Process for hydrogenation of 6,7-epoxysteroids

Abstract

The invention relates to a process for the hydrogenation of a compound of formula (II) over a sponge nickel catalyst to give a compound of formula (I) herein X and R1 are as defined herein.

Description

[0001] REDUCTION PROCESS

[0002] The present invention relates to a method of preparing compounds which are intermediates in the synthesis of bile acid derivatives with pharmacological activity. More especially, the invention relates to a catalytic hydrogenation process and, in particular to a process for the catalytic hydrogenation of a 6,7-epoxide derivative of a bile acid using a sponge nickel catalyst.

[0003] Background of the Invention

[0004] Bile acids are steroid acids which are found in the bile of mammals and include compounds such as cholic acid, chenodeoxycholic acid, lithocholic acid and deoxycholic acid, all of which are found in humans. Many bile acids are natural ligands of the farnesoid X receptor (FXR) and / or the TGR5 receptor. FXR is expressed in the liver and intestine of mammals, including humans. The G protein-coupled receptor TGR5 is a member of the rhodopsin-like superfamily of G-protein coupled receptors and has an important role in the bile acid signalling network, which complements the role of the FXR. TGR5 is expressed in nonparenchymal cells of the liver of mammals, including humans.

[0005] Bile acids are derivatives of steroids and are numbered in the same way. The following shows the general numbering system for steroids and the numbering of the carbon atoms in ursodeoxycholic acid.

[0006] General steroid numbering LIDCA numbering

[0007] Agonists of FXR and TGR5 have been found to be of use in the treatment of cholestatic liver disorders including primary biliary cholangitis and non-alcoholic steatohepatitis (Jonker (2012) and Keitel and Haussinger (2018)).

[0008] Ursodeoxycholic acid (UDCA), a bile acid originally isolated from the gall bladder of bears, is currently used in the treatment of cholestatic liver disorders, although it appears to be inactive at the FXR receptor.

[0009] Chenodeoxycholic acid (CDCA) is a primary bile acid synthesised in the liver of humans, other mammals and birds. Unlike UDCA, CDCA is an FXR receptor agonist.

[0010] Because of the importance of FXR and TGR5 agonists in the treatment of cholestatic liver disorders, efforts have been made to develop new compounds which have agonist activity at these receptors. One particularly active compound is obeticholic acid, which is a potent agonist of both FXR and TGR5. Obeticholic acid is described in WO02 / 072598 and EP1568706, both of which describe a process for the preparation of obeticholic acid from 7-keto lithocholic acid, which is derived from cholic acid. Further processes for the production of obeticholic acid and its derivatives are described in W02006 / 122977, US2009 / 0062256 and WO2013 / 192097 and all of these processes also start from 7-keto lithocholic acid.

[0011] Other synthetic bile acid derivatives with medicinal properties are described in WO 2008 / 091540, WO 2010 / 014836, WO 2016 / 073767, WO 2016 / 086115, WO 2016 / 086134, WO 2016 / 086169, WO 2016 / 086218, WO 2016 / 130809 and WO 2016 / 161003. These documents all relate to bile acid derivatives which are agonists of TGR5, or agonists of TGR5 and FXR.

[0012] Other bile acid derivatives having medicinal properties include 3-oxo-7a-hydroxy-4- cholestenoic acid (7-HOCA) (Nikolaou, 2022).

[0013] Bile acids and their derivatives are by no means easy to synthesise, and the processes employed often have many steps and low overall yield.

[0014] In addition to the inefficiency and high cost of these processes, there are also problems with the cost and availability of the starting materials. Cholic acid, which is often used as a starting material for the production of bile acid derivatives, is a natural bile acid which is usually obtained from the slaughter of cows and other animals. This means that the availability of cholic acid and other bile acids is limited by the number of cattle available for slaughter. Since the incidence of cholestatic liver disease is increasing worldwide, the demand for synthetic bile acids such as obeticholic acid is also likely to increase and it is doubtful whether the supply of naturally derived bile acids will continue to be sufficient to meet demand.

[0015] Furthermore, the use of a starting material derived from animals means that there is the possibility of the contamination of the material with infectious agents such as viruses or prions, which can not only be hazardous to workers but could potentially contaminate the end products if steps are not taken to prevent this.

[0016] Although some patients with cholestatic liver disease can be treated with ursodeoxycholic acid, this is also a natural bile acid and faces the same problems of limited availability and high cost.

[0017] In an attempt to solve the problems associated with the use of bile acids as starting materials, there has been interest in deriving environmentally sustainable processes for the synthesis of bile acids and their derivatives which use starting materials which are not necessarily derived from animals. For example, our earlier applications WO 2016 / 079517, WO 2016 / 079518, WO 2016 / 079519 and WO 2016 / 079520, WO 2017 / 199033 and WO 2017 / 199036 relate to intermediates in a process for preparing obeticholic acid and analogues of obeticholic acid as well as processes for preparing these compounds and for converting them to the desired products. Some of the compounds are also suitable as intermediates in the preparation of other bile acids and bile acid derivatives. The starting materials in the processes described in these documents are suitably plant sterols or plant sterol derivatives such as bis-norcholenol (also known as 20-hydroxymethylpregn-4-en-3-one), androstenedione, androstadienedione, dehydroepiandrosterone, stigmasterol, brassicasterol, campesterol and p-sitosterol. These compounds are widely available, often at lower cost than bile acids and, indeed, are often waste products of other processes. llekawa (2004) describes the production of 6a, 7a epoxide derivatives of sterol compounds and the palladium-catalysed hydrogenation of the epoxides which opens the epoxide to produce 7-OH derivatives with concurrent reduction of the 4,5-alkene bond.

[0018] WO 2017 / 199039 describes 6|3,7p epoxide derivatives of sterol compounds and a process for preparing these compounds. Theoretically, these 6p,7p-epoxide compounds can be hydrogenated in the same way as the 6a, 7a epoxide derivatives to produce 7-hydroxy sterol derivatives, in which the 4,5-ene has also been reduced.

[0019] However, although the ring opening of the 6a,7a-epoxides and reduction to the 5-p motif characteristic for bile acids can be conducted selectively for a-epoxides, when the same chemistry is applied to p-epoxides, the selectivity is diminished, resulting in formation of complex mixtures including products resulting from the elimination of the hydroxy group and subsequent reduction to precursors of lithocholic acid as well as various 5a derivatives.

[0020] There is therefore a need for an alternative route which can be applied both to a- and to p- epoxide derivatives of bile acids. The inventors have devised a method of opening the epoxide ring without reducing the 4-5 alkene bond to produce 3-keto-4-ene-7-hydroxy bile acid derivatives. The 3-keto-4-ene-7-hydroxy motif is known in biology; for example 7a-hydroxy-3- oxochol-4-en-24-oic acid is fetal bile acid, levels of which can also be indicator for severity of liver cirrhosis in adults (Mocan, 2021).

[0021] The present inventors have investigated the reaction conditions for the hydrogenation of 6,7- epoxy sterol derivatives and have devised an improved process which consistently gives high yields of the desired reduction product for both the a- and the p-epoxides.

[0022] Summary of the Invention

[0023] In the present invention there is provided a process for the preparation of a compound of formula (I): wherein

[0024] X is selected from a bond, CH2, CH[C(O)OR3a], CH2CH2, CH2CH[C(O)OR3a], CH=CH and CH=C[C(O)OR3a]; and

[0025] R1is selected from -OR2, -C(O)OR3b, -C(O)R3c, -CH(OR5)R3cand -C(R3c)(OR6a)(OR6b);

[0026] R2and R5are each independently selected from H and an OH protecting group; each R3a, R3band R3cis independently selected from H, Ci-e alkyl and benzyl;

[0027] R6aand R6bare each independently selected from Ci-e alkyl and benzyl; the process comprising the catalytic hydrogenation of a compound of formula (II): wherein X and R1are as defined for formula (I); over a sponge nickel catalyst; characterised in that: the hydrogenation is carried out in a reaction solvent comprising pyridine, a pyridine derivative or a mixture thereof and optionally water, wherein water is present in an amount of 0% to 10% w / w; and the reaction temperature is from about 15 °C to 60 °C. The inventors have found that careful selection of the solvent, as well as controlling both the amount of water in the reaction mixture and the reaction temperature leads not only to improved consistency, but also to improved conversion of the desired product and lower amounts of undesired side products, especially in the case of the p-epoxides.

[0028] The products of the process of the invention are 3-keto-4-ene-7-hydroxy bile acid derivatives of formula (I), which are not easy to prepare by other routes. The compounds of formula (I) can be further reduced to form 5- systems, characteristic for bile acids such as LIDCA and CDCA. Although, as noted above, the two steps can be carried out simultaneously for a- epoxides of formula (II) using palladium-catalysed hydrogenation (llekawa 2004), the stepwise approach of the invention allows the utilisation of p-epoxides for synthesis of LIDCA and its derivatives. This was not previously possible as the simultaneous reduction of the epoxide and the 4,5-alkene bond in a p-epoxide compound of formula (II) cannot be carried out selectively using the method described by llekawa. Furthermore, even when the compound of formula (II) is an a-epoxide, the possibility of a stepwise reduction gives the process greater flexibility.

[0029] Detailed Description of the Invention

[0030] In the present specification, except where the context requires otherwise due to express language or necessary implication, the word “comprises”, or variations such as “comprises” or “comprising” is used in an inclusive sense i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

[0031] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference to the fullest extent possible as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[0032] In the present application the term “C1.5 alcohol” refers to a straight or branched fully saturated hydrocarbon group having from 1 to 5 carbon atoms and substituted with an OH moiety. Examples of C1.5 alcohols include methanol, ethanol, isopropanol, s-butanol, t-butanol and n- pentanol.

[0033] The term “C1.6 alkyl” refers to a straight or branched hydrocarbon chain having from one to six carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, s- butyl, isobutyl, n-pentyl and n-hexyl. Other alkyl groups, for example C1.4 alkyl, C1.3 alkyl, or Ci-2 alkyl are as defined above but contain different numbers of carbon atoms. The term “5- or 6-membered cyclic ether” refers to a non-aromatic cyclic group having 5 or 6 ring atoms, of which one is oxygen and the remainder are carbon and wherein the cyclic ether may be substituted by methyl or ethyl. Examples include tetrahydrofuran, 2-methyl tetra hydrofuran and tetrahydropyran.

[0034] In the present specification, the term “OH protecting group” refers to any known hydroxyl protecting group. Examples of OH protecting groups of this type include -C(O)R4, where R4is Ci-6 alkyl or benzyl, especially methyl such that -C(O)R4is acetyl. Silyl ether protecting groups may also be used and, alternatively, OH can be protected as an ether, for example a Ci-e alkyl ether. Other suitable protecting groups for OH are well known to those of skill in the art (see e.g. Wuts, PGM and Greene, TW (2006) “Greene’s Protective Groups in Organic Synthesis”, 4thEdition, John Wiley & Sons, Inc., Hoboken, NJ, USA).

[0035] In the present application a pyridine derivative refers to pyridine substituted with one or more Ci-4 alkyl substituents for example 1 , 2 or 3 C1.4 alkyl substituents and especially 1 or 2 methyl substituents. Examples of pyridine derivatives include lutidines, picolines and collidines, for example 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine and 3,5-lutidine, 2- picoline and 4-picoline, and 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine and 3,4,5-collidine.

[0036] The starting materials of formula (II) can be obtained by the methods described in our earlier applications WO 2017 / 199036 and WO 2017 / 199039.

[0037] The process of the invention is as set out above. However, in a further aspect of the invention there is provided a process for the preparation of a compound of formula (Iz): wherein

[0038] X is CH2, CH[C(O)OR3a], CH2CH2, CH2CH[C(O)OR3a], CH=CH or CH=C[C(O)OR3a]; and R1is -OR2, -C(O)OR3b, -C(O)R3cor -CH(OR5)R3c;

[0039] R2and R5are each independently H or an OH protecting group; each R3a, R3band R3cis independently H, Ci-e alkyl or benzyl; the process comprising the catalytic hydrogenation of a compound of formula (Hz): wherein X and R1are as defined for formula (Iz); over a sponge nickel catalyst; characterised in that: the hydrogenation is carried out in a reaction solvent comprising pyridine, a pyridine derivative or a mixture thereof and optionally water, wherein water is present in an amount of 0% to 10% w / w; and the reaction temperature is from about 15 °C to 60 °C.

[0040] The process of the invention is as shown in Scheme 1 below.

[0041] In Scheme (I), the compound of formula (III) is an unwanted side product.

[0042] In some embodiments of the invention, in the compounds of formulae (I), (II) and (III), X is a bond.

[0043] In some embodiments of the invention, in the compounds of formulae (I), (II) and (III), X is CH2.

[0044] In other embodiments of the invention, in the compounds of formulae (I), (II) and (III), X is CH2CH2.

[0045] In still other embodiments of the invention, in the compounds of formulae (I), (II) and (III), X is CH=CH. In still other embodiments of the invention, in the compounds of formulae (I), (II) and (III), X is CH[C(O)OR3a],

[0046] In still other embodiments of the invention, in the compounds of formulae (I), (II) and (III), X is CH2CH[C(O)OR3a],

[0047] In still other embodiments of the invention, in the compounds of formulae (I), (II) and (III), X is CH=C[C(O)OR3a].

[0048] Suitably, X is CH2CH2, CH2, CH2CH[C(O)OR3a], CH=CH or CH=C[C(O)OR3a], especially CH2CH2, CH2, CH=CH or CH2CH[C(O)OR3a] and more especially CH2CH2, CH2or CH=CH.

[0049] In some embodiments, in the compounds of formulae (I), (II) and (III), R1is -OR2, wherein R2is as defined above.

[0050] In some such compounds, R2is H.

[0051] In other cases, in the compounds of formulae (I), (II) and (III), R2is an OH protecting group. Suitably, the OH protecting group is a group of formula -C(O)R4, where R4is Ci-e alkyl or benzyl, more suitably C1.4 alkyl, for example methyl or ethyl, and especially methyl such that R1is acetyl.

[0052] In some cases, the process may comprise the additional step of converting a compound of formula (I) in which R1is -OR2to an alternative compound of formula (I) in which R1is -OR2. For example, a compound of formula (I) in which R1is OH may be converted to a compound of formula (I) in which R1is -OC(O)R4, wherein R4is as defined above, for example by reaction with an alkanoyl chloride of formula CI-C(O)R4or an alkanoyl anhydride of formula [R4C(O)]2O Appropriate conditions for these reactions are well known to skilled chemists. Alternatively, a compound of formula (I) in which R1is -OC(O)R4may be converted to a compound of formula (I) in which R1is OH, typically by acid or base hydrolysis, again under conditions known to those of skill in the art.

[0053] A process step of this type may be included, for example, when R1in the product of formula (I) is -OR2, wherein R2is H. In this case, a protection step may be required to convert H to an alternative R2group (an OH protecting group such as -C(O)R4), especially if the compound of formula (I) is intended for use as a synthetic intermediate in the production of a desired bile acid derivative. In some embodiments, in the compounds of formulae (I) (II) and (III), R1is -C(O)OR3b, where R3bis as defined above.

[0054] In some compounds of formulae (I), (II) and (III), R1is -C(O)OR3b, and R3bis H. Alternatively, and especially in cases where the compound of formula (I) is intended for use as a synthetic intermediate in a process where further reduction steps are required, R3bis Ci-e alkyl or benzyl, especially C1.4 alkyl, for example methyl, ethyl, n-propyl, / so-propyl or terf-butyl.

[0055] In some cases, the process may comprise the additional step of converting a compound of formula (I) in which R1is -C(O)OR3b, to an alternative compound of formula (I) in which R1is - C(O)OR3b. For example, a carboxylic acid of formula (I) in which R1is -C(O)OH may be esterified to give a compound of formula (I) in which R1is -C(O)O(Ci-6 alkyl) or -C(O)Obenzyl, for example by reaction with a suitable alkanoyl or benzyl chloride or anhydride. Alternatively, an ester may be hydrolysed to give a compound of formula (I) in which R1is -C(O)OH.

[0056] In other embodiments, in the compounds of formulae (I) (II) and (III), R1is -C(O)R3c; or R1is - CH(OR5)R3c; or R1is -C(R3c)(OR6a)(OR6b) where R3c, R5, R6aand R6bare as defined above.

[0057] When R1is -C(O)R3c, -CH(OR5)R3cor -C(R3c)(OR6a)(OR6b), R3cmay be H. Alternatively, R3cmay be Ci-e alkyl or benzyl, especially C1.4 alkyl, for example methyl, ethyl, n-propyl, / so-propyl or terf-butyl.

[0058] In some cases, R5is H and in others R5is an OH protecting group. When R5is an OH protecting group, it is suitably C1.4 alkyl, such that OR5is an ether, or a group of formula -C(O)R4, where R4is Ci-6 alkyl or benzyl, more suitably C1.4 alkyl, for example methyl or ethyl, and especially methyl.

[0059] R6aand R6bare more suitably independently selected from C1.4 alkyl.

[0060] In some cases, R6aand R6bare the same and in other cases R6aand R6bare different.

[0061] In some cases, the compound of formula (I) is a compound of formula (la): which is produced by the reduction of a compound of formula (Ila): wherein X and R1are as defined above.

[0062] Alternatively, the compound of formula (I) is a compound of formula (lb): which is produced by the reduction of a compound of formula (lib): wherein X and R1are as defined above.

[0063] In the process of the invention, any suitable sponge nickel catalyst may be used. Sponge nickel catalysts are commercially available from a number of sources. Sponge nickel catalysts comprise nickel together with aluminium and may also comprise other metals, for example iron, chromium, manganese and molybdenum. Particularly suitable sponge nickel catalysts may contain aluminium in an amount of about 5-10% by weight and may have a particle size of about 10 to 100 pm, for example about 20 to 60 pm. Examples of suitable catalysts include those sold by W R Grace & Co under the trade mark Raney® Nickel, for example Raney® Nickel 2800 (sponge Ni catalyst, particle size 20 to 60 pm, containing 6-9% Al) and Raney® Nickel 2400 (sponge Ni catalyst particle size 25-55 pm, containing 6.0-13.0% aluminum, 2.0- 3.0% iron, and 2.0-3.0% chromium) as well as catalysts sold by Johnson Matthey under catalogue numbers A-7B63 (sponge Ni / molybdenum catalyst, mean particle size 50 pm) and A-5000 (sponge Ni catalyst, mean particle size 33 pm) and sold by Strem under catalogue number 28-1890 (sponge Ni catalyst, 50% slurry in water).

[0064] In some cases, the sponge nickel catalyst is suitably not the catalyst sold as JM AMCAT 5 (Johnson Matthey) or Raney® Ni 3202(W R Grace & Co).

[0065] Suitably, the sponge nickel catalyst is present in an amount of about 15% to 40% by weight with respect to the weight of the starting material, more suitably about 20% to 35% by weight, still more suitably 25% to 35% by weight, for example about 30% by weight with respect to the weight of the starting material. Alternatively, the amount of catalyst may be calculated on the basis of moles per mole of starting material. For example about 0.7 to 2.0 moles of nickel per mole of starting material may be used, more suitably 1.0 to 1.6 moles of nickel per mole of starting material, for example about 1.3 moles of nickel per mole of starting material.

[0066] Sponge nickel catalysts are available commercially and are supplied as a slurry in water. The sponge nickel catalyst is suitably washed before being used in the process of the invention. Washing may be carried out with the reaction solvent and removes water from the sponge nickel catalyst. However, the catalyst will often still contain a residue of water after washing, the amount of which can be measured by any known method, suitably by Karl Fischer analysis.

[0067] As discussed above, the reaction solvent is used for washing the catalyst to remove excess water. Therefore, suitably the solvent is capable of dissolving some water, although it is not necessary for it to be fully miscible with water. Thus, suitable reaction solvents are miscible or partially miscible with water such that they can take up at least 5% by weight water, preferably at least 10% by weight water without formation of a two phase system.

[0068] As noted above, the reaction solvent comprises pyridine, a pyridine derivative or a mixture thereof and optionally water. Suitably, the solvent comprises pyridine or a lutidine, for example 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine or 3,5-lutidine.

[0069] More suitably, the reaction solvent comprises pyridine. The reaction solvent may comprise one or more additional solvents in admixture with the pyridine and / or pyridine derivative. Examples of suitable additional solvents include: a Ci-5 alcohol; a 5- or 6-membered cyclic ether, wherein the 5- or 6-membered cyclic ether is optionally substituted with one or more methyl or ethyl substituents; an ether of formula CH3(CH2)PO(CH2)qCH3, wherein each of p and q is 0, 1 or 2, provided that p+q is from 0 to 3; and mixtures thereof

[0070] In some cases, the one or more additional solvents may comprise a C1.5 alcohol, more suitably a C3-5 alcohol. Particularly suitable C3-5 alcohols include isopropanol and s-butanol, especially s-butanol.

[0071] Alternatively, the one or more additional solvents may be a cyclic ether, suitably a fully saturated 5- or 6-membered cyclic ether, more suitably tetrahydrofuran, which may be unsubstituted or substituted with methyl or ethyl, especially methyl. Examples of more suitable cyclic ether additional solvents include tetrahydrofuran and 2-methyltetrahydrofuran, and 2- methyltetrahydrofuran is particularly suitable.

[0072] As a further alternative, the one or more additional solvents may comprise an ether of formula CH3(CH2)pO(CH2)qCH3. Examples of ethers of this type include dimethyl ether, methyl ethyl ether, methyl propyl ether, diethyl ether and ethyl propyl ether.

[0073] The reaction solvent may comprise one or more additional solvents, for example one or two additional solvents and more suitably one additional solvent.

[0074] When an additional solvent is present, the volume ratio of the additional solvent to pyridine or pyridine derivative may be from about 15:1 to 1 :15, more suitably from about 10:1 to 1 :10. In some cases, the ratio of additional solvent to pyridine or pyridine derivative is from about 10:1 to 1 :1.

[0075] The presence of an additional solvent in the reaction solvent appears to minimise the amount of by-product of formula (III) obtained, as can be seen from the results of Example 3 below.

[0076] For example in one particularly suitable case, the solvent consists of a mixture of toluene and pyridine in a ratio of toluene: pyridine of from about 15:1 to 1 :15, more suitably from about 10:1 to 1 : 10, for example about 10:1. In an alternative particularly suitable case, the solvent consists of a mixture of 2- methyltetrahydrofuran and pyridine in a ratio of 2-methyltetrahydrofuran: pyridine of from about 15: 1 to 1 : 15, more suitably from about 10: 1 to 1 : 10, for example about 10:1.

[0077] In still another particularly suitable case, the solvent consists of a mixture of 2-butanol and pyridine in a ratio of 2-butanol:pyridine of from about 15:1 to 1 :15, more suitably from about 10:1 to 1 :10, for example about 1 :1 to 10:1 , such as 1 :1 , 5:1 or 10:1.

[0078] In other cases, however, the reaction solvent consists of pyridine or a pyridine derivative and optionally water, and no additional solvent is present.

[0079] The reaction solvent optionally comprises water, which is present in an amount of 0% to 10% w / w, and which includes any residual water present in the sponge nickel catalyst after washing.

[0080] Additionally, however, either or both of the pyridine or pyridine derivative and any additional solvent may be a non-anhydrous solvent.

[0081] In the present application, non-anhydrous solvent (including pyridine or pyridine derivative) is defined as comprising water in an amount of < 6% w / w. The amount of water in the non- anhydrous solvent may be determined by any suitable method, for example by Karl Fischer analysis. Alternatively, the pyridine or pyridine derivative and any additional solvent may be anhydrous. However, more suitably, non-anhydrous solvents are used.

[0082] When a non-anhydrous solvent is used, the reaction solvent comprises both residual water present in the sponge nickel catalyst after washing and additional water present in the non- anhydrous solvent on purchase. When an anhydrous solvent is used, the reaction solvent comprises any residual water present in the sponge nickel catalyst after washing.

[0083] The amount of the side product of formula (III) produced in the reaction increases as the amount of water in the reaction solvent increases. Therefore, it is preferable to ensure that the reaction solvent comprises water in an amount of 0% to 10% w / w, and suitably 0% to 6% w / w with respect to the total weight of solvent. Since it is difficult to remove all of the water from the sponge nickel catalyst and since the solvent is often non-anhydrous, the reaction solvent more usually comprises water in an amount of 0.1 to 10% w / w, and suitably 0.1 to 6% w / w with respect to the total weight of solvent.

[0084] More suitably, the reaction solvent comprises water in an amount of 0% to 5.7% w / w, still more suitably 0% to 3% w / w, 0% to 1 % w / w or 0% to 0.5% w / w with respect to the total weight of solvent. As noted above, water is not usually completely absent from the reaction solvent, and therefore water may be present in the reaction solvent in an amount of about 0.1 % to 5.7% w / w or still more suitably 0.1% to 3% w / w, 0.1 % to 1 % w / w or 0.1 % to 0.5% w / w with respect to the total weight of solvent.

[0085] As noted above, the reaction temperature is from about 15 °C to 60 °C. When the reaction is conducted at temperatures lower than 15 °C the reaction time is unacceptably long, for example longer than 48 hours. For economic considerations, the reaction time is suitably < 48 hours, more suitably < 36 hours, and still more suitably < 24 hours or < 12 hours.

[0086] When conducted at temperatures higher than 60 °C, the amount of the elimination side product of formula (III) in the product mixture is unacceptably high such that the content of the product in the mixture may be < 60%.

[0087] When the reaction temperature is maintained within these limits, the content of the desired product in the mixture is typically > 60%, suitably > 70%, more suitably > 80%, still more suitably > 85% for example > 90% or > 95% (where percentages may be measured by NMR or HPLC peak area).

[0088] More suitably, in order to obtain an acceptable reaction time and to limit the amount of the elimination side product of formula (III), the reaction temperature is from about 25 °C to 45 °C, still more suitably from about 30 °C to 40 °C and typically about 35 °C.

[0089] Compounds of formula (I) may be synthetic precursors of other bile acid derivatives. For example, compounds of formula (la) may be converted to derivatives of ursodeoxycholic acid and compounds of formula (lb) may be converted to derivatives of chenodeoxycholic acid.

[0090] Therefore, the process of the invention may comprise the additional step of reducing the compound of formula (I) to obtain a compound of formula (IV): wherein X1is a bond, CH2, CH[C(O)OR3a], CH2CH2or CH2CH[C(O)OR3a], and R1is as defined above for formula (I).

[0091] Compounds of formula (IV) have the 5p motif which is characteristic of many natural bile acids.

[0092] When the group X of the compound of formula (I) is CH=CH or CH=C[C(O)OR3a], the carboncarbon double bond is also reduced such that the product is a compound of formula (IV) in which X1is CH2CH2 or CH2CH[C(O)OR3a] respectively.

[0093] Suitably, the reduction is conducted by hydrogenation over a suitable catalyst, for example over a palladium catalyst, e.g. palladium on carbon. Suitable reaction solvents include pyridine and pyridine derivatives as defined above.

[0094] The reaction may be conducted in an organic solvent, which may be the same solvent as used in the hydrogenation of the compound of formula (II) to obtain the compound of formula (I). Suitably, the solvent is pyridine. The hydrogenation may take place at a temperature of about 15° to 35°C, more suitably at about 25° to 35°C.

[0095] When the compound of formula (I) is a compound of formula (la), the product will be a compound of formula (IVa) and when the compound of formula (I) is a compound of formula (lb), the product will be a compound of formula (IVb):

[0096] In an optional further additional step, compounds of formula (IV) may be reduced to give compounds of formula (V): wherein X1is as defined for formula (IV) and R1is as defined for formula (I).

[0097] Suitable reducing agents include hydride reducing agents such as sodium borohydride. Suitable reaction solvents for the reaction include mixtures of an organic solvent such as tetra hydrofuran with water.

[0098] When the compound of formula (IV) is a compound of formula (IVa), the product will be a compound of formula (Va) and when the compound of formula (IV) is a compound of formula

[0099] (IVb), the product will be a compound of formula (Vb):

[0100] Suitably, in the compounds of formulae (I), (IV) and (V), when R1is OR2, or comprises a group OR5, R2and R5are independently OH protecting groups, for example a group -C(O)R4, where R4is Ci-e alkyl or benzyl, especially methyl.

[0101] When R1is -C(O)OR3b, R3bis suitably Ci-e alkyl or benzyl. Similarly, when X1comprises a group -C(O)OR3a, R3ais suitably Ci-e alkyl or benzyl.

[0102] Compounds of formula (V) in which R1is -OR2, where R2is other than H, for example R2is acetyl, can be converted to other compounds of formula (V) in which R1is OH by hydrolysis with a base such as sodium, potassium or lithium hydroxide in an alcoholic solvent such as methanol, ethanol or isopropanol.

[0103] Compounds of formula (V) in which R1is -C(O)OR3band / or X1is CH[C(O)OR3a] or CH2CH[C(O)OR3a] where R3band R3aare other than H can be converted to compounds in which R1comprises -C(O)OH and / or X1comprises -C(O)OH by hydrolysis, for example base hydrolysis using sodium, potassium or lithium hydroxide in an alcoholic solvent such as methanol, ethanol or isopropanol.

[0104] Compounds of formula (Va) are ursodeoxycholic acid and derivatives thereof while compounds of formula (Vb) are chenodeoxycholic acid and derivatives thereof. The process of the invention is therefore suitable as a step in the preparation of ursodeoxycholic acid and chenodeoxycholic acid and their derivatives from plant-based starting materials.

[0105] The invention will now be described in greater detail with reference to the Examples. In Examples 1 , 2 and 4, reduction of the 6,7-beta epoxide moiety in the epoxide starting material of formula (II) was achieved using the commercially available sponge nickel catalyst Raney Nickel® Grace 2800 under hydrogenation conditions. In Example 3, other sponge nickel catalysts were also tested. Pyridine was used in the reaction as solvent / co-solvent to avoid both the over reduction of the 4,5 double bond and elimination to yield the by-product of formula (III). A degree of batch-to-batch variability was observed in relation to reaction rate (starting material consumption), formation of by-product of formula (III) (elimination) and overall reaction profile. It appears that this variability may arise from differences of water content in the reaction solvent since the catalyst is sold as a slurry in water.

[0106] The effect of water on the reaction progress and profile was evaluated in Example 3.

[0107] General information:

[0108] In the general procedure and the Examples below, cycling consists of evacuating the vessel with vacuum and back filling with nitrogen or hydrogen from a balloon, cycling to be carried out a minimum of 3 times.

[0109] NMR information

[0110] Proton (1H) and carbon (13C) NMR-spectra were recorded on a Bruker AV400 spectrometer at 298K unless otherwise stated. Chemical shifts (5) are quoted in parts per million (ppm) and coupling constants (J) in Hertz (Hz). Abbreviations indicating multiplicity are: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hept = heptet, m = multiplet, br = broad, app. apparent. NMR spectra were referenced using residual solvent peaks set to 5 7.26 and 77.16 ppm (CDCI3), or b 3.31 and 49.00 ppm (CD3OD), or 2.50 and 39.52 ppm (cftS-DMSO), or b 2.05 and 29.82 ppm (acetone-d6).

[0111] HPLC Method for Examples 3 and 4

[0112] The analytical method used in Examples 3 and 4 employs reverse phase C18 chromatography with refractive index detection (RID). The amounts of starting material, product and by-product and related compounds were evaluated by peak area normalisation and reported as percent peak area (% area).

[0113] Chromatographic Conditions

[0114] Retention Times

[0115] Percent peak area

[0116] Percent peak area was calculated as follows:

[0117] Individual Peak Area

[0118] Area (%) = x 100 X (All Peak Areas)

[0119] General Procedure for Reduction on a 10 g Scale of a Compound of Formula (II) to give a Compound of Formula (I)

[0120] 1. Weigh 30% w / w of sponge nickel catalyst into a 250 mL, 1 neck round bottomed flask.

[0121] 2. Wash the wet catalyst twice with pyridine or appropriate solvent* approximately 2 vol., decanting off the liquors. 3. transfer starting epoxide (10 g) to the reaction vessel with the chosen reaction solvent / solvent mixture*.

[0122] 4. The water content of the mixture is evaluated by Karl Fischer analysis.

[0123] 5. The reaction flask is evacuated and purged with nitrogen, then hydrogen. 6. The process is set to a desired temperature and stirring rate.

[0124] 7. The reaction progression is monitored by1H NMR in CDCh.

[0125] 8. Upon completion, the reaction mixture is filtered, and the residual catalyst is washed with additional reaction solvent (approx. 10 mL).

[0126] 9. The mixture is concentrated in vacuo.

[0127] * Reactions carried out in neat toluene or 2-MeTHF were washed twice with THF and once with the reaction solvent to avoid catalyst contact with pyridine.

[0128] * where appropriate water is added to the solvent prior to transfer of the starting epoxide.

[0129] Example 1 : Synthesis of (7 , 22E)-7-hydroxy-3-oxo-4,22-choladien-24-oic acid ethyl ester

[0130] Following the general procedure, (60,70, 22E)-6,7-epoxy-3-oxo-4,22-choladien-24-oic acid ethyl ester (3.9 g, 9.45 mmol, obtained from (22E)- 3-oxo-4,6,22-cholatrien-24-oic acid ethyl ester as described in Example 1 of WO 2017 / 199039) was transferred to the reaction vessel using pyridine (24 mL, 6 vol.) containing sponge nickel (1.17g, 30%w / w wet, Raney® nickel 2800) which had been washed twice with pyridine (2 x 10 mL). The resultant mixture was purged with nitrogen prior to applying hydrogen. The mixture was stirred under an atmosphere of hydrogen until complete and then cycled under nitrogen and filtered. Reaction mixture is concentrated and purified by column chromatography (SiO2, 5-20% acetone in toluene).

[0131] 1H NMR (400 MHz, CDCh): 6 = 6.81 (1 H, dd, J = 15.6, 9.0, C22), 5.73 (1 H, d, J = 1.6, C4), 5.72 (1 H, dd, J = 15.6, 0.7, C23), 4.15 (2H, q, J = 7.1 , OCH2CH3), 3.43 (1 H, dp, J = 15.6, 9.0, C7), 2.52 (1 H, dd, J = 14.1 , 5.2), 2.45-2.22 (4H, m), 2.04-1.99 (3H, m), 1.87-1.39 (7H, m), 1.34-1.13 (4H, m), 1.26 (3H, t, J = 7.1 , CH2CH3), 1.19 (3H, s, C19), 1.08 (3H, d, J = 6.6, C21), 0.93 (1 H, dt, J = 17.4, 4.2), 0.76 (3H, s, C18)

[0132] 13C NMR (100MHz, CDCh): 6 = 199.3, 167.8, 167.1 , 154.3, 124.6, 119.3, 74.7, 60.2, 55.1 , 54.1 , 50.7, 43.7, 43.1 , 42.3, 39.5, 39.4, 38.0, 35.7, 35.0, 28.5, 27.0, 21.0, 19.4, 17.4, 14.3, 12.4. Example 2: Synthesis of (7a, 22E)-7-hydroxy-3-oxo-4,22-choladien-24-oic acid ethyl ester

[0133] Following the general procedure, (6a, 7a, 22E)-6,7-epoxy-3-oxo-4,22-choladien-24-oic acid ethyl ester (10.0 g, 24.2 mmol, obtained from (22E)- 3-oxo-4,6,22-cholatrien-24-oic acid ethyl ester as described in Example 1 of WO 2017 / 199036 and in llekawa, 2004) was transferred to the reaction vessel using pyridine (24 mL, 6 vol.) containing sponge nickel (3.00 g, 30%w / w wet, Raney® Nickel 2800) which had been washed twice with pyridine (2 x 10 mL). The resultant mixture was purged with nitrogen prior to applying hydrogen. The mixture was stirred under an atmosphere of hydrogen. After reaction completion the reaction is cycled under nitrogen and filtered. The filtrate was concentrated under reduced pressure, and the product purified by crystallisation from CH3CN for characterisation purposes.

[0134] 1H NMR (400 MHz, CDCI3): 5 = 6.83 (1 H, dd, J = 15.6, 9.0, C22), 5.80 (1 H, d, J = 1.1 , C4), 5.74 (1 H, dd, J = 15.6, 0.8, C23), 4.18 (2H, q, J = 7.1 , OCH2CH3), 3.96 (1 H, bs, C7), 2.68 to 2.58 (1 H, m), 2.50 to 2.21 (4H, m), 2.09 to 1.94 (2H, m), 1.85 to 1.66 (3H, m), 1.65 - 1.37 (5H, m), 1.37 - 1.12 (5H, m), 1.29 (3H, t, J = 7.1 , OCH2CH3), 1.20 (3H, s, C19), 1.10 (3H, d, J = 6.6 Hz, C21), 0.76 (3H, s, C18).

[0135] 13C NMR (100MHz, CDCI3): 5 = 198.9, 168.0, 167.1 , 154.4, 126.7, 119.1 , 68.2, 30.2, 54.8, 50.2, 45.1 , 42.7, 41.0, 39.8, 39.7, 39.0, 38.5, 35.4, 33.9, 28.1 , 23.6, 20.8, 19.2, 17.0, 14.3, 12.1.

[0136] Example 3 (screening reactions): Synthesis of (7 , 20S)-20-acetoxymethyl-7-hydroxy-3- oxo-pregna-4-ene

[0137] This example tests the effects of using alternative sponge nickel catalysts and varying the amount of water in the reaction solvent as well as evaluating the effect of temperature.

[0138] Water can be introduced into the reaction via starting material, and the solvent but if the catalyst were to be used as supplied, it would be the largest contributor to the water levels since sponge nickel catalysts are distributed as slurries in water. In addition, the catalystwater ratio varies between batches of catalyst, which could lead to variations in the amount of water present in the reaction mixture. The content of water in the reaction mixture was therefore controlled by successive washes of the catalyst with solvent (to remove the water added with the catalyst), followed by the addition of measured amounts of water. The precise water of each reaction was evaluated by coulometric Karl-Fischer analysis.

[0139] Following the general procedure, (6p,7p, 20S)-20-acetoxymethyl-6,7-epoxy-pregn-4-en-3-one (10.0 g, 25.9 mmol, obtained from (20S)-20-acetoxymethyl-pregna-4,6-dien-3-one as described in Example 45 of WO 2017 / 199039) was transferred to the reaction vessel using the chosen reaction solvent (60 mL, 6 vol., where required water was dosed to the reaction solvent at this stage) containing sponge nickel (3.00 g, 30%w / w wet) which had been washed twice with pyridine or suitable solvent (2 x 20 mL). The resultant mixture was purged with nitrogen prior to cycling to hydrogen. The mixture was stirred under an atmosphere of hydrogen as the desired temperature. After reaction completion the reaction is purged with nitrogen, the catalyst filtered and the mixture concentrated in vacuo.

[0140] 1H NMR (400 MHZ, CDCh): 6 = 5.74 (1 H, d, J = 1.6, C4), 4.07 (1 H, dd, J = 10.7, 3.5, C22Ha), 3.77 (1 H, dd, J = 10.7, 7.4, C22Hb), 3.44 (1 H, dp, J = 10.9, 4.9, C7), 2.53 (1 H, dd, J = 14.0, 5.2, C6Ha), 2.45-2.29 (3H, m, C6Hb& C2), 2.06-1.98 (2H, m), 2.04 (3H, s, OAc), 1.93-1.81 (3H, m), 1.77-1.33 (4H, m), 1.93-1.81 (3H, m), 1.23-1.11 (3H, m), 1.20 (3H, s, C19) , 1.01 (3H, d, J = 6.6, C21), 0.95 (1 H, dt, J = 17.4, 4.2), 0.74 (3H, s, C18)

[0141] 13C NMR (100.6 Hz, CDCh): 5 = 199.3, 171.4, 167.7, 124.6, 74.7, 69.4, 54.9, 51.8, 50.7, 43.5, 43.1 , 42.2, 39.3, 38.0, 35.7, 35.6, 33.9, 28.1 , 27.0, 21.0, 21.0, 17.3, 17.2, 12.1

[0142] The results are set out in Table 1 below. The data presented in Table 1 shows:

[0143] • Increasing the water content of the reaction mixture leads to increased amount of byproduct.

[0144] • Increasing the reaction temperature mixture leads to increased amount of by-product.

[0145] • Increasing the pressure has no effect on the reaction rate or the proportions of product and by-product.

[0146] • A broad range of sponge nickel catalysts can be used.

[0147] It was also found that absence or lower content of pyridine in the reaction mixture leads to the formation of a variety of overreduction by-products, for example through reduction of the 4,5 double bond and the ketone group. Table 1

[0148] a10 vol solvent.bReactions with 15%w / w wet catalyst loading, reactions left for 7 days.cReaction at 5 barg. pressure.dAlternative batch of catalyst used.eAttempted reuse of the spent catalyst after wash with pyridinefReaction run for 24h under IX^then 6 d under H2

[0149] Example 4 (scale up and isolation): Synthesis of (7p)-20-acetoxymethyl-7-hydroxy-3- oxo-pregna-4-ene

[0150] (6p,7p)-20-acetoxymethyl-6,7-epoxy-3-oxo-pregna-4-ene (400 g, 1.03 mol, obtained from (20S)-20-acetoxymethyl-pregna-4,6-dien-3-one as described in Example 45 of WO 2017 / 199039) was dissolved in 2-MeTHF (4 L, 6 vol) and pyridine (400 mL, 1 vol.) and transferred to the vessel containing sponge nickel (88.5 g, 22%w / w wet, Raney® nickel 2800). The vessel was cycled under nitrogen prior to cycling to hydrogen. The mixture was stirred under an atmosphere of hydrogen at 50 °C for 24 h. After reaction completion, the reaction was cycled under nitrogen and the catalyst filtered. The filtrate was concentrated using rotary evaporation and the resulting crude solid crystallised form CH3CN (2 L, 5 vol) to give the desired product in 75% yield and 97% purity by HPLC.

[0151] Example 5 (alkene reduction): Synthesis of (5p,7p)-7-hydroxy-3-oxo-cholan-24-oic acid

[0152] To a flask containing (7a, 22E)-7-hydroxy-3-oxo-4,22-choladien-24-oic acid ethyl ester (3.90 g, 9.41 mmol) dissolved in pyridine (50 mL, 13 vol.) was added palladium on carbon, 246 mg, 6.3 %w / w). The mixture was purged with nitrogen then hydrogen and stirred at 25 °C. After complete reduction of the 4,5 double bond (as established by1H NMR in CDCh) the temperature was raised to 35 °C and stirring continued for further 24h. After reaction completion, the mixture was purged with nitrogen and filtered through a 0.2 pm syringe filter. The filtrate was concentrated, and the resulting syrup (4.1 g) was used directly in the next step without further purification. Crude material contained approximately 12% 5Ha isomer (as established by1H NMR in CDCh).

[0153] 1H NMR (400 MHz, CDCh): 6 = 4.12 (2H, q, J = 7.1 , OCH2CH3), 3.43 (1 H, dq, J = 6.7, 5.2, C7), 2.51 (1 H, t, J = 14.5), 2.38-2.14 (5H, m), 2.08-2.00 (2H, m), 1.97-1.87 (2H, m), 1.87- 1.76 (3H, m), 1.62 (1 H, ddd, J = 13,5, 5.1 , 2.3, C6Ha) 1.57-1.16 (11 H, m), 1.25 (3H, t, J = 7.1 , CH2CH3), 1.09 (1 H, q, J = 9.6), 1.05 (3H, s, C19), 1.08 (3H, d, J = 6.7, C21), 0.71 (3H, s, C18)13C NMR (100 MHz, CDCh): 6 = 212.0, 174.2, 70.9, 60.2, 55.7, 54.9, 44.4, 43.8, 43.4, 43.2, 40.0, 39.4, 37.0, 36.4, 36.2, 35.2, 34.4, 31.3, 31.0, 28.6, 26.8, 22.7, 21.7, 18.4, 14.3, 12.2.

[0154] Example 6 (3-keto reduction): Synthesis of ursodeoxycholic acid ethyl ester

[0155] Product

[0156] To a flask containing crude (5p,7p)-7-hydroxy-3-oxo-cholan-24-oic acid ethyl ester (2.15 g) dissolved in THF (21 mL, 10 vol.) and water (0.21 mL, 0.1 vol.) at ca. 0 °C was added solid NaBH4 (156 mg, 4.13 mmol, 0.8 eq.). After 10 minutes, the reaction was warmed to room temperature and stirred for further 2 h. The mixture was cooled to 0 - 5 °C and quenched by the careful addition of 2M H2SO4 (2.05 mL) before neutralising with 5% NaHCO3. The mixture was diluted with water (20 mL) and extracted with TBME (20 mL). The aqueous layer was back extracted with TBME (10 mL) and the combined organics washed with water (20 mL), dried over MgSCU, filtered and concentrated. The obtained crude material was purified by flash column chromatography (SiO2, 5 - 15% acetone in toluene) to give ursodeoxycholic acid ethyl ester (1 .30 g, 63% yield over two steps).

[0157] 1H NMR (400 MHZ, CDCh): 6 = 4.12 (2H, q, J = 7.1 , OCH2CH3), 3.58 (2H, m, C3&C7), 2.33 (1 H, ddd, J = 15.3, 10.1 , 5.2), 2.20 (1 H, ddd, J = 15.6, 9.3, 6.5), 2.00 (1 H, dt, J = 12.4, 3.1) 1.96-1.85 (1 H, m), 1.85-1.74 (4H, m), 1.71-0.97 (20H, m), 1.25 (3H, t, J = 7.1 , CH2CH3), 0.95 (3H, s, C19), 0.93 (3H, d, J = 6.4, C21), 0.67 (3H, s, C18).

[0158] Example 7: Synthesis of ursodeoxycholic acid

[0159] UDCA

[0160] To a flask containing ursodeoxycholic acid ethyl ester (1.15 g, 2.73 mmol) dissolved in isopropyl alcohol (15 mL, 13 vol.) was added 1 M NaOH (9 mL, 8 vol.). The resulting solution was stirred at 40 °C for 16h. The mixture was then cooled to room temperature and acidified by the careful addition of 2M H2SC>4 (2.4 mL) to pH 3-4. The mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL), the aqueous portion is back extracted with EtOAc (20 mL) and the combined organics washed with water (20 mL), dried over MgSC , filtered and concentrated. Crude ursodeoxycholic acid was obtained as a white foam in quantitative yield.1H NMR (400 MHz, MeOD): 5 = 4.55-4.40 (2H, m, C3 & C7), 2.39-2.27 (1 H, m), 2.26-2.14 (1 H, m), 2.04 (1 H, ft, J = 12.3, 2.9), 1.97-1.75 (5H, m), 1.67-0.99 (21 H, m), 0.97 (3H, s, C19), 0.96 (3H, d, J = 6.4, C21), 0.72 (3H, s, C18).

[0161] References

[0162] Jonker, J. W., Liddle, C., Downes, M. FXR and PXR: Potential therapeutic targets in cholestasis”, Journal of Steroid Biochemistry & Molecular Biology. 2012, 130, 147-158. DOI: 10.1016 / j.jsbmb.2011.06.012

[0163] Keitel, V., Haussinger, D. Role of TGR5 (GPBAR1) in Liver Disease. Semin. Liver Dis. 2018, 38(4), 333-339. DOI: 10.1055 / S-0038-1669940

[0164] Mocan T, Kang DW, Molloy BJ, Jeon, H, Sparchez ZA, Beyoglu D, Idle JR, Plasma fetal bile acids 7a-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxachola-4,6-dien-24-oic acid indicate severity of liver cirrhosis, Nature Scientific Reports, 2021 , 11 , 8298.

[0165] Nikolaou, N., Arvaniti, A., Sanna, F., da Conceigao, I., Dempster, N., Gathercole, L., Tomlinson, J. 7a-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA) is a novel AKR1 D1 substrate driving metabolic dysfunction and hepatocellular cancer risk in patients with nonalcoholic fatty liver disease (NAFLD). Endocrine Abstracts, 2022, 86, OC5.2. DOI: 10.1530 / endoabs.86.OC5.2

[0166] Uekawa, T., Ishigami, K., Kitahara, T. Short-step Synthesis of Chenodiol from Stigmasterol. Bioscience, Biotechnology, and Biochemistry, 2004, 68(6), 1332-1337. DOI: 10.1271 / bbb.68.1332

[0167] Wuts, P. G. M., Greene, T. W. (2006). Protective Groups in Organic Synthesis, 4thEdition, John Wiley & Sons, Inc., Hoboken, NJ, USA.

Claims

CLAIMSA process for the preparation of a compound of formula (I):whereinX is selected from a bond, CH2, CH[C(O)OR3a], CH2CH2, CH2CH[C(O)OR3a], CH=CH and CH=C[C(O)OR3a]; andR1is selected from -OR2, -C(O)OR3b, -C(O)R3c, -CH(OR5)R3cand -C(R3c)(OR6a)(OR6b);R2and R5are each independently selected from H and an OH protecting group; each R3a, R3band R3cis independently selected from H, Ci-e alkyl and benzyl;R6aand R6bare each independently selected from Ci-e alkyl and benzyl; the process comprising the catalytic hydrogenation of a compound of formula (II):wherein X and R1are as defined for formula (I); over a sponge nickel catalyst; characterised in that: the hydrogenation is carried out in a reaction solvent comprising pyridine, a pyridine derivative or a mixture thereof and optionally water, wherein water is present in an amount of 0% to 10% w / w; and the reaction temperature is from about 15 °C to 60 °C.

2. A process according to claim 1 wherein X is CH2CH2, CH2, CH2CH[C(O)OR3a], CH=CH or CH=C[C(O)OR3a].

3. A process according to claim 2 wherein X is CH2CH2, CH2or CH=CH.

4. A process according to any one of claims 1 to 3 wherein R1is -OR2, wherein R2is asdefined in claim 1.

5. A process according to claim 4, wherein R2is H or -C(O)R4, wherein R4is Ci-e alkyl or benzyl.

6. A process according to any one of claims 1 to 3 wherein R1is -C(O)OR3b, wherein R3bis as defined in claim 1.

7. A process according to any one of claims 1 to 3 wherein R1is -C(O)R3c, -CH(OR5)R3cor -C(R3c)(OR6a)(OR6b) where R3c, R5, R6aand R6bare as defined in claim 1.

8. A process according to any one of claims 1 to 7 wherein the compound of formula (I) is a compound of formula (la):which is produced by the reduction of a compound of formula (Ila):wherein X and R1are as defined in claim 1.

9. A process according to any one of claims 1 to 7 wherein the compound of formula (I) is a compound of formula (lb):which is produced by the reduction of a compound of formula (lib):wherein X and R1are as defined in claim 1.

10. A process according to any one of claims 1 to 9 wherein the sponge nickel catalyst contains aluminium in an amount of about 5-10% by weight and may has a particle size of about 10 to 100 pm.

11. A process according to any one of claims 1 to 10 wherein the sponge nickel catalyst is present in an amount of about 15% to 40% by weight with respect to the weight of the starting material.

12. A process according to claim 11 wherein the sponge nickel catalyst is present in an amount of 25% to 35% by weight with respect to the weight of the starting material.

13. A process according to any one of claims 1 to 12 wherein the reaction solvent comprises pyridine or a lutidine.

14. A process according to claim 13 wherein the reaction solvent comprises pyridine.

15. A process according to any one of claims 1 to 14 wherein the reaction solvent comprises one or more additional solvents in admixture with the pyridine and / or pyridine derivative, wherein the one or more additional solvents are selected from: a Ci-5 alcohol; a 5- or 6-membered cyclic ether, wherein the 5- or 6-membered cyclic ether is optionally substituted with one or more methyl or ethyl substituents; an ether of formula CH3(CH2)PO(CH2)qCH3, wherein each of p and q is 0, 1 or 2, provided that p+q is from 0 to 3; and mixtures thereof.

16. A process according to claim 15 wherein the one or more additional solvents are selected from a C3-5 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, and an ether of formula CH3(CH2)pO(CH2)qCH3, wherein p and q are as defined in claim 15.

17. A process according to claim 15 or claim 16 wherein the reaction solvent comprises one additional solvent.

18. A process according to any one of claims 15 to 17 wherein the volume ratio of the additional solvent to pyridine or pyridine derivative is from about 15:1 to 1 :15.

19. A process according to any one of claims 1 to 14 wherein the reaction solvent consists of pyridine or a pyridine derivative, and optionally water.

20. A process according to claim 19, wherein the reaction solvent comprises water in an amount of 0.1 to 10% w / w with respect to the total weight of solvent.

21. A process according to claim 20, wherein the reaction solvent comprises water in an amount of 0.1 to 6% w / w with respect to the total weight of solvent.

22. A process according to claim 21 , wherein the reaction solvent comprises water in an amount of 0.1 % to 0.5% w / w with respect to the total weight of solvent.

23. A process according to any one of claims 1 to 22 wherein the reaction temperature is from about 30 °C to 40 °C.

24. A process according to any one of claims 1 to 23 further comprising the additional step of reducing the compound of formula (I) to obtain a compound of formula (IV):wherein X1is a bond, CH2, CH[C(O)OR3a], CH2CH2or CH2CH[C(O)OR3a], and R1is as defined in claim 1.

25. A process according to claim 24, further comprising reducing a compound of formula (IV) to give a compound of formula (V):wherein X1is as defined in claim 24 and R1is as defined in claim 1.

26. A process according to claim 24 or claim 25 wherein the reduction of the compound of formula (I) is conducted by hydrogenation over a suitable catalyst; and / or the reduction of the compound of formula (IV) is conducted using a hydride reducing agent.

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