Processes and intermediates for preparation of 3 [alpha]-hydroxy-3 [beta]-alkyl steroids

Abstract

The present invention relates to a process for the preparation of 3 [alpha]-hydroxy-3 [beta]-alkyl steroids, such as giravanone and structurally related compounds, comprising the use as an intermediate of a compound of formula (I) or a salt or solvate thereof: wherein X is selected from the group consisting of Cl, Br and I. The invention also relates to a process for the preparation of a compound of formula (I) or a salt or solvate thereof.

Description

Technical Field

[0001] This invention relates to novel intermediates for the preparation of 3α-hydroxy-3β-alkyl steroids such as zuranolone and structure-related compounds, and methods for preparing said intermediates. Background Technology

[0002] Zuranolone and other related 3α-hydroxy-3β-alkyl steroids have been disclosed in the prior art as neuroactive compounds and are therefore used for the prevention and treatment of CNS-related diseases.

[0003]

[0004] Several synthetic methods for preparing these compounds and their intermediates have been disclosed. Specifically, different methods for introducing alkyl and hydroxyl groups at the 3-position of steroids have been described; however, most of them do not provide the desired product (α-hydroxy-β-alkyl product) in a stereoselective manner.

[0005] WO2013 / 056181 discloses a method that includes protecting the 3-ketone prior to olefination of the 17-ketone. Subsequent deprotection of the 3-ketone and the addition of MeMgBr produce 3-hydroxy- and 3-methyl-functionality, but with very low selectivity for the desired isomer (Example 1 discloses an α / β ratio of hydroxyl groups of about 25 / 75 (6b / 6a) after chromatographic purification).

[0006]

[0007]

[0008] This document discloses other strategies for functionalization at the third position, such as the addition of sulfone fluoride, but still results in low selectivity (Example 2 discloses an α / β ratio of hydroxyl groups of about 57 / 43 (11b / 11a) after chromatographic purification).

[0009]

[0010] The compounds of formulas 9a / 9b and 15a / 15b in WO2013 / 056181 are then converted into neuroactive steroids by reacting with different heterocyclic and heteroaryl compounds.

[0011] WO2014 / 169832 discloses a method for synthesizing the key intermediate SA, wherein 3-hydroxy,3-methyl functionality is obtained by adding MeMgBr to a 3-one in the presence of MAD (methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxy)).

[0012]

[0013] In this case, stereoselectivity in the addition of MeMgBr is achieved by using MAD. However, three equivalents of MAD are required, and MAD is an expensive and difficult-to-handle reagent that must be prepared in situ via the reaction of trimethylaluminum (self-igniting) with 2,6-di-tert-butyl-4-methylphenol. Therefore, this method is not suitable for industrial production.

[0014] Furthermore, the inventors of this invention did not obtain good results when attempting to reproduce this strategy (Comparative Example 3).

[0015] A similar strategy using MeMgBr and MAD was disclosed in WO2016 / 061527.

[0016] WO2014 / 169832 and WO2014 / 169836 disclose the preparation of 3-hydroxy, 3-fluoromethyl derivatives via ring-opening of epoxides. However, the resulting epoxides exhibit poor stereoselectivity, and the corresponding isomers separate in approximately a 50 / 50 ratio at the end of the synthesis.

[0017]

[0018] WO2014 / 169832 also describes compounds with a vinyl group at position 17 (compounds SA-G) as useful intermediates for the preparation of active steroids.

[0019]

[0020] WO2014 / 169833 and WO2015 / 180679 disclose the preparation of 3-hydroxy, 3-alkoxymethyl derivatives by ring-opening of epoxides using MeONa or EtONa, respectively. However, the resulting epoxides exhibit poor stereoselectivity, and the corresponding isomers are separated in approximately a 50 / 50 ratio at the end of the synthesis.

[0021]

[0022] WO2014 / 169833 describes the stereoselective preparation of 3α-hydroxy,3β-ethoxymethyl derivatives in which the two linked cyclohexane rings are in the trans-decaline form, as in the following compound SB.

[0023]

[0024] However, as shown in WO2020 / 118060, this strategy produces low stereoselectivity when applied to cis-decahydronaphthalene (such as compound 87 below). Specifically, this document discloses the synthesis of 3-hydroxy, 3-alkoxymethyl derivatives via epoxidation of 3,17-dione and subsequent ring-opening with sodium alkoxide epoxide; however, Example 87 discloses that the ratio of isomers at position 3 of compound 87.3 is about 71 / 29.

[0025]

[0026] WO2020 / 118060 also describes compounds having a vinyl group at position 17 (compound A34) as useful intermediates for the preparation of active steroids.

[0027]

[0028] Despite the existence of these methods in the prior art, there is still a need to develop new methods for the preparation of 3α-hydroxy-3β-alkyl steroids such as zuranolone and key intermediates in their synthesis, which overcome all or part of the problems associated with known methods belonging to the prior art. Summary of the Invention

[0029] The problem faced by this invention is to provide a new method for preparing α-hydroxy-β-alkyl steroids and their intermediates.

[0030] Specifically, the inventors discovered that compound (I) can be obtained by the haloalcohol formation reaction of compound (III). This reaction proceeds in a stereoselective manner. Furthermore, compound (III) can be obtained by the olefination of compound (II). This olefination proceeds in a regioselective manner, thus requiring no protecting / deprotecting step. Due to the regioselectivity of the olefination reaction and the stereoselectivity of the haloalcohol formation reaction, this synthetic strategy provides a very direct and efficient method for preparing compound (I) and therefore 3α-hydroxy-3β-alkyl steroids.

[0031]

[0032] Furthermore, compounds of formula (I) are very versatile intermediates because group X can be readily converted into other functional groups. Therefore, compounds of formula (I) can serve as common key intermediates for the preparation of various steroids.

[0033] Therefore, in a first aspect, the present invention relates to a method for preparing a compound of formula (I) or a salt or solvate thereof.

[0034]

[0035] X is selected from Cl, Br, and I;

[0036] The method includes

[0037] (a) olefination of a compound of formula (II) or its salt or solvate

[0038]

[0039] To provide a compound of formula (III) or a salt or solvate thereof;

[0040]

[0041] and

[0042] (b) A haloalcohol formation reaction of a compound of formula (III) or its salt or solvate to provide a compound of formula (I) or its salt or solvate.

[0043] In a second aspect, the present invention relates to a method for preparing a compound of formula (IX) or a salt or solvate thereof.

[0044]

[0045] in

[0046] R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and N(R')2, wherein each R' is independently selected from H and C. 1-6 Alkyl; and

[0047] R 3 Selected from 5-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 5-10-membered heterocyclic group and 5-10-membered heteroaryl group are unsubstituted or selected from C. 1-6 Alkyl, C 1-6 Alkyl halogen, halogen, -CN, NO2, -N(R) a (R) b -OR c -SR d -C(O)Re -C(O)OR f -C(O)N(R) g (R) h ) and -OC(O)R i Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl;

[0048] The method includes

[0049] (a) olefination of a compound of formula (II) or its salt or solvate

[0050]

[0051] To provide a compound of formula (III) or a salt or solvate thereof.

[0052]

[0053] (b) A haloalcohol formation reaction of a compound of formula (III) or its salt or solvate to provide a compound of formula (I) or its salt or solvate.

[0054]

[0055] X is selected from Cl, Br, and I;

[0056] (c) A compound of formula (I) or its salt or solvate is converted into a compound of formula (IV) or its salt or solvate.

[0057]

[0058] (d) olefination of a compound of formula (IV) or its salt or solvate to provide a compound of formula (Va) or its salt or solvate.

[0059]

[0060] (e) Hydroxylation of a compound of formula (Va) or a salt or solvation thereof to provide a compound of formula (VI) or a salt or solvation thereof.

[0061]

[0062] (f) Oxidation of a compound of formula (VI) or a salt or solvate thereof to provide a compound of formula (VII) or a salt or solvate thereof.

[0063]

[0064] (g) Halogenation of a compound of formula (VII) or a salt or solvate thereof to provide a compound of formula (VIII) or a salt or solvate thereof.

[0065]

[0066] Where Y is a halogen; and

[0067] (h) The reaction of a compound of formula (VIII) or its salt or solvate with a 5-10 membered heterocycle or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocycle and the 5-10 membered heteroaryl group are unsubstituted or selected from C 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl;

[0068] To provide a compound of formula (IX) or a salt or solvate thereof.

[0069] Compounds of formula (I) and (III), and their salts or solvates, can be used as intermediates in the preparation of zuranolone and other related compounds of formula (IX). Therefore, on the other hand, the present invention relates to compounds selected from the following:

[0070]

[0071] Or its salts or solvates, wherein X is selected from Cl, Br and I. Detailed Implementation

[0072] As used herein, the singular forms “a,” “an,” and “the / that” include plural references unless the context clearly indicates otherwise.

[0073] The term "C1-C6 alkyl" refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which is unsaturated and has 1 to 6 or 1 to 3 ("C1-C3 alkyl") carbon atoms attached to the rest of the molecule by single bonds. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and hexyl.

[0074] The term "C3-C7 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic aliphatic group having 3-7 or 3-6 ("C3-C6 cycloalkyl") carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0075] The term "C1-C6 alkoxy" refers to an alkyl group as defined above, which is attached to the rest of the molecule by oxygen and has 1 to 6 carbon atoms or 1 to 3 carbon atoms ("C1-C3 alkoxy"). Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0076] The term "halogen" refers to bromine, chlorine, iodine, or fluorine.

[0077] The term “C1-C6 haloalkyl” refers to an alkyl group as defined above in which at least one hydrogen atom has been replaced by a halogen atom, such as, for example, CF3, CCl3, CHF2, CH2F, CF2CF3.

[0078] The term "C6-C" 10 "Aryl" refers to an aromatic group having 6 to 10 carbon atoms, including one or two aromatic nuclei. Examples of aryl groups include phenyl, naphthyl, indene, and phenanthrene.

[0079] The term "(C6-C)" 10 "Aryl (C1-C6)alkyl" refers to an aryl group as defined above that is attached to the rest of the molecule by an alkyl group as defined above. Examples of such groups include benzyl, phenethyl, phenylpropyl, and naphthylmethyl.

[0080] The term “5-10 membered heterocyclic group” refers to a saturated or partially unsaturated monocyclic or bicyclic system comprising 5-10 or 5-7 ring atoms, wherein the ring atoms consist of a carbon atom and 1-5 or even 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0081] The term "5-10 heteroaryl" refers to an aromatic monocyclic or bicyclic system containing 5-10 or 5-7 ring atoms, wherein the ring atoms consist of a carbon atom and 1-5 or even 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur.

[0082] As understood in the art, the aforementioned free radicals can contain a certain degree of substitution. Therefore, substitution can be present in any group of the present invention. The aforementioned group can be substituted at one or more available positions by one or more substituents (e.g., one, two, or three substituents). The substituents include, for example, C... 1-6 Alkyl, C 1-6 Halogenated, C 3-7 cycloalkyl, (C6-C 10 aryl (C1-C6)alkyl, C6-C 10 Aryl, 5-10 heterocyclic, 5-10 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 ) and -OC(O)R i ;where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl, C 1-6 Halogenated groups, (C6-C) 10 aryl (C1-C6)alkyl, C6-C 10 Aryl, 5-10 heterocyclic and 5-10 heteroaryl.

[0083] The present invention also provides “salts” of the compounds described herein. As an example, the salt may be an acid addition salt, a base addition salt, or a metal salt, and can be synthesized from a parent compound containing a base or acid moiety by conventional chemical methods known to those skilled in the art. Such salts are generally prepared, for example, by reacting the free acid or base form of the compound with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof. Non-aqueous media such as diethyl ether, ethyl acetate, ethanol, acetone, isopropanol, or acetonitrile are generally preferred. Exemplary examples of acid addition salts include inorganic acid addition salts, such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, etc., and organic acid addition salts, such as acetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, p-toluenesulfonates, camphorsulfonates, etc. Exemplary examples of base addition salts include inorganic base salts, such as ammonium salts, and organic base salts, such as ethylenediamine, ethanolamine, N,N-dialkylethanolamine, triethanolamine, glutamine, basic amino acid salts, etc. Exemplary examples of metal salts include, for example, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and lithium salts.

[0084] The term "solvent" according to the present invention will be understood to mean any compound form in which another molecule (most likely a polar solvent) is attached by non-covalent bonding. Examples of solvates include hydrates and alcohols, such as methanol compounds. Solvation methods are generally known in the prior art.

[0085] 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., EtOAc, iPrOAc, BuOAc), nitriles (e.g., acetonitrile, benzonitrile), amides (e.g., DMF, DMA, HMPA, NMP), alcohols (e.g., methanol, ethanol, propanol, isopropanol, sec-butanol, tert-butanol), sulfoxide (DMSO), and mixtures thereof.

[0086] The term "proton-free organic solvent" refers to any organic solvent that does not produce protons under the 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., EtOAc, iPrOAc, BuOAc), nitriles (e.g., acetonitrile, benzonitrile), amides (e.g., DMF, DMA, HMPA, NMP), sulfoxide (DMSO), and mixtures thereof.

[0087] On one hand, the present invention relates to a method for preparing a compound of formula (I) or a salt or solvate thereof.

[0088]

[0089] X is selected from Cl, Br, and I;

[0090] The method includes

[0091] (a) olefination of a compound of formula (II) or its salt or solvate

[0092]

[0093] To provide a compound of formula (III) or a salt or solvate thereof.

[0094]

[0095] and

[0096] (b) A haloalcohol formation reaction of a compound of formula (III) or its salt or solvate to provide a compound of formula (I) or its salt or solvate.

[0097] In one embodiment, the method of the present invention further includes:

[0098] (c) A compound of formula (I) or its salt or solvate is converted into a compound of formula (IV) or its salt or solvate.

[0099]

[0100] Where R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and N(R')2, wherein each R' is independently selected from H and C. 1-6 alkyl.

[0101] Therefore, on the other hand, the present invention relates to a method for preparing a compound of formula (IV) or a salt or solvate thereof, the method comprising steps (a), (b) and (c) as defined herein.

[0102] In another embodiment, the method of the present invention further includes:

[0103] (c) A compound of formula (I) or its salt or solvate is converted into a compound of formula (IV) or its salt or solvate.

[0104]

[0105] Where R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and N(R')2, wherein each R' is independently selected from H and C. 1-6 Alkyl; and

[0106] (d) olefination of a compound of formula (IV) or its salt or solvate to provide a compound of formula (V) or its salt or solvate.

[0107]

[0108] in

[0109] R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and N(R')2, wherein each R' is independently selected from H and C. 1-6 Alkyl; and

[0110] R 2 Selected from H and C 1-6 alkyl.

[0111] Therefore, on the other hand, the present invention relates to a method for preparing a compound of formula (V) or a salt or solvate thereof, the method comprising steps (a), (b), (c) and (d) as defined herein.

[0112] In another embodiment, the method of the present invention further includes:

[0113] (c) A compound of formula (I) or its salt or solvate is converted into a compound of formula (IV) or its salt or solvate.

[0114]

[0115]

[0116] Where R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and N(R')2, wherein each R' is independently selected from H and C. 1-6 alkyl;

[0117] (d) olefination of a compound of formula (IV) or its salt or solvate to provide a compound of formula (Va) or its salt or solvate.

[0118]

[0119] (e) Hydroxylation of a compound of formula (Va) or a salt or solvation thereof to provide a compound of formula (VI) or a salt or solvation thereof.

[0120]

[0121] (f) Oxidation of a compound of formula (VI) or a salt or solvate thereof to provide a compound of formula (VII) or a salt or solvate thereof.

[0122]

[0123] (g) Halogenation of a compound of formula (VII) or a salt or solvate thereof to provide a compound of formula (VIII) or a salt or solvate thereof.

[0124]

[0125] Where Y is a halogen; and

[0126] (h) The reaction of a compound of formula (VIII) or its salt or solvate with a 5-10 membered heterocycle or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocycle and the 5-10 membered heteroaryl group are unsubstituted or selected from C 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f Rg R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl;

[0127] To provide a compound of formula (IX) or a salt or solvate thereof.

[0128]

[0129] Where R 3 Selected from 5-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 5-10-membered heterocyclic group and 5-10-membered heteroaryl group are unsubstituted or selected from C. 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl.

[0130] Therefore, on the other hand, 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.

[0131] In one embodiment, X is Br or I. In a further embodiment, X is Br.

[0132] In one implementation, R 1 Selected from H, F, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and N(R')2, wherein each R' is independently selected from H and C. 1-3 alkyl.

[0133] In one implementation, R 1 Selected from H, F, C 1-6 Alkyl and C 1-6 Alkyl group. In a further embodiment, R 1 Selected from H, F, Me, Et, -OMe, and -OEt. According to one specific implementation, R... 1 It is H.

[0134] In one implementation, R 2 Selected from H and C 1-3 Alkyl group. In a further embodiment, R 2 Selected from H and Me. According to one specific implementation, R... 2 It is Me. According to another implementation, R 2 It is H.

[0135] In one implementation, R 3 The 5-10 membered heterocyclic groups and 5-10 membered heteroaryl groups include an N atom, which is bonded to the rest of the molecule. Therefore, in one embodiment, R... 3 This is the formula The group, wherein Cy is selected from 5-10 membered heterocyclic groups and 5-10 membered heteroaryl groups, wherein the 5-10 membered heterocyclic groups and 5-10 membered heteroaryl groups are unsubstituted or selected from C 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R, wherein R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl.

[0136] Therefore, in one specific embodiment, step (h) includes the compound of formula (VIII) or a salt or solvate thereof with formula (VIII). The reaction of compounds, where Cy is as defined herein.

[0137] In one implementation, R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C3 alkyl and C 1- C3 haloalkyl.

[0138] In one specific implementation, R 3 Cy is selected from 5-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 5-10-membered heterocyclic group and 5-10-membered heteroaryl group are unsubstituted or selected from C. 1-3 Alkyl, C 1-3 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C3 alkyl and C 1- C3 haloalkyl.

[0139] In one implementation, R 3 Cy is selected from 5-6-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 5-6-membered heterocyclic group and 5-6-membered heteroaryl group are unsubstituted or selected from C. 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl.

[0140] In a further embodiment, R 3 Cy is selected from 5-6-membered heterocyclic groups and 5-6-membered heteroaryl groups, wherein the 5-6-membered heterocyclic group and 5-6-membered heteroaryl group are unsubstituted or selected from C. 1-3 Alkyl, C 1-3 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C3 alkyl and C 1- C3 haloalkyl.

[0141] According to one implementation, R 3Cy is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrolepyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, indole, isoyindole, benzimidazole, indazole, benzotriazole, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-c]pyridine, imidazole[4,5]pyridine, etc. -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, 1,2,3-triazolo[4,5-b]pyrazine, wherein the group may be unsubstituted or C 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Replace; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl.

[0142] In one implementation, R 3 The substituents on the Cy group may be selected from C. 1-3 Alkyl, C 1-3 Alkyl halogen, 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 ;where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C3 alkyl and C 1- C3 haloalkyl. In a further embodiment, R 3 The substituents on the group can be selected from Me, Et, CF3, F, Cl, -CN, -NH2, OMe, OEt, SMe, OCF3, -COMe, -COOH, -COOMe, -CONH2, -CONHMe and -CONMe2.

[0143] In one specific implementation, R 3 Or Cy is In one implementation, R 3 Or Cy is

[0144] In one specific embodiment, the compound of formula (IX) is selected from:

[0145] Or its salts or solvates.

[0146] In one embodiment, the compound of formula (IX) is a zuranolone or a salt or solvation thereof.

[0147] (a) Alkenylation of compound (II)

[0148] Compound (III) or its salt or solvate is obtained by olefination of compound (II) or its salt or solvate.

[0149]

[0150] The olefination of ketones (such as the Wittig reaction) and suitable reaction conditions are known in the art.

[0151] In one embodiment, olefination is carried out by reaction with a compound of formula (X) in the presence of a base.

[0152] [MeP(R”)3]W

[0153] (X)

[0154] in

[0155] W is a halogen, such as Br; and

[0156] Each "R" is independently selected from C6-C 10 Aryl groups, such as phenyl groups.

[0157] In one embodiment, the compound of formula (X) is methyltriphenylphosphonium bromide.

[0158] Suitable bases include organolithium bases, alkali metal hydrides, and alkali metal C. 1-6 Alcohols, such as nBuLi, tBuLi, sBuLi, MeLi, PhLi, HMDSLi, LDA, NaH, NaOtBu, KOtBu, NaOMe, and NaOEt. In one specific embodiment, the base is an alkali metal C. 1-6 Alcohols, such as KOtBu.

[0159] Preferably, the reaction is carried out in the presence of an organic solvent, such as, 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), amides (e.g., DMF, DMA), or mixtures thereof. In one specific embodiment, the solvent is a cyclic or acyclic ether, such as THF.

[0160] In one specific embodiment, in the olefination reaction of step (a), the compound of formula (X) is methyltriphenylphosphonium bromide, the base is KOtBu, and the organic solvent is THF.

[0161] In one embodiment, the reaction is carried out at a temperature of -20°C to 50°C, or 0°C to 20°C.

[0162] The compound of formula (X) and / or the base are preferably used in an amount of 1.0-1.5 molar equivalents or 1.0-1.2 molar equivalents relative to the compound of formula (II) or its salt or solvate.

[0163] Furthermore, in one specific embodiment, a mixture of compound (X) and a base is first formed in an organic solvent, and the resulting mixture is added to a mixture of compound (II) or its salt or solvate with an organic solvent.

[0164] (b) Haloalcohol Formation Reaction

[0165] Compound (I) or its salt or solvate is obtained by a haloalcohol formation reaction of compound (III) or its salt or solvate.

[0166]

[0167] In this reaction, olefins are converted into haloalcohols. The inventors observed that this reaction proceeds in a regioselective and stereoselective manner to produce haloalcohols in which the halogen atom is bonded to the terminal carbon atom and has a β-halomethyl α-hydroxy configuration as the major or only product.

[0168] This reaction can be carried out in the presence of a haloalcohol forming agent. Common haloalcohol forming agents include HOCl, HOBr, HOI, and combinations of halogenating agents (such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, Cl2, Br2, I2, DCDMH, DBDMH, or DIDMH) with water.

[0169] In one embodiment, X is Br, and the haloalcohol forming agent is selected from HOBr, N-bromosuccinimide with water, Br2 with water, and DBDMH with water. In a specific embodiment, it is selected from N-bromosuccinimide with water, DBDMH with water, or even N-bromosuccinimide with water.

[0170] In another embodiment, X is I, and the haloalcohol forming agent is selected from HOI, N-iodosuccinimide with water, I2 with water, and DIDMH with water. In one specific embodiment, it is selected from N-iodosuccinimide with water, DIDMH with water, or even N-iodosuccinimide with water.

[0171] The amount of haloalcohol forming agent used can be 1-8 molar equivalents or 1-3 molar equivalents—relative to the compound of formula (III) or its salts or solvates. When the haloalcohol forming agent is a combination of a halogenating agent and water, the amount of the halogenating agent used can be 1-8 molar equivalents or 1-3 molar equivalents relative to the compound of formula (III) or its salts or solvates. In this case, water can be used in excess, for example, it can be used in an amount of 1-100 molar equivalents or 5-60 molar equivalents relative to the compound of formula (III) or its salts or solvates.

[0172] 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, CF3CO2H. In one embodiment, the reaction is carried out in the presence of HClO4.

[0173] The reaction can 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.

[0174] In one specific embodiment, 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.

[0175] In one embodiment, the reaction is carried out at a temperature of -30°C to 50°C, or -20°C to 20°C.

[0176] In another embodiment, the reaction is carried out at a temperature between -20°C and 0°C. In a further embodiment, the reaction is carried out at a temperature between -15°C and -10°C.

[0177] The inventors observed that the haloalcohol formation reaction of the compound of formula (III) yields the compound of formula (I) with high stereoselectivity. In one embodiment, the amount of compound of formula (I) obtained is at least 75%—relative to the sum of the two ()3-position stereoisomers of the steroid. That is, the α / β ratio of the hydroxyl group is ≥75 / ≤25. In a specific embodiment, the amount is at least 80% (α / β ratio of the hydroxyl group is ≥80 / ≤20) or even at least 85% (α / β ratio of the hydroxyl group is ≥85 / ≤15). In a further embodiment, the amount is at least 90% (α / β ratio of the hydroxyl group is ≥90 / ≤10). The ratio of stereoisomers can be determined by HPLC.

[0178] The inventors observed that even if a certain amount of the undesirable stereoisomer (the β-hydroxy isomer at position 3) is formed in the haloalcohol formation reaction, the purification of the compound of formula (I) allows for easy removal or significant reduction of low amounts of the undesirable stereoisomer.

[0179] In one specific embodiment, after step b), the compound of formula (I) is purified, for example by column chromatography (column chromatography) or by recrystallization. In one embodiment, recrystallization may be carried out in an organic solvent or 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, EtOAc, iPrOAc, BuOAc, acetonitrile, methanol, ethanol, propanol, isopropanol, sec-butanol, tert-butanol, DMSO, and mixtures thereof. In one embodiment, recrystallization may be carried out in a mixture of iPr₂O and heptane.

[0180] (c) Converting compound (I) into compound (IV)

[0181] Compounds of formula (IV) or their salts or solvates may be obtained from compounds of formula (I) or their salts or solvates.

[0182]

[0183] In one specific embodiment, R in the compound of formula (IV) or its salt or solvate is... 1 It is H. In the embodiment, step (c) includes the dehalogenation of the compound of formula (I) or its salt or solvate to provide wherein R 1 It is a compound of formula (IV) of H or a salt or solvation thereof.

[0184] Dehalogenation reactions and suitable reaction conditions are known in the art. In one embodiment, such a dehalogenation reaction is carried out in the presence of tin hydride and a free radical initiator.

[0185] Tin hydrides include, for example, 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, triphenyltin hydride, or even tributyltin hydride.

[0186] The amount of tin hydride used can be 1-8 molar equivalents or 1.2-3 molar equivalents – relative to the compound of formula (I) or its salt or solvate.

[0187] Free radical initiators are well known in the art and include alkyl and aryl peroxides, alkyl and aryl hydroperoxides, acyl peroxides, peroxy esters, persulfates, perborates, percarbonates, and azo compounds, etc. Some specific examples include hydrogen peroxide, dibenzoyl peroxide, didecanoyl peroxide, dilauroyl peroxide, tert-butyl hydroperoxide, benzoyl peroxide, di-tert-butyl peroxide, di(3,5,5-trimethylhexanoyl) peroxide, diisobutyryl peroxide, t-butylperoxy diethyl acetate, t-butyl peroctoate, t-butyl peroxy isobutyrate, t-butyl peroxy 3,5,5-trimethyl hexanoate, t-butyl perbenzoate, t-butyl peroxy pivalate, t-butyl peroxy-2-ethylhexanoate, and tert-amyl peroxy-2-ethylhexanoate. The free radical initiator is 1,1,3,3-tetramethylbutyl peroxy-2-ethylhexanoate, cumene hydroperoxide, AIBN, and 2,2'-azobis-(2-methylbutyronitrile). In one embodiment, the free radical initiator is AIBN.

[0188] The free radical initiator can be used in catalytic amounts, such as 0.01-0.6 molar equivalents relative to the compound of formula (I) or its salts or solvates.

[0189] The dehalogenation reaction can be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In one specific embodiment, the solvent is a cyclic ether or an acyclic ether, such as THF.

[0190] In one specific embodiment, the dehalogenation reaction is carried out in the presence of tin hydride, a free radical initiator, and an organic solvent.

[0191] In one embodiment, the dehalogenation reaction is carried out at a temperature of 20°C to 150°C, or 40°C to 100°C.

[0192] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1It is F. In the described embodiment, step (c) includes treating the compound of formula (I) or its salt or solvate with an alkali and then with a fluoride source to provide wherein R 1 It is a compound of formula (IV) of F or a salt or solvation thereof.

[0193] In the 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 one embodiment, the base is K₂CO₃.

[0194] Following treatment with an alkali, the fluorination reaction involves treating the resulting compound with a fluorine source. Fluorine sources are well known in the art and include, for example, KF, tetramethylammonium fluoride, tetrabutylammonium fluoride, ammonium fluoride, ammonium hydrogen fluoride, ammonium fluoroborate, and fluoroboric acid. In one embodiment, the fluorine source is tetrabutylammonium fluoride.

[0195] The amount of base and fluorine source used may be 1.5 to 50 molar equivalents or 5 to 40 molar equivalents relative to the compound of formula (I) or its salt or solvate.

[0196] The fluorination reaction can be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In one specific embodiment, the solvent is a cyclic ether or an acyclic ether (such as THF) or an aromatic solvent (such as toluene).

[0197] In one embodiment, the fluorination reaction is carried out at a temperature of 20°C to 150°C (e.g., 60°C to 120°C).

[0198] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1 It is C 1-6 Alkyl group. In the embodiments described, step (c) comprises a compound of formula (I) or a salt or solvation thereof reacting with a compound of formula (C). 1-6Alkyl)MgZ compounds (where Z is selected from Cl, Br, I) or with formula (C 1-6 The reaction of alkyl)2CuLi compounds to provide R 1 It is C 1-6 Alkyl compounds of formula (IV) or their salts or solvates.

[0199] Formula (C) 1-6 alkyl)MgZ or (C 1-6 The amount of the alkyl)2CuLi compound may be 1.5 to 10 molar equivalents, or 2 to 6 molar equivalents, relative to the compound of formula (I) or its salt or solvate.

[0200] In one implementation, C 1-6 Alkyl is C 1-3 Alkyl groups, such as Me or Et.

[0201] With formula (C) 1-6 alkyl)MgZ or (C 1-6 The reaction of alkyl)2CuLi compounds can be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In one specific embodiment, the solvent is a cyclic ether or an acyclic ether, such as THF.

[0202] In one implementation, with equation (C) 1-6 alkyl)MgZ or (C 1-6 The reaction of alkyl)2CuLi compounds is carried out at temperatures ranging from -80°C to 20°C, or from -80°C to 0°C, or even from -80°C to -40°C.

[0203] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1 It is C 1-6 Alkyl group. In the embodiments described, step (c) comprises a compound of formula (I) or a salt or solvation thereof reacting with a compound of formula (C). 1-6 The reaction of an alkoxy)M compound (where M is selected from Na and K) to provide R 1 It is C 1-6 Alkoxy compounds of formula (IV) or their salts or solvates.

[0204] Formula (C) 1-6 The amount of the alkoxy)M compound may be 1.5 to 10 molar equivalents, or 2 to 8 molar equivalents, relative to the compound of formula (I) or its salt or solvate.

[0205] In one implementation, C 1-6 Alkyl groups are C 1-3 Alkyl groups, such as -OMe or -OEt.

[0206] With formula (C) 1-6The reaction of alkoxy (M) compounds can be carried out in the presence of organic solvents, such as alcohols (e.g., MeOH, EtOH, nPrOH, iPrOH, sBuOH, tBuOH).

[0207] In one implementation, with equation (C) 1-6 The reaction of the alkoxy)M compound is carried out at temperatures ranging from 20°C to 150°C (e.g., from 50°C to 120°C).

[0208] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1 It is C 1-6 Halogenated compounds. In the embodiments described, step (c) comprises a compound of formula (I) or a salt or solvation thereof with a compound of formula (C). 1-6 Halogenated alkyl)MgZ compounds (where Z is selected from Cl, Br, I) or with formula (C 1-6 The reaction of haloalkyl)2CuLi compounds to provide R 1 It is C 1-6 A haloalkyl compound of formula (IV) or its salt or solvation.

[0209] Preferably, the haloalkyl group is a fluoroalkyl group, i.e., an alkyl group in which at least one H atom has been replaced by an F atom.

[0210] Formula (C) 1-6 (Halogenated)MgZ or (C 1-6 The amount of the haloalkyl)2CuLi compound may be 1.5 to 10 molar equivalents or 2 to 6 molar equivalents relative to the compound of formula (I) or its salt or solvate.

[0211] In one implementation, C 1-6 Haloalkyl is C 1-3 Alkyl halides, such as CF3, CHF2, CH2F, or CF2CF3.

[0212] With formula (C) 1-6 (Halogenated)MgZ or (C 1-6 The reaction of the (haloalkyl)2CuLi compound can be carried out in the presence of an organic solvent, such as an aprotic organic solvent. In one specific embodiment, the solvent is a cyclic ether or an acyclic ether, such as THF.

[0213] In one implementation, with equation (C) 1-6 (Halogenated)MgZ or (C 1-6 The reaction of the haloalkyl)2CuLi compound is carried out at temperatures ranging from -80°C to 20°C, or from -80°C to 0°C, or even from -80°C to -40°C.

[0214] In another embodiment, R in the compound of formula (IV) or its salt or solvate 1It is -N(R')2, where each R' is independently selected from H and C. 1-6 Alkyl group. In the embodiments described, step (c) comprises reacting a compound of formula (I) or a salt or solvation thereof with a compound of formula HN(R')2 to provide wherein R 1 It is -N(R')2, where each R' is independently selected from H and C. 1-6 Alkyl compounds of formula (IV) or their salts or solvates.

[0215] In one implementation, each R' is independently selected from H and C. 1-3 Alkyl groups, such as H, Me, or Et.

[0216] The amount of compound HN(R')2 can be 1 to 10 molar equivalents or 1 to 6 molar equivalents relative to compound (I) or its salt or solvate.

[0217] The reaction with compounds of formula HN(R')2 can be carried out in the presence of organic solvents, such as aprotic organic solvents.

[0218] 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.

[0219] (d) Alkenylation of compound (IV)

[0220] Compounds of formula (V) or their salts or solvates can be obtained by olefination of compounds of formula (IV) or their salts or solvates.

[0221]

[0222] In one specific implementation, R 2 It is Me, therefore the compound of formula (V) has formula (Va) as defined herein.

[0223] The olefination of ketones (such as the Wittig reaction) and suitable reaction conditions are known in the art.

[0224] In one embodiment, olefination is carried out by reaction with a compound of formula (XI) in the presence of a base.

[0225]

[0226] in

[0227] W is a halogen, such as Br.

[0228] R 2 Selected from H and C 1-6 Alkyl, and

[0229] Each R' is independently selected from C6-C 10Aryl groups, such as phenyl groups.

[0230] In one implementation, R 2 Selected from H and C 1-3 Alkyl groups, such as H, Me, or Et. In a further embodiment, R 2 Selected from H and Me.

[0231] In one embodiment, the compound of formula (XI) is methyltriphenylphosphonium bromide or ethyltriphenylphosphonium bromide.

[0232] Suitable bases include organolithium bases, alkali metal hydrides, and alkali metal C. 1-6 Alcohols, such as nBuLi, tBuLi, sBuLi, MeLi, PhLi, HMDSLi, LDA, NaH, NaOtBu, KOtBu, NaOMe, and NaOEt. In one specific embodiment, the base is an alkali metal C. 1-6 Alcohols, such as KOtBu.

[0233] In the olefination reaction, the amount of compound (XI) and / or base may be 1 to 10 molar equivalents or 1 to 6 molar equivalents relative to compound (IV) or its salt or solvate.

[0234] In one embodiment, the olefination reaction is carried out in the presence of an organic solvent, such as, 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), amides (e.g., DMF, DMA), or mixtures thereof. In one specific embodiment, the solvent is a cyclic or acyclic ether, such as THF.

[0235] In one specific embodiment, in the olefination reaction of step (d), the compound of formula (XI) is methyltriphenylphosphonium bromide or ethyltriphenylphosphonium bromide, the base is KOtBu, and the organic solvent is THF.

[0236] In one embodiment, the reaction is carried out at a temperature of -20°C to 60°C, or 0°C to 40°C.

[0237] Compounds of formula (IV) and (V) are converted into other active compounds.

[0238] The prior art has disclosed compounds of formula (IV) and formula (V) as key intermediates for the preparation of biologically active compounds, such as those disclosed in WO2013 / 156181, WO2014 / 169832, WO2014 / 169833, WO2014 / 169836, WO2015 / 180679 or WO2020 / 118060, including zuranolone.

[0239] Therefore, the method of the present invention provides a very efficient method for preparing a very general key intermediate.

[0240] In one embodiment, the invention further includes converting a compound of formula (V) or a salt or solvation thereof into a compound of formula (IX) or a salt or solvation thereof. Methods for such conversion are known in the art (e.g., in WO2013 / 156181, WO2014 / 169832, WO2014 / 169833, WO2014 / 169836, WO2015 / 180679).

[0241] In one specific embodiment, the invention further includes converting a compound of formula (Va) or a salt or solvation thereof into a compound of formula (IX) or a salt or solvation thereof by means of the following methods:

[0242]

[0243] (e) Hydroxylation of a compound of formula (Va) or a salt or solvation thereof to provide a compound of formula (VI) or a salt or solvation thereof;

[0244] (f) Oxidation of a compound of formula (VI) or a salt or solvation thereof to provide a compound of formula (VII) or a salt or solvation thereof;

[0245] (g) Halogenation of a compound of formula (VII) or a salt or solvate thereof to provide a compound of formula (VIII) or a salt or solvate thereof; and

[0246] (h) The reaction of a compound of formula (VIII) or its salt or solvate with a 5-10 membered heterocycle or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocycle and the 5-10 membered heteroaryl group are unsubstituted or C-substituted. 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Replace; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl;

[0247] To provide a compound of formula (IX) or a salt or solvate thereof;

[0248] in

[0249] Y is a halogen.

[0250] R 1 Selected from H, F, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-6 Halogenated alkyl groups and N(R')2, wherein each R' is independently selected from H and C. 1-6 Alkyl, and

[0251] R 3 Selected from 5-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 5-10-membered heterocyclic group and 5-10-membered heteroaryl group are unsubstituted or selected from C 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl.

[0252] In one implementation, Y is Br.

[0253] In one implementation, R 1 Selected from H, F, C 1-3 Alkyl and C 1-3 Alkyl groups, such as H, F, Me, Et, -OMe, and -OEt.

[0254] In one specific implementation, R 1 It is H, and R 3 It is 4-cyanopyrazole.

[0255] In a further embodiment, the compound of formula (IX) is a zuranolone or a salt or solvation thereof.

[0256]

[0257] The methods and conditions for steps (e), (f), (g), and (h) are disclosed in the prior art (e.g., in WO2013 / 156181, WO2014 / 169832, WO2014 / 169833, WO2014 / 169836, WO2015 / 180679). In a specific embodiment, the steps may be performed as follows.

[0258] In one embodiment, the hydroxylation in step (e) can be achieved by borohydride-oxidation, such as treating the compound of formula (Va) or its salt or solvate with borane, followed by treatment with an oxidant.

[0259] Hydroboration can be carried out in the presence of boranes selected from: BH3, BH3·SMe2, BH3·THF, BH3·Et2O, 9BBN, catechol borane, or di-secondary isopentylborane.

[0260] The oxidation of the resulting borane can be carried out in the presence of an oxidizing agent (such as sodium perborate, hydrogen peroxide, or sodium hypochlorite).

[0261] The hydroxylation in step (e) can be carried out in the presence of an organic solvent and optionally water. In one embodiment, the organic solvent is a cyclic ether or an acyclic ether, such as THF.

[0262] In one specific embodiment, the hydroxylation in step (e) is carried out by treating the compound of formula (Va) or its salt or solvate in an organic solvent with borane (such as BH3, BH3·SMe2, BH3·THF, BH3·Et2O, 9BBN), followed by treatment with sodium perborate, or treatment with hydrogen peroxide and an alkali (e.g., NaOH).

[0263] 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.

[0264] In one embodiment, the oxidation in step (f) can be carried out by treating the compound of formula (VI) or its salt or solvate with an oxidizing agent.

[0265] Suitable oxidants include IBX, Dysmartin periodane (DMP), and pyridine chlorochromate. Salt (PCC), pyridine dichromate Salts (PDC), K2Cr2O7, KMnO4, MnO2, CrO3, RuO4, Jones reagent, Collins reagent, and others.

[0266] In one embodiment, the oxidation in step (f) is carried out in the presence of an organic solvent, such as DMSO or dichloromethane.

[0267] In one embodiment, the oxidation in step (f) is performed by treatment with an oxidant selected from IBX, DMP, PCC or PDC and an organic solvent.

[0268] In one embodiment, the oxidation in step (f) is carried out at a temperature of 0°C to 80°C (e.g., 10°C to 70°C).

[0269] In one implementation, the halogenation in step (g) can be carried out in the presence of a halogen source and an acid.

[0270] Suitable halogen sources include Cl2, N-chlorosuccinimide, DCDMH, Br2, N-bromosuccinimide, DBDMH, I2, N-iodosuccinimide, DIDMH, etc.

[0271] Suitable acids include, for example, HClO4, MeSO3H, p-TolSO3H, CF3SO3H, PhCO2H, CH3CO2H, PhSO3H, HCl, HBr, HI, H2SO4, HNO3, CF3CO2H, and CCl3CO2H.

[0272] 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).

[0273] In one embodiment, the halogenation in step (g) is carried out in the presence of an organic solvent, such as an alcohol, like MeOH.

[0274] In one embodiment, the oxidation in step (f) is carried out at a temperature of 0°C to 80°C (e.g., 10°C to 50°C).

[0275] In one embodiment, the reaction in step (h) can be carried out in the presence of a base and a 5-10 membered heterocycle or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocycle and the 5-10 membered heteroaryl group are unsubstituted or C-substituted. 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Replace; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl.

[0276] 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, for example, Na₂CO₃, K₂CO₃, Cs₂CO₃. In a specific embodiment, the base is K₂CO₃.

[0277] In one embodiment, the 5-10 membered heterocyclic or 5-10 membered heteroaryl is of the formula... Compounds wherein Cy is selected from 5-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 5-10-membered heterocyclic groups and 5-10-membered heteroaryl groups are unsubstituted or C-substituted. 1-6Alkyl, C 1-6 Alkyl halogen, 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 Replace; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl. In one embodiment, R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C3 alkyl and C 1- C3 haloalkyl.

[0278] According to one embodiment, the 5-10 membered heterocycle or 5-10 membered heteroaryl group is selected from pyrrolidine, piperidine, morpholine, piperazine, pyrrolidinepyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, 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, imidazole[4,5-b]pyridine, imidazole[...]. [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, 1,2,3-triazolo[4,5-b]pyrazine, wherein the compounds may be unsubstituted or C-substituted. 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Replace; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl.

[0279] In one embodiment, the substituents on the 5-10 membered heterocycle or 5-10 membered heteroaryl compound may be selected from C. 1-3 Alkyl, C 1-3 Alkyl halogen, 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 ;where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C3 alkyl and C 1- C3 haloalkyl. In a further embodiment, the substituents on the 5-10 membered heterocyclic or 5-10 membered heteroaryl compound may be selected from Me, Et, CF3, F, Cl, -CN, -NH2, OMe, OEt, SMe, OCF3, -COMe, -COOH, -COOMe, -CONH2, -CONHMe, -CONMe2.

[0280] In one specific embodiment, the 5-10 membered heterocyclic or 5-10 membered heteroaryl compound is 4-cyanopyrazole, imidazole, 5-methyl-2H-tetrazole, 5-chloro-2H-benzotriazole, or 1-piperazinyl-ethanone. In one embodiment, it is 4-cyanopyrazole.

[0281] In one embodiment, the reaction in step (h) is carried out in the presence of an organic solvent, such as an aprotic organic solvent, for example DMSO, DMF, THF, CAN, or acetone.

[0282] In one embodiment, the reaction in step (h) is carried out at a temperature of 0°C to 80°C (e.g., 10°C to 50°C).

[0283] In one specific embodiment, the present invention relates to a method for preparing zuranolone or its salts or solvates, said method comprising (a) to (h) as disclosed herein, wherein R 1 It is H and R 3 It is 4-cyanopyrazole. In the embodiments described, X and Y can be Br.

[0284] In one embodiment, the present invention relates to a preparative formulation A method for processing a compound or its salt or solvate, said method comprising (a) to (h) as disclosed herein, wherein R 1 It is -H and R 3 It is imidazole. In the described embodiment, X and Y can be Br.

[0285] In one embodiment, the present invention relates to a preparative formulation A method for processing a compound or its salt or solvate, said method comprising (a) to (h) as disclosed herein, wherein R 1 Yes -OMe and R 3 It is 5-methyl-2H-tetrazole. In the embodiments described, X and Y can be Br.

[0286] In one embodiment, the present invention relates to a preparative formulation A method for processing a compound or its salt or solvate, said method comprising (a) to (h) as disclosed herein, wherein R 1 Yes -OMe and R 3 It is 5-chloro-2H-benzotriazole. In the embodiments described, X and Y can be Br.

[0287] In one embodiment, the present invention relates to a preparative formulation A method for processing a compound or its salt or solvate, said method comprising (a) to (h) as disclosed herein, wherein R 1 It is H and R3 It is 1-piperazinyl-ethyl ketone. In the embodiments described, X and Y can be Br.

[0288] intermediate compounds

[0289] The inventors have discovered that compounds of formula (I) and their salts or solvates are useful and versatile intermediates for the synthesis of active compounds such as zuranolone and their intermediates.

[0290] Therefore, on the other hand, the present invention relates to compounds of formula (I) or their salts or solvates.

[0291]

[0292] X is selected from Cl, Br, and I.

[0293] Compound (III) is a useful intermediate in the preparation of compound (I) and therefore in the synthesis of zuranone and structurally related compounds such as compound (IX).

[0294] Therefore, on the other hand, the present invention relates to compounds of formula (III) or their salts or solvates.

[0295]

[0296] It should be understood that the scope of this disclosure includes all possible combinations of the embodiments disclosed herein.

[0297] The following embodiments illustrate the present invention, but are not intended to limit the scope of the invention.

[0298] Example

[0299] Synthesis of Compound 2

[0300]

[0301] A suspension of MePPh3Br (87.7 g, 24.05 mmol) and t-BuOK (27.0 g, 24.05 mmol) in THF (330 mL) was stirred at 20–25 °C under a nitrogen atmosphere for 1 hour. The mixture was slowly added to suspension 1 (60 g, 21.87 mmol) in THF (330 mL) at 0–5 °C. After the starting material was consumed, 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). DCM replaced heptane to promote phosphine precipitation. Compound 2 (white solid, 58.7 g, 98% yield) was isolated in MeOH / H2O. 1H NMR(500MHz, 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=19.1,8.6Hz,1H),2.33(t,J=13.3Hz,1H),2.40(ddd,J=19.1,8.6,0.82Hz,1H),4.55(s,2H). 13 C NMR (125MHz, 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.

[0302] Synthesis of Compound 3

[0303]

[0304] Water (95 mL) was added to a solution of acetone (495 mL) containing 2 (38.1 g, 139.94 mmol), and the reaction mixture was cooled to -10 / -15 °C. Then, 70% HClO4 (16.7 mL, 195.9 mmol) was slowly added without raising the temperature above -10 °C. The temperature was then adjusted to -10 °C, and NBS (29.9 g, 167.92 mmol) was added in one go. The reaction was stirred at this temperature until the starting material was consumed (α / β isomer ratio 92 / 8%). The reaction mixture was allowed to stand at 10 / 15 °C. Then, the reaction mixture was added to a sodium metabisulfite solution (5% in H2O, 580 mL). The resulting solid was filtered and purified in a mixture of isopropyl ether / heptane to give 3, a white solid (36.2 g, 70% yield, α / β isomer ratio 97.5 / 2.5%). 1 H NMR(500MHz, CDCl3):0.89(s,3H),1.06-1.41(m,7H),1.48-1.54(m,2H),1.54-1.59(m,4H),1.67-1.8 5(m,5H),1.87-1.98(m,3H),2.07-2.14(m,2H),2.45(dd,J=19.3,8.6Hz,1H),3.70(q,J=10.6Hz,2H). 13C NMR (125MHz, 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.

[0305] Synthesis of Compound 4

[0306]

[0307] Water (12.5 mL) was added to a solution of acetone (65 mL) containing 2 (5 g, 18.2 mmol). The reaction mixture was cooled to 0 °C, and HClO4 (2.65 mL, 31.0 mmol) was added without raising the temperature above 5 °C. Then, N-iodosuccinimide (6.17 g, 27.4 mmol) was added in a single addition, and the reaction mixture was stirred at 0 °C for 1 h. After the starting material was consumed, an aqueous solution of sodium metabisulfite was slowly added, and the reaction mixture was stirred for 10 min. The acetone was then removed under vacuum, and the aqueous phase was extracted with DCM. The aqueous phase was extracted again with another portion of DCM, and the solvent was removed under vacuum to give a yellow oil (α / β isomer ratio 79 / 21%). The compound was purified by column chromatography to give a white solid (4.9 g, 65% yield). 1 H NMR(500MHz, 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=19.2,8.7Hz,1H),3.54(s,2H). 13 C NMR (125MHz, 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.

[0308] Synthesis of Compound 5

[0309]

[0310] AIBN (1.38 g, 8.4 mmol) was added to a solution of 3 (34.5 g, 93.4 mmol) of THF (380 mL) under a nitrogen atmosphere, followed by heating under reflux. Then, Bu3SnH (42.37 mL, 156 mmol) was added fractionally (4 fractions). The reaction was stirred until the starting material was consumed (TLC: toluene / EtOAc, 4 / 1). The reaction mixture was then cooled at rt and the compound was isolated in heptane as a white solid (23.8 g, 69% yield, isomer ratio 99.3 / 0.7%). 1 H NMR(500MHz, 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=19.3,8.6Hz,1H). 13 CNMR (125MHz, 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.

[0311] Synthesis of Compound 6

[0312]

[0313] Potassium tert-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 and stirred at 60 °C for 1 hour. Then, 5 g (86.3 g, 297 mmol) of THF suspension was added, and the reaction mixture was stirred at 60 °C overnight. After the starting material was consumed, the temperature was lowered to 20–25 °C, followed by the addition of acetone (22 mL, 297 mmol) and water (860 mL). The THF was then evaporated under reduced pressure, and DCM (860 mL) was added. The resulting aqueous layer was extracted with DCM (200 mL), and the two organic layers were combined. DCM replaced heptane to promote phosphine precipitation. 6 g was not separated and was used in solution for the next step.

[0314] Synthesis of Compound 7

[0315]

[0316] BH3·SMe2 (143.5 mL, 286.7 mmol) was added to a THF (752 mL) solution of 6 (57.8 g, 191.1 mmol) via an addition funnel. The temperature was set at 20–25 °C and stirred for 3 h. Water (289 mL) was slowly added as the boron intermediate formed. Then, a portion of sodium perborate (91.1, 573.3 mmol) was added. The reaction was heated to 40 °C and stirred for 16 h. After confirmation by a positive control, the reaction was cooled to 20–25 °C and the salt was filtered off. THF was removed, and the aqueous phase was extracted with dichloromethane (580 mL). The resulting aqueous phase was extracted with dichloromethane (290 mL). The organic phases were combined, and DCM was replaced with methanol. Water (175 mL) was added. The reaction was cooled to 0 / 5 °C for 1 h and filtered to give a white solid (58.1 g, 94.9% yield).

[0317] Synthesis of Compound 8

[0318]

[0319] The suspensions of IBX (7.54 g, 26.97 mmol) and 7 (7.86 g, 24.52 mmol) in DMSO (150 mL) were heated at 60 °C. The reaction mixture was stirred at this temperature for 1 hour. After the starting material was consumed, the mixture was cooled to 20–25 °C. It was then slowly added to an aqueous solution (160 mL) of sodium metabisulfite (7 g, 36.78 mmol) 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 successively with NaHCO3 solution and water. The compound was then precipitated in MeOH / water (5 g, 78.5% yield).

[0320] Synthesis of Compound 9

[0321]

[0322] HClO4 (1.89 mL, 21.9 mmol) was added to a suspension of 8 (5 g, 15.6 mmol) and NBS (3.35 g, 18.8 mmol) in MeOH (20 mL). The reaction mixture was stirred at 20–25 °C for 1 h 10 min. After the starting material was consumed, MeOH (10 mL) and a solution of sodium metabisulfite (1.49 g, 7.84 mmol) in water (5 mL) were 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, 92.9% yield).

[0323] Synthesis of Zouranone

[0324]

[0325] 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 h. After the starting material was consumed, the reaction mixture was slowly added to water (660 mL) and stirred for 1 h. The suspension was filtered and the solid (17 g, 99.8% yield) was washed with water. The compound (13.7 g, 80.5% yield) was subsequently purified in MTBE and in EtOAc / heptane.

[0326] Synthesis of Compound 10

[0327]

[0328] Add 50 mL of THF and 10 g of K₂CO₃ to a 250 mL flask containing 3 (1.28 g, 3.4670 mmol), and heat the mixture to reflux for two days. Cool to 100 °C, add water, and extract three times with ethyl acetate. Concentrate in a 100 mL flask containing 10 mL of toluene and TBAF (50 mL solution, 1 M, in THF, 50 mmol), and concentrate to one-third of the volume in a rotary evaporator. Repeat this process twice, adding 10 mL of toluene and TBAF (40 mL solution, 1 M, in THF, 40 mmol), and concentrate to one-third of the volume in a rotary evaporator. Add 20 mL of toluene and concentrate to a final volume of 50 mL in a rotary evaporator. Heat to reflux (120 °C) for 72 hours, cool to 100 °C, add water, extract three times with ethyl acetate, dry with Na₂SO₄, filter, and concentrate. The crude product (13.6 g) was purified by column chromatography using heptane / ethyl acetate 3 / 1 as eluent to give 10 (660 mg, 62% yield). 1 H NMR(400MHz, 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=19.2,8.6Hz,1H),4.36(q,J=9.4Hz,1H),4.48(q,J=9.4Hz,1H).

[0329] Synthesis of Compound 11

[0330]

[0331] The reaction mixture was subjected to three vacuum / Ar cycles in a 50 mL flask containing MePPh3Br (2.7 g, 7.6 mmol), followed by the addition of 20 mL of dry THF and t-BuOK (7.6 mmol, 7.6 mL, 1 M solution in THF). The reaction turned yellow and was allowed to stand at rt with stirring for 1 hour. Compound 9 (586 mg, 1.9 mmol) dissolved in 5 mL of dry THF under Ar conditions was added, and the mixture was allowed to stand at rt with stirring for 15 hours. Water was added, and the mixture was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The resulting crude product (2.1 g) was purified by column chromatography using heptane / ethyl acetate 8 / 1 as eluent to give compound 11 (55 mg, 9% yield). 1 HNMR(400MHz, 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).

[0332] Synthesis of Compound 12

[0333]

[0334] Methanol (50 mL) and 25% MeONa (2.5 mL, 10.83 mmol) were added to a 100 mL flask containing 3 (1 g, 2.70 mmol), and the mixture was heated under reflux for 29 hours. The mixture was cooled to rt, water was added, and the mixture was extracted twice with DCM. The extract was dried over Na2SO4, filtered, and concentrated. The resulting yellow oily substance yielded product 12 (782 mg, 90% yield) without further purification. 1 HNMR(400MHz, CDCl3):0.85(s,3H),1.01-1.15(m,2H),1.18-1.57(m,11H),1.59-1.67(m,2H),1.73-1.77(m,3H),1 .79-1.85(m,2H),1.90-1.95(m,1H),2.07(dt,J=19.2,8.9Hz,1H),2.43(dd,J=19.2,8.6Hz,1H)3.35-3.45(m,5H).

[0335] Synthesis of Compound 13

[0336]

[0337] Three vacuum / Ar cycles were performed in a 25 mL flask containing MePPh3Br (812 mg, 2.27 mmol) and t-BuOK (255 mg, 2.27 mmol), followed by the addition of dry THF (7 mL) and incubation at rt with stirring for 1 hour. Compound 11 (607 mg, 1.89 mmol) in 3 mL of dry THF under an inert Ar atmosphere was added to the previously prepared ylide. The mixture was incubated at rt with stirring for 22 hours, followed by the addition of saturated aqueous NH4Cl solution, extraction three times with ethyl acetate, drying with Na2SO4, filtration, and concentration. The resulting crude product (1.1 g) was purified by column chromatography using heptane / ethyl acetate 4 / 1 as eluent to give compound 13 (270 mg, 45% yield). 1 H NMR (400MHz, 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).

[0338] Synthesis of Compound 14

[0339]

[0340] Anhydrous EtOH (50 mL) and 20% EtONa (13.5 mmol, 4.9 mL) were added to a 100 mL flask containing 3 (1 g, 2.70 g) and the mixture was heated to reflux for 5 hours. The mixture was cooled to 100 mL and saturated aqueous NH4Cl solution was added. The mixture was extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The crude product (1.03 g) was purified by column chromatography using heptane / ethyl acetate 1.5 / 1 as eluent to give product 14 (561 mg, 62% yield). 1 ¹H NMR (400MHz, 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).

[0341] Synthesis of Compound 15

[0342]

[0343] The 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, followed by stirring at rt for 1 hour. A THF solution of 14 (200 mg, 0.5979 mmol) was added under an inert Ar atmosphere, and the mixture was stirred at rt for 3 days. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The crude product (533 mg) was purified by column chromatography using heptane / ethyl acetate 6 / 1 as eluent to give compound 15 (153 mg, 73% yield). 1 ¹H NMR (400MHz, 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).

[0344] Synthesis of Compound 16

[0345]

[0346] The mixture was subjected to three vacuum / Ar cycles in a flask equipped with CuI (2.1 g, 10.8 mmol) and a large stirrer, and dried 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. The mixture was stirred at -30 °C for 30 min, cooled to -78 °C, and 3 (1.0 g, 2.7 mmol, 10 mL, dried THF solution, under Ar) was added dropwise. The mixture was stirred at -78 °C for 2 h, the flask was opened, and 28% aqueous NH3 solution was added. The mixture was heated and saturated aqueous NH4Cl solution was added. The mixture was extracted twice with DCM, the organic phase was washed with NH4Cl(aq), dried with Na2SO4, filtered, and concentrated. The resulting crude product (760 mg) was purified by column chromatography using heptane / methyl tert-butyl ether 1 / 1 as eluent to give 16 (350 mg, 42% yield). 1 H NMR (400MHz, CDCl3): 0.85-0.88(m,6H), 1.03-1.81(m,22H), 1.88-1.95(m,1H), 2.06(dt,J=19.2,8.9Hz,1H), 2.41(dd,J=11.2,8.0Hz,1H).

[0347] Synthesis of Compound 17

[0348]

[0349] The reaction mixture was subjected to three vacuum / Ar cycles in a 25 mL flask containing MePPh3Br (714 mg, 2.0 mmol), followed by the addition of 2 mL of dry THF and t-BuOK (1.2 mmol, 1.2 mL, 1 M solution in THF). The reaction turned yellow and was allowed to stand at rt with stirring for 1 h. Compound 16 (160 mg, 0.55 mmol) dissolved in 2 mL of dry THF under Ar conditions was added, and the mixture was allowed to stand at rt with stirring for 15 h. Water was added, and the mixture was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The crude product (527 mg) was purified by column chromatography using heptane / ethyl acetate 6 / 1 as eluent to give compound 17 (102 mg, 64% yield). 1 H NMR (400MHz, CDCl3): 0.77 (s, 3H), 0.87 (t, J = 7.6Hz, 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).

[0350] Synthesis of Compound 18

[0351]

[0352] The mixture was subjected to three vacuum / Ar cycles in a flask equipped with CuI (2.1 g, 10.8 mmol) and a large stirrer, and dried 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. The mixture was stirred at -30 °C for 30 min, then cooled to -78 °C, and 3 (1.0 g, 2.7 mmol, in 10 mL dried THF solution under Ar) was added dropwise. The mixture was stirred at -78 °C for 3.5 h, the flask was opened, and 28% aqueous NH3 solution was added to raise the temperature. A saturated aqueous NH4Cl solution was added, and the mixture was extracted twice with AcOEt. The organic phase was washed with NH4Cl(ac), dried with Na2SO4, filtered, and concentrated. The resulting crude product (1.04 g) was purified by column chromatography using heptane / methyl tert-butyl ether 1 / 1 as eluent to give 18 (428 mg, 50% yield). 1H NMR (400MHz, CDCl3): 0.86 (s, 3H), 0.92 (t, J = 7.2Hz, 3H), 1.04-1.84 (m, 24H), 1.89-1.95(m,1H),2.07(dt,J=19.3,8.7Hz,1H),2.42(dd,J=19.3,8.7Hz,1H).

[0353] Synthesis of Compound 19

[0354]

[0355] The flask containing EtPPh3Br (280 mg, 0.7535 mmol) was subjected to three vacuum / Ar cycles, and 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 rt for 1 h. A THF solution of 18 (120 mg, 0.3768 mmol) under an inert Ar atmosphere was added, and the mixture was stirred at rt for 3 days. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The crude product (256 mg) was purified by column chromatography using heptane / ethyl acetate 6 / 1 as eluent to give compound 19 (46 mg, 37% yield). 1 H NMR (500MHz, CDCl3): 0.87 (s, 3H), 0.93 (t, J = 7.3Hz, 3H), 1.02-1.39 (m, 16H), 1.41-1.50 (m, 4H), 1.5 1-1.56(m,2H),1.65-1.86(m,6H),2.12-2.27(m,2H),2.31-2.40(m,1H),5.11(dt,J=4.2,2.5Hz,1H).

[0356] Synthesis of Compound 20

[0357]

[0358] 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 the starting material was consumed, 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). Solvent was removed under vacuum (0.95 g, 99% yield). 1H(500MHz, 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=10.0Hz,1H),4.76(d,J=5.0Hz,2H),6.88(s,1H),7.08(s,1H),7.57(s,1H). 13 C(125MHz, CDCl3):14.0,23.3,24.3,24.4,25.7,26.1,31.4,31.5,34.7,38.9,39.3 ,40.3,41.2,41.7,45.4,55.8,55.9,58.8,61.1,72.0,123.1,128.6,138.5,203.3.

[0359] Comparative Example 1

[0360] The addition of MeMgCl to compound 1 was performed according to, for example, the method disclosed in WO2020 / 118060 (synthesis A25 in that document). However, this strategy resulted in the formation of the β isomer (undesirable) rather than the α isomer. When a smaller amount of MeMgCl (6 equivalents) was used, the reaction was not completed. For this reaction, 10 equivalents of MeMgCl were used in the examples shown below.

[0361]

[0362] FeCl3 (0.48 g, 3.1 mmol) was added to a solution of LiCl (0.32 g, 7.65 mmol) in THF (15 mL). The reaction mixture was cooled to -30 °C, and MeMgCl (3 M, 6.1 mL) was slowly added without raising the temperature above -20 °C. After stirring the mixture for 30 min, 1 g (0.5 g, 1.82 mmol) was added all at once. After the starting material was consumed, the reaction mixture was heated to 10 °C and 10% citric acid (1 mL) was slowly added. EtOAc (10 mL) was added and the mixture was stirred for 15 min. 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 give a white solid (0.5 g, β isomer).

[0363] Comparative Example 2

[0364] The addition of MeMgCl to compound 1 was carried out using a method similar to WO2014 / 169832 (SA-C synthesis in that document). However, this strategy yielded a mixture of four compounds. When the reaction was carried out in toluene at -78°C, the reaction mixture froze, as is the case with existing techniques. The same occurred at -10°C. For this reaction, a mixture of toluene and THF at -10°C was used in the examples shown below.

[0365]

[0366] Preparation of MAD: AlMe3 (2.8 mL, 5.46 mmol) was added dropwise to a solution of 2,6-di-tert-butyl-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.

[0367] Then, 1 (0.5 g, 1.82 mmol) of toluene / THF (3 mL / 0.5 mL) solution 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 viscous slurry was observed (the temperature was readjusted to -5 °C, and better stirring was observed). Different reaction controls were used to observe the formation of the four compounds.

[0368] Similar results were obtained when using MeMgCl without MAD.

Claims

1. A method for preparing a compound of formula (I) or a salt or solvate thereof, in X is selected from Cl, Br, and I; The method includes (a) olefination of a compound of formula (II) or its salt or solvate To provide a compound of formula (III) or a salt or solvate thereof. and (b) The haloalcohol formation reaction of the compound of formula (III) or its salt or solvation to provide the compound of formula (I) or its salt or solvation.

2. The method according to claim 1, wherein step (a) comprises reacting the compound of formula (II) or a salt or solvation thereof with the compound of formula (X) in the presence of a base. [MeP(R”)3]W (X) in W is a halogen, such as Br; and Each "R" is independently selected from C6-C 10 Aryl groups, such as phenyl groups.

3. The method according to any one of claims 1 or 2, wherein step (b) comprises the reaction of the compound of formula (III) or a salt or solvate thereof with a haloalcohol selected from HOCl, HOBr, HOI to form a reagent in the presence of water, the reaction with N-chlorosuccinimide in the presence of water, the reaction with N-bromosuccinimide in the presence of water, the reaction with N-iodosuccinimide in the presence of water, the reaction with Cl2 in the presence of water, the reaction with Br2 in the presence of water, the reaction with I2 in the presence of water, the reaction with DCDMH in the presence of water, the reaction with DBDMH in the presence of water, and the reaction with 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; preferably X is Br.

5. The method according to any one of claims 1 to 4, further comprising: (c) The compound of formula (I) or its salt or solvation is converted into the compound of formula (IV) or its salt or solvation. in R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl halides and N(R')2, wherein each R' is independently selected from H and C. 1-6 alkyl.

6. The method of claim 5, wherein step (c) comprises dehalogenating the compound of formula (I) or a salt or solvate thereof to provide wherein R 1 It is a compound of formula (IV) of H or a salt or solvation thereof.

7. The method of claim 5, wherein step (c) comprises reacting the compound of formula (I) or a salt or solvation thereof with a base and then with a fluorine source to provide wherein R 1 It is a compound of formula (IV) of F or a salt or solvation thereof.

8. The method according to claim 5, wherein step (c) comprises the compound of formula (I) or a salt or solvation thereof with formula (C) 1-6 The reaction of alkyl)MgZ compounds, wherein Z is selected from Cl, Br, I, or with the formula (C 1-6 The reaction of alkyl)2CuLi compounds to provide R 1 It is C 1-6 Alkyl compounds of formula (IV) or their salts or solvates.

9. The method according to claim 5, wherein step (c) comprises the compound of formula (I) or a salt or solvation thereof with formula (C) 1-6 The reaction of alkoxy)M compounds, wherein M is selected from Na and K, to provide R in which 1 It is C 1-6 Alkoxy compounds of formula (IV) or their salts or solvates.

10. The method according to claim 5, wherein step (c) comprises the compound of formula (I) or a salt or solvation thereof with formula (C) 1-6 The reaction of alkyl halogenated (MgZ) compounds, wherein Z is selected from Cl, Br, I, or with (C 1-6 The reaction of haloalkyl)2CuLi compounds to provide R 1 It is C 1-6 A haloalkyl compound of formula (IV) or its salt or solvation.

11. The method according to claim 5, wherein step (c) comprises reacting the compound of formula (I) or a salt or solvation thereof with a compound of formula HN(R')2, wherein each R' is independently selected from H and C. 1-6 Alkyl groups, to provide R 1 It is a compound of formula (IV) of N(R')2 or a salt or solvation thereof, wherein each R' is independently selected from H and C. 1-6 alkyl.

12. The method according to any one of claims 5 to 11, further comprising: (d) olefination of the compound of formula (IV) or its salt or solvate to provide the compound of formula (V) or its salt or solvate. in R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl halides and N(R')2, wherein each R' is independently selected from H and C. 1-6 Alkyl; and R 2 Selected from H and C 1-6 alkyl.

13. A method for preparing a compound of formula (IX) or a salt or solvate thereof, in R 1 Selected from H, F, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl halides and N(R')2, wherein each R' is independently selected from H and C. 1-6 Alkyl; and R 3 Selected from 5-10 membered heterocyclic groups and 5-10 membered heteroaryl groups, wherein the 5-10 membered heterocyclic group and the 5-10 membered heteroaryl group are unsubstituted or selected from C 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen and C 1- C6 alkyl and C 1- C6 haloalkyl; The method includes (a) olefination of a compound of formula (II) or its salt or solvate To provide a compound of formula (III) or a salt or solvate thereof. (b) The haloalcohol formation reaction of the compound of formula (III) or its salt or solvate to provide the compound of formula (I) or its salt or solvate. X is selected from Cl, Br, and I; (c) The compound of formula (I) or its salt or solvation is converted into the compound of formula (IV) or its salt or solvation. (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. (e) Hydroxylation of the compound of formula (Va) or its salt or solvation to provide the compound of formula (VI) or its salt or solvation. (f) Oxidation of the compound of formula (VI) or its salt or solvation to provide the compound of formula (VII) or its salt or solvation. (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. Where Y is a halogen; and (h) The reaction of a compound of formula (VIII) or a salt or solvate thereof with a 5-10 membered heterocycle or a 5-10 membered heteroaryl group, wherein the 5-10 membered heterocycle and the 5-10 membered heteroaryl group are unsubstituted or selected from C 1-6 Alkyl, C 1-6 Alkyl halogen, 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 Substituents of R; where R a R b R c R d R e R f R g R h and R i Independently selected from hydrogen, C 1- C6 alkyl and C 1- C6 haloalkyl; To provide a compound of formula (IX) or a salt or solvate thereof.

14. The method of claim 13, wherein the compound of formula (IX) is a zuranolone or a salt or solvation thereof.

15. A compound or a salt or solvate thereof, said compound being selected from... X is selected from Cl, Br, and I.

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