Method and intermediate for preparing 3-alpha-hydroxy-3-beta-alkylsteroids

Abstract

The present invention relates to a compound of formula (I) or its salt or solvate as an intermediate. [Formula 1] The present invention relates to a method for preparing 3α-hydroxy-3β-alkylsteroids, such as zulanolone and structurally related compounds, including the use of JPEG2026509303000099.jpg35153 (wherein X is selected from Cl, Br, and I). The present invention also relates to a method for preparing compounds of formula (I) or salts or solvates thereof.

Description

[Technical Field]

[0001] The present invention relates to novel intermediates useful for the preparation of 3α-hydroxy-3β-alkylsteroids, such as zulanolone and structurally related compounds, and to methods for preparing such intermediates. [Background technology]

[0002] Zulanolon and other related 3α-hydroxy-3β-alkylsteroids have been disclosed in the prior art as neuroactive compounds and are therefore useful for the prevention and treatment of CNS-related diseases. [ka]

[0003] Several synthetic methods for preparing this type of compound and its intermediates have been disclosed. In particular, various methods for introducing alkyl and hydroxyl groups at the 3-position of steroids have been described. However, most of these do not stereoselectively provide the desired product (α-hydroxy-β-alkyl product).

[0004] WO2013 / 056181 discloses a method that involves protecting the ketone at position 3 before olefinization at position 17. Subsequent deprotection of the 3-ketone and addition of MeMgBr yield the 3-hydroxy, 3-methyl functional group, but with very low selectivity for the desired isomer (an alpha / beta ratio of approximately 25 / 75 (6b / 6a) of hydroxyl groups after chromatographic purification is disclosed in Example 1). [ka] [ka]

[0005] This document discloses other strategies for 3-position functionalization, such as the addition of fluorinated sulfones, but these also result in low selectivity (an alpha / beta ratio of approximately 57 / 43 (11b / 11a) of hydroxyl groups after chromatographic purification is disclosed in Example 2). [ka]

[0006] Next, the compounds of formulas 9a / 9b and 15a / 15b of WO2013 / 056181 are converted into neuroactive steroids by reaction with different heterocyclic and heteroaryl compounds.

[0007] WO2014 / 169832 discloses a method for synthesizing an important intermediate SA, in which 3-hydroxy, 3-methyl functional groups are obtained by adding MeMgBr to a 3-ketone in the presence of MAD (methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide)). [ka] [ka]

[0008] In this case, stereoselectivity in the addition of MeMgBr is achieved by the use of MAD. However, this requires 3 equivalents of MAD, and furthermore, MAD is an expensive and difficult-to-handle reagent that must be prepared in situ by the reaction of trimethylaluminum (spontaneously combustible) with 2,6-di-tert-butyl-4-methylphenol. Therefore, this method is not suitable for industrial production.

[0009] Furthermore, when the inventors attempted to reproduce this strategy, they were unable to obtain favorable results (Comparative Example 3).

[0010] A similar strategy using MeMgBr and MAD is disclosed in WO2016 / 061527.

[0011] WO2014 / 169832 and WO2014 / 169836 disclose the preparation of 3-hydroxy,3-fluoromethyl derivatives by epoxide ring-opening. However, the epoxides are formed with low stereoselectivity, and the corresponding isomers are separated at the end of the synthesis in a ratio of approximately 50 / 50. [ka]

[0012] WO2014 / 169832 also describes compounds having a vinyl group at position 17 (compounds of formula SA-G) as useful intermediates in the preparation of active steroids. [ka] [ka]

[0013] WO2014 / 169833 and WO2015 / 180679 disclose the preparation of 3-hydroxy,3-alkoxymethyl derivatives by epoxide ring-opening with MeONa or EtONa, respectively. However, the epoxides are formed with low stereoselectivity, and the corresponding isomers are separated at the end of the synthesis in a ratio of approximately 50 / 50. [ka]

[0014] WO2014 / 169833 describes the preparation of stereoselective 3α-hydroxy,3β-ethoxymethyl derivatives for steroids, where the two bonded cyclohexane rings are in the trans-decalin form, as in the compound SB below. [ka]

[0015] However, as shown in WO2020 / 118060, this strategy results in low stereoselectivity when applied to cis-decalin (as compound 87 below). In particular, this document discloses the synthesis of 3-hydroxy,3-alkoxymethyl derivatives by epoxidation of 3,17-diketone and subsequent epoxide ring-opening with sodium alkoxide. However, a ratio of approximately 71 / 29 isomers at the 3-position is disclosed in Example 87 for compound 87.3. [ka]

[0016] WO2020 / 118060 also describes compounds having a vinyl group at position 17 (compounds of formula A34) as useful intermediates in the preparation of active steroids. [ka]

[0017] Despite prior art methods, there is still a need to develop novel methods for preparing 3α-hydroxy-3β-alkylsteroids, such as zulanolone, as well as key intermediates in their synthesis, that overcome all or some of the problems associated with known methods belonging to the latest technology. [Overview of the project]

[0018] The present invention addresses the problem of providing a novel method for preparing α-hydroxy-β-alkyl steroids and their intermediates.

[0019] In particular, the inventors have found that the compound of formula (I) can be obtained by the halohydrin formation reaction of the compound of formula (III). This reaction proceeds stereoselectively. Furthermore, the compound of formula (III) can be obtained by the olefination of the compound of formula (II). Since this olefination proceeds regioselectively, no protection / deprotection steps are required. Due to the regioselectivity of the olefination reaction and the stereoselectivity of the halohydrin formation reaction, this synthetic strategy provides a very simple and effective method for preparing the compound of formula (I), and therefore 3α-hydroxy-3β-alkylsteroids. [ka]

[0020] Furthermore, the compound of formula (I) is a highly versatile intermediate because group X can be easily converted to other functional groups. Therefore, the compound of formula (I) can be used as a common and important intermediate in the manufacture of different steroids.

[0021] Therefore, in the first aspect, the present invention relates to a compound of formula (I) or a salt or solvate thereof. [ka] (In the formula, X is selected from Cl, Br, and I) A method for preparing, (a) Compounds of formula (II) or their salts or solvates [ka] Olefining of the compound of formula (III) or its salt or solvate [ka] To provide, and (b) To provide a compound of formula (I) or a salt or solvate thereof by a halohydrin formation reaction of a compound of formula (III) or a salt or solvate thereof. Relates to a method comprising.

[0022] In a second aspect, the present invention relates to a compound of formula (IX) or a salt or solvate thereof

Chemical formula

Chemical formula

[0023] The compounds of formulas (I) and (III), as well as their salts or solvates, can be used as intermediates in the preparation of zulanolone and other related compounds of formula (IX). Therefore, in another embodiment, the present invention is [ka] The present invention relates to compounds selected from or from salts or solvates thereof (wherein X is selected from Cl, Br, and I). [Modes for carrying out the invention]

[0024] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise explicitly indicated by the context.

[0025] The term "C1-C6 alkyl" refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms that is unsaturated and has 1-6 or 1-3 ("C1-C3 alkyl") carbon atoms, which are bonded to the rest of the molecule via single bonds. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, and hexyl.

[0026] The term "C3-C7 cycloalkyl" refers to saturated or partially saturated monocyclic or bicyclic aliphatic groups having 3-7 or 3-6 carbon atoms ("C3-C6 cycloalkyl"). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] The term "C1-C6 alkoxyl" refers to the alkyl group defined above, having 1 to 6 carbon atoms, or 1 to 3 carbon atoms ("C1-C3 alkoxyl"), linked to the rest of the molecule via oxygen. Examples of alkoxys include methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0028] The term "halogen" refers to bromine, chlorine, iodine, or fluorine.

[0029] The term "C1-C6 haloalkyl" refers to alkyl groups as defined above, in which at least one hydrogen atom is replaced by a halogen atom, such as CF3, CCl3, CHF2, CH2F, or CF2CF3.

[0030] "C6~C 10The term "aryl" refers to an aromatic group having 6 to 10 or 6 or 10 carbon atoms, containing one or two aromatic nuclei. Examples of aryl groups include phenyl, naphthyl, indenyl, and phenanthryl.

[0031] (C6~C 10 The term "(C1-C6) alkyl" refers to an aryl group, as defined above, that is bonded to the rest of the molecule via an alkyl group as defined above. Examples of such groups include benzyl, phenylethyl, phenylpropyl, and naphthylmethyl.

[0032] The term "5-10 membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic system containing 5-10 or 5-7 ring atoms, each consisting of a carbon atom and 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, as well as 1, 2, or 3 heteroatoms.

[0033] The term "5-10 membered heteroaryl" refers to an aromatic monocyclic or bicyclic system containing 5-10 or 5-7 ring atoms, each consisting of a carbon atom and 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, as well as 1, 2, or 3 heteroatoms.

[0034] As is understood in this art, the radicals described above may be substituted to some extent. Therefore, any of the groups of the present invention may be substituted. The preceding group may be substituted with one or more substituents, for example, one, two or three substituents, at one or more available positions. Such substituents may include, for example, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~7 Cycloalkyl, (C 6~ C 10 ) Aryl (C1-C6) alkyl, C6-C 10 Aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d, -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ), -OC(O)R i R a , R b , R c , R d , R e , R f , R g , R h and R i These are independently hydrogen, C1-C6 alkyl, and C 1~6 Haloalkyl, (C6~C 10 ) Aryl (C1-C6) alkyl, C6-C 10 The selection is made from aryls, 5-10 membered heterocyclines, and 5-10 membered heteroaryls.

[0035] The present invention also provides “salts” of the compounds described herein. For example, such salts may be acid addition salts, base addition salts, or metal salts, and can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical processes known to those skilled in the art. Such salts are generally prepared by reacting the free acid or base form of the compound with a stoichiometric amount of a suitable base or acid, for example, in water, an organic solvent, or a mixture thereof. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol, or acetonitrile are generally preferred. Specific examples of acid addition salts include inorganic acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, and organic acid addition salts, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, and camphorsulfonate. Specific examples of base addition salts include inorganic base salts, such as ammonium salts, and organic base salts, such as ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glutamine, and amino acid base salts. Specific examples of metal salts include sodium, potassium, calcium, magnesium, aluminum, and lithium salts.

[0036] The term "solvate" in this invention should be understood to mean any form of a compound having another molecule (possibly a polar solvent) bonded via a non-covalent bond. Examples of solvates include hydrates and alkoxides, such as methanolates. Solvation methods are generally known in the modern art.

[0037] The term "organic solvent" includes, for example, cyclic and acyclic ethers (e.g., Et2O, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g., pentane, hexane, heptane), halogenated solvents (e.g., dichloromethane, chloroform), aromatic solvents (e.g., toluene, xylene), ketones (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g., ethyl, iPrOAc, BuOAc), nitriles (e.g., acetonitrile, benzonitrile), amides (e.g., DMF, DMA, HMPA, NMP), alcohols (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), sulfoxides (DMSO), and mixtures thereof.

[0038] The term "aprotic organic solvent" refers to an organic solvent that does not produce protons under reaction conditions. Suitable examples include, but are not limited to, cyclic and acyclic ethers (e.g., Et2O, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g., pentane, hexane, heptane), halogenated solvents (e.g., dichloromethane, chloroform), aromatic solvents (e.g., toluene, xylene), ketones (e.g., acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g., ethyl, iPrOAc, BuOAc), nitriles (e.g., acetonitrile, benzonitrile), amides (e.g., DMF, DMA, HMPA, NMP), sulfoxides (DMSO), and mixtures thereof.

[0039] In one embodiment, the present invention relates to a compound of formula (I) or a salt or solvate thereof. [ka] (In the formula, X is selected from Cl, Br, and I) A method for preparing, (a) Compounds of formula (II) or their salts or solvates [ka] Olefining of the compound of formula (III) or its salt or solvate [ka] To provide, and (b) To provide a compound of formula (I) or a salt or solvate thereof by a halohydrin formation reaction of a compound of formula (III) or a salt or solvate thereof. Regarding methods including

[0040] In one embodiment, the method of the present invention is (c) Compounds of formula (I) or their salts or solvates of formula (IV) or their salts or solvates [ka] (In the formula, R 1 H, F, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Selected from haloalkyl and N(R')2, where each R' is independently H and C 1~6 (Selected from alkyl groups) conversion to It also includes.

[0041] Accordingly, in another aspect, the present invention relates to a method for preparing a compound of formula (IV) or a salt or solvate thereof, comprising steps (a), (b), and (c) as defined herein.

[0042] In another embodiment, the method of the present invention is (c) A compound of formula (I) or its salt or solvate A compound of formula (IV) or its salt or solvate [Chemical formula] (wherein, R 1 is selected from H, F, C 1~6 alkyl, C 1~6 alkoxyl, C 1~6 haloalkyl, and N(R’)2, and each R’ is independently selected from H and C 1~6 alkyl) to convert, and (d) by olefination of a compound of formula (IV) or a salt or solvate thereof, a compound of formula (V) or a salt or solvate thereof [Chemical formula] (wherein, R 1 is selected from H, F, C 1~6 alkyl, C 1~6 alkoxyl, C 1~6 haloalkyl, and N(R’)2, and each R’ is independently selected from H and C 1~6 alkyl, R 2 is selected from H and C 1~6 alkyl) to provide further comprises.

[0043] Thus, in another aspect, the present invention relates to a method for preparing a compound of formula (V) or a salt or solvate thereof, comprising steps (a), (b), (c) and (d) as defined herein.

[0044] In another embodiment, the method of the present invention (c) a compound of formula (I) or a salt or solvate thereof to a compound of formula (IV) or a salt or solvate thereof [Chemical formula] (wherein, R 1 is selected from H, F, C 1~6 alkyl, C 1~6 alkoxyl, C 1~6Selected from haloalkyl and N(R’)2, wherein each R’ is independently selected from H and C 1~6 (to convert to) (wherein the selection is from alkyl), (d) Olefination of the compound of formula (IV) or its salt or solvate to provide the compound of formula (Va) or its salt or solvate [Chemical formula] (e) Hydroxylation of the compound of formula (Va) or its salt or solvate to provide the compound of formula (VI) or its salt or solvate [Chemical formula] (f) Oxidation of the compound of formula (VI) or its salt or solvate to provide the compound of formula (VII) or its salt or solvate [Chemical formula] (g) Halogenation of the compound of formula (VII) or its salt or solvate to provide the compound of formula (VIII) or its salt or solvate [Chemical formula] (wherein Y is halogen) and (h) The reaction of the compound of formula (VIII) or its salt or solvate with a 5- to 10-membered heterocycle or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heterocycle and the 5- to 10-membered heteroaryl are unsubstituted or are substituted with C 1~6 alkyl, C 1~6 haloalkyl, halogen, -CN, NO2, -N(R a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f , -C(O)N(R g )(R​h ) and -OC(O)R i Substituted with a substituent selected from the group consisting of R a , R b , R c , R d , R e , R f , R g , R h and R i However, the compound of formula (IX) or its salt or solvate is obtained by a reaction independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. [ka] (In the formula, R 3 The 5-10 member heterocyclyl and 5-10 member heteroaryl are selected from 5-10 member heterocyclyl and 5-10 member heteroaryl, and the 5-10 member heterocyclyl and 5-10 member heteroaryl are unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ) and -OC(O)R i Substituted with a substituent selected from the group consisting of R a , R b , R c , R d , R e , R f , R g , R h and R i (These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.) To provide Includes.

[0045] Thus, in another aspect, the present invention relates to a method for preparing a compound of formula (IX) or a salt or solvate thereof, the method comprising steps (a), (b), (c), (d), (e), (f), (g) and (h) as defined herein.

[0046] In one embodiment, X is Br or I. In a further embodiment, X is Br.

[0047] In one embodiment, R 1 is selected from H, F, C 1~3 alkyl, C 1~3 alkoxyl, C 1~3 haloalkyl, and N(R’)2, where each R’ is independently selected from H and C 1~3 alkyl.

[0048] In one embodiment, R 1 is selected from H, F, C 1~6 alkyl and C 1~6 alkoxyl. In a further embodiment, R 1 is selected from H, F, Me, Et, -OMe and -OEt. According to a particular embodiment, R 1 is H.

[0049] In one embodiment, R 2 is selected from H and C 1~3 alkyl. In a further embodiment, R 2 is selected from H and Me. According to a particular embodiment, R 2 is Me. According to another embodiment, R 2 is H.

[0050] In one embodiment, the 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl of R 3 contain the N atom through which it is attached to the rest of the molecule. Thus, in one embodiment, R 3 is of the formula

Chemical formula

[0051] Therefore, in a particular embodiment, step (h) is to combine a compound of formula (VIII) or a salt or solvate thereof with formula [ka] This includes the reaction with a compound of (wherein Cy is as defined herein).

[0052] In one embodiment, R a , R b , R c , R d , R e , R f , R g , R h and R i These are independently selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0053] In a particular embodiment, R 3Alternatively, Cy is selected from 5-10 member heterocyclyls and 5-10 member heteroaryls, and the 5-10 member heterocyclyls and 5-10 member heteroaryls are unsubstituted or C 1~3 Alkyl, C 1~3 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ) and -OC(O)R i Substituted with a substituent selected from the group consisting of R a , R b , R c , R d , R e , R f , R g , R h and R i These are independently selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0054] In one embodiment, R 3 Alternatively, Cy is selected from 5 or 6-membered heterocyclyls and 5 or 6-membered heteroaryls, and the 5 or 6-membered heterocyclyls and 5 or 6-membered heteroaryls are unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ) and -OC(O)R i Substituted with a substituent selected from the group consisting of R a , R b , R c , R d , R e , R f , R g , Rh and R i These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0055] In further embodiments, R 3 Alternatively, Cy is selected from 5 or 6-membered heterocyclyls and 5 or 6-membered heteroaryls, and the 5 or 6-membered heterocyclyls and 5 or 6-membered heteroaryls are unsubstituted or C 1~3 Alkyl, C 1~3 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ) and -OC(O)R i Substituted with a substituent selected from the group consisting of R a , R b , R c , R d , R e , R f , R g , R h and R i These are independently selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0056] According to one embodiment, R 3Alternatively, Cy is pyrrolidine, piperidine, piperazine, morpholine, pyrrolepyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, indole, isoindole, benzimidazole, indazole, benzotriazole, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-c]pyridine, imidazo[4,5-b]pyridine, imidazo[4, Selected from [5-c]pyridine, pyrazolo[3,4-d]pyrimidine, pyrazolo[4,3-d]pyrimidine, purine, pyrazolo[3,4-b]pyrazine, imidazo[4,5-b]pyrazine, benzotriazole, 1,2,3-triazolo[4,5-b]pyridine, 1,2,3-triazolo[4,5-c]pyridine, 1,2,3-triazolo[4,5-d]pyrimidine, and 1,2,3-triazolo[4,5-b]pyrazine, wherein the group may be unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ) or -OC(O)R i It may be replaced with R a , R b , R c , R d , R e , R f , R g , R h and R i These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0057] In one embodiment, R 3 Alternatively, the substituent on the Cy group is C 1~3 Alkyl, C 1~3 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c, -SR d , -C(O)R e , -C(O)OR f , -C(O)N(R g )(R h ) and -OC(O)R i [[ID=1'], R a , R b , R c , R d , R e , R f , R g , R h and R i are independently selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl. In a further embodiment, the substituent of the R 3 group can be selected from Me, Et, CF3, F, Cl, -CN, -NH2, OMe, OEt, SMe, OCF3, -COMe, -COOH, -COOMe, -CONH2, -CONHMe, and -CONMe2.

[0058] In certain embodiments, R 3 or Cy is [Chemical formula] is. In one embodiment, R 3 or Cy is [Chemical formula] is.

[0059] In certain embodiments, the compound of formula (IX) is [Chemical formula] or a salt or solvate thereof.

[0060] In one embodiment, the compound of formula (IX) is zuranolone or a salt or solvate thereof.

[0061] (a) Olefinization of the compound of formula (II) The compound of formula (III) or its salt or solvate is obtained by olefinization of the compound of formula (II) or its salt or solvate. [ka]

[0062] The olefination reactions of ketones, such as the Wittig reaction, and suitable reaction conditions are well known in the art.

[0063] In one embodiment, olefinization is performed in the presence of a base, formula (X) [ka] (In the formula, W is a halogen such as Br. Each R'' independently comprises C6-C6 such as phenyl. 10 (Selected from the alphabet), This is carried out by a reaction with a compound.

[0064] In one embodiment, the compound of formula (X) is methyltriphenylphosphonium bromide.

[0065] Suitable bases include organolithium bases, alkali metal hydrides, and alkali metal C. 1~6 Examples of alkoxides include nBuLi, tBuLi, sBuLi, MeLi, PhLi, HMDSLi, LDA, NaH, NaOtBu, KOtBu, NaOMe, and NaOEt. In certain embodiments, the base is an alkali metal C such as KOtBu. 1~6 It is an alkoxide.

[0066] Preferably, the reaction is carried out in the presence of an organic solvent such as a cyclic or acyclic ether (e.g., Et2O, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g., pentane, hexane, heptane), a halogenating solvent (e.g., dichloromethane, chloroform), an aromatic solvent (e.g., toluene, xylene), an amide (e.g., DMF, DMA), or a mixture thereof. In certain embodiments, the solvent is a cyclic or acyclic ether, such as THF.

[0067] In a particular embodiment, in the olefination reaction in step (a), the compound of formula (X) is methyltriphenylphosphonium bromide, the base is KOtBu, and the organic solvent is THF.

[0068] In one embodiment, the reaction is carried out at a temperature of -20°C to 50°C or 0°C to 20°C.

[0069] The compound and / or base of formula (X) is preferably used in an amount of 1.0 to 1.5 molar equivalents or 1.0 to 1.2 molar equivalents relative to the compound of formula (II) or its salt or solvate.

[0070] In certain embodiments, a mixture of the compound of formula (X) and a base is first formed in an organic solvent, and the resulting mixture is added to a mixture of the compound of formula (II) or its salt or solvate and an organic solvent.

[0071] (b) Halohydrin formation reaction The compound of formula (I) or its salt or solvate is obtained by the halohydrin formation reaction of the compound of formula (III) or its salt or solvate. [ka]

[0072] In this reaction, the alkene is converted to a halohydrin. The inventors observed that this reaction proceeds regioselectively and stereoselectively, with the halogen atom bonded to a terminal carbon atom, yielding a halohydrin having a beta-halomethylalpha-hydroxy configuration as the major or sole product.

[0073] This reaction can be carried out in the presence of a halohydrin-forming reagent. Typical halohydrin-forming reagents include HOCl, HOBr, HOI, and combinations of a halogenating agent (e.g., N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, Cl2, Br2, I2, DCDMH, DBDMH, or DIDMH) with water.

[0074] In one embodiment, X is Br, and the halohydrin-forming reagent is selected from HOBr, N-bromosuccinimide and water, Br2 and water, and DBDMH and water. In a particular embodiment, it is selected from N-bromosuccinimide and water, and DBDMH and water, or even N-bromosuccinimide and water.

[0075] In another embodiment, X is I, and the halohydrin-forming reagent is selected from HOI, N-iodosuccinimide and water, I2 and water, and DIDMH and water. In a particular embodiment, it is selected from N-iodosuccinimide and water, and DIDMH and water, or even N-iodosuccinimide and water.

[0076] The halohydrin-forming reagent can be used in an amount of 1 to 8 molar equivalents or 1 to 3 molar equivalents relative to the compound of formula (III) or its salt or solvate. If the halohydrin-forming reagent is a combination of a halogenating agent and water, the halogenating agent may be used in an amount of 1 to 8 molar equivalents or 1 to 3 molar equivalents relative to the compound of formula (III) or its salt or solvate. In this case, water can be used in excess, for example, in an amount of 1 to 100 molar equivalents or 5 to 60 molar equivalents relative to the compound of formula (III) or its salt or solvate.

[0077] In one embodiment, the reaction is carried out in the presence of an acid, such as a strong acid (e.g., pKa < 1) such as HClO4, MeSO3H, p-TolSO3H, CF3SO3H, PhSO3H, HCl, HBr, HI, H2SO4, HNO3, or CF3CO2H. In another embodiment, the reaction is carried out in the presence of HClO4.

[0078] The reaction may be carried out in the presence of an organic solvent, such as an aprotic organic solvent, water, or a mixture thereof. In one embodiment, the reaction is carried out in the presence of acetone or a mixture of acetone and water.

[0079] In certain embodiments, the reaction in step (b) is carried out in the presence of N-bromosuccinimide or N-iodosuccinimide, water, HClO4, and an organic acid such as acetone.

[0080] In one embodiment, the reaction is carried out at a temperature of -30°C to 50°C or -20°C to 20°C.

[0081] In another embodiment, the reaction is carried out at a temperature of -20°C to 0°C. In yet another embodiment, the reaction is carried out at a temperature of -15°C to -10°C.

[0082] The inventors have observed that the halohydrin formation reaction of the compound of formula (III) yields a compound of formula (I) with high stereoselectivity. In one embodiment, the compound of formula (I) is obtained in an amount of at least 75% of the sum of the two stereoisomers at the 3-position of the steroid, i.e., the alpha / beta ratio of the hydroxyl group is ≥75 / ≤25. In certain embodiments, the amount is at least 80% (alpha / beta ratio of the hydroxyl group is ≥80 / ≤20), and even more at least 85% (alpha / beta ratio of the hydroxyl group is ≥85 / ≤15). In further embodiments, the amount is at least 90% (alpha / beta ratio of the hydroxyl group is ≥90 / ≤10). The ratio of stereoisomers can be determined by HPLC.

[0083] The inventors have observed that even when some amount of undesirable stereoisomers (beta-hydroxyl isomers at position 3) are formed in the halohydrin formation reaction, small amounts of these undesirable stereoisomers can be easily removed or significantly reduced by purifying the compound of formula (I).

[0084] In certain embodiments, after step b), the compound of formula (I) is purified, for example, by column chromatography or recrystallization. In one embodiment, recrystallization can be carried out in an organic solvent or a mixture of organic solvents such as Et2O, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, tetrahydrofuran, methyltetrahydrofuran, pentane, hexane, heptane, dichloromethane, chloroform, toluene, xylene, acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone, RINKAN, iPrOAc, BuOAc, acetonitrile, methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol, DMSO, and mixtures thereof. In one embodiment, recrystallization can be carried out in a mixture of iPr2O and heptane.

[0085] (c) Conversion of compound (I) to compound (IV) The compound of formula (IV) or its salt or solvate can be obtained from the compound of formula (I) or its salt or solvate.

[0086] [ka]

[0087] In certain embodiments, R in the compound of formula (IV) or its salt or solvate 1 is H. In this embodiment, step (c) is to dehalogenate the compound of formula (I) or its salt or solvate to obtain the compound of formula (IV) or its salt or solvate (wherein R 1 This includes providing that (is H).

[0088] Dehalogenation reactions and suitable reaction conditions are known in the art. In one embodiment, the dehalogenation reaction is carried out in the presence of tin hydride and a radical initiator.

[0089] Examples of tin hydride include tributyltin hydride, triphenyltin hydride, trimethyltin hydride, dimethyltin dihydride, dioctyltin dihydride, diisobutyltin dihydride, and tridecyltin hydride. In one embodiment, the tin hydride is selected from tributyltin hydride and triphenyltin hydride, and is even more specifically tributyltin hydride.

[0090] Tin hydride may be used in amounts of 1 to 8 molar equivalents or 1.2 to 3 molar equivalents relative to the compound of formula (I) or its salt or solvate.

[0091] Radical initiators are well known in the art, and include, in particular, alkyl and aryl peroxides, alkyl and aryl hydroperoxides, acyl peroxides, peroxyesters, persulfates, perborates, percarbonates, and azo compounds. Some specific examples include hydrogen peroxide, dibenzoyl peroxide, didecanoyl peroxide, dilauroyl peroxide, t-butyl hydroperoxide, benzoyl peroxide, di-t-butyl peroxide, di(3,5,5-trimethylhexanoyl) peroxide, diisobutyryl peroxide, t-butyl peroxydiethyl acetate, t-butyl peroctoate, t-butyl peroxyisobutyrate, t-butyl peroxy 3,5,5-trimethylhexanoate, t-butyl perbenzoate, t-butyl peroxypivalate, t-butyl peroxy-2-ethylhexanoate, tert-amyl peroxy-2-ethylhexanoate, 1,1,3,3-tetramethylbutyl peroxy-2-ethylhexanoate, and cumene hydroperoxide, AIBN, and 2,2'-azobis-(2-methylbutyronitrile). In one embodiment, the radical initiator is AIBN.

[0092] The radical initiator can be used in a catalytic amount, such as 0.01 to 0.6 molar equivalents, relative to the compound of formula (I), or its salt or solvate.

[0093] The dehalogenation reaction may be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In certain embodiments, the solvent is a cyclic or acyclic ether, such as THF.

[0094] In certain embodiments, the dehalogenation reaction is carried out in the presence of tin hydride, a radical initiator, and an organic solvent.

[0095] In one embodiment, the dehalogenation reaction is carried out at a temperature of 20°C to 150°C, or 40°C to 100°C.

[0096] In another embodiment, R in the compound of formula (IV) or its salt or solvate1 is F. In this embodiment, step (c) is to treat the compound of formula (I) or a salt or solvate thereof with a base, and then treat it with a fluoride source to obtain the compound of formula (IV) or a salt or solvate thereof (wherein R 1 This includes providing that is F.

[0097] In a fluorination reaction, the compound of formula (IV) or its salt or solvate is first treated with a base. Suitable bases include inorganic and organic bases, such as alkali metal carbonates or bicarbonates (e.g., Na2CO3, K2CO3, Cs2CO3, Li2CO3, NaHCO3, KHCO3, CsHCO3, LiHCO3), alkali metal phosphates (e.g., Na3PO4, K3PO4, Na2HPO4, K2HPO4, NaH2PO4, KH2PO4), alkali metal alkoxides (e.g., NaOMe, KOMe, NaOEt, KOEt, NaOtBu, KOtBu), alkali metal hydroxides (e.g., NaOH, KOH, LiOH, CsOH), and aliphatic or aromatic amines (e.g., Me2NH, Et2NH, iPr2NH, Bu2NH, Me3N, Et3N, Bu3N, iPr2EtN, N-methylmorpholine, pyridine, DMAP, aniline, N,N-dimethylaniline). In one embodiment, the base is an inorganic base such as an alkali metal carbonate, bicarbonate, or phosphate. In another embodiment, the base is K2CO3.

[0098] After treatment with a base, the fluorination reaction involves treating the resulting compound with a fluoride source. Fluoride sources are well known in the art and include, for example, KF, tetramethylammonium fluoride, tetrabutylammonium fluoride, ammonium fluoride, ammonium hydrogen fluoride, ammonium borofluoride, and fluoroboric acid. In one embodiment, the fluoride source is tetrabutylammonium fluoride.

[0099] The base and fluoride source can be used in amounts of 1.5 to 50 molar equivalents or 5 to 40 molar equivalents relative to the compound of formula (I), or its salt or solvate.

[0100] The fluorination reaction may be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In certain embodiments, the solvent is a cyclic or acyclic ether, such as THF, or an aromatic solvent, such as toluene.

[0101] In one embodiment, the fluorination reaction is carried out at a temperature of 20°C to 150°C, for example, 60°C to 120°C.

[0102] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1 C 1~6 It is alkyl. In this embodiment, step (c) is to mix a compound of formula (I) or a salt or solvate thereof with formula (C 1~6 A compound of the form alkyl)MgZ (wherein Z is selected from Cl, Br, or I) or the formula (C 1~6 Reaction with alkyl)2CuLi compounds yields the compound of formula (IV) or its salt or solvate (wherein R, R 1 is C 1~6 This includes providing (that which is alkyl).

[0103] Formula (C 1~6 Alkyl)MgZ or (C 1~6 The alkyl)2CuLi compound may be used in an amount of 1.5 to 10 molar equivalents or 2 to 6 molar equivalents relative to the compound of formula (I) or its salt or solvate.

[0104] In one embodiment, C 1~6 Alkyls are C such as Me or Et. 1~3 It is alkyl.

[0105] Formula (C 1~6 Alkyl)MgZ or (C 1~6 The reaction with alkyl)2CuLi compounds can be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In certain embodiments, the solvent is a cyclic or acyclic ether, such as THF.

[0106] In one embodiment, formula (C 1~6Alkyl)MgZ or (C 1~6 The reaction with alkyl)2CuLi compounds takes place at temperatures of -80°C to 20°C, -80°C to 0°C, or even -80°C to -40°C.

[0107] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1 C 1~6 It is an alkoxyl. In this embodiment, step (c) is to mix a compound of formula (I) or a salt or solvate thereof with formula (C 1~6 Reaction with a compound of alkoxyl)M (wherein M is selected from Na and K) yields a compound of formula (IV) or its salt or solvate (wherein R 1 is C 1~6 The invention includes providing an alkoxyl.

[0108] Formula (C 1~6 The alkoxy(M) compound can be used in an amount of 1.5 to 10 molar equivalents or 2 to 8 molar equivalents relative to the compound of formula (I), or its salt or solvate.

[0109] In one embodiment, C 1~6 Alkoxyls are C such as -OMe or -OEt. 1~3 It is an alkoxyl.

[0110] Formula (C 1~6 The reaction of alkoxyl)M with compounds can be carried out in the presence of organic solvents such as alcohols (e.g., MeOH, EtOH, nPrOH, iPrOH, sBuOH, tBuOH).

[0111] In one embodiment, formula (C 1~6 The reaction with the alkoxyl) M compound takes place at a temperature of 20°C to 150°C, for example, 50°C to 120°C.

[0112] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1 C 1~6It is a haloalkyl compound. In this embodiment, step (c) is a compound of formula (I) or a salt or solvate thereof, and formula (C 1~6 A compound of the formula (haloalkyl)MgZ (wherein Z is selected from Cl, Br, and I) or a compound of the formula (C 1~6 Reaction with a compound of haloalkyl)2CuLi yields the compound of formula (IV) or its salt or solvate (wherein R, R 1 is C 1~6 This includes providing a haloalkyl product.

[0113] Preferably, the haloalkyl is a fluoroalkyl, i.e., an alkyl group in which at least one H atom is replaced by a F atom.

[0114] Formula (C 1~6 (Haloalkyl) MgZ or (C 1~6 The compound of (haloalkyl)2CuLi may be used in an amount of 1.5 to 10 molar equivalents or 2 to 6 molar equivalents relative to the compound of formula (I) or its salt or solvate.

[0115] In one embodiment, C 1~6 Haloalkyls are C such as CF3, CHF2, CH2F, or CF2CF3. 1~3 It is a haloalkyl group.

[0116] Formula (C 1~6 (Haloalkyl) MgZ or (C 1~6 The reaction with the haloalkyl)2CuLi compound can be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In certain embodiments, the solvent is a cyclic or acyclic ether, such as THF.

[0117] In one embodiment, formula (C 1~6 (Haloalkyl) MgZ or (C 1~6 The reaction with the haloalkyl)2CuLi compound takes place at temperatures of -80°C to 20°C, or -80°C to 0°C, or even -80°C to -40°C.

[0118] In another embodiment, R in the compound of formula (IV) or its salt or solvate1 is -N(R')², where each R' is independently H and C 1~6 Selected from alkyl. In this embodiment, step (c) is the reaction of a compound of formula (I) or a salt or solvate thereof with a compound of formula HN(R')2 to produce a compound of formula (IV) or a salt or solvate thereof (wherein R 1 is -N(R')², and each R' is independently H and C 1~6 This includes providing (selected from alkyl groups).

[0119] In one embodiment, each R' is independently H and C 1~3 Alkyl elements are selected from, for example, H, Me, or Et.

[0120] The compound of formula HN(R')2 can be used in an amount of 1 to 10 molar equivalents or 1 to 6 molar equivalents relative to the compound of formula (I), or its salt or solvate.

[0121] The reaction with the compound of formula HN(R')2 can be carried out in the presence of an organic solvent, such as an aprotic organic solvent.

[0122] In one embodiment, the reaction with the compound of formula (HN(R')2) is carried out at a temperature of 20°C to 120°C.

[0123] (d) Olefination of the compound of formula (IV) The compound of formula (V) or its salt or solvate can be obtained by olefinization of the compound of formula (IV) or its salt or solvate. [ka]

[0124] In a particular embodiment, R 2 Since is Me, the compound of formula (V) has formula (Va) as defined herein.

[0125] The olefination reactions of ketones, such as the Wittig reaction, and suitable reaction conditions are well known in the art.

[0126] In one embodiment, olefinization is performed on the compound of formula (XI) in the presence of a base. [ka] (In the formula, W is a halogen such as Br. R 2 H and C 1~6 Selected from alkyl groups, Each R''' independently comprises C6~C such as phenyl. 10 (Selected from the arrows) This is done through a reaction.

[0127] In one embodiment, R 2 H and C 1~3 Alkyl, selected from, for example, H, Me, or Et. In further embodiments, R 2 It is selected from H and Me.

[0128] In one embodiment, the compound of formula (XI) is methyltriphenylphosphonium bromide or ethyltriphenylphosphonium bromide.

[0129] Suitable bases include organolithium bases, alkali metal hydrides, and alkali metal C. 1~6 Examples of alkoxides include nBuLi, tBuLi, sBuLi, MeLi, PhLi, HMDSLi, LDA, NaH, NaOtBu, KOtBu, NaOMe, and NaOEt. In certain embodiments, the base is an alkali metal C such as KOtBu. 1~6 It is an alkoxide.

[0130] In olefination reactions, the compound and / or base of formula (XI) may be used in amounts of 1 to 10 molar equivalents or 1 to 6 molar equivalents relative to the compound of formula (IV) or its salt or solvate.

[0131] In one embodiment, the olefination reaction is carried out in the presence of an organic solvent, for example, a cyclic or acyclic ether (e.g., Et2O, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g., pentane, hexane, heptane), a halogenating solvent (e.g., dichloromethane, chloroform), an aromatic solvent (e.g., toluene, xylene), an amide (e.g., DMF, DMA), or a mixture thereof. In a particular embodiment, the solvent is a cyclic or acyclic ether, for example, THF.

[0132] In certain embodiments, the olefinization reaction in step (d) is performed with the compound of formula (XI) being methyltriphenylphosphonium bromide or ethyltriphenylphosphonium bromide, the base being KOtBu, and the organic solvent being THF.

[0133] In one embodiment, the reaction is carried out at a temperature of -20°C to 60°C or 0°C to 40°C.

[0134] Conversion of compounds of formulas (IV) and (V) to other active compounds Compounds of formulas (IV) and (V) have been disclosed in the prior art as important intermediates in the production of biologically active compounds, such as those disclosed in WO2013 / 156181, WO2014 / 169832, WO2014 / 169833, WO2014 / 169836, WO2015 / 180679 or WO2020 / 118060, which include zulanolone.

[0135] Therefore, the method of the present invention provides a highly efficient method for producing very versatile and important intermediates.

[0136] In one embodiment, the present invention further comprises converting a compound of formula (V) or a salt or solvate thereof to a compound of formula (IX) or a salt or solvate thereof. Methods for such conversion are known in the art (e.g., WO2013 / 156181, WO2014 / 169832, WO2014 / 169833, WO2014 / 169836, WO2015 / 180679).

[0137] In certain embodiments, the present invention further includes converting a compound of formula (Va) or a salt or solvate thereof to a compound of formula (IX) or a salt or solvate thereof by a method comprising: [ka] (e) To provide a compound of formula (VI) or a salt or solvate thereof by hydroxylation of a compound of formula (Va) or a salt or solvate thereof, (f) To provide a compound of formula (VII) or a salt or solvate thereof by oxidation of a compound of formula (VI) or a salt or solvate thereof, (g) To provide a compound of formula (VIII) or a salt or solvate thereof by halogenation of a compound of formula (VII) or a salt or solvate thereof, and (h) A reaction between a compound of formula (VIII) or a salt or solvate thereof and a 5-10 membered heterocycle or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocycle and the 5-10 membered heteroaryl are unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ), -OC(O)R i Replaced with R a , R b , R c , R d , Re , R f , R g , R h and R i These are independently reacted with hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl to form a compound of formula (IX) or its salt or solvate. (In the formula, Y is a halogen, R 1 H, F, C 1~3 Alkyl, C 1~6 Alkoxyl, C 1~6 Selected from haloalkyl and N(R')2, where each R' is independently H and C 1~6 Selected from alkyl groups, R 3 The 5-10 member heterocyclyl and 5-10 member heteroaryl are selected from 5-10 member heterocyclyl and 5-10 member heteroaryl, and the 5-10 member heterocyclyl and 5-10 member heteroaryl are unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ) and -OC(O)R i Substituted with a substituent selected from the group consisting of R a , R b , R c , R d , R e , R f , R g , R h and R i (These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.) To provide.

[0138] In one embodiment, Y is Br.

[0139] In one embodiment, R 1 H, F, C1~3 Alkyl and C 1~3 Alkoxyls are selected from, for example, H, F, Me, Et, -OMe, and -OEt.

[0140] In a particular embodiment, R 1 H is R 3 It is 4-cyanopyrazole.

[0141] In further embodiments, the compound of formula (IX) is zulanolone or a salt or solvate thereof. [ka]

[0142] The methods and conditions for steps (e), (f), (g), and (h) are disclosed in the prior art (e.g., WO2013 / 156181, WO2014 / 169832, WO2014 / 169833, WO2014 / 169836, WO2015 / 180679). In certain embodiments, the steps may be carried out as follows:

[0143] In one embodiment, the hydroxylation in step (e) may be carried out by hydroboration-oxidation, such as treating the compound of formula (Va) or its salt or solvate with borane followed by treatment with an oxidizing agent.

[0144] Hydroboration can be carried out in the presence of a borane selected from BH3, BH3·SMe2, BH3·THF, BH3·Et2O, 9BBN, catecholborane, or diciamilborane.

[0145] The resulting borane can be oxidized in the presence of an oxidizing agent such as sodium perborate, hydrogen peroxide, or sodium hypochlorite.

[0146] The hydroxylation in step (e) may be carried out in the presence of an organic solvent and optionally water. In one embodiment, the organic solvent is a cyclic or acyclic ether, such as THF.

[0147] In certain embodiments, the hydroxylation in step (e) is carried out by treating the compound of formula (Va) or its salt or solvate with borane (e.g., BH3, BH3·SMe2, BH3·THF, BH3·Et2O, 9BBN) in an organic solvent, followed by treatment with sodium perborate or hydrogen peroxide and a base (e.g., NaOH).

[0148] In one embodiment, the hydroxylation in step (e) is carried out at a temperature of -20°C to 60°C, or 0°C to 40°C.

[0149] In one embodiment, the oxidation in step (f) may be carried out by treating the compound of formula (VI) or its salt or solvate with an oxidizing agent.

[0150] Suitable oxidizing agents include, in particular, IBX, Des-Martin periodinane (DMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), K2Cr2O7, KMnO4, MnO2, CrO3, RuO4, Jones reagent, and Collins reagent.

[0151] In one embodiment, the oxidation in step (f) is carried out in the presence of an organic solvent, such as DMSO or dichloromethane.

[0152] In one embodiment, the oxidation in step (f) is carried out by treatment with an oxidizing agent selected from IBX, DMP, PCC, or PDC and an organic solvent.

[0153] In one embodiment, the oxidation in step (f) is carried out at a temperature of 0°C to 80°C, for example, 10°C to 70°C.

[0154] In one embodiment, the halogenation in step (g) may be carried out in the presence of a halogen source and an acid.

[0155] Suitable sources of halides include, in particular, Cl2, N-chlorosuccinimide, DCDMH, Br2, N-bromosuccinimide, DBDMH, I2, N-iodosuccinimide, and DIDMH.

[0156] Suitable acids include, for example, HClO4, MeSO3H, p-TolSO3H, CF3SO3H, PhCO2H, CH3CO2H, PhSO3H, HCl, HBr, HI, H2SO4, HNO3, CF3CO2H, and CCl3CO2H.

[0157] In one embodiment, the halogenation in step (g) is carried out in the presence of NBS or Br and an acid, such as HClO4 or HBr.

[0158] In one embodiment, the halogenation in step (g) is carried out in the presence of an organic solvent, such as an alcohol such as MeOH.

[0159] In one embodiment, the oxidation in step (f) is carried out at a temperature of 0°C to 80°C, for example, 10°C to 50°C.

[0160] In one embodiment, the reaction of step (h) may be carried out in the presence of a base and a 5-10 membered heterocycle or a 5-10 membered heteroaryl, wherein the 5-10 membered heterocycle and the 5-10 membered heteroaryl are unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ), -OC(O)R i Replaced with R a , R b , R c , R d , R e , R f , R g , R h and Ri These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0161] Suitable bases include inorganic and organic bases, such as alkali metal carbonates or bicarbonates (e.g., Na2CO3, K2CO3, Cs2CO3, Li2CO3, NaHCO3, KHCO3, CsHCO3, LiHCO3), alkali metal phosphates (e.g., Na3PO4, K3PO4, Na2HPO4, K2HPO4, NaH2PO4, KH2PO4), alkali metal alkoxides (e.g., NaOMe, KOMe, NaOEt, KOEt, NaOtBu, KOtBu), alkali metal hydroxides (e.g., NaOH, KOH, LiOH, CsOH), and aliphatic or aromatic amines (e.g., Me2NH, Et2NH, iPr2NH, Bu2NH, Me3N, Et3N, Bu3N, iPr2EtN, N-methylmorpholine, pyridine, DMAP, aniline, N,N-dimethylaniline). In one embodiment, the base is an inorganic base, such as an alkali metal carbonate, such as Na2CO3, K2CO3, or Cs2CO3. In a particular embodiment, the base is K2CO3.

[0162] In one embodiment, a 5-10 membered heterocycle or a 5-10 membered heteroaryl is defined by formula [ka] (In the formula, Cy is selected from 5-10 member heterocyclyls and 5-10 member heteroaryls, and the 5-10 member heterocyclyls and 5-10 member heteroaryls are either unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ), -OC(O)R i Replaced with R a , R b, R c , R d , R e , R f , R g , R h and R i R is a compound independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In one embodiment, R a , R b , R c , R d , R e , R f , R g , R h and R i These are independently selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl.

[0163] According to one embodiment, a 5-10 membered heterocycle or 5-10 membered heteroaryl is pyrrolidine, piperidine, morpholine, piperazine, pyrrolepyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, indole, isoindole, benzimidazole, indazole, benzotriazole, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-c]pyridine, imidazo[4, Selected from [5-b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[3,4-d]pyrimidine, pyrazolo[4,3-d]pyrimidine, purine, pyrazolo[3,4-b]pyrazine, imidazo[4,5-b]pyrazine, benzotriazole, 1,2,3-triazolo[4,5-b]pyridine, 1,2,3-triazolo[4,5-c]pyridine, 1,2,3-triazolo[4,5-d]pyrimidine, and 1,2,3-triazolo[4,5-b]pyrazine, the compound is either unsubstituted or C 1~6 Alkyl, C 1~6 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(Rg )(R h ), -OC(O)R i It may be replaced with R a , R b , R c , R d , R e , R f , R g , R h and R i These are independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0164] In one embodiment, the substituents of a 5-10 membered heterocyclic or 5-10 membered heteroaryl compound are C 1~3 Alkyl, C 1~3 Haloalkyl, halogen, -CN, NO2, -N(R) a )(R b ), -OR c , -SR d , -C(O)R e , -C(O)OR f ,-C(O)N(R g )(R h ), -OC(O)R i You can choose from R a , R b , R c , R d , R e , R f , R g , R h and R i The substituents are independently selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl. In further embodiments, substituents on 5-10 membered heterocyclic or 5-10 membered heteroaryl compounds can be selected from Me, Et, CF3, F, Cl, -CN, -NH2, OMe, OEt, SMe, OCF3, -COMe, -COOH, -COOMe, -CONH2, -CONHMe, and -CONMe2.

[0165] In certain embodiments, the 5- to 10-membered heterocyclic or 5- to 10-membered heteroaryl compound is 4-cyanopyrazole, imidazole, 5-methyl-2H-tetrazole, 5-chloro-2H-benzotriazole, or 1-piperazin-yl-ethanone. In one embodiment, this is 4-cyanopyrazole.

[0166] In one embodiment, the reaction in step (h) is carried out in the presence of an organic solvent, such as an aprotic organic solvent, such as DMSO, DMF, THF, CAN, or acetone.

[0167] In one embodiment, the reaction in step (h) is carried out at a temperature of 0°C to 80°C, for example, 10°C to 50°C.

[0168] In certain embodiments, the present invention relates to a zulanolone or a salt or solvate (wherein R) comprising (a) to (h) disclosed herein. 1 H is R 3 The present invention relates to a method for preparing (where is 4-cyanopyrazole). In this embodiment, X and Y may be Br.

[0169] In one embodiment, the present invention comprises formulas (a) to (h) disclosed herein. [ka] Compounds of or salts or solvates of (wherein R 1 is -H, and R 3 The present invention relates to a method for preparing (where is imidazole). In this embodiment, X and Y may be Br.

[0170] In one embodiment, the present invention comprises formulas (a) to (h) disclosed herein. [ka] Compounds of or salts or solvates of (wherein R 1 is -OMe, R 3The present invention relates to a method for preparing (where is 5-methyl-2H-tetrazole). In this embodiment, X and Y may be Br.

[0171] In one embodiment, the present invention comprises formulas (a) to (h) disclosed herein. [ka] Compounds of or salts or solvates of (wherein R 1 is -OMe, R 3 The present invention relates to a method for preparing (where is 5-chloro-2H-benzotriazole). In this embodiment, X and Y may be Br.

[0172] In one embodiment, the present invention comprises formulas (a) to (h) disclosed herein. [ka] Compounds of or salts or solvates of (wherein R 1 H is R 3 The present invention relates to a method for preparing (where is 1-piperazin-yl-ethanone). In this embodiment, X and Y may be Br.

[0173] intermediate compound The compounds of formula (I) and their salts or solvates have been found by the present inventors to be useful and versatile intermediates for the synthesis of active compounds such as zulanolone and their intermediates.

[0174] Therefore, in another embodiment, the present invention relates to a compound of formula (I) or a salt or solvate thereof. [ka] (In the formula, X is selected from Cl, Br, and I) Regarding.

[0175] The compound of formula (III) is a useful intermediate in the preparation of the compound of formula (I), and therefore in the synthesis of zulanolone and structurally related compounds, such as the compound of formula (IX).

[0176] Therefore, in another embodiment, the present invention relates to a compound of formula (III), or a salt or solvate thereof. [ka] Regarding.

[0177] It should be understood that the scope of this disclosure includes all possible combinations of the embodiments disclosed herein.

[0178] The following examples illustrate the present invention, but are not intended to limit its scope. [Examples]

[0179] Synthesis of Compound 2 [ka] Suspensions of MePPh3Br (87.7 g, 24.05 mmol) and t-BuOK (27.0 g, 24.05 mmol) in THF (330 mL) were stirred under a nitrogen atmosphere at 20–25°C for 1 hour. The mixture was slowly added to suspension 1 (60 g, 21.87 mmol) in THF (330 mL) at a temperature of 0–5°C. After consumption of the starting materials, water (600 mL) was added to the suspension, the solvent was removed under vacuum, and the aqueous layer was extracted twice with DCM (300 mL). Substitution of heptane with DCM promotes phosphine precipitation. Compound 2 was isolated in MeOH / H2O. (White solid, 58.7 g, yield 98%) 1 H NMR(500 MHz, CDCl3):0.85(s,3H),1.03-1.39(m,7H),1.45-1.66(m,5H),1.75-1.99(m,8H),2.04(dt,J=19.1,8.6 Hz,1H),2.33(t,J=13.3 Hz,1H),2.40(ddd,J=19.1,8.6,0.82 Hz,1H),4.55(s,2H).13 C NMR(125 MHz, CDCl3):13.9,21.8,25.0,25.2,29.4,29.5,31.4,31.8,35.8,36.0,38.6,38.8,40.9,41.4,48.1,50.7,106.7,150.2,221.4.

[0180] Synthesis of Compound 3 [ka] To a solution of 2 (38.1 g, 139.94 mmol) in acetone (495 mL), water (95 mL) was added, and the reaction mixture was cooled to -10 / -15°C. Then, HClO 470% (16.7 mL, 195.9 mmol) was slowly added without raising the temperature to -10°C. Next, the temperature was adjusted to -10°C, and NBS (29.9 g, 167.92 mmol) was added all at once. The reaction mixture was stirred at that temperature until the starting materials were consumed (isomer ratio 92 / 8%, α / β). The reaction mixture was left to stand at 10 / 15°C. Then, the reaction mixture was added to a solution of sodium metabisulfite (5% in H2O, 580 mL). The resulting solid was filtered and purified in an isopropyl ether / heptane mixture to obtain 3 as a white solid (36.2 g, yield 70%, isomer ratio α / β 97.5 / 2.5%). 1 H NMR(500 MHz, CDCl3):0.89(s,3H),1.06-1.41(m,7H),1.48-1.54(m,2H),1.54-1.59(m,4H ),1.67-1.85(m,5H),1.87-1.98(m,3H),2.07-2.14(m,2H),2.45(dd,J=19.3,8.6 Hz,1H),3.70(q,J=10.6 Hz,2H). 13 C NMR(125 MHz, CDCl3):13.9,21.8,24.9,25.0,25.1,30.5,31.1,31.7,34.4,36.0,37.0,38.1,40.2,41.2,44.1,48.0,50.7,71.6,221.4.

[0181] Synthesis of Compound 4 [ka] To a solution of 2 (5 g, 18.2 mmol) in acetone (65 mL), water (12.5 mL) was added. The reaction mixture was cooled to 0°C, and HClO4 (2.65 mL, 31.0 mmol) was added without raising the temperature to 5°C. Next, N-iodosuccinimide (6.17 g, 27.4 mmol) was added all at once, and the reaction mixture was stirred at 0°C for 1 hour. After consumption of the starting material, an aqueous solution of sodium metabisulfite was slowly added, and the reaction mixture was stirred for 10 minutes. Next, the acetone was removed under vacuum, and the aqueous phase was extracted by DCM. The aqueous phase was re-extracted in another part of the DCM, and the solvent was removed under vacuum to obtain a yellow oily substance (isomer ratio 79 / 21 α / β%). Purification of the compound by column chromatography yielded a white solid (4.9 g, yield 65%). 1 H NMR(500 MHz, CDCl3):0.83(s,3H),1.02-1.35(m,7H),1.41-1.58(m,6H),1.61-1.76(m,4H),1.79-1.96(m,4H),1.99-2.08(m,2H),2.41(dd,J=19.2,8.7 Hz,1H),3.54(s,2H). 13 C NMR(125 MHz, CDCl3):13.9,21.8,22.3,25.0,25.1,31.1,31.4,31.7,34.4,36.0,37.9,38.0,40.2,41.1,48.0,50.6,70.9,221.3.

[0182] Synthesis of Compound 5 [ka] AIBN (1.38 g, 8.4 mmol) was added under a nitrogen atmosphere to a solution of 3 (34.5 g, 93.4 mmol) in THF (380 mL), and then heated under reflux. Bu3SnH (42.37 mL, 156 mmol) was then added little by little (four times). The reaction mixture was stirred until the starting materials were consumed (TLC: toluene / siRNA, 4 / 1). The reaction mixture was then cooled to room temperature, and the compound was isolated in heptane as a white solid (23.8 g, yield 69%, isomer ratio 99.3 / 0.7%).1 H NMR(500 MHz, CDCl3):0.89(s,3H),1.05-1.25(m,3H),1.29(s,3H),1.32-1.56(m,11H), 1.65-1.90(m,6H),1.92-1.97(m,1H),2.06-2.13(m,1H),2.45(dd,J=19.3,8.6 Hz,1H). 13 C NMR(125 MHz, CDCl3):13.9,21.8,25.1,25.3,25.6,26.6,31.4,31.8,34.6,34.9,36.1,38.2,40.5,41.2,41.3,48.1,50.7,72.1,221.6.

[0183] Synthesis of Compound 6 [ka]

[0184] Potassium t-butoxide (50.1 g, 445 mmol) was added to a suspension of ethyltriphenylphosphonium bromide (165.4 g, 445 mmol) in THF (650 mL). The mixture was heated at 60°C and stirred for 1 hour. Then, a suspension of 5 (86.3 g, 297 mmol) in THF was added, and the reaction mixture was stirred overnight at 60°C. After consumption of the starting material, the temperature was lowered to 20-25°C, followed by the addition of acetone (22 mL, 297 mmol) and water (860 mL). Then, the THF was evaporated under reduced pressure, and DCM (860 mL) was added. The resulting aqueous layer was extracted with DCM (200 mL), and both organic layers were joined. Substitution of heptane with DCM promotes phosphine precipitation. 6 was not isolated but used in solution in the next step.

[0185] Synthesis of Compound 7 [ka] To a solution of 6 (57.8 g, 191.1 mmol) in THF (752 mL), BH3·SMe2 (143.5 mL, 286.7 mmol) was added through an additive funnel. The temperature was set to 20-25°C and the mixture was stirred for 3 hours. Once the boron intermediate was formed, water (289 mL) was slowly added. Then, a portion of sodium perborate (91.1 g, 573.3 mmol) was added. The reaction mixture was heated to 40°C and stirred for 16 hours. After a positive control, the reaction mixture was cooled to 20-25°C and the salt was filtered. The THF was removed and the aqueous phase was extracted with methylene chloride (580 mL). The obtained aqueous phase was extracted with methylene chloride (290 mL). The organic phase was joined and DCM was replaced with methanol. Water (175 mL) was added. The reaction mixture was cooled to 0 / 5°C for 1 hour, and filtered to obtain a white solid (58.1 g, yield 94.9%).

[0186] Synthesis of compound 8 [ka] A suspension of IBX (7.54 g, 26.97 mmol) and 7 (7.86 g, 24.52 mmol) in DMSO (150 mL) was heated to 60°C. The reaction mixture was stirred at that temperature for 1 hour. After consumption of the starting materials, the mixture was cooled to 20-25°C. This was then slowly added to a solution of sodium metabisulfite (7 g, 36.78 mmol) in water (160 mL) and stirred for 1 hour. The suspension was filtered and washed with water. The solid was resuspended in water. The resulting solid was dissolved in DCM and washed sequentially with a solution of NaHCO3 and water. The compound was then precipitated in MeOH / water (5 g, 78.5% yield).

[0187] Synthesis of compound 9 [ka] To a suspension of 8 (5 g, 15.6 mmol) and NBS (3.35 g, 18.8 mmol) in MeOH (20 mL), HClO4 (1.89 mL, 21.9 mmol) was added. The reaction mixture was stirred at 20-25°C for 1 hour and 10 minutes. After consumption of the starting materials, MeOH (10 mL) and a solution of sodium metabisulfite (1.49 g, 7.84 mmol) in water (5 mL) were subsequently added. Then, additional water was added very slowly, and the precipitation of the product was observed. The solid was filtered and washed with water (5.79 g, yield 92.9%).

[0188] Synthesis of zuranolone [ka] A suspension of 9 (16.5 g, 41.67 mmol), K2CO3 (7.14 g, 51.67 mmol), and 4-cyanopyrazole (4.62 g, 49.59 mmol) in DMSO (165 mL) was stirred at 20-25°C for 1 hour. After consumption of the starting materials, the reaction mixture was slowly added to water (660 mL) and stirred for 1 hour. The suspension was filtered, and the solid was washed with water (17 g, 99.8% yield). The compound was then purified with MTBE and SiO / heptane (13.7 g, 80.5% yield).

[0189] Synthesis of compound 10 [ka] To a 250 mL flask containing 3 (1.28 g, 3.4670 mmol), THF (50 mL) and K2CO3 (10 g) were added, and the mixture was heated under reflux for 2 days. After cooling to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The mixture was concentrated into a 100 mL flask, and toluene (10 mL) and TBAF (50 mL of 1 M solution in THF, 50 mmol) were added to the flask. The mixture was concentrated to one-third of its volume using a rotary evaporator. This procedure was repeated twice, and toluene (10 mL) and TBAF (40 mL of 1 M solution in THF, 40 mmol) were added. The mixture was concentrated to one-third of its volume using a rotary evaporator, and 20 mL of toluene was added. The mixture was concentrated to a final volume of 50 mL using a rotary evaporator. This mixture was heated under reflux (120 °C) for 72 hours, cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over Na2SO4, filtered, and concentrated. The resulting crude reaction product (13.6 g) was purified by column chromatography using heptane / ethyl acetate 3 / 1 as the eluent to obtain 10 (660 mg, yield 62%). 1 H NMR(400 MHz, CDCl3):0.87(s,3H),1.02-1.43(m,10H),1.44-1.70(m,6H),1.73-1.98(m,5H),2.01-2.16(m,1H),2.44(dd,J=19.2,8.6 Hz,1H),4.36(q,J=9.4 Hz,1H),4.48(q,J=9.4 Hz,1H).

[0190] Synthesis of compound 11 [ka] A 50 mL flask containing MePPh3Br (2.7 g, 7.6 mmol) was subjected to three vacuum / Ar cycles, and dry THF (20 mL) and t-BuOK (7.6 mmol, 7.6 mL, 1 M solution in THF) were added. The reaction product turned yellow and was left to stand at room temperature with stirring for 1 hour. Compound 9 (586 mg, 1.9 mmol) dissolved in 5 mL of anhydrous THF was added under Ar conditions, and the mixture was left to stand at room temperature with stirring for 15 hours. Water was added, the mixture was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The resulting crude reaction product (2.1 g) was purified by column chromatography using heptane / ethyl acetate 8 / 1 as the eluent to obtain compound 11 (55 mg, yield 9%). 1 H NMR(400 MHz, CDCl3):0.79(s,3H),1.08-1.16(m,4H),1.18-1.35(10H),1.57-1.85(9H),2.18-2.30(m,2H),2.47(m,1H),4.48(dq,2H),4.62(m,2H).

[0191] Synthesis of compound 12 [ka] A 100 mL flask containing 3 (1 g, 2.70 mmol) was mixed with methanol (50 mL) and 25% MeONa (2.5 mL, 10.83 mmol) and heated under reflux for 29 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted twice with DCM, dried over Na2SO4, filtered, and concentrated. The resulting yellow oily substance did not require purification, and product 12 (782 mg, 90% yield) was obtained directly. 1 H NMR(400 MHz, CDCl3):0.85(s,3H),1.01-1.15(m,2H),1.18-1.57(m,11H),1.59-1.67(m,2 H),1.73-1.77(m,3H),1.79-1.85(m,2H),1.90-1.95(m,1H),2.07(dt,J=19.2,8.9 Hz,1H),2.43(dd,J=19.2,8.6 Hz,1H)3.35-3.45(m,5H).

[0192] Synthesis of compound 13 [ka] A 25 mL flask containing MePPh3Br (812 mg, 2.27 mmol) and t-BuOK (255 mg, 2.27 mmol) was subjected to three vacuum / Ar cycles, and dry THF (7 mL) was added. The mixture was left to stand at room temperature with stirring for 1 hour. Compound 11 (607 mg, 1.89 mmol), which had been placed in 3 mL of dry THF under an inert Ar atmosphere, was added to the previously prepared ylide. This mixture was left to stand at room temperature with stirring for 22 hours, a saturated aqueous solution of NH4Cl was added, and the mixture was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The resulting crude reaction product (1.1 g) was purified by column chromatography using heptane / ethyl acetate 4 / 1 as the eluent to obtain compound 13 (270 mg, yield 45%). 1 H NMR(400 MHz, CDCl3):0.77(s,3H),1.06-1.88(m,21H),2.23(m,1H),2.46-2.51(m,1H),3.37-3.43(m,5H),4.62(m,2H).

[0193] Synthesis of compound 14 [ka] To a 100 mL flask containing 3 (1 g, 2.70), anhydrous EtOH (50 mL) and 20% EtONa (13.5 mmol, 4.9 mL) were added, and the mixture was heated under reflux for 5 hours. The mixture was cooled to room temperature, saturated aqueous solution of NH4Cl was added, and the mixture was extracted twice with ethyl acetate. It was dried over Na2SO4, filtered, and concentrated. The resulting crude reaction product (1.03 g) was purified by column chromatography using heptane / ethyl acetate 1.5 / 1 as the eluent to obtain product 14 (561 mg, yield 62%). 1H NMR(400 MHz, CDCl3):0.82(s,3H),1.15-1.92(m,24H),2.04(dt,J=19.2,8.9 Hz 1H),2.38(dd,J=19.3,8.4 Hz,1H),3.38(AB system,J=9.2 Hz,2H),3.49(q,J=9.2 Hz,2H).

[0194] Synthesis of Compound 15 [ka] A flask containing EtPPh3Br (444 mg, 1.2 mmol) was subjected to three vacuum / Ar cycles, and dry THF (2 mL) and t-BuOK (1.2 mmol, 1.2 mL, in 1 M THF) were added. The mixture was stirred at room temperature for 1 hour. A solution of 14 (200 mg, 0.5979 mmol) in THF under an inert Ar atmosphere was added, and the mixture was stirred at room temperature for 3 days. Water was added to the reactants, extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The crude reaction product (533 mg) was purified by column chromatography using heptane / ethyl acetate 6 / 1 as the eluent to obtain compound 15 (153 mg, yield 73%). 1 H NMR(400 MHz, CDCl3):0.86(s,3H),1.04-1.84(m,26H),2.13-2.25(m,2H),2.32-2.37(m,1H),3.41(AB system,J=9.2 Hz,2H),3.52(q,J=7.0 Hz,2H),5.10(m,1H).

[0195] Synthesis of compound 16 [ka]

[0196] CuI (2.1 g, 10.8 mmol) and a flask containing a large stirring core were subjected to three vacuum / Ar cycles, and dry ether (70 mL) was added. The mixture was cooled to -30°C, and MeLi (21.7 mmol, 13.5 mL in 1.6 M ether solution) was added dropwise. This was stirred at -30°C for 30 minutes, then the temperature was lowered to -78°C, and 3 (under Ar, 1.0 g, 2.7 mmol, in 10 mL of dry THF solution) was added dropwise. This was stirred at -78°C for 2 hours, the flask was opened, 28% NH3 in water was added, the temperature was raised, saturated aqueous solution of NH4Cl was added, and the mixture was extracted twice with DCM. The organic phase was washed with NH4Cl (aqueous solution), dried over Na2SO4, filtered, and concentrated. The resulting crude reaction product (760 mg) was purified by column chromatography using heptane / methyl tert-butyl ether 1 / 1 as the eluent to obtain 16 (350 mg, yield 42%). 1 H NMR(400 MHz, CDCl3):0.85-0.88(m,6H),1.03-1.81(m,22H),1.88-1.95(m,1H),2.06(dt,J=19.2,8.9 Hz,1H),2.41(dd,J=11.2,8.0 Hz,1H).

[0197] Synthesis of Compound 17 [ka] A 25 mL flask containing MePPh3Br (714 mg, 2.0 mmol) was subjected to three vacuum / Ar cycles, and dry THF (2 mL) and t-BuOK (2.0 mmol, 2 mL, 1 M solution in THF) were added. The reaction product turned yellow and was left to stand at room temperature with stirring for 1 hour. Compound 16 (160 mg, 0.55 mmol) dissolved in 2 mL of dry THF was added under Ar conditions, and the mixture was left to stand at room temperature with stirring for 15 hours. Water was added, the mixture was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The resulting crude reaction product (527 mg) was purified by column chromatography using heptane / ethyl acetate 6 / 1 as the eluent to obtain compound 17 (102 mg, yield 64%). 1H NMR(400 MHz, CDCl3):0.77(s,3H),0.87(t,J=7.6 Hz,3H),1.04-1.16(m,4H),1.20-1.48(12H),1.57-1.85(7H),2.18-2.66(m,1H),2.47(m,1H),4.60-4.62(m,2H).

[0198] Synthesis of compound 18 [ka] CuI (2.1 g, 10.8 mmol) and a flask containing a large stirring core were subjected to three vacuum / Ar cycles, and dry ether (70 mL) was added. The mixture was cooled to -30°C, and EtLi (21.7 mmol, 43.3 mL in 0.5 M benzene solution) was added dropwise. This was stirred at -30°C for 30 minutes, then the temperature was lowered to -78°C, and 3 (under Ar, 1.0 g, 2.7 mmol, in 10 mL of dry THF solution) was added dropwise. This was stirred at -78°C for 3.5 hours, the flask was opened, 28% NH3 in water was added, the temperature was raised, saturated aqueous solution of NH4Cl was added, and the mixture was extracted twice with AcOEt. The organic phase was washed with NH4Cl(ac), dried over Na2SO4, filtered, and concentrated. The resulting crude reaction product (1.04 g) was purified by column chromatography using heptane / methyl tert-butyl ether 1 / 1 as the eluent to obtain 18 (428 mg, 50% yield). 1 H NMR(400 MHz, CDCl3):0.86(s,3H),0.92(t,J=7.2 Hz,3H),1.04-1.84(m,24H),1.89-1.95(m,1H),2.07(dt,J=19.3,8.7 Hz,1H),2.42(dd,J=19.3,8.7 Hz,1H).

[0199] Synthesis of compound 19 [ka] A flask containing EtPPh3Br (280 mg, 0.7535 mmol) was subjected to three vacuum / Ar cycles. Dry THF (2 mL) and t-BuOK (0.7535 mmol, 0.75 mL, in 1 M THF) were added, and the mixture was stirred at room temperature for 1 hour. A solution of 18 (120 mg, 0.3768 mmol) in THF under an inert Ar atmosphere was added, and the mixture was stirred at room temperature for 3 days. Water was added to the reactants, extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The crude reaction product (256 mg) was purified by column chromatography using heptane / ethyl acetate 6 / 1 as the eluent to obtain compound 19 (46 mg, yield 37%). 1 H NMR(500 MHz, CDCl3):0.87(s,3H),0.93(t,J=7.3 Hz,3H),1.02-1.39(m,16H),1.41-1.50(m,4H),1.51-1.56(m,2H),1.65 -1.86(m,6H),2.12-2.27(m,2H),2.31-2.40(m,1H),5.11(dt,J=4.2,2.5 Hz,1H).

[0200] Synthesis of compound 20 [ka] A suspension of 9 (1 g, 2.51 mmol), K2CO3 (0.174 g, 1.25 mmol), and imidazole (0.174 g, 2.56 mmol) in THF (10 mL) was stirred under reflux for 6 hours. After consumption of the starting materials, the reaction mixture was cooled to 20-25°C. Water was then slowly added, and the mixture was stirred for 10 minutes. Tetrahydrofuran was removed under vacuum, and the product was extracted with DCM (15 mL). The solvent was removed under vacuum (0.95 g, 99% yield). 1 H(500 MHz, CDCl3):0.85(s,3H),1.03-1.39(m,10H),1.45-1.66(m,6H),1.75-1.99(m,8H),2.04(m,1H),2.10(m,1H),2.59(t,J=10.0 Hz, 1H), 4.76 (d, J=5.0Hz, 2H), 6.88 (s, 1H), 7.08 (s, 1H), 7.57 (s, 1H).13 C(125 MHz, CDCl3):14.0,23.3,24.3,24.4,25.7,26.1,31.4,31.5,34.7,38.9,39.3,4 0.3,41.2,41.7,45.4,55.8,55.9,58.8,61.1,72.0,123.1,128.6,138.5,203.3.

[0201] Comparative Example 1 For example, the addition of MeMgCl to compound 1 was carried out according to the method disclosed in WO2020 / 118060 (synthesis of A25 in that document). However, this strategy resulted in the formation of a β-isomer (undesirable) instead of an α-isomer. When a smaller amount of MeMgCl was used (6 equivalents), the reaction did not complete. Therefore, in the example shown below, 10 equivalents of MeMgCl were used. [ka]

[0202] To a solution of LiCl (0.32 g, 7.65 mmol) in THF (15 mL), FeCl3 (0.48 g, 3.1 mmol) was added. The reaction mixture was cooled to -30°C, and without raising the temperature to -20°C, MeMgCl (3 M, 6.1 mL) was slowly added. After stirring the mixture for 30 minutes, 1 (0.5 g, 1.82 mmol) was added all at once. After consumption of the starting material, the reaction mixture was heated to 10°C, and 10% citric acid (1 mL) was slowly added. RINKAN (10 mL) was added, and the mixture was stirred for 15 minutes. Then, another portion of 10% citric acid (11 mL) was added, and the mixture was stirred until completely dissolved. After decantation, the organic phase was washed with brine (10 mL), and the solvent was removed under reduced pressure to obtain a white solid (0.5 g, β-isomer).

[0203] Comparative Example 2 The addition of MeMgCl to compound 1 was carried out according to a method similar to that described in WO2014 / 169832 (synthesis of SA-C in the said document). However, this strategy resulted in a mixture of four compounds. As in the prior art, when the reaction was carried out in toluene at -78°C, the reaction mixture froze. The same thing happened at -10°C. Therefore, in the example shown below, a mixture of toluene and THF was used at -10°C. [ka]

[0204] Preparation of MAD: AlMe3 (2.8 mL, 5.46 mmol) was added dropwise to a solution of 2,6-ditertbutyl-4-methylphenol (2.04 g, 10.94 mmol) in toluene (3 mL) at 0 / 5 °C. The reaction mixture was heated at 20-25 °C for 1 hour.

[0205] Next, a solution of 1 (0.5 g, 1.82 mmol) in toluene / THF (3 mL / 0.5 mL) was added, and the reaction mixture was cooled to -10°C and stirred for 15 minutes. MeMgCl (1.9 mL, 5.46 mmol) was added and a concentrated slurry was observed (the temperature was readjusted to -5°C to observe better stirring). The formation of four compounds was observed using different reaction controls.

[0206] Similar results were obtained when MeMgCl was used in the absence of MAD.

Claims

1. Compound of formula (I) or its salt or solvate 【Chemistry 1】 (In the formula, X is selected from Cl, Br, and I) A method for preparing, (a) Compounds of formula (II) or their salts or solvates 【Chemistry 2】 Olefining of the compound of formula (III) or its salt or solvate 【Transformation 3】 To provide, and (b) To provide a compound of formula (I) or a salt or solvate thereof by a halohydrin formation reaction of a compound of formula (III) or a salt or solvate thereof. A method that includes this.

2. Step (a) is the compound of formula (II) or a salt or solvate of the compound of formula (X) in the presence of a base. 【Chemistry 4】 (In the formula, W is a halogen such as Br, Each R'' independently comprises C such as phenyl. ６ ~C １０ (Selected from the arrows) The method according to claim 1, comprising the reaction of

3. Step (b) involves the compound of formula (III) or a salt or solvate thereof, and HOCl, HOBr, HOI, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and Cl in the presence of water. ２ Br in the presence of water ２ I in the presence of water ２ The method according to any one of claim 1 or 2, comprising a reaction with a halohydrin-forming reagent selected from DCDMH, DBDMH, and DIDMH in the presence of water.

4. The method according to any one of claims 1 to 3, wherein X is selected from Br and I, and preferably X is Br.

5. (c) Compound of formula (IV) or a salt or solvate of the compound of formula (I) or a salt or solvate of the compound 【Transformation 5】 (In the formula, R １ is selected from H, F, C １～６ alkyl, C １～６ alkoxyl, C １～６ haloalkyl, and N(R') ２ where each R' is independently selected from H and C １～６ alkyl). The method according to any one of claims 1 to 4, further comprising conversion to

6. Step (c) is the dehalogenation of the compound of formula (I) or its salt or solvate to obtain the compound of formula (IV) (wherein R １ The method according to claim 5, comprising providing (where is H) or a salt or solvate thereof.

7. Step (c) is a reaction in which the compound of formula (I) or a salt or solvate thereof is reacted with a base, and then with a fluoride source to form the compound of formula (IV) (wherein R １ The method according to claim 5, comprising providing F or a salt or solvate thereof.

8. Step (c) involves a compound of formula (I) or a salt or solvate thereof, and formula (C １～６ A compound of the form (alkyl)MgZ (wherein Z is selected from Cl, Br, and I) or the formula (C １～６ Alkyl) ２ The reaction with a CuLi compound yields the compound of formula (IV) (wherein R is R). １ is C １～６ The method according to claim 5, comprising providing an alkyl (or a salt or solvate thereof).

9. Step (c) involves a compound of formula (I) or a salt or solvate thereof, and formula (C １～６ The reaction of an alkoxyl) M (wherein M is selected from Na and K) with a compound of formula (IV) (wherein R) １ is C １～６ The method according to claim 5, comprising providing an alkoxyl (or a salt or solvate thereof).

10. Step (c) involves a compound of formula (I) or a salt or solvate thereof, and formula (C １～６ A compound of the formula (Haloalkyl)MgZ (wherein Z is selected from Cl, Br, and I) or a compound of the formula (C １～６ (Haloalkyl) ２ The reaction with a CuLi compound yields the compound of formula (IV) (wherein R is R). １ is C １～６ The method according to claim 5, comprising providing a haloalkyl (or a salt or solvate thereof).

11. Step (c) involves a compound of formula (I) or a salt or solvate thereof, and a compound of formula NH(R') ２ (In the formula, each R' is independently H and C １～６ Reaction with a compound of an alkyl group (selected from alkyl groups) yields a compound of formula (IV) (wherein R is selected from the formula). １ is N(R') ２ And each R' is independently H and C １～６ The method according to claim 5, comprising providing an alkyl group (selected from alkyl groups) or a salt or solvate thereof.

12. (d) By olefinization of the compound of formula (IV) or its salt or solvate, the compound of formula (V) or its salt or solvate 【Transformation 6】 (In the formula, R １ H, F, C １～６ Alkyl, C １～６ Alkoxyl, C １～６ Haloalkyl and N(R') ２ Selected from, each R' independently of H and C １～６ Selected from alkyl groups, R ２ H and C １～６ (Selected from alkyl groups) The method according to any one of claims 5 to 11, further comprising providing

13. Compound of formula (IX) or its salt or solvate 【Transformation 7】 (In the formula, R １ H, F, C １～６ Alkyl, C １～６ Alkoxyl, C １～６ Haloalkyl and N(R') ２ Selected from, each R' independently of H and C １～６ Selected from alkyl groups, R ３ The 5-10 member heterocyclyl and 5-10 member heteroaryl are selected from 5-10 member heterocyclyl and 5-10 member heteroaryl, and the 5-10 member heterocyclyl and 5-10 member heteroaryl are unsubstituted or C １～６ Alkyl, C １～６ Haloalkyl, halogen, -CN, NO ２ , -N(R ａ ) (Caution ｂ ), - OR ｃ , -SR ｄ , -C(O)R ｅ , -C(O)OR ｆ , -C(O)N(R ｇ ) (Caution ｈ ) and -OC(O)R ｉ Substituted with a substituent selected from the group consisting of R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ and R ｉ Hydrogen and C are independent of each other. １ ~C ６ Alkyl and C １ ~C ６ (Selected from haloalkyls) A method for preparing, (a) Compounds of formula (II) or their salts or solvates 【Transformation 8】 Olefining of the compound of formula (III) or its salt or solvate 【Chemistry 9】 To provide (b) A compound of formula (III) or a salt or solvate thereof is subjected to a halohydrin formation reaction, thereby forming a compound of formula (I) or a salt or solvate thereof. 【Chemistry 10】 (In the formula, X is selected from Cl, Br, and I) To provide (c) The compound of formula (I) or its salt or solvate The compound of formula (IV) or its salt or solvate 【Chemistry 11】 Converting to (d) By olefinization of the compound of formula (IV) or its salt or solvate, the compound of formula (Va) or its salt or solvate 【Chemistry 12】 To provide (e) Hydroxylation of the compound of formula (Va) or its salt or solvate yields the compound of formula (VI) or its salt or solvate 【Chemistry 13】 To provide (f) By oxidation of the compound of formula (VI) or its salt or solvate, the compound of formula (VII) or its salt or solvate 【Chemistry 14】 To provide (g) By halogenation of the compound of formula (VII) or its salt or solvate, a compound of formula (VIII) or its salt or solvate 【Chemistry 15】 (In the formula, Y is a halogen.) To provide, and (h) A reaction of the compound of formula (VIII) or a salt or solvate thereof with a 5- to 10-membered heterocycle or a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heterocycle and the 5- to 10-membered heteroaryl are unsubstituted or substituted with a substituent selected from the group consisting of C １～６ alkyl, C １～６ haloalkyl, halogen, -CN, NO ２ , -N(R ａ )(R ｂ ), -OR ｃ , -SR ｄ , -C(O)R ｅ , -C(O)OR ｆ , -C(O)N(R ｇ )(R ｈ ), and -OC(O)R ｉ , and wherein R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ are independently hydrogen, C １ -C ６ alkyl, and C １ -C ６ haloalkyl, to provide a compound of formula (IX) or a salt or solvate thereof. A method that includes this.

14. The method according to claim 13, wherein the compound of formula (IX) is zulanolone or a salt or solvate thereof. 【Request Item 15】 【Chemistry 16】 or its salt or solvate (wherein X is selected from Cl, Br, and I) A compound selected from the following.

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