WO2017207648A1

WO2017207648A1 - Process and intermediates for the preparation of obeticholic acid and derivatives thereof

Info

Publication number: WO2017207648A1
Application number: PCT/EP2017/063184
Authority: WO
Inventors: Antonio Lorente Bonde-Larsen; Anthony J. Lepine; Alexander J. L. CLEMENS
Original assignee: Bionice SL
Current assignee: Bionice SL
Priority date: 2016-05-31
Filing date: 2017-05-31
Publication date: 2017-12-07
Anticipated expiration: 2018-11-30

Abstract

The invention relates to a process for the preparation of obeticholic acid and derivatives thereof comprising: (a) olefination of a compound of formula (II) or a salt or solvate thereof to obtain a compound of formula (III) or a salt or solvate thereof and (b) conversion of a compound of formula (III), or a salt or solvate thereof, into a compound of formula (I), or a salt or solvate thereof.

Description

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF OBETICHOLIC

ACID AND DERIVATIVES THEREOF

Field of the Invention

The invention relates to a process for the preparation of obeticholic acid and derivatives thereof and to intermediates useful in the synthesis of these compounds.

Background of the Invention

The present invention relates to a process for the preparation of obeticholic acid and derivatives thereof of potential pharmaceutical value as highly potent FXR-agonist. These compounds can be used for the treatment of liver and gastrointestinal disorders, such as primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NASH), portal hypertension, etc.

Obeticholic acid

Up to now, obeticholic acid and its derivatives have been always obtained from chenodeoxycholic acid as starting material in multi-step syntheses.

Preparation of obeticholic acid was first disclosed in EP 1392714 B1 , where the total yield from chenodeoxycholic acid was only 3.1 %.

Chenodeoxycholic acid

EP 1776377 B1 discloses the synthesis of 3a-73-dihydroxy-6a-ethyl-53-cholanic acid, a derivative of obeticholic acid.

A very similar approach was used to obtain obeticholic acid in EP 1888614 B1 . In this case, the compound was obtained in 25% total yield after nine synthetic steps.

A similar approach for the synthesis of obeticholic acid was also disclosed in CN

105399793 A. In this case, the common intermediate 3ohydroxy-6-ethyliden-7-keto- 53-cholanic acid was first subjected to reduction of the 7-keto group followed by reduction of the ethylene group in position 6.

Chenodeoxycholic acid is the starting material in all these processes. However, this compound is expensive, since it is obtained from cholic acid in a five-step synthesis, as disclosed in EP 0424232 B1 .

It is therefore necessary to develop a new process for obtaining obeticholic acid and derivatives thereof as well as key intermediates in the synthesis of these compounds which overcome all or part of the problems associated with the known processes belonging to the state of the art.

Summary of the Invention

The invention faces the problem of providing a new process for the preparation of obeticholic acid and derivatives thereof which does not require the use of chenodeoxycholic acid as starting material. In particular, the inventors have found that compounds of formula (II) can be efficiently used as intermediates in the synthesis of obeticholic acid and related compounds. Therefore, the invention refers to the use of compounds of formula (II), or salts or solvates thereof, as intermediates in the synthesis of compounds of formula (I), or salts or solvates thereof, such as obeticholic acid.

Compounds of formula (II) can be readily obtained from hyodeoxycholic acid, for instance, as disclosed by Q. Dou et al. (Synthesis 2016, 48, 588-594), or as disclosed herein below. Hyodeoxycholic acid is cheaper and can be more easily obtained than chenodeoxycholic acid. Therefore, the process of the present invention for the synthesis of obeticholic acid and derivatives thereof is more convenient than previously disclosed processes using chenodeoxycholic acid as starting material.

Accordingly, in a first aspect the invention is directed to a process for preparing a compound of formula (I) or a salt or solvate thereof

(I)

wherein

Z is selected from the group consisting of -COOR³, -CONR⁴R⁵, -CH₂OP and

wherein R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from H, Ci-C₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl, and P is selected from

H and hydroxyl protecting group;

R¹ is selected from the group consisting of H and hydroxyl protecting group; R² is selected from the group consisting of H and hydroxyl protecting group; — indicates that the substituent may be in position a or β;

which comprises:

(a) olefination of a compound of formula (II) or a salt or solvate thereof

(II)

wherein Z, R¹ and R² can take the meanings defined above, to obtain a compound of formula (III) or a salt or solvate thereof

(HI)

wherein Z, R¹ and R² can take the meanings defined above, and

(b) conversion of a compound of formula (III), or a salt or solvate thereof, into compound of formula (I), or a salt or solvate thereof.

In a second aspect, the invention is directed to a compound of formula (III), or salt or solvate thereof

(III)

wherein

Z is selected from the group consisting of -COOR³, -CONR⁴R⁵, -CH₂OP and

wherein R³ is selected from H , CrC₆ alkyi and C₆-Ci₀ aryl; R⁴,

R⁵, R⁶ and R⁷ are independently selected from H , CrC₆ alkyi, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl; and P is selected from H and hydroxyl protecting group;

R¹ is selected from the group consisting of H and hydroxyl protecting group; and R² is selected from the group consisting of H and hydroxyl protecting group, provided that when R¹ and R² are H, then Z is not -COOH.

In another aspect, the invention is directed to a compound of formula (IV), or a salt or solvate thereof

(IV)

wherein

Z is selected from the group consisting of -CONR⁴R⁵, -CH₂OP and

wherein R⁴, R⁵, R⁶ and R⁷ are independently selected from H, CrC₆ alkyi, C₆- Cio aryl and (C6-Cio)aryl(Ci-C₆)alkyl, and P is selected from H and hydroxyl protecting group; and

R¹ is selected from the group consisting of H and hydroxyl protecting group.

Brief Description of Drawings

Figure 1. Scheme with processes for preparing compounds of formula (I) according to the invention.

Detailed Description of the Invention

The term "alkyi" refers to a linear or branched alkane derivative containing from 1 to 6 ("Ci-C₆ alkyi"), preferably from 1 to 3 ("CrC₃ alkyi"), carbon atoms and which is bound to the rest of the molecule through a single bond. Illustrative examples of alkyi groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl. Preferably, it is methyl or ethyl. The term "aryl" refers to an aromatic group having between 6 and 10, preferably 6 or 10 carbon atoms, comprising 1 or 2 aromatic nuclei fused to one another. Illustrative examples of aryl groups include phenyl, naphthyl, indenyl, phenanthryl, etc. Preferably, it is phenyl

The term "(C6-Cio)aryl(Ci-C₆)alky refers to an alkyl group as defined above substituted with an aryl group as defined above. Examples of such groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, etc. Preferably, it is benzyl.

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

The term "C₃-C₇ cycloalkyl" refers to a radical derived from cycloalkane containing from 3 to 7, preferably from 3 to 6 ("C₃-C₆ cycloalkyl") carbon atoms. Illustrative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "CrC₆ alkoxy" designates an alkyl group as defined above having between 1 and 6 carbon atoms, more preferably between 1 and 3 carbon atoms ("Cr C₃ alkoxy"), linked to the rest of the molecule through oxygen. Examples of alkoxy include methoxy, ethoxy, isopropoxy, tertbutoxy, and the like.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic system containing from 3 to 10, preferably 5 to 7, ring atoms containing one or more, specifically one, two, three or four ring heteroatoms independently selected from N, O, and S, and the remaining ring atoms being carbon.

The term "heteroaryl" refers to an aromatic monocyclic or bicyclic system containing from 3 to 10, preferably 5 to 7, ring atoms containing one or more, specifically one, two, three or four ring heteroatoms independently selected from O, N and S, and the remaining ring atoms being carbon.

The term "hydroxyl protecting group" (HPG) refers to a group blocking the OH function for subsequent reactions that can be removed under controlled conditions. Hydroxyl protecting groups are well known in the art. Illustrative examples of hydroxyl protecting groups have been described by Green TW et al. in "Protective Groups in Organic Synthesis", 3rd Edition (1999), Ed. John Wiley & Sons. Virtually any hydroxyl protecting group can be used to put the invention into practice. Illustrative, non-limiting examples of HPGs include:

- silyl ethers [-Si(R)(R')(R")]. R, R' and R" can be independently selected from CrC₆ alkyl, C₃-C₇ cycloalkyl, C₆-Ci₀ aryl, CrC₆ alkoxy and halogen. Examples of silyl ethers include trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert- butyldiphenylsilyl ether, tri-isopropylsilyl ether, diethylisopropylsilyl ether, hexyldimethylsilyl ether, triphenylsilyl ether, di-tert-butylmethylsilyl ether;

- ethers [-R], including alkoxy and aryloxy methyl ethers [-CH₂-OR]. R can be selected from Ci-C₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl. Examples of ethers include methyl ether, tert-butyl ether, benzyl ether, p-methoxybenzyl ether, 3,4- dimethoxybenzyl ether, trityl ether, allyl ether, methoxymethyl ether, 2- methoxyethoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, 2-(trimethylsilyl)ethoxymethyl ether; tetrahydropyranyl and related ethers;

- esters [-COR]. R can be selected from Ci-C₆ alkyl, C₆-Ci₀ aryl and (C₆-Ci₀)aryl(Ci- C₆)alkyl. Examples of esters include acetate ester, benzoate ester, pivalate ester, methoxyacetate ester, chloroacetate ester, levulinate ester; and

- carbonates [-COOR]. R can be selected from Ci-C₆ alkyl, C₆-Ci₀ aryl and (C₆- Cio)aryl(Ci-C₆)alkyl. Examples of carbonates include benzyl carbonate, p- nitrobenzyl carbonate, tert-butyl carbonate, 2,2,2-trichloroethyl carbonate, 2- (trimethylsilyl)ethyl carbonate, allyl carbonate.

As understood in this technical area, there may be a certain degree of substitution in the aforementioned radicals. Therefore, there may be substitution in any of the groups of the present invention. The previous groups can be substituted in one or more available positions with one or more substituents. Said substituents include, for example and in non-limiting sense, Ci_-6 alkyl, C3-7 cycloalkyl, C₆-Ci₀ aryl, 3- to 10- membered heterocyclyl, 3- to 10-membered heteroaryl, halogen, -CN, N0₂, CF₃, - N(R_a)(R_b), -ORc, -SR_d, -C(0)R_e, -C(0)OR_f, -C(0)N(R_g)(R_h), -OC(0)R_i; wherein R_a, R_b, R_c, R_d, R_e, R_f, R_g, R_h and R are independently selected from hydrogen, CrC₆ alkyl, C₆- C10 aryl, 3- to 10-membered heterocyclyl, 3- to 10-membered heteroaryl and trifluoromethyl.

The invention also provides "salts" of the compounds described in the present description. By way of illustration, said salts can be base addition salts or metal salts, and can be synthesized from the parent compounds containing an acid moiety by means of conventional chemical processes known in the art. Such salts are generally prepared, for example, by reacting the free acid form of said compounds with a stoichiometric amount of the suitable base in water or in an organic solvent or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred. Illustrative examples of base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc. Illustrative examples of metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts. In a particular embodiment, the salt is a metal salt, such as sodium salt.

The term "solvate" according to this invention is to be understood as meaning any form of the compound which has another molecule (most likely a polar solvent) attached to it via non-covalent bonding. Examples of solvate include hydrates and alcoholates, e.g. methanolates.

The term "organic solvent" includes for example cyclic and acyclic ethers (e.g Et₂0, iPr₂0, tBu₂0, MeOtBu, 1 ,4-dioxane, tetrahydrofuran, methyltetrahydrofuran) hydrocarbon solvents (e.g. pentane, hexane, heptane), halogenated solvents (e.g dichloromethane, chloroform), aromatic solvents (e.g. toluene, xylene), esters (e.g EtOAc), nitriles (e.g. acetonitrile), amides (e.g. DMF, DMA), alcohols (e.g. methanol ethanol, propanol, isopropanol), sulfoxides (DMSO) and mixtures thereof.

In a first aspect, the invention is directed to a process for preparing a compound of formula (I) or a salt or sol

(I)

wherein

Z is selected from the group consisting of -COOR³, -CONR⁴R⁵, -CH₂OP and

wherein R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from

H, Ci-C₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl, and P is selected from H and hydroxyl protecting group;

R¹ is selected from the group consisting of H and hydroxyl protecting group;

R² is selected from the group consisting of H and hydroxyl protecting group;

— indicates that the substituent may be in position a or β;

which comprises:

(a) olefination of a compound of formula (II) or a salt or solvate thereof

(ii)

(HI)

wherein Z, R¹ and R² can take the meanings defined above, and

(b) conversion of a compound of formula (III), or a salt or solvate thereof, into a compound of formula (I), or a salt or solvate thereof. The dashed bond in position 6 and 7 indicates that the substituents may be in position a or β. Therefore, compounds of formula (I) include those having the following stereochemistry (6a, a), (6a, 7β), (6β,7α), (6β,7β). In a particular embodiment, the compound of formula (I) is selected from a compound of formula (Ι-6α,7α), or a salt or solvate thereof, a compound of formula (Ι-6α,7β), or a salt or solvate thereof, a compound of formula (Ι-6β,7α), or a salt or solvate thereof, and mixtures thereof

(Ι-6α,7α) (Ι-6α,7β) (Ι-6β,7α) wherein Z, R¹ and R² can take the meanings defined herein. In an embodiment, R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from H, d-

C₆ alkyl, phenyl and benzyl. Preferably, they are independently selected from H, methyl, ethyl, n-propyl, i-propyl, t-butyl, neo-pentyl, phenyl and benzyl. In an embodiment, Z is -COOR³ wherein R³ is as defined herein. Preferably, Z is -COOR³ wherein R³ is selected from H, methyl, ethyl, n-propyl, i-propyl, t-butyl, phenyl and benzyl. More preferably, Z is selected from -COOH, -COOMe -COOEt, -COO'Pr, - COO'Bu and -COOneo-Pent.

In a particular embodiment, the hydroxyl protecting groups are independently selected from ethers and silyl ethers.

In a particular embodiment, the invention refers to a process for the preparation of a compound of formula (I), or a salt or solvate thereof, wherein Z is -COOH and R¹ and R² are H. Preferably, the compound of formula (I) is obeticholic acid, or a salt or solvate thereof, such as obeticholic acid sodium salt. More preferably, the compound of formula (I) is obeticholic acid.

Depending on the desired compound of formula (I) and on the starting compound, the process of the invention can comprise, if necessary, one or more of the following steps in any order:

- removal of any hydroxyl protecting group,

protection of any hydroxyl group,

conversion of Z into a different Z group.

Olefination reaction (Position 6)

The compound of formula (III), or a salt or solvate thereof, is obtained by olefination of a compound of formula (II), or a salt or solvate thereof.

Olefination reactions of ketones and suitable reaction conditions are known in the art (e.g. M.B. Smith, J. March, March's Advanced Organic Chemistry, Wiley- Interscience, 5^th ed., pp. 1541 -1542; Science of Synthesis: Houben-Weyl methods of molecular transformations, Thieme). For instance, a compound of formula (II), or a salt or solvate thereof, can be olefinated to a compound of formula (III), or a salt or solvate thereof, through Wittig reaction, Julia olefination, Peterson olefination, and the like.

In an embodiment, a compound of formula (III), or a salt or solvate thereof, is obtained by olefination of a compound of formula (II), or a salt or solvate thereof, via Wittig-type reaction. In a particular embodiment, olefination is performed by reaction of a compound of formula (II), or a salt or solvate thereof, with a compound of formula (VI), (VII) or (VIII)

(VI) (Vll) (Vlll) wherein X is halogen;

each R' is selected from C₆-Ci₀ aryl, preferably phenyl; and

each R" is selected from Ci-C₆ alkyl and (C6-Cio)aryl(Ci-C₆)alkyl, preferably methyl or ethyl,

in the presence of a base, to obtain a compound of formula (III), or a salt or solvate thereof.

Suitable bases include organolithium bases, alkali metal hydrides and alkali metal alcoholates, such as e.g. nBuLi, tBuLi, sBuLi, MeLi, PhLi, HMDSLi, LDA, NaH, NaOtBu, KOtBu, NaOMe, NaOEt.

Preferably, the reaction is carried out in the presence of an organic solvent, such as for example a cyclic or acyclic ether (e.g. Et₂0, iPr₂0, tBu₂0, 1 ,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g. pentane, hexane, heptane), a halogenated solvent (e.g. dichloromethane, chloroform), an aromatic solvent (e.g. toluene, xylene), dimethylformamide, dimethylacetamide or mixtures thereof. In a particular embodiment, the reaction is performed in the presence of an ether, an aromatic solvent or a halogenated solvent. In an embodiment, the reaction is carried out at a temperature between -20°C and 150°C, preferably between 0°C and 100°C.

Preferably, R¹ and R² in the compound of formula (II) are selected from a hydroxyl protecting group, such as an ether or a silyl ether. In a particular embodiment, R¹ and R² in the compound of formula (II) are selected from a hydroxyl protecting group, such as an ether or a silyl ether, and Z is -COOR³ wherein R³ is as defined herein.

Conversion of a compound of formula (III), or a salt or solvate thereof, into a compound of formula (I) or a salt or solvate thereof

Conversion of compounds of formula (III) into compounds of formula (I) has been disclosed in the prior art (EP 1776377 B1 , EP 1888614 B1 , CN 105399793 A). The stereochemistry at positions 6 and 7 of the compound of formula (I) depends on the reaction conditions used for the reduction of the double bond at position 6 and on the group R² in the starting material.

In a particular embodiment, step (b) of the process of the invention comprises subjecting a compound of formula (III), or a salt or solvate thereof, to a reduction reaction of the double bond at position 6 to obtain a compound of formula (l-7a) or a salt or solvate thereof

(l-7a)

wherein Z, R¹, R² and— can take the meanings defined above.

In an embodiment, the compound (l-7a) is a mixture of the compound of formula (Ι-6α,7α) and the compound of formula (Ι-6β,7α), which is separated to obtain a compound of formula (Ι-6α,7α) and a compound of formula (Ι-6β,7α), or a salt or solvate thereof. Separation can be carried out, for example, by chromatography or by crystallization.

In an embodiment, a comp or a salt or solvate thereof

(Ι-6α,7α)

wherein Z, R¹ and R² can take the meanings defined above, is obtained by the process of the invention wherein step (b) comprises:

(i) if R² is a hydroxyl protecting group in the compound of formula (III), deprotection of the hydroxyl group at position 7 of the compound of formula (III), or a salt or solvate thereof, to obtain a compound of formula (III-70H) or a salt or solvate thereof

(III-70H),

(ii) reduction of the double bond at position 6 of a compound of formula (III-70H), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

, and

(iii) if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group.

One or more of the steps in (iii) may be needed or not depending on the desired compound of formula (Ι-6α,7α).

In another embodiment, a compound of formula (Ι-6α,7α) or a salt or solvate thereof is obtained by the process of the invention wherein step (b) comprises:

(i) if R² is a hydroxyl protecting group in the compound of formula (III), deprotection of the hydroxyl group at position 7 of the compound of formula (III), or a salt or solvate thereof, to obtain a compound of formula (III-70H) or a salt or solvate thereof,

(ii) oxidation of the hydroxyl group at position 7 of a compound of formula (III-70H), or a salt or solvate thereof, to obtain a compound of formula (IV) or a salt or solvate thereof

(IV),

(iii) reduction of the double bond at position 6 of a compound of formula (IV), or a salt or solvate thereof, to obtain a compound of formula (V-6a) or a salt or solvate thereof

(V-6a)

(iv) reduction of the keto group at position 7 of a compound of formula (V-6a), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

, and

(v) if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group.

One or more of the steps in (v) may be needed or not depending on the desired compound of formula (Ι-6α,7α).

(ii) oxidation of the hydroxyl group at position 7 of a compound of formula (III-70H), or a salt or solvate thereof, to obtain a compound of formula (IV) or a salt or solvate thereof,

(iii) reduction of the double bond at position 6 of a compound of formula (IV), or a salt or solvate thereof, to obtain a compound of formula (V-θβ) or a salt or solvate thereof,

(V-θβ),

(iv) epimerization at position 6 of a compound of formula (V-θβ), or a salt or solvate thereof, to obtain a compound of formula (V-6a) or a salt or solvate thereof

(V-6a)

(v) reduction of the keto group at position 7 of a compound of formula (V-6a), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

R

and

(vi) if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group.

One or more of the steps in (vi) may be needed or not depending on the desired compound of formula (Ι-6α,7α).

In an embodiment, a compou or a salt or solvate thereof

R

(Ι-6α,7β)

(i) preparing a compound of formula (V-6a), or a salt or solvate thereof, by any of the processes defined above

(V-6a),

(ii) reduction of the keto group at position 7 of a compound of formula (V-6a), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

R

and

(iii) if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group.

One or more of the steps in (iii) may be needed or not depending on the desired compound of formula (Ι-6α,7β).

In an embodiment, a compou or a salt or solvate thereof

R

(Ι-6β,7α)

(iv) reduction of the keto group at position 7 of a compound of formula (V-θβ), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

(v) if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group,

One or more of the steps in (v) may be needed or not depending on the desired compound of formula (Ι-6β,7α).

Protection / Deprotection of hydroxyl groups

If needed during the process of the invention, protection and/or deprotection of the hydroxyl groups can be performed at any stage of the synthesis. The most suitable stage for said protection and/or deprotection can be readily determined by those skilled in the art.

Protection and deprotection of the hydroxyl groups in the compounds of the invention can be performed by conventional methods known by those skilled in the art (e.g. Green TW et al. in "Protective Groups in Organic Synthesis", 3rd Edition (1999), Ed. John Wiley & Sons (ISBN 0-471 -16019-9)).

For example, compounds wherein R¹ and/or R² represent an ester (COR) or a carbonate (COOR) can be easily deprotected by hydrolysis in basic or acid media according to well-established procedures of the state of the art.

Compounds wherein R¹ and/or R² represent a silyl ether (Si(R)(R')(R") can be easily deprotected by the use of fluoride reagents such as fluoride salts or HF, acid media, oxidizing media, etc.

Compounds wherein R¹ and/or R² represent an ether (R) can be easily deprotected through hydrolysis in acid media (for example, for methyl ethers (CH₂OR)), hydrogenation (for example, for benzyl ethers), oxidation (for example, for aryl ethers), etc.

Reduction of the double bond (position 6)

Reduction of the double bond at position 6 can be carried out by any of the methods described in EP 1776377 B1 , EP 1888614 B1 or CN 105399793 A, or by any other conventional means known by the skilled person (e.g. M.B. Smith, J. March, March's Advanced Organic Chemistry, Wiley-lnterscience, 5^th ed., pp. 1007-1009).

In an embodiment, the double bond at position 6 of the compounds of the invention is reduced by catalytic hydrogenation. Preferably, catalytic hydrogenation is performed in the presence of a homogeneous or heterogeneous metal catalyst, such as one based on Pd, Pt, Ni, Rh or Ru, preferably based on Pd or Pt. When the metal catalyst is heterogeneous, it is preferably supported on an inert support such as charcoal, barium hydroxide, alumina or calcium carbonate, preferably charcoal.

In a particular embodiment, the metal catalyst is Pd/C, Pd(OH)₂/C, Pt/C, or Pt0₂. The hydrogen pressure can range between about 1 atm and 4 atm, preferably between 1 and 3 atm. In a particular embodiment, the reaction is carried out at atmospheric pressure. The reaction is preferably carried out at a temperature between 0°C and the reflux temperature of the solvent, preferably between 0°C and 40°C.

The reaction can be carried out in the presence of water, an organic solvent, or mixtures thereof. The organic solvent can be selected from cyclic and acyclic ethers (e.g. Et₂0, iPr₂0, tBu₂0, MeOtBu, 1 ,4-dioxane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g. pentane, hexane, heptane), halogenated solvents (e.g. dichloromethane, chloroform), aromatic solvents (e.g. toluene, xylene), esters (e.g. EtOAc), nitriles (e.g. acetonitrile), amides (e.g. DMF, DMA), alcohols (e.g. methanol, ethanol, propanol, isopropanol) and mixtures thereof.

In a particular embodiment, the hydrogenation reaction is carried out in the presence of a base, such as an alkali metal base and an organic amine. In a particular embodiment, the base is selected from alkaline metal hydroxides (LiOH, NaOH, KOH, CsOH), alkaline metal carbonates or bicarbonates (NaHC0₃, KHC0₃, Na₂C0₃, K₂C0₃, Cs₂C0₃), aliphatic amines (trimethylamine, diisopropilamine, N-methylmorpholine) and aromatic amines (pyridine, aniline, N,N-dimethylaniline).

In a particular embodiment, a compound of formula (III) is reduced to a compound of formula (l-7a) by catalytic hydrogenation in the presence of Pd/C, Pd(OH)₂/C, Pt/C or Pt0₂ as catalyst and a hydrogen pressure between 1 and 4 atm.

In another embodiment, a compound of formula (III-70H) is reduced to a compound of formula (Ι-6α,7α) by catalytic hydrogenation in the presence of Pd/C, Pd(OH)₂/C, Pt/C or Pt0₂, preferably Pd/C, as catalyst and a hydrogen pressure between 1 and 4 atm.

In a particular embodiment, a compound of formula (IV) is reduced to a compound of formula (V-6a) by catalytic hydrogenation in the presence of Pt0₂ as catalyst and a hydrogen pressure between 1 and 3 atm.

In another embodiment, a compound of formula (IV) is reduced to a compound of formula (V-θβ) by catalytic hydrogenation in the presence of Pd/C or Pd(OH)₂/C as catalyst and a hydrogen pressure between 1 and 4 atm.

Oxidation of the hydroxy! group to a keto group (position 7)

Oxidation of the hydroxyl group at position 7 can be carried out by any conventional means known by the skilled person (e.g. M.B. Smith, J. March, March's Advanced Organic Chemistry, Wiley-lnterscience, 5^th ed., pp. 1514-1517).

In an embodiment, the hydroxyl group at position 7 of the compounds of the invention is oxidized to a keto group in the presence of an oxidizing agent. Suitable oxidizing agents include K₂Cr₂0₇, KMn0₄, Mn0₂, Cr0₃, Ru0₄, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin reagent, Jones reagent, Collins reagent and the like.

The reaction can be carried out in the presence of water, an organic solvent, or mixtures thereof and is preferably carried out at a temperature between 0°C and the reflux temperature of the solvent, preferably between 0°C and 40°C.

Reduction of the keto group to a hydroxyl group (position 7)

Reduction of the keto group at position 7 can be carried out by any of the methods described in EP 1776377 B1 , EP 1888614 B1 or CN 105399793 A, or by any other conventional means known by the skilled person (e.g. M.B. Smith, J. March, March's Advanced Organic Chemistry, Wiley-lnterscience, 5^th ed., pp. 1 197-1203).

In an embodiment, the keto group at position 7 of the compounds of the invention is reduced in the presence of a metallic hydride, sodium and an alcohol, a borane, or a silane and a base.

Preferably, the reduction is performed in the presence of a metallic hydride (e.g.

LiAIH₄, LiBH₄, LiBHEt₃, NaBH₄, NaBH(OAc)₃, Ca(BH₄)₂), or in the presence of Na and an alcohol (e.g. a C C₆ aliphatic alcohol such as MeOH, EtOH, nPrOH, iPrOH, nBuOH, sBuOH or tBuOH).

The reaction can be carried out in the presence of water, an organic solvent, or mixtures thereof. Preferably, the reaction is carried out in the presence of an organic solvent.

The reaction is preferably carried out at a temperature between 0°C and the reflux temperature of the solvent, preferably between 0°C and 40°C.

In a particular embodiment, a compound of formula (V-6a) is reduced to a compound of formula (Ι-6α,7α) in the presence of a metallic hydride, preferably NaBH₄ or LiBH₄.

In another embodiment, a compound of formula (V-θβ) is reduced to a compound of formula (Ι-6β,7α) in the presence of a metallic hydride, preferably NaBH₄ or LiBH₄.

In another embodiment, a compound of formula (V-6a) is reduced to a compound of formula (Ι-6α,7β) in the presence of sodium and an alcohol, preferably a Ci-C₆ aliphatic alcohol such as MeOH, EtOH, nPrOH, iPrOH, nBuOH, sBuOH or tBuOH.

Epimerization of the stereocenter at position 6

Epimerization of the stereocenter at position 6 can be carried out as described in EP 1888614 B1 or by any other conventional means known by the skilled person.

In an embodiment, the stereocenter at position 6 of the compounds of the invention is epimerized by heat treatment or by treatment with a base.

In a particular embodiment, a compound of formula (V-θβ) is epimerized to a compound of formula (V-6a) by heat treatment, preferably at a temperature between 50 and 120°C, more preferably between 80 and 1 10°C.

In another embodiment, epimerization of a compound of formula (V-θβ) to a compound of formula (V-6a) is carried out in the presence of a base. Suitable bases include alkali metal hydroxides (e.g. LiOH, NaOH, KOH, CsOH) and alkali metal alcoholates (e.g. NaOMe, NaOEt, NaOiPr, NaOnBu, NaOtBu, KOMe, KOEt, KOiPr, KOnBu, KOtBu). The reaction is preferably carried out in the presence of an alcohol, preferably a Ci-C₆ aliphatic alcohol. The reaction can be carried out at a temperature between 0°C and the reflux temperature of the solvent, preferably between 0°C and 40°C.

Conversion of Z into a different Z group

Transformation of the Z group into a different Z group can be carried out by any of the methods described in EP 1776377 B1 , EP 1888614 B1 or CN 105399793 A, or by any other conventional means known by the skilled person (e.g. M.B. Smith, J. March, March's Advanced Organic Chemistry, Wiley-lnterscience, 5^th ed.). For instance, when Z is an ester or an amide group, it can be converted into a carboxylic acid group by hydrolysis under basic or acid conditions; or into a CH₂OP group by reduction in the presence of a suitable reducing agent and, if needed, protection of the hydroxyl group by conventional means.

When Z is an oxazoline group, it can be converted into a carboxylic acid group by hydrolysis under acid conditions.

When Z is a carboxylic acid group, it can be converted into an ester by treatment with an alcohol under acid conditions; or into an amide by treatment with ammonia or an amine; or into a CH₂OP group by reduction in the presence of a suitable reducing agent and, if needed, protection of the hydroxyl group by conventional means; or into an oxazoline by treatment with the corresponding aminoalcohol.

Synthesis of compounds of formula (II)

Compounds of formula (II) can be readily obtained from hyodeoxycholic acid, for instance, as disclosed in Q. Dou et al., Synthesis 2016, 48, 588-594.

In order to obtain the desired compound of formula (II) from the compound of formula (II) disclosed by Dou et al. it may be necessary to perform one or more of the following steps in any order:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group.

All these chemical transformations are well-known in the art and can be carried out by conventional means known by those skilled in the art or by the methods disclosed herein.

Compounds of formula (II) can be also obtained from hyodeoxycholic acid by a process according to the following scheme:

wherein

R¹ represents hydroxyl protecting group;

R³ is selected from Ci-C₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl; and each R' is independently selected from the group consisting of Ci-C₆ alkyl, C₆-Ci₀ aryl, CrC₆ alkoxy and halogen.

In an embodiment, R¹ is selected from -COR, wherein R is selected from CrC₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl; preferably R is CrC₆ alkyl; more preferably R¹ is Ac.

In an embodiment, R³ is selected from Me, Et and Bn; preferably R³ is Bn.

In an embodiment, -OSiR'₃ is selected from -OSiMe₃ and -OSiEt₃; preferably it is -OSiEt₃.

In a particular embodiment, in the process according to the above scheme, R¹ is selected from -COR, wherein R is selected from Ci-C₆ alkyl, C₆-Ci₀ aryl and (C₆- Cio)aryl(Ci-C₆)alkyl; R³ is selected from Me, Et and Bn; and -OSiR'₃ is selected from - OSiMe₃ and -OSiEt₃. Preferably, R¹ is selected from -COR, wherein R is C C₆ alkyl, preferably Me; R³ is Bn; and -OSiR'₃ is -OSiEt₃.

In order to obtain the desired compound of formula (II) from the compound of formula (II) obtained according to the above scheme, it may be necessary to perform one or more of the following steps in any order:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group.

Therefore, in a particular embodiment, the starting compound of formula (II), or a salt or solvate thereof, is obtained from hyodeoxycholic acid by a process comprising: (i) converting the carboxylic acid group into an ester wherein R³ is as defined above; (ii) protecting the hydroxyl group at position 3; (iii) oxidizing the hydroxyl group at position 6 to the ketone; (iv) converting the ketone at position 6 into the silyl enol ether; and (v) oxidizing the silyl enol ether to the 7-hydroxyl-6-oxo compound.

In a particular embodiment, hyodeoxycholic acid is converted into the ester wherein R³ is Bn in step (i) by treatment with BnOH, BnBr, BnCI or Bnl in the presence of an organic solvent and an acid, a base or a coupling agent. Suitable bases include alkali metal carbonates, such as Li, Na, K or Cs carbonates; and tertiary amines, such as Me₃N, Et₃N, DIPEA, Pyr or DMAP. Suitable acids include p-TsOH, MsOH, AcOH or TFA. Suitable coupling agents include DCC, DIC or EDC.

In an embodiment, step (ii) is performed in the presence of vinyl acetate and an enzyme (such as Novozym 435) and an organic solvent, to obtain a compound wherein R¹ is Ac.

In an embodiment, step (iii) is carried out in the presence of an oxidant and an organic solvent. Suitable oxidants include PDC, PCC, NBS, NCS and TCCA.

In a preferred embodiment, steps (i) to (iii) are carried out in a one-pot process, that is, without isolation of the intermediate compounds.

In an embodiment, step (iv) is carried out in the presence of silylating agent, such as TESCI, TESBr, TESOTf, a base and an organic solvent to obtain a compound wherein -OSiR'₃ is -OSiEt₃. Suitable bases include tertiary amines, such as Me₃N, Et₃N, DIPEA, Pyr, DMAP, 2,6-lutidine.

In an embodiment, step (v) is carried out in the presence of a peroxycarboxylic acid, such as m-CPBA, and an organic solvent.

In a preferred embodiment, steps (iv) and (v) are carried out in a one-pot process, that is, without isolation of the intermediate compound.

Compounds of formula (III) and (IV)

In another aspect, the invention is directed to a compound of formula (III), or a salt or solvate thereof,

(III) wherein

Z is selected from the group consisting of -COOFr, -CONFrFr, -CH₂OP and

wherein R³ is selected from H, CrC₆ alkyl and C₆-Ci₀ aryl; R⁴, R⁵, R⁶ and R⁷ are independently selected from H, CrC₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl; and P is selected from H and hydroxyl protecting group;

Preferred embodiments for Z, R¹ and R² are as defined above.

In another aspect, the invention is directed to a compound of formula (IV), or a salt or solvate thereof,

(IV)

wherein

Z is selected from the group consisting of -CONR⁴R⁵, -CH₂OP and

wherein R⁴, R⁵, R⁶ and R⁷ are independently selected from H, CrC₆ alkyl, C₆- Cio aryl and (C6-Cio)aryl(Ci-C₆)alkyl, and P is selected from H and hydroxyl protecting group; and

R¹ is selected from the group consisting of H and hydroxyl protecting group.

Preferred embodiments for Z and R¹ are as defined above.

It should be understood that the scope of the present disclosure includes all the possible combinations of embodiments disclosed herein.

EXAMPLES

Synthesis of obeticholic acid from hyodeoxycholic acid

hyodeoxycholic acid (HDCA)

Preparation of compound 1

A 1 L 3-neck round bottom flask equipped with magnetic stir bar, N₂ inlet/outlet, and thermocouple was charged with HDCA (50 g, 127 mmol) and MeTHF (250 mL, 5 volumes). EDC-HCI (26.9 g, 140 mmol, 1 .1 equivalents) was slurried in CH₂CI₂ (250 mL, 5 volumes) in a separate flask and transferred to the HDCA solution in portions over 10 minutes. DMAP (0.80 g, 6.55 mmol, 0.05 equivalents) was added and the slurry was stirred for 16 hours at room temperature before TLC analysis showed starting material remaining. Additional EDC-HCI (2.4 g, 12.7 mmol, 0.1 equivalents) was added and after 3.5 hours at room temperature the reaction was complete by TLC analysis. Water (200 mL, 4 volumes) was added and the biphasic mixture was separated. The bottom organic layer was washed with water (200 mL, 4 volumes), 0.5 M aqueous HCI (200 mL, 4 volumes), water (200 mL, 4 volumes) and saturated aqueous NaHC0₃ (200 mL, 4 volumes). The organic layer was dried over MgS0₄, filtered, and concentrated to a dark tan foam that was dissolved in EtOAc (460 mL) to use crude in the next reaction. HPLC analysis of EtOAc solution: 80.2% (AUC), f_R = 1 1.1 min. MS Analysis: [M+H]⁺ 483 m/z, [M+H+MeCN]⁺ 524 m/z.

Preparation of compound 2

A 1 L 3-neck round bottom flask equipped with magnetic stir bar, heating mantle, and a condenser was charged with the EtOAc solution of compound 1 (127 mmol), vinyl acetate (23.5 mL, 255 mmol, 2.0 equivalents), and Novozym 435-impregnated beads (2.93 g,≥5,000 U/g). The mixture was heated at reflux (76°C) for 17 hours at which point HPLC analysis showed complete consumption of compound 1. The mixture was cooled to room temperature and the lipase beads were removed by filtration and washed with EtOAc. The filtrate was concentrated to a residue that was dissolved in CH₂CI₂ (20 mL), concentrated again, and held overnight in a 30°C vacuum oven to remove additional solvent residue to provide 66.6 g (96% yield) of crude compound 2 as an amber oil. HPLC Analysis: 84.1 % (AUC), t_R = 18.2 min. ¹H NMR (CDCI₃): δ 7.30- 7.40 (m, 5H), 5.00-5.20 (m, 2H), 4.60-4.80 (m 1 H), 4.00-4.15 (m, 1 H), 2.20-2.50 (m, 3H), 2.01 (s, 3H), 1 .00-2.00 (m, 29H), 0.91 (s, 3H), 0.90 (d, J = 6.0 Hz, 3H), 0.61 (s, 3H). ¹³C NMR (CDCI₃): δ 174.0 (C), 170.5 (C), 136.1 (C), 129.0 (C), 128.5 (CH), 128.21 (CH), 128.15 (CH), 74.2 (CH), 67.7 (CH), 66.1 (CH2), 56.1 (CH), 56.0 (CH), 48.3 (CH), 42.8 (C), 39.9 (CH₂), 39.8 (CH), 35.9 (CH₂), 34.8 (C), 31.3 (CH₂), 30.9 (CH₂), 28.0 (CH₂), 26.6 (CH₂), 25.3 (CH₂), 24.2 (CH₂), 23.5 (CH₃), 21.4 (CH₃), 20.8 (CH₂), 18.2 (CH₃), 12.0 (CH₃). MS Analysis: [M+H]⁺ 525 m/z, [M+H-AcOH-H₂0]⁺ 447 m/z, [M+H- AcOH+MeCN]⁺ 506 m/z, [M+H-H₂0+MeCN]⁺ 548 m/z.

Preparation of compound 3

A 2 L 4-neck round bottom flask equipped with overhead stirrer, thermocouple, and N₂ inlet/outlet was charged with compound 2 (63.8 g, 122 mmol), CH₂CI₂ (600 mL), and Dicalite® (128 g). The slurry was cooled to 1 °C and PCC (31.8 g, 148 mmol, 1.2 equivalents) was added. After 27 minutes, the slurry was allowed to warm to room temperature and after 2.9 hours TLC analysis showed only trace compound 2 remaining. The slurry was filtered through additional CH₂CI₂-wet Dicalite® (243 g) and the filter cake washed with additional CH₂CI₂ (2.8 L) in 5 fractions. The filtrate was concentrated onto silica gel (100 g), which was added to a 2-3 inch pad of Si0₂ and washed with EtOAc (5x500 mL). The filtrate was concentrated to residue, then dissolved in hot EtOAc (224 mL) and filtered hot to remove a dark brown solid. The filtrate was concentrated and dissolved in refluxing heptane (300 mL), then cooled to room temperature. The resulting solids were collected by filtration and washed with heptane (90 mL), and dried in a 33°C vacuum oven to provide 25.5 g of compound 3 (40% yield from HDCA over three steps). HMBC and NOE NMR spectroscopy experiments confirmed the C3 acetate and the C6 ketone regioisomer. HPLC Analysis: 97.4% (AUC) , f_R = 18.3 min. ¹H NMR (CDCI₃): δ 7.30-7.45 (m, 5H), 5.0-5.2(m, 2H), 4.60-4.80 (m, 1 H), 2.20-2.50 (m, 2H), 2.10-2.20 (m, 3H), 2.00-2.10 (m 1 H), 2.03 (s, 3H), 1.65-1 .95 (m, 8H), 1.00-1 .65 (m, 13H), 0.92 (d, J = 6.0 Hz, 3H), 0.85 (s, 3H), 0.63 (s, 3H). ¹³C NMR (CDCIs): δ 212.7 (C), 173.9 (C), 170.2 (C), 136.1 (C), 128.5 (CH), 128.24 (CH), 128.19 (CH), 72.4 (CH), 66.1 (CH₂), 59.1 (CH), 56.8 (CH), 55.9 (CH), 43.1 (CH₂), 42.8 (C), 39.9 (CH), 39.6 (CH₂), 37.9 (C), 37.1 (CH), 35.2 (C), 34.1 (CH₂), 31.3 (CH₂), 31.0 (CH₂), 30.9 (CH₂), 28.0 (CH₂), 26.2 (CH₂), 23.9 (CH₂), 23.1 (CH₃), 21.3 (CH₃), 20.8 (CH₂), 18.2 (CH₃), 1 1 .9 (CH₃). MS Analysis: [M+H]⁺ 523 m/z, [M+H+MeCN]⁺ 564 m/z.

Preparation of compound 4

A 100 mL round bottom flask was equipped with a magnetic stir bar and N₂ inlet/outlet, charged with compound 3 (2.16 g, 4.13 mmol) and CH₂CI₂ (41 mL), and cooled in an ice-water bath. Triethylamine (2.3 mL, 16.5 mmol, 4.0 equivalents) was added to the solution. To this cold solution was added TESOTf (2.3 mL, 10.2 mmol, 2.5 equivalents) dropwise. The reaction was allowed to warm to room temperature while stirring for 23 hours. TLC analysis showed the consumption of compound 3. The reaction was quenched with saturated aqueous NaCI (10 mL) and the biphasic mixture separated. The organic layer was dried over MgS0₄ and concentrated to 5.99 g of a residue that was used crude in the next reaction. Preparation of compound 5

To a magnetically stirring solution of crude compound 4 (5.99 g) in CH₂CI₂ (8.3 mL) was added mCPBA (1 .90 g, 8.48 mmol, 2.1 equivalents) at ambient temperature. The resulting slurry was stirred for 17 hours and TLC analysis showed the formation of a polar major product. The reaction was quenched with saturated aqueous Na₂C0₃ and diluted with CH₂CI₂ and water to break up the resulting emulsion. The lower organic layer was removed and washed with 1 M aqueous HCI, dried over MgS0₄, and concentrated to a yellow oil. LC/MS analysis of the oil suggested the C7 hydroxyl was an OTES ether and so the oil was dissolved in THF (43 mL) and treated with TBAF- H₂0 (1 .1 1 g, 4.25 mmol, 1 .0 equivalent). After 6.9 hours the reaction mixture was poured into water (100 mL) and extracted with EtOAc. The organic phase was dried over MgS0₄ and concentrated to 3.13 g of a residue that was purified by flash column chromatography (EtOAc/heptane). The fractions were examined by TLC and HPLC analysis and the four purest fractions were combined and concentrated to provide 0.69 g (31 % yield) of compound 5 as a white solid. HPLC Analysis: 92.8% (AUC), t_R = 15.1 min. ¹H NMR (CDCI₃): δ 7.30-7.45 (m, 5H), 5.10-5.16 (m, 2H), 5.50-4.65 (m, 1 H), 3.80- 3.85 (m, 1 H), 2.10-2.60 (m, 7H), 2.02 (s, 3H), 1.0-2.0 (m, 22 H), 0.93 (d, J = 6.3 Hz, 3H), 0.83 (s, 3H), 0.64 (s, 3H).¹³C NMR (CDCI₃): δ 21 1 .4 (C), 174.0 (C), 170.5 (C), 136.1 (C), 128.5 (CH), 128.23 (CH), 128.18 (CH), 76.1 (CH), 72.4 (CH), 66.1 (CH₂), 58.3 (CH), 55.6 (CH), 49.1 (CH), 42.8 (C), 40.0 (CH), 39.1 (CH₂), 38.1 (C), 35.3 (CH), 34.2 (CH₂), 33.2 (CH), 31.3 (CH₂), 30.9 (CH₂), 30.7 (CH₂), 28.0 (CH₂), 26.2 (CH₂), 23.3 (CH₂), 23.1 (CH₃), 21 .3 (CH₃), 20.8 (CH₂), 18.2 (CH₃), 1 1 .7 (CH₃). MS Analysis: [M+H]⁺ 539 m/z, [M+H-AcOH-H₂0]⁺ 461 m/z, [M+H-AcOH]⁺ 479 m/z.

Preparation of compound 6

A 20 mL vial was charged with a magnetic stir bar, ethyltriphenylphosphonium bromide (0.41 g, 1 .10 mmol, 3.1 equivalents) and THF (1 .0 mL). A THF solution of KHMDS was added dropwise (1 .0 M, 1 .1 mL, 1 .10 mmol, 3.1 equivalents) and the resulting orange slurry was warmed to 50°C. A solution of compound 5 (0.19 g, 0.353 mmol, 1.0 equivalents) in 3 mL THF was added dropwise to the ylide mixture. After 4 hours, HPLC analysis showed consumption of compound 5.

Preparation of compound 7 and obeticholic acid

Compound 6 can be converted into compound 7 and then into obeticholic acid by following standard procedures from the state of the art.

Obeticholic acid can be also obtained from compound 8 following the process disclosed in CN 105399793.

Preparation of compounds 10a and 11a

Compounds of formula 10a and 1 1 a can be obtained from compound 9a following the processes disclosed in Examples 2A and 2C of WO 2015/181275.

Compounds of formula 10b, 1 1 b, 12b, 13b and obeticholic acid can be obtained from compound 9b following the processes disclosed in Examples 1 -3 of EP 1888614 B1.

Compounds of formula 1 1 c, 13c and 13b can be obtained from compound 9c following the processes disclosed in Example 3 of EP 1776377 B1 .

Preparati

Compound 14d and obeticholic acid can be obtained from compound 1 1 d following the processes disclosed in EP 1392714 B1 .

Claims

A process for preparing a compound of formula (I) or a salt or solvate thereof

(I)

wherein

Z is selected from the group consisting of -COOR³, -CONR⁴R⁵, -CH₂OP and

wherein R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from H, Ci-C₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl, and P is selected from H and hydroxyl protecting group;

R¹ is selected from the group consisting of H and hydroxyl protecting group;

R² is selected from the group consisting of H and hydroxyl protecting group; — indicates that the substituent may be in position a or β;

which comprises

(a) olefination of a compound of formula (II) or a salt or solvate thereof

(II)

wherein Z, R¹ and R² take the meanings defined above, to obtain a compound of formula (III) or a salt or solvate thereof

(HI)

wherein Z, R¹ and R² take the meanings defined above, and (b) conversion of a compound of formula (III), or a salt or solvate thereof, into a compound of formula (I), or a salt or solvate thereof.

Process according to claim 1 , wherein the compound of formula (I) is selected from a compound of formula (Ι-6α,7α), or a salt or solvate thereof, a compound of formula (Ι-6α,7β), or a salt or solvate thereof, a compound of formula (Ι-6β,7α), or a salt or solvate thereof, and mixtures thereof

Process according to claim 1 or 2, wherein step (a) comprises reacting a compound of formula (II), or a salt or solvate thereof, with a compound of formula (VI), (VII) or (VIII)

(VI) (VII) (VIII)

wherein

X is halogen;

each R' is selected from C₆-Ci₀ aryl; and

each R" is selected from Ci-C₆ alkyl and (C6-Cio)aryl(Ci-C₆)alkyl, in the presence of a base.

4. Process according to any one of claims 1 to 3, wherein step (b) comprises subjecting a compound of formula (III) or a salt or solvate thereof

(III) to a reduction reaction of the double bond at position 6 to obtain a compound of formula (l-7a) or a salt or solvate thereof

wherein Z, R¹, R² and— take the meanings defined in claim 1.

5. Process according to any one of claims 1 to 4, wherein step (b) comprises:

- if R² is a hydroxyl protecting group in the compound of formula (III), deprotection of the hydroxyl group at position 7 of the compound of formula (III), or a salt or solvate thereof, to obtain a compound of formula (III-70H) or a salt or solvate thereof

(III-70H),

reduction of the double bond at position 6 of a compound of formula (III-70H), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

R¹

and

- if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group,

to obtain a compound of formula (Ι-6α,7α) or a salt or solvate thereof

(Ι-6α,7α)

wherein Z, R¹ and R² take the meanings defined in claim 1 .

6. Process according to any one of claims 1 to 3, wherein step (b) comprises:

(III-70H),

oxidation of the hydroxyl group at position 7 of a compound of formula (III-70H), or a salt or solvate thereof, to obtain a compound of formula (IV) or a salt or solvate thereof

(IV),

reduction of the double bond at position 6 of a compound of formula (IV), or a salt or solvate thereof, to obtain a compound of formula (V-6a) or a salt or solvate thereof

(V-6a)

reduction of the keto group at position 7 of a compound of formula (V-6a), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

R

and

- if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group,

to obtain a compound of formula (Ι-6α,7α) or a salt or solvate thereof

(Ι-6α,7α)

wherein Z, R¹ and R² take the meanings defined in claim 1.

7. Process according to any one of claims 1 to 3, wherein step (b) comprises:

(III-70H),

(IV),

reduction of the double bond at position 6 of a compound of formula (IV), or a salt or solvate thereof, to obtain a compound of formula (V-θβ) or a salt or solvate thereof,

(V-63),

epimerization at position 6 of a compound of formula (V-θβ), or a salt or solvate thereof, to obtain a compound of formula (V-6a) or a salt or solvate thereof

(V-6a)

and

- if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group,

to obtain a compound of form solvate thereof

R¹

(Ι-6α,7α)

wherein Z, R¹ and R² take the meanings defined in claim 1.

Process according to any one of claims 1 to 3, wherein step (b) comprises:

- preparing a compound of formula (V-6a) or a salt or solvate thereof, by process as defined in any one of claims 6 or 7

(V-6a), and

R

and - if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group,

to obtain a compound of fo solvate thereof

(Ι-6α,7β)

wherein Z, R¹ and R² take the meanings defined in claim 1.

Process according to any one of claims 1 to 3, wherein step (b) comprises:

(III-70H),

(IV),

(V-θβ),

reduction of the keto group at position 7 of a compound of formula (V-θβ), or a salt or solvate thereof, to obtain a compound of the following formula or a salt or solvate thereof

R¹

- if needed, carrying out one or more of the following steps:

- protection of any hydroxyl group,

- removal of any hydroxyl protecting group,

- conversion of Z into a different Z group,

to obtain a compound of form solvate thereof

R¹

(Ι-6β,7α)

wherein Z, R¹ and R² take the meanings defined in claim 1.

10. Process according to any one of claims 1 to 9, wherein Z is -COOR³, wherein R³ is selected from H, Ci-C₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl.

Process according to any one of claims 1 to 10, wherein in the compound of formula (II), or a salt or solvate thereof, R¹ and R² are independently selected from a hydroxyl protecting group.

12. Process according to any one of claims 1 to 11 , wherein in the compound of formula (II), or a salt or solvate thereof, R¹ and R² are independently selected from a hydroxyl protecting group and Z is -COOR³, wherein R³ is selected from Ci-C₆ alkyl, C₆-Ci₀ aryl and (C6-Cio)aryl(Ci-C₆)alkyl.

13. Process according to any one of claims 1 to 12, wherein the compound of formula (I) is Obeticholic acid, or a salt or solvate thereof.

14. A compound of formula (III), or a salt or solvate thereof

wherein

Z is selected from the group consisting of -COOR³, -CONR⁴R⁵, -CH₂OP and

wherein R is selected from H, CrC₆ alkyl and C₆-Ci₀ aryl; R , R⁵, R⁶ and R⁷ are independently selected from H, CrC₆ alkyl, C₆-Ci₀ aryl and

(C6-Cio)aryl(Ci-C₆)alkyl; and P is selected from H and hydroxyl protecting group;

15. A compound of formula (IV), or a salt or solvate thereof

wherein Z is selected from the group consisting of -CONR⁴R⁵, -CH₂OP and

wherein R⁴, R⁵, R⁶ and R⁷ are independently selected from H, Ci-C₆ alkyl, C₆-Ci₀ aryl and (C₆-Cio)aryl(Ci-C₆)alkyl, and P is selected from H and hydroxyl protecting group; and

R¹ is selected from the group consisting of H and hydroxyl protecting group.