bicyclo[3.1.0]hex-3-one) (4) (93.5 g, 94.1% chemical purity and 85.4% chiral purity, 70.4% determined yield).

[0178] 1 H 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).

[0179] Step 2: Synthesize the intermediate of formula (VI-a1) (2-((3bS,4aS)-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate) (6):

[0180]

[0181] Add aminoglycine hydrochloride (5) (1.2 equivalents) to the reaction vessel. Add 2-MeTHF (15 volumes) and purge the vessel with nitrogen for 10-15 minutes. Cool the contents to 10°C. A solution of ((1S,5S)-2-(2,2-difluoroacetyl)bicyclo[3.1.0]hexane-3-one (4) (99.6 g, 1 wt., 1.0 equivalent) in EtOH (15 volumes) was prepared in a separate container. 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 allowed to heat to 10–20 °C until complete depletion of the starting material was observed (by GC). The mixture was added to a 5% NaHCO3 aqueous solution (15 wt.) at 0–10 °C, followed by the addition of EtOAc (25 volumes). The phases were separated. The aqueous phase was drained. The organic phase was washed with water (10 volumes), concentrated to approximately 8–10 volumes, loaded with 2-MeTHF (10 volumes), and then treated with IPA (2 × 10⁻⁶). The solvent was exchanged (3 volumes) and concentrated to 2 volumes. MCH (4 volumes) was added dropwise at 20°C, and the contents were then cooled to 0°C and stirred for 1 hour. The mixture was filtered, the filter cake was washed with MCH (1 volume) and dried in vacuum at 35°C to obtain ethyl acetate (2-((3bS,4aS)-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) (6) (57.2 g, 99.9% chemical purity and 99.5% chiral purity, 39.5% determined yield) as a pale yellow solid.

[0182] 1H NMR (400 MHz, CDCl3-d) δ ppm 6.38 - 6.84 (m, 1 H), 4.72 (d, J=8.37Hz, 2 H), , 4.24 (q, J=7.14 Hz, 2 H), 2.83 - 3.00 (m, 1 H), 2.64 -2.79 (m, 1H), 2.06 - 2.24 (m, 2 H), 1.30 (t, J=7.14 Hz, 3 H), 1.12 (td, J=7.75, 4.92Hz, 1 H), 0.33 (q, J=4.35 Hz, 1 H).

[0183] Step 3: Synthesize the intermediate of formula (IX-1) (ethyl acetate of 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)) (7):

[0184]

[0185] Ethyl 2-((3bS,4aS)-3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate (6) (51.2 g, 1 wt., 1.0 equivalent) and N-hydroxyphthalimide (HOPht, 0.1 equivalent) were loaded into a reaction vessel. ACN (7 volumes) was added and the mixture was heated to 60°C. A solution of NaClO2 (1.8 equivalent) in water (4.3 volumes) 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 volumes) was added, while maintaining the temperature below 30°C for at least 30 minutes. (Starch-potassium iodide test paper test - result: negative). Add EtOAc (4 volumes), then separate the phases and extract the aqueous phase with EtOAc (5 volumes). Wash the combined organic phases with saturated NaHCO3 aqueous solution (6 x 5 volumes), followed by saturated Na2SO4 aqueous solution (5 volumes). Evaporate the solvent under vacuum to obtain a yellow residue. Add IPA (0.5 volumes) to the residue and heat the contents to 50°C. Add MCH (7 volumes) at 45-55°C and stir the contents for 1-3 hours. Filter the mixture at 50°C. Evaporate the filtrate under vacuum to obtain a yellow residue. Add IPA to the residue. (1 volume) and heat the contents to 50°C. Add MCH (7 volumes) and stir the contents for 1–3 hours. Cool the contents to 0°C and stir for 1–10 hours. Filter the mixture at 0°C, wash the filter cake with MCH (1.5 volumes) and further dry it under vacuum to give ethyl acetate (2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) as a white solid (7) (43.9 g, 98.1% chemical purity, 81.8% yield).

[0186] 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).

[0187] Step 4: Synthesize the intermediate of formula (VII-1) (2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-5,2'-[1,3]dithiacyclopentane]-1(3bH)-yl)ethyl acetate) (9):

[0188]

[0189] BF3•2AcOH (3.0 equivalents) was added to a solution of (2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate)(7) (43.6 g, 1 wt, 1.0 equivalents) and ethane-1,2-dithiol (8) (1.2 equivalents) in DCM (10 volumes) at -5–5 °C. The mixture was stirred at 0–10 °C for 40 hours until the reaction was complete. KHCO3 aqueous solution (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 exchanged with EtOH (2 × 3 volumes), and then further diluted with EtOH (3 volumes). Water (9 volumes) was added, and the mixture was cooled and stirred, then filtered and the wet filter cake was vacuum dried to give ethyl acetate 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-5,2'-[1,3]dithiacyclopentane]-1(3bH)-yl) in solid form (9) (52.4 g, 98.0% chemical purity and 93.6% determined yield).

[0190] 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).

[0191] Step 5: Synthesize the intermediate of formula (IV-b1) (ethyl acetate of 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)) (11):

[0192]

[0193] TEA.3HF (13.3 equivalents) was added dropwise to a suspension of DBDMH (10) (3.1 equivalents) in DCM (7 volumes) at -15 to -5 °C. Then, a solution of 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-5,2'-[1,3]dithiacyclopentane]-1(3bH)-yl)ethyl acetate) (9) (51.9 g, 1 wt, 1.0 equivalents) in DCM (3 volumes) was added to the mixture 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, and the mixture was filtered through diatomaceous earth and washed with DCM. The combined filtrates were separated. The aqueous phase was extracted with DCM (3 volumes). The combined organic phases were alkalized with 20% KHCO3 aqueous solution (2.7 wt). The two-phase mixture was separated and the organic phase was washed with water (2 volumes). The organic phase was concentrated under vacuum and the solvent was exchanged with THF to give (2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate) (11) in THF (51.9 g, 166.7 g after post-treatment in THF solution, 89.3% chemical purity and 23.8% determination, 90.5% determination yield). 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.

[0194] Step 6: Synthesize the intermediate of formula (VI-b1) (2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid) (12):

[0195]

[0196] A solution of LiOH·H₂O (1.6 equivalents) in water (3.5 volumes) was added to a solution of (2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate)(11) (95.4 g, 1 wt, 1.0 equivalent) in THF. HCl was added at 10–20 °C to adjust the pH to 5.5–6.5. The mixture was concentrated under vacuum below 35 °C to remove THF. Water (6 volumes) 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 filter cake was washed with water (2 × 2 volumes). The wet filter cake was dissolved in ACN (8-10 volumes) at 15-25°C, then filtered, and the filter cake was washed with ACN (1-1.5 volumes). After circulating the filtrate through CUNO with activated carbon and washing with ACN (2-3 volumes), the filtrate was concentrated under vacuum, and the solvent was exchanged with water. After stirring at 2-7°C for 2-3 hours, the mixture was filtered, and the filter cake was washed with water (0.5-1 volumes). The wet filter cake was dried under vacuum at 45-50°C to obtain a yellow solid (2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid)(12). Further purification: The solid was dissolved in EtOAc, circulated through CUNO with activated carbon, and washed with another EtOAc. The solvent was exchanged with ACN, then circulated through CUNO with activated carbon and washed with ACN. The filtrate was concentrated under vacuum, and the solvent was exchanged with water and filtered. The filter cake was washed with water and further dried under vacuum to give a yellow solid (2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid)(12) (66.6 g, 99.6% chemical purity, 99.9% chiral purity, 77.3% yield as determined).

[0197] 1 H 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, 1.11Hz, 1H), 0.89 - 1.02 (m, 1H).

[0198] Example 2

[0199] Step A: Preparation of the intermediate of formula (I-a2) ((1S,5S)-2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one) (A):

[0200]

[0201] (R)-bis((R)-1-phenylethyl)amine hydrochloride (2) (1.1 equivalents) was loaded into a reaction vessel equipped with a stirrer and an internal thermometer. THF (31 mL) was added, followed by LiCl (57.2 mL, 1.1 equivalents) 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 equivalents, 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 heated to 20°C over 1 hour. The contents were then cooled back to -65 to -75°C. A solution of bicyclo[3.1.0]hexane-3-one (1) (2.5 g, 1 wt, 1.0 equivalent) in THF (12.0 mL) was prepared in a separate container, and the container was purged with nitrogen for 10–15 min. The freshly prepared ketone solution was added dropwise to a lithium aminoalkali solution at -65–-75 °C while maintaining an internal temperature <-65 °C. The contents were stirred at -65–-75 °C for 20 min. Next, ethyl 2,2,2-trifluoroacetate (X) (3.71 mL, 1.2 equivalent) was added dropwise at -65–-75 °C while maintaining an internal temperature <-65 °C. The contents were stirred at -65–-75 °C for 1–4 h. The reaction was quenched by rapidly adding HCl (19.07 mL, 3 M CPME solution) to the cold mixture. The mixture was then heated to 20 °C while stirring. Add water (60 mL) and MTBE (60 mL) and stir the solution for 10 minutes. Separate the phases and then drain the aqueous phase. Wash the organic phase with 2M HCl (2 × 60 mL), then with water (2 × 60 mL), then with brine (60 mL), and concentrate the solution under vacuum to obtain the crude product ((1S,5S)-2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one) (A) (6.57 g) in an oily state, and subject it directly to step B.

[0202] Step B: Preparation of the intermediate of formula (VI-a2) ((2-((3bS,4aS)-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate) (B):

[0203]

[0204] Aminoglycine hydrochloride (5 g, 1.2 equivalents) was loaded into a 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. A solution of 2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one (A) (5 g, 1 wt, 1.0 equivalents) in EtOH (75 mL) was prepared in a separate vessel. The freshly prepared solution of 2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one (A) was added to the reaction vessel containing hydrazine at 0 °C. The mixture was heated to 20 °C until complete depletion of the starting material was observed (by GC). Water (150 mL) and EtOAc (200 mL) were added. The phases were separated. The aqueous phase was washed with EtOAc (3 × 50 mL), and the combined organic phases were washed with brine (2 × 50 mL) and concentrated to give a crude brown oil (regioisomer ratio 3.2:1, B: regioisomer-B). The crude oil was purified by column chromatography to give ethyl 2-((3bS,4aS)-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) ethyl acetate (B) (2.65 g, 90.1% chiral purity, 79% ee, favorable enantiomer unknown, 37.1% yield relative to steps A and B) as a white solid.

[0205] 1 H NMR (400 MHz, CDCl3-d) δ ppm 4.63 - 4.84 (m, 2 H), 4.23 (q, J=7.14Hz, 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, 1H). 13 C NMR (101 MHz, CDCl3-d) δ ppm 166.8, 151.3, 13.9, 134.8 - 136.4 (m, 1C), 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+] Calculated value: C 12 H 14 F3N2O2: 275.0929; Measured value: 275.1020.

[0206] Step C: Preparation of the intermediate of formula (I-a3) ((1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one)(C):

[0207]

[0208] (R)-bis((R)-1-phenylethyl)amine hydrochloride (2) (1.1 equivalents) was loaded into a reaction vessel equipped with a stirrer and an internal thermometer. THF (25 mL) was added, followed by LiCl (45.8 mL, 1.1 equivalents) 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 equivalents, 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 heated to 20°C over 1 hour. The contents were then cooled back to -65 to -75°C. A solution of bicyclo[3.1.0]hexane-3-one (1) (10.4 mL, 1 wt, 1.0 equivalent) in THF (10.0 mL) was prepared in a separate container, and the container was purged with nitrogen for 10–15 min. The freshly prepared ketone solution was added dropwise to an aminolithium base solution at -65–-75 °C while maintaining an internal temperature <-65 °C. The contents were stirred at -65–-75 °C for 20 min. Next, cyclopropaneformyl chloride (Y) (2.7 mL) was added dropwise at -65–-75 °C while maintaining an internal temperature <-65 °C. The contents were stirred at -65–-75 °C for 1–4 h. The reaction was quenched by rapidly adding HCl (15.3 mL, 3 M CPME solution) to the cold mixture. The mixture was then heated to 20 °C while stirring. 2 M HCl aqueous solution (50 mL) and MTBE (50 mL) were added, and the solution was stirred for 10 min. The phases were separated, and the aqueous phase was discharged. The organic phase was washed with 2M HCl (2 × 50 mL), then with water (2 × 50 mL), then with brine (30 mL), filtered through a hydrophobic glass frit, and the solvent was evaporated under vacuum to obtain an oily crude product ((1S,5S)-2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexane-3-one)(C) (4.00 g), which was then subjected directly to step D.

[0209] Step D: Preparation of intermediate (ethyl acetate of formula (VI-a3)) (2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)

[0210]

[0211] Aminoglycine hydrochloride (5) (3.86 g, 1.2 equivalents) was loaded into a reaction vessel. 2-MeTHF (50 mL) was added, and the vessel was purged with nitrogen for 10–15 min. The mixture was cooled to -10–0 °C. Sulfuric acid (5.55 mL) was added dropwise. A solution of 2-(cyclopropanecarbonyl)bicyclo[3.1.0]hex-3-one (3.42 g, 1 wt, 1.0 equivalent) in EtOH (50 mL) was prepared in a separate vessel. The freshly prepared solution of 2-(cyclopropanecarbonyl)bicyclo[3.1.0]hex-3-one was added to the reaction vessel containing hydrazine at 0 °C. The mixture was heated to 20 °C until complete depletion of the starting material was observed (by GC). Water (100 mL) and EtOAc (150 mL) were added. The phases were separated. The aqueous phase was washed with EtOAc (3 × 30 mL), and the combined organic phases were washed with brine (2 × 30 mL) and concentrated under vacuum to obtain a brown oil. The oil was dissolved in EtOAc (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 concentrated under vacuum to obtain 2.18 g of crude oil (42.5% crude yield of steps A and B, 60.7% purity, regioisomer ratio 2.5:1, D: regioisomer-D). A portion (0.1 g) of the crude oil was purified by quality-directed automated purification (MDAP; water / ACN, formic acid additive), followed by aqueous post-treatment with EtOAc (50 mL) and saturated NaHCO3 aqueous solution (10 mL). Vacuum evaporation yielded ethyl acetate (2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) (D) as a white solid (0.03 g, 87.5% chiral purity, 75% ee, favorable enantiomer unknown).

[0212] 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+] Calculated values: C 14 H 19 N2O2: 247.1368; Measured value: 247.1450.

[0213] Example 3

[0214] Preparation of 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid

[0215] Synthesis scheme:

[0216]

[0217] Step 1: Preparation of the intermediate (1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one of formula (I-a3)

[0218]

[0219] Anhydrous lithium chloride (238 mg, 5.61 mmol) was added to a stirred solution of (R)-bis((R)-1-phenylethyl)amine HCl salt (1263 mg, 5.61 mmol) in tetrahydrofuran (THF) (2 mL) under a nitrogen atmosphere. The reaction mixture was cooled to -78 °C, and then n-butyllithium (2.5 M hexane solution, 4.49 mL, 11.21 mmol) was added dropwise at -78 °C. The solution was stirred for 10 min and then heated to 20 °C. The mixture was stirred for 1 h. The reaction mixture was cooled to -78 °C again, 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 min. Cyclopropaneformyl chloride (0.510 mL, 5.61 mmol) was added dropwise to the mixture at -78 °C, and the mixture was stirred at the same temperature for 4 h. The reaction progress was monitored by TLC (SiO2, 10% EtOAc / petroleum ether, Rf=0.4, PMA activation). After completion, the reaction mixture was quenched with 4M HCl in ethyl acetate (4 mL), 5 mL of 2N HCl aqueous solution, and 10 mL of MTBE, and the resulting mixture was stirred for 20 min. The mixture was filtered and the filtrate was divided. The aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with 2N HCl aqueous solution (2 × 5 mL) and water (2 × 5 mL). The organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude product (1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hex-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 x 50 mm; Mobile Phase C: 0.05% formic acid / water, Mobile Phase D: 0.05% formic acid / 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℃. LCMS Results: Retention Time = 2.31 min; Observed Ions = 165.06 (M+H).

[0220] Step 2: Preparation of the intermediate of formula (VI-a3) (2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate)

[0221]

[0222] Aminoglycine ethyl ester hydrochloride (737 mg, 4.77 mmol) was added in portions to a stirred solution of 2-(cyclopropanecarbonyl)bicyclo[3.1.0]hex-3-one (870 mg, 3.97 mmol, see previous step) in ethanol (10 mL), 2-methyltetrahydrofuran (2-MeTHF) (10 mL), and sulfuric acid (0.087 mL, 1.641 mmol) at 10 °C under a nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 16 h. The reaction progress was monitored by TLC (SiO2, 20% acetone / petroleum ether; Rf=0.3, UV activated). Upon completion, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (50 mL) and 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) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (1 g) that was a brown liquid. The crude product was subjected to silica gel chromatography (12 g, Flashpure-Buchi filter cartridge) with gradient elution of 10-20% EtOAc in petroleum ether to obtain the enriched product ethyl acetate 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) (400 mg, LCMS purity 33%), which was a mixture of regioisomers and a pale yellow liquid. The substance was then adsorbed onto diatomaceous earth, and the resulting powder was subjected to C18 chromatography using a Combi-Flash system equipped with a RediSep Gold C18 column (40 g, Teledyne Isco), eluting with a gradient of 50–65% MeCN (containing 0.1% TFA) in water (containing 0.1% TFA) at a flow rate of 20 mL / min. Fractions containing the pure product were combined and concentrated under reduced pressure. The resulting aqueous solution was adjusted to pH ~7 by adding saturated NaHCO3. The solution was extracted with EtOAc (3 × 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give enriched ethyl acetate 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) (210 mg, 15% yield in two steps), a pale yellow gelatinous oil, a mixture of two regioisomers. This substance is used directly in the next step without further purification. 1H 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), 1.961.83 (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 x 30 mm; Mobile phase A: 0.05% formic acid / water, Mobile phase B: 0.05% formic acid / 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 min; Observed ions = 247.56 (M+H). LCMS purity = 88%, HPLC: Purity: 64.8%, 21.9%, RT = 3.68, 4.15 min.

[0223] Step 3: Preparation of the intermediate of formula (V-a1) (2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid)

[0224]

[0225] A solution of LiOH·H₂O (91 mg, 3.79 mmol) dissolved in water (1 mL) was added to a stirred solution of ethyl 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cycloprop[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) (210 mg, 0.758 mmol, see previous step) in tetrahydrofuran (THF) (2 mL) and methanol (1 mL). The reaction mixture was heated to 27 °C and stirred for 2 hours. The reaction progress was monitored by TLC (SiO₂, 10% MeOH / DCM; Rf=0.1, UV activated). After completion, the organic solvent was evaporated under reduced pressure. The pH of the resulting aqueous layer was adjusted to ~2 by adding 1N 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 dried under vacuum to give 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid (120 mg) as a mixture of regioisomers and enantiomers. LCMS method: Column: CORTECSUPLC C18 (30 x 3 mm, 1.6 μm); Mobile phase A: 0.05% formic acid / water; Mobile phase B: 0.05% formic acid / 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 & 0.92 min; Observed ions = 219.16 (M+H); LCMS purity = 54% & 27% (mixture of regioisomers). Chiral SFC method: Column: CHIRALPAK IC (4.6 x 150 mm) 5 μm; Co-solvent: 0.5% triethylamine / methanol; Total flow rate: 3 mL / min; Eluent: 70% CO2, 30% co-solvent; ABPR: 1500 psi; Column temperature: 30 °C; Detection: Spectroscopic PDA 237.0 nm. Note: Co-injection of a true pure chiral sample of 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid was used to confirm the identity of the desired product peak.Chiral SFC results: Purity % (retention time; identity): 9.37% (2.82 min; 2-((3bR,4aR)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid), 29.41% (3.31 min; 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-2-yl)acetic acid, stereochemistry not specified), 56.32% (4.25 min). 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid), 4.9% (6.02 min, 2-(3-cyclopropyl-3b,4,4a,5-tetrahydro-2H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-2-yl)acetic acid, stereochemistry not specified). Summary: 2:1 regioisomeric mixture with the title compound as the major component; 71% enantiomer excess with the title compound (S,S stereochemistry) as the major component.

[0226] Example 4

[0227] Preparation of 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetic acid

[0228] Synthesis scheme:

[0229]

[0230] Step 1: Preparation of the intermediate of formula (I-a3) ((1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hexane-3-one)

[0231]

[0232] 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 equivalents) in tetrahydrofuran (THF) (1 L) under a nitrogen atmosphere. The reaction mixture was cooled to -78 °C. Butyllithium (2.5 M hexane solution; 897 mL, 2.24 mol) was slowly added to the mixture at -78 °C. 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]hex-3-one (100 g, 1.019 mol) in tetrahydrofuran (100 mL) was added to the mixture over 20 minutes. Cyclopropaneformyl chloride (101.8 mL, 1.121 mol) was added dropwise to the mixture at -78 °C. The mixture was stirred for 3 hours, and then the reaction mixture was quenched by adding 2N HCl aqueous solution (500 mL). 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 separated organic layer was washed with water (2 × 500 mL), followed by washing with brine (2 × 500 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and then concentrated under reduced pressure to give a crude product (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. LCMS method: Column = ACQUITY UPLC BEH C18 1.7 μm (2.1 x 50 mm); Mobile phase A = 0.05% formic acid / water; Mobile phase B = 0.05% formic acid / 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℃. LCMS results: Retention time = 2.13 min; Observed ions = 164.99 [M+H] + LCMS purity = 56.7%.

[0233] Step 2: Preparation of the intermediate of formula (VI-a3) (2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)ethyl acetate)

[0234]

[0235] Aminoglycine ethyl ester hydrochloride (122 g, 789 mmol) and sodium acetate (163 g, 1.99 mol) were added to a stirred solution of (1S,5S)-2-(cyclopropanecarbonyl)bicyclo[3.1.0]hex-3-one (160 g, 56% wt, 546 mmol, from the previous step) in methanol (2.4 L) at -15 °C under a N2 atmosphere. 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 give a crude product (200 g) as a brown gel. The crude compound was adsorbed onto silica gel, and the resulting powder was subjected to silica gel chromatography (100-200 mesh). The powder was eluted with a gradient of 13-40% ethyl acetate / petroleum ether to obtain a brown gel-like substance, ethyl acetate (85 g, yield = 33%), a mixture of regioisomers and enantiomers. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ = 4.94 – 4.81 (m, 2H (minor)), 4.70 (s, 2H (major)), 4.21 – 4.11 (m, 2H (major)), 4.11–4.02 (m, 2H (minor)), 2.75–2.65 (m, 1H (major + minor)), 2.61–2.51 (m, 1H (major + minor)), 2.01 – 1.82 (m, 2H (major + minor)), 1.81 – 1.71 (m, 1H (major + minor)), 1.23 – 1.16 (m, 3H (major + minor)), 1.02 – 0.75 (m, 3H) (Major + Minor)), 0.72 – 0.59 (m, 2H (Major + Minor)), 0.08 – -0.03 (m, 1H (Major + Minor)). LCMS method: Column = ACQUITY UPLC BEH C18 1.7 μm (2.1 X 50 mm); Mobile phase A = 0.05% formic acid / water; Mobile phase B = 0.05% formic acid / 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℃. LCMS results: Retention time = 3.92, 4.05 min; Observed ion = 247.02 [M+H] +LCMS purity = 51.9% & 27.8%. HPLC: retention time = 3.07, 3.48 min, HPLC purity = 77.2% & 16.5%.

[0236] Step 3: Preparation of the lithium salt of the intermediate of formula (V-a1) (2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadienano[1,2-c]pyrazol-1-yl)lithium acetate)

[0237]

[0238] A solution of lithium hydroxide monohydrate (62.0 g, 1.48 mol) in water (150 mL) was added to a stirred solution of ethyl 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl) in tetrahydrofuran (700 mL) and methanol (300 mL). The reaction mixture was stirred at 0 to 10 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue was acidified to pH ~5-6 with 1N HCl aqueous solution (200 mL) and stirred for 10 minutes. The solid precipitate was collected by filtration, washed with water (100 mL) and n-pentane (200 mL), and then dried under vacuum to obtain the title compound 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadienano[1,2-c]pyrazol-1-yl)lithium acetate (68 g, HPLC: 98% purity, chiral SFC: 88.7% purity) as a grayish-white solid. 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 = ACQUITY UPLCBEH C18 1.7 μm (2.1 x 50 mm); Mobile Phase A = 0.05% formic acid / water; Mobile Phase B = 0.05% formic acid / 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℃. LCMS Results: Retention Time = 2.66 min; Observed Ions = 218.97 [M+H] + HPLC method: XSelect CSHC18 3.5 μm (4.6 x 150 mm); Mobile phase A: 0.05% trifluoroacetic acid / water; Mobile phase B: 100% 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: Ambient temperature; HPLC results: Retention time: 7.57 min, Purity: 98%; Chiral SFC method: Column: CHIRALPAKIC 5 μm (2.1 x 50 mm); Eluent: CO2:0.5% triethylamine / MeOH (70:30); Back pressure: 1500 psi; Flow rate: 4 mL / min; Column temperature: 30℃. Chiral SFC results: 88.7% main peak, main peak retention time = 2.96 min, secondary peak retention time = 2.13 min. Li content = 3.60% w / w (1.2 equivalents). Note: Analysis of the filtrate revealed a mixture of regioisomers (70 g, LCMS: 63% title compound, 25% regioisomers of the title compound).

[0239] Step 4: SFC purification of the lithium salt intermediate (V-a1) (2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate)

[0240]

[0241] Lithium 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)acetate (70 g) was purified by SFC chromatography according to the following method: column = Chiralpak IC 5µ (250 x 30 mm); eluent = CO2:0.5% triethylamine / MeOH (70:30); flow rate = 100 g / min; back pressure = 100 bar; detection = 240 nm (UV); stacking time = 6.7 min; injection load = 1.50 g. The pure main peak fraction (peak-2) was collected and concentrated under reduced pressure to obtain a grayish-white solid, 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate (45 g, LCMS: 98% purity, chiral SFC: 99.9% purity). The obtained compound was further treated at 0 °C with 1N HCl aqueous solution (150 mL) and stirred for 10 min. 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 30.08 g of 2-((3bS,4aS)-3-cyclopropyl-3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentadieno[1,2-c]pyrazol-1-yl)lithium acetate, which was a grayish-white solid. 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 = X Bridge C18 3.5 μm (4.6 x 150 mm); Mobile Phase A = 10 mM ammonium bicarbonate / 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 = Ambient Temperature; Flow Rate = 1.0 mL / min. LCMS Results: Retention Time = 6.68 min; 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 x 150 mm); Eluent = CO2:0.5% diethylamine / methanol (65:35); Total flow rate: = 3 mL / min; Back pressure = 1500 psi; Temperature = 30 ℃. Chiral SFC results: Retention time = 1.78 min; Purity: 99.8%. Specific rotation [α] 25 D (0.34% in methanol) = -11.824°. Li content = 3.60% w / w (1.15 eq). Water content = 1.33%.

Claims

1. A method for preparing a mixture comprising the following: Compound of formula (Ia) (I-a), and compound of formula (Ib) (I-b), Including combinations: (a) Compound of formula (II), (II); (b) Compound of formula (III), (III), Where X is cyclopropyl, difluoromethyl, or trifluoromethyl, and Y is a leaving group; (c) Chiral amines; (d) Lithium alkali; (e) Optionally, lithium salts; and (f) Aprotic solvents; To provide the mixture.

2. The method according to claim 1, wherein the chiral amine (c) is a compound selected from formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), or (IV-f): in G1 is an unsubstituted phenyl or a phenyl substituted by one, two or three substituents independently selected from the following: halogen, 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 by one, two or three substituents independently selected from the following: halogen, 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 aziridine, pyrrolidine, morpholine, piperidine or quinine ring, each of which is optionally substituted by one or two independent substituents 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.

3. The method according to claim 2, wherein G1 is an unsubstituted phenyl group; G2 is an unsubstituted phenyl group; G3 is a methyl group; G4 is a methyl group; G5 is selected from aziridine, pyrrolidine, morpholine, piperidine or quinine ring, each of which is optionally substituted by one or two independent substituents selected from methyl or fluorine; G6 is selected from allyl, cyclopropyl, unsubstituted C1-C5 alkyl, or C1-C5 alkyl substituted with one phenyl atom or with one, two, or three fluorine atoms; and R1 is an unsubstituted C1-C4 alkyl group or a C1-C4 alkyl group substituted with one, two or three fluorine atoms.

4. The method according to claim 2 or 3, wherein the chiral amine (c) is a compound of formula (IV-a). (IV-a), in: G1 and G2 are each unsubstituted phenyl groups; and G3 and G4 are both methyl groups.

5. The method according to any one of claims 1-4, wherein the compound of formula (Ia) is present in the mixture in an enantiomeric excess of 10% or greater than that of the compound of formula (Ib).

6. The method according to any one of claims 1-5, wherein the compound of formula (Ia) is present in an enantiomeric excess of 80% or more relative to the compound of formula (Ib).

7. The method according to any one of claims 1-6, wherein the lithium base (d) is selected from Li-C1-C6-alkyl, Li-C5-C6-cycloalkyl, Li (aryl), LiH, LiNH2 or lithium metal (Li 0 ).

8. The method according to any one of claims 1-7, 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 1-8, 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 1-9, wherein the aprotic solvent (f) is THF.

11. The method according to any one of claims 1-10, 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 1-12, wherein X is cyclopropyl.

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

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

16. The method according to any one of claims 1-15, wherein Y is selected from -F, -Cl, -Br, -I, -CN, -O-C1-C6 alkyl, -O-C3-C6 cycloalkyl, -O(CO)C1-C6 alkyl, -O(CO)C3-C6 cycloalkyl, -O-aryl or -O-heteroaryl; wherein -O(CO)C1-C6 alkyl or -O(CO)C3-C6 cycloalkyl may optionally be substituted with 1, 2 or 3 fluorine atoms, and wherein O-aryl and O-heteroaryl may optionally be substituted 1, 2 or 3 times with substituents independently selected from halogen atoms or C1-C3 alkyl groups.

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

18. The method according to any one of claims 1-17, wherein the method further comprises separating the compound of formula (Ia) from the mixture.

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

20. Compound of formula (Ia), (I-a), It is made by the method according to any one of claims 1-19, wherein X is as defined therein.

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