ES2724725A1 - Synthesis of obetolic acid and synthesis intermediate (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Synthesis of obteticolic acid and synthesis intermediate. The present invention relates to a new intermediate for the synthesis of obetolic acid, compound of formula (I) or a geometric isomer thereof, with its method of obtaining it, as well as to the use of said intermediate in the synthesis of obetolic acid. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

Synthesis of obetolic acid and synthesis intermediate

Field of the Invention

The present invention relates to a new intermediate for the synthesis of obetolic acid, with the use of said intermediate in the synthesis of said obetolic acid, as well as the process for obtaining this new intermediate.

Background of the invention

The obeticholic acid (OCA) or 3a, 7a-dihydroxy-6a-ethyl-5p-colan-24-oic acid or compound of formula (IV) in the present invention, is a 6a-ethylated derivative of chenodeoxycholic bile acid (CDCA) . The chemical structure of obetolic acid is shown below.

Obetolic acid is a farnesoid X receptor ligand (FXR), which is used in the treatment of primary biliary cholangitis and is under development for the treatment of other liver diseases.

The obetolic acid and its synthesis procedure is disclosed in WO 02/072598 A1. The synthetic route comprises: protecting the hydroxyl group in the C3 position of 3a-hydroxy-7-keto-5p-colan-24-oic acid with a tetrahydropyranyl group to give 3a-tetrahydroprianyloxy-7-keto-5p-colan-24 acid -oic, alkylation of the carbon in C6 position and esterification of the carboxylic group with ethyl bromide and deprotection of the tetrahydropyranyl group to give ethyl 3a-hydroxy-6a-ethyl-7-keto-5p-colan-24-oate, reduction of the Ketone group in C7 position to hydroxyl with sodium borohydride to give ethyl 3a, 7adihydroxy-6a-ethyl-5p-colan-24-oato acid and finally deprotection of the ester group to yield the obetolic acid.

The problem of this synthetic route is the low yield (3%) and that also involves multiple stages of purification by column chromatography, which makes it difficult to implement it on an industrial scale.

Zampella et al. [J. Med. Chem., 2012, 55, 84-93] disclose another route of synthesis of the obetolic acid comprising the oxidation of chenodeoxycholic acid (CDCA) with a solution of sodium hypochlorite / NaBr and tetrabutylammonium bromide in a methanol / acid mixture acetic acid / water / ethyl acetate as solvent, followed by benzylation of carboxylic acid in position C24, to give the benzyl ester of 7-cetolitocolic acid. Silylenol ether is then generated followed by aldol addition with acetaldehyde in the presence of BF3 OEt2 to give ethyl 3a-hydroxy-6a-ethylinden-7-keto-5p-colan-24-oato. Then, they carry out the selective reduction of the ketone in C7 position with NaBH4 / CeCl3 in a mixture of THF / methanol and subsequently hydrogenation of the exocyclic double bond together with the removal of the benzyl protecting group to give the obetolic acid.

The yield of this synthesis route is 32%. Despite improving performance, this synthetic route still involves several stages of purification by column chromatography, so it is not suitable for industrial implementation.

US 8338628 B2 discloses a process for obtaining obetolic acid comprising the steps of oxidizing the C7 hydroxyl of the CDCA to a ketone group with pyridinium chlorochromate, protection of the hydroxyl in C3 position with a tetrahydropyranyl group, carbon alkylation in C6 position with ethyl iodide and deprotection of the tetrahydropyranyl group, and finally reduction of the ketone group in C7 position to hydroxyl with sodium borohydride to give the obetolic acid, as shown below.

However, this synthetic route also includes several stages of purification by column chromatography, so it is not suitable for industrial implementation.

CN 107400154 A discloses the following synthesis procedure for obtaining obetolic acid, wherein R is C1-C6 alkyl:

Similar to the previous procedure, CN 106589039 A also discloses a method of synthesis of obetolic acid in which intermediates having a methyl ester are used as the carboxylic acid protecting group and / or a tetrahydropyranyl (THP) as the hydroxyl protecting group in position C3

In these last two synthetic procedures described in CN 107400154 A and CN 106589039 A, the intermediates obtained in each of the stages are isolated, which is a disadvantage for carrying out the process in an industrial manner.

Therefore, there is a need in the prior art for alternative procedures for the synthesis of obetolic acid that present improvements with respect to those already existing, for example improvements in performance, purity, the number of independent stages that involve isolating the intermediates obtained and / or the purity of the obetolic acid.

Summary of the invention

The inventors have discovered a new process for the synthesis of obetolic acid that allows obtaining the precursor of obetolic acid (the compound of formula (NI)) in a single reaction vessel and without the need to isolate the synthesis intermediates. In this way, the inventors manage to reduce the number of independent stages that involve isolating the intermediates obtained as well as the corresponding purification stages, achieving good yields and high purity. This procedure uses the compound of formula (I) as a key intermediate:

Therefore, in a first aspect, the present invention relates to the compound of formula (I) or a geometric isomer thereof.

In a second aspect, the present invention relates to the use of a compound of formula (I) or a geometric isomer thereof in an obetolic acid preparation process, in particular where the obetolic acid preparation process comprises the following stages:

(a) treating the compound of formula (I) or a geometric isomer thereof with a base and hydrogen and in the presence of a catalyst, to give a salt of the compound of formula (II)

(b) treating the salt of the compound of formula (II) with sodium borohydride to give a salt of the compound of formula

(c) optionally treating the salt of the compound of formula (III) with an acid at a pH between 4 and 6 to give the compound of formula (III); Y

(d) treating the salt of the compound of formula (III) or the compound of formula (III) with an acid at a pH of between 0 and 3 to give the obetolic acid of formula (IV)

(IV).

In a third aspect, the present invention relates to a process for preparing a compound of formula (I) or a geometric isomer thereof which comprises treating a compound of formula (V) or a geometric isomer thereof with 2,3- dihydropyran in the presence of an acid.

Description of the drawings

Figure 1 shows the powder X-ray diffractogram (XRPD) of the amorphous form of the obetolic acid obtained in example 8.

Figure 2 shows the differential scanning calorimetry diagram of the amorphous form of the obetolic acid obtained in example 8.

Figure 3 shows the differential scanning calorimetry diagram of 3atetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-collanic acid obtained in example 7.

Detailed description of the invention

The first aspect of the present invention relates to the compound of formula (I) or a geometric isomer thereof.

The term "geometric isomer" refers to stereoisomers that differ only in the position of substituents linked to a double bond, in the present case, the exocyclic double bond of the compound of formula (I). Possible geometric isomers are cis ( E) and trans (Z).

In the present invention, the compound of formula (I) may be the Z isomer, the E isomer or a mixture of said isomers. Preferably it is the E isomer.

The second aspect of the present invention relates to the use of the compound of formula (I) or a geometric isomer thereof in an obetolic acid preparation process, in particular in which the obetolic acid preparation process comprises the following steps:

(a) treating the compound of formula (I) or a geometric isomer thereof with a base and hydrogen and in the presence of a catalyst, to give a salt of the compound of formula (II)

(b) treating the salt of the compound of formula (II) with sodium borohydride to give a salt of the compound of formula (III)

(c) optionally treating the salt of the compound of formula (III) with an acid at a pH of 4 to 6 to give the compound of formula (III); Y

(d) treating the salt of the compound of formula (III) or the compound of formula (III) with an acid at a pH of 0 to 3 to give the obetolic acid of formula (IV)

(IV).

The advantage of the present invention is that steps (a) and (b) can be carried out in the same reaction vessel without the need to isolate the intermediate products obtained, which is why it is especially convenient for its industrial implementation. After steps (a) and (b) the compound of formula (III) is obtained which is the precursor of the obetolic acid.

In step (a) the benzyl group of the compound of formula (I) or a geometric isomer thereof is deprotected, the exocyclic double bond in C6 position is reduced and said carbon in C6 position is epimerized to the alpha form (a) , thus obtaining a salt of the compound of formula (II). These transformations are achieved by treating the compound of formula (I) or a geometric isomer thereof with a base and hydrogen and in the presence of a catalyst.

Examples of suitable bases for step (a) are sodium hydroxide, potassium hydroxide, ammonia, preferably sodium hydroxide.

The salt of the compound of formula (II) is formed by the anion of the carboxylic acid (carboxylate) of the compound of formula (II) and a cation that comes from the base used in step (a). For example, if the base is sodium hydroxide, the salt of the compound of formula (II) is the sodium salt, if the base is potassium hydroxide the salt of the compound of formula (II) is the potassium salt, and if the base is ammonia The salt of the compound of formula (II) is the ammonium salt. Therefore, in a preferred embodiment, the cation is selected from the group consisting of Na +, K + and NH4 +, preferably Na +.

In a particular embodiment, the base is mixed with a solvent selected from water, C1-C3 alcohol and mixture thereof. Examples of C1-C3 alcohols are methanol, ethanol, n-propanol and isopropanol. Preferably the base is mixed with water, more preferably the base is an aqueous solution, in particular an aqueous solution of sodium hydroxide.

In a preferred embodiment, in step (a) between 1.5 and 2.5 moles of base (preferably sodium hydroxide) are used with respect to each mole of compound of formula (I) or a geometric isomer thereof, preferably between 1.5 and 2.1 moles, more preferably between 1.8 and 2.1 moles, more preferably between 1.9 and 2.1 moles, most preferably about 2 moles.

In another preferred embodiment, the catalyst of step (a) is selected from the group consisting of palladium on carbon, palladium on calcium carbonate and platinum oxide, preferably the catalyst is palladium on carbon.

In a particular embodiment, step (a) is carried out at a temperature between 15 ° C and 50 ° C, more preferably between 15 ° C and 45 ° C, more preferably between 20 ° C and 45 ° C, more preferably between 25 ° C and 45 ° C, more preferably between 30 ° C and 45 ° C, more preferably between 35 ° C and 45 ° C, preferably between 38 ° C and 42 ° C, more preferably about 40 ° C. Working in the temperature range of 35 ° C to 45 ° C is especially advantageous since the impurity content is reduced.

In another preferred embodiment, step (a) is performed at a pressure of between 4.5 and 5.5 bar, preferably between 4.5 and 5.2 bar, more preferably between 4.8 and 5.2 bar, even more preferably between 4.8 and 5.0 bars, most preferably about 5 bars. Working in these pressure ranges is also especially advantageous since the impurity content is reduced.

In a particular embodiment, the hydrogen treatment of step (a) is maintained between 4 and 10 hours, preferably between 4 and 8 hours, more preferably between 4 and 6 hours, most preferably about 5 hours.

In a preferred embodiment, step (a) is performed in the presence of a solvent selected from a C1-C3 alcohol. Examples of C1-C3 alcohols are methanol, ethanol, npropanol and isopropanol. Preferably, the C1-C3 alcohol of step (a) is methanol. In a preferred embodiment, between 5 and 15 ml of C1-C3 alcohol are used for each gram of compound of formula (I) or a geometric isomer thereof, more preferably between 8 and 12 ml, even more preferably about 10 ml.

In particular, step (a) is carried out by first adding the base, the resulting mixture is treated with activated carbon and then the resulting mixture is filtered by any conventional method known to the person skilled in the art, for example, by means of a ground filter diatoms, and then hydrogenation is performed.

In a particular embodiment, after hydrogenation the resulting mixture is filtered to remove the catalyst. Said filtering can be carried out by any conventional method known to the person skilled in the art, for example, by a diatomaceous earth filter.

In a particular embodiment, after hydrogenation and removal of the catalyst at least 70% of the volume of the solvent is removed, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, even more preferably at least 95%. The removal of the solvent is preferably carried out by distillation, in particular by distillation at a temperature below 40 ° C and at reduced pressure (at a pressure below 1 atm and which is capable of removing the solvent at a temperature below 40 ° C, this pressure is easily determined by the person skilled in the art).

Once the salt of the compound of formula (II) in step (a) is obtained, step (b) of reducing the ketone group in position C7 to hydroxyl group is carried out to give a salt of the compound of formula (III) . Step (b) comprises treating the salt of the compound of formula (II) with sodium borohydride to give the salt of the compound of formula (III).

The salt of the compound of formula (III) is formed by the anion of the carboxylic acid (carboxylate) of the compound of formula (III) and a cation that comes from salt of the compound of formula (II) and, if in cases where there is additionally a base in the reaction medium, the cation can also come from said base, as explained later in this document. In a preferred embodiment, the cation is selected from the group consisting of Na +, K + and NH4 +, preferably Na +.

In a preferred embodiment, between 2 and 3.5 moles of sodium borohydride is used with respect to each mole of salt of compound of formula (II), preferably between 2 and 3 moles, more preferably between 2.3 and 2.8 moles , even more preferably about 2.5 moles. In a more preferred embodiment, between 2 and 3.5 moles of sodium borohydride is used with respect to each mole of compound of formula (I) or a geometric isomer thereof, preferably between 2 and 3 moles, more preferably between 2.3 and 2.8 moles, even more preferably about 2.5 moles. This more preferred embodiment is applied in particular when steps (a) and (b) are carried out in the same reaction vessel without the need to isolate the intermediate products obtained.

In a preferred embodiment, step (b) is performed in the presence of a solvent selected from the group consisting of C1-C3 alcohol, water and mixtures thereof. Examples of C1-C3 alcohols are methanol, ethanol, n-propanol and isopropanol, preferably methanol. In a preferred embodiment the solvent is a mixture of methanol and water, preferably a mixture of methanol and water with a ratio of between 4 and 6 volumes of methanol per volume of water, more preferably between 4.5 and 5.5 volumes of methanol per volume of water, even more preferably about 5 volumes of methanol per volume of water.

In a particular embodiment, the solvent is a mixture of methanol and water containing at least 80% by volume of methanol relative to the total volume of solvent, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%

In another preferred embodiment, in step (b) between 3.5 and 4.5 ml of solvent is used for each mmol of salt of compound of formula (II), more preferably between 3.75 and 4.25 ml, even more preferably about 4 ml. In a more preferred embodiment, in step (b) between 3.5 and 4.5 ml of solvent is used for each mmol of compound of formula (I), more preferably between 3.75 and 4.25 ml, even more preferably about 4 ml. This more preferred embodiment is applied in particular when steps (a) and (b) are carried out in the same reaction vessel without the need to isolate the intermediate products obtained. Using these solvent volumes is especially advantageous since the impurity content is reduced.

In a preferred embodiment, step (b) is performed at a temperature between 70 ° C and 95 ° C, preferably between 70 and 90 ° C, more preferably between 75 ° C and 90 ° C. In a particular embodiment, said temperature is maintained between 2.5 and 4 hours, preferably between 2.5 and 3.5 hours, more preferably about 3 hours.

In a particular embodiment, in step (b) a solution of sodium hydroxide in water is also added, preferably between 0.05 and 0.2 moles of sodium hydroxide are added with respect to each mole of salt of compound of formula (II ), preferably between 0.05 and 0.15 moles, more preferably between 0.08 and 0.12 moles, even more preferably about 0.1 moles. In a more preferred embodiment, between 0.05 and 0.2 moles of sodium hydroxide are added with respect to each mole of compound of formula (I) or a geometric isomer thereof, preferably between 0.05 and 0.15 moles, plus preferably between 0.08 and 0.12 moles, even more preferably about 0.1 moles. This more preferred embodiment is applied in particular when steps (a) and (b) are carried out in the same reaction vessel without the need to isolate the intermediate products obtained. In these preferred embodiments, the salt of the compound of formula (III) is formed by the carboxylic acid (carboxylate) anion of the compound of formula (III) and a sodium cation.

In particular, step (b) is performed by dissolving the product obtained after stage (a) in the solvent of stage (b), preferably by heating the mixture obtained at the temperature described above for stage (b), followed by addition of sodium borohydride and optionally the addition of the solution of sodium hydroxide in water.

In a particular embodiment, after reduction, that is, after treatment with sodium borohydride, at least 70% of the solvent volume, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, even more preferably at least 95%. Solvent removal is preferably carried out by distillation, in particular by distillation at atmospheric pressure, that is at about 1 atmosphere.

After step (b) an optional step, step (c), of treating the salt of the compound of formula (III) with an acid at a pH of 4 to 6 can be performed to give the compound of formula (III).

Examples of suitable acids for step (c) are phosphoric acid, hydrochloric acid acetic acid, sulfurous acid and oxalic acid. Preferably the acid used in step (c) is phosphoric acid or hydrochloric acid, more preferably phosphoric acid.

In a particular embodiment, the acid treatment of step (c) is performed at a pH of 4.5 to 5.5, more preferably about 5.

It is part of the usual routine of the person skilled in the art to determine the pH value, for example by using a pH-meter.

In a preferred embodiment step (c) is carried out.

Preferably, step (c) comprises one or more washes with aqueous acid solution, in particular phosphoric acid or hydrochloric acid, preferably phosphoric acid. In particular, for such washes with acidic aqueous solution, the product is dissolved in a suitable organic solvent such as, for example, ethyl acetate. Even more preferably, the product obtained is further purified by crystallization in linear, branched or cyclic C5-C8 alkane. Examples of linear, branched or cyclic C5-C8 alkane are n-pentane, cyclopentane, isopentane, n-hexane, cyclohexane, n-heptane, cycloheptane, n-octane, isooctane, preferably n-heptane.

The next step is step (d) of obtaining obetolic acid (compound of formula (IV)) by deprotection of tetrahydropyranyl group in the compound of formula (III) or in the salt of the compound of formula (III). This step comprises treating the compound of formula (III) or the salt of the compound of formula (III) with an acid at a pH of 0 to 3 to give the obetolic acid of formula (IV).

Any acid suitable for the deprotection of hydroxyl groups protected with a tetrahydropyranyl group can be used.

Examples of suitable acids for step (d) are hydrochloric acid, ptoluenesulfonic acid, sulfuric acid, phosphoric acid and methanesulfonic acid, among others. Preferably the acid of step (d) is hydrochloric acid.

Preferably, when step (c) is performed, in step (d) between 1 and 2 moles of hydrochloric acid are used for each mole of compound of formula (III), more preferably between 1.2 and 2 moles, more preferably between 1, 4 and 1.8 moles, even more preferably about 1.5 moles.

In a preferred embodiment, step (d) is carried out in the presence of a solvent selected from the group consisting of C1-C4 alkyl acetates, ketones, cyclic or linear ethers, acetonitrile, water and mixtures thereof. Examples of C1-C4 alkyl acetates are ethyl acetate, n-butyl acetate and tere-butyl acetate. Examples of ketones are acetone and methyl- / so-butyl ketone. Examples of cyclic or linear ethers are diethyl ether, tetrahydrofuran and dioxane. In a more preferred embodiment the solvent is a mixture of acetone and water. Preferably, between 2.5 and 7.5 ml of acetone are used for each mmol of compound of formula (III) or of salt of compound of formula (III), more preferably between 4 and 6 ml, even more preferably about 5 ml .

Preferably, between 0.5 and 2.5 ml of water and / or C1-C3 alcohol are used for each mmol of compound of formula (III) or salt of compound of formula (III), more preferably between 0.5 and 1.25 ml, more preferably between 0.5 and 1 ml, more preferably between 0.6 and 0.9 ml, even more preferably between 0.75 and 0.85 ml.

In another preferred embodiment, step (d) is performed at a temperature between 15 ° C and 35 ° C, more preferably between 15 ° C and 30 ° C, more preferably between 20 ° C and 25 ° C.

In a particular embodiment, the acid treatment of step (d) lasts between 6 and 10 hours, preferably between 7 and 9 hours, more preferably about 8 hours.

In another particular embodiment, after treatment with acid in the presence of a solvent, at least 70% of the volume of the solvent is removed, preferably at least 75%, more preferably at least 80%, more preferably at least 85% , more preferably at least 90%, even more preferably at least 95%. Solvent removal is preferably carried out by distillation, in particular by distillation at a temperature below 40 ° C, more preferably about 35 ° C. In particular, said distillation is carried out under reduced pressure, that is, at a pressure below 1 atm and which is capable of removing the solvent at a temperature below 40 ° C or 35 ° C. This pressure is easily determined by the person skilled in the art. Preferably, the product obtained after removal of the solvent is purified by one or more washes with basic aqueous solution, in particular sodium hydroxide, until a pH of about 12 is obtained. In particular, for purification by said washes with basic aqueous solution, the product is dissolved in a suitable organic solvent such as ethyl acetate. The basic aqueous phase obtained after washing is brought to a pH between 2 and 3, in particular by the addition of hydrochloric acid. Even more preferably, the product obtained is isolated by filtration.

In a third aspect, the present invention relates to a process for preparing a compound of formula (I) or a geometric isomer thereof which comprises treating a compound of formula (V) or a geometric isomer thereof with 2,3- dihydropyran in the presence of an acid.

As defined with respect to the compound of formula (I), geometric isomers refer to stereoisomers that differ only in the position of substituents linked to a double bond, in this case, the exocyclic double bond of the compound of formula ( V). Possible geometric isomers are cis (Z) and trans (E).

In the present invention, the compound of formula (V) may be the Z isomer, the E isomer or a mixture of said isomers. Preferably it is the E isomer.

Any suitable acid can be used for the protection of hydroxyl groups by formation of tetrahydropyranyl ether, such as camforsulfonic acid and ptoluenesulfonic acid, among others. Preferably the acid is camforsulfonic acid, more preferably (1S) - (+) - 10-camforsulfonic acid.

In a preferred embodiment, between 0.04 and 0.06 moles of acid are used with respect to each mole of compound of formula (V) or a geometric isomer thereof, preferably between 0.05 and 0.06 moles, more preferably about 0.05 moles These amounts are especially advantageous since they allow a higher conversion of the product of formula (V) or a geometric isomer thereof.

In another preferred embodiment, between 1 and 3 moles of 2,3-dihydropyran are used with respect to each mole of compound of formula (V) or a geometric isomer thereof, preferably between 1 and 2 moles, most preferably about 1.5 moles

In another preferred embodiment, the treatment of the compound of formula (I) with 2,3-dihydropyran is carried out in the presence of a solvent selected from the group consisting of dichloromethane, tetrahydrofuran and mixtures thereof, preferably dichloromethane. The use of dichloromethane is particularly advantageous since it achieves higher yields and lower impurity content. Preferably, between 5 and 15 ml of solvent is used with respect to each gram of compound of formula (V) or a geometric isomer thereof, more preferably about 10 ml.

In another preferred embodiment, the treatment of the compound of formula (I) with 2,3-dihydropyran is carried out at a temperature between 15 ° C and 35 ° C, preferably between 20 ° C and 25 ° C.

In a particular embodiment, the treatment of the compound of formula (I) with 2,3-dihydropyran has a duration of between 4 and 10 hours, preferably between 4 and 7 hours, more preferably about 5 hours.

In another particular embodiment, said treatment is carried out in an inert atmosphere, for example in a nitrogen or argon atmosphere.

In another particular embodiment, after the treatment of the compound of formula (I) or a geometric isomer thereof with 2,3-dihydropyran, the pH is adjusted to about 9, for example by the addition of triethylamine. Preferably, after adjusting the pH at least 70% of the volume of the solvent is removed, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, even more preferably at least 95%. The elimination of the solvent is preferably carried out by distillation, in particular by distillation under reduced pressure, that is, at a pressure below 1 atm and which is capable of removing the solvent at the temperature used (this pressure is easily determined by the person skilled in the art) , and preferably at a temperature below 40 ° C.

The compound of formula (V), as well as its method of production, have been described in Zampella et al. [J. Med. Chem., 2012, 55, 84-93]. Said compound can be obtained by the procedure described in this article or by the steps described below.

In a preferred embodiment, the compound of formula (V) or a geometric isomer thereof is obtained by treating a compound of formula (VI) with acetaldehyde in the presence of boron diethyl ether trifluoride.

In a particular embodiment, between 1.5 and 2.5 moles of acetaldehyde are used with respect to each mole of compound of formula (VI), preferably between 1.8 and 2.2 moles, more preferably about 2 moles.

In another particular embodiment, between 1.5 and 3.5 moles of boron diethyl ether trifluoride are used with respect to each mole of compound of formula (VI), preferably between 2 and 3 moles, most preferably about 2, 5 moles

In another particular embodiment, the treatment of the compound of formula (VI) with acetaldehyde in the presence of boron diethyl ether trifluoride is carried out in dichloromethane. Preferably, between 2 and 15 ml of solvent is used with respect to each gram of compound of formula (VI), more preferably between 5 and 10 ml.

In another particular embodiment, the treatment of the compound of formula (VI) with acetaldehyde in the presence of boron diethyl ether trifluoride is carried out at a temperature between -60 ° C and 65 ° C, in particular for 1.5 to 3 hours, preferably for about 2 hours, followed by a temperature between 20 ° C and 25 ° C, in particular for 2 to 5 hours, preferably for about 3 hours.

In another particular embodiment, after treatment of the compound of formula (VI) with acetaldehyde in the presence of boron diethyl ether trifluoride, one or more washes are carried out with an aqueous solution of sodium bicarbonate. Preferably, after washing at least 70% of the solvent volume is removed, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, even more preferably at least 95%. The removal of the solvent is preferably carried out by distillation, in particular by distillation under reduced pressure, that is, at a pressure below 1 atm and which is capable of removing the solvent at the temperature used (this pressure is easily determined by the person skilled in the art. matter) and preferably at a temperature below 40 ° C.

In a preferred embodiment, the compound of formula (VI) is obtained by treating a compound of formula (VII) with trimethylsilyl chlorotrimethylsilane or trifluoromethanesulfonate in the presence of a base.

Suitable bases for this treatment are for example hexyl lithium and n-butyllithium, preferably further comprising diisopropylamine. Preferably, the compound of formula (VI) is obtained by treating a compound of formula (VII) with chlorotrimethylsilane and hexyl lithium in the presence of diisopropylamine. Preferably between 4 and 5 moles of chlorotrimethylsilane are used per mole of compound of formula (VII), more preferably about 4.5 moles. In particular, the treatment is carried out in a suitable solvent, such as tetrahydrofuran, hexane and mixtures thereof, preferably in a mixture of tetrahydrofuran and hexane. Preferably between 5 and 20 ml of solvent are used per gram of compound of formula (VII), more preferably between 10 and 25 ml. In particular, this treatment is carried out in an atmosphere inert (for example, nitrogen or argon) and preferably at a temperature between -70 ° C and -80 ° C. In a particular embodiment, after treatment of the compound of formula (VII) with trimethylsilyl chlorotrimethylsilane or trifluoromethanesulfonate in the presence of a base and a solvent one or more washes are carried out with aqueous citric acid solution and optionally one or more washes with aqueous solution of bicarbonate. Preferably, at least 70% of the volume of the solvent is removed, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, even more preferably at least 95% The removal of the solvent is preferably carried out by distillation, in particular by distillation under reduced pressure, that is, at a pressure below 1 atm and which is capable of removing the solvent at the temperature used (this pressure is easily determined by the person skilled in the art. matter) and preferably at a temperature below 40 ° C.

In a preferred embodiment, the compound of formula (VII) is obtained by treating a compound of formula (VIII) with benzyl bromide in the presence of a base.

Suitable bases for this treatment are any suitable base for the protection of carboxylic acids by formation of the corresponding benzyl ester, such as tertiary amines containing three identical or different C1-C4 alkyl groups, such as triethylamine, and cesium carbonate, between others. Preferably the base is triethylamine.

Preferably between 1 and 2 moles of benzyl bromide are used for each mole of compound of formula (VIII), more preferably about 1.5 moles. In particular, the treatment is carried out in a suitable solvent, such as toluene. Preferably between 2 and 8 ml of solvent are used per gram of compound of formula (VII), more preferably about 5 ml. In particular, this treatment is carried out for 4 to 6 hours, preferably for approximately 5 hours. In particular, the treatment is carried out at a temperature between 90 ° C and 120 ° C, preferably between 105 ° C and 115 ° C. In a particular embodiment, after treatment of the compound of formula (VIII) with benzyl bromide in the presence of a base and a solvent, one or more washings with water and one or more washings with aqueous sodium hydroxide solution and one or more are carried out. washed with aqueous hydrochloric acid solution. Preferably, at least 70% of the volume of the solvent is removed, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, even more preferably at least 95% The removal of the solvent is preferably carried out by distillation, in particular by distillation under reduced pressure, that is, at a pressure below 1 atm and which is capable of removing the solvent at the temperature used (this pressure is easily determined by the person skilled in the art. matter) and preferably at a temperature below 40 ° C. Optionally, the product obtained can be purified by crystallization, in particular from a mixture of ethyl acetate and hexane.

In a preferred embodiment, the compound of formula (VIII) is obtained by treating a compound of formula (IX) with sodium bromide and sodium hypochlorite.

Preferably between 0.05 and 0.15 moles of sodium bromide are used for each mole of compound of formula (IX), more preferably about 0.1 moles. Preferably 1 to 2 moles of sodium hypochlorite are used for each mole of compound of formula (IX), more preferably 1.3 to 1.4 moles. In particular, the treatment of the compound of formula (IX) with sodium bromide and sodium hypochlorite is carried out in the presence of acetic acid. In particular, this treatment is carried out for 10 to 20 hours, preferably for approximately 15 hours. In particular, the treatment is carried out at a temperature between -5 ° C and 5 ° C. In a particular embodiment, after this treatment of the compound of formula (IX) water and sodium bisulfite are added. Preferably, compound of formula (VIII) is isolated by filtration.

In a particular embodiment, the compound of formula (I) or a geometric isomer thereof is obtained by a process comprising the steps of:

(a) treating a compound of formula (IX) with sodium bromide and sodium hypochlorite to give a compound of formula

(VIII);

(b) treating the compound of formula (VIII) with benzyl bromide in the presence of a base to give a compound of formula (VII)

(VII);

(c) treating the compound of formula (VII) with trimethylsilyl chlorotrimethylsilane or trifluoromethanesulfonate in the presence of a base to give a compound of formula (VI)

(SAW);

(d) treating the compound of formula (VI) with acetaldehyde in the presence of borodiethyl ether trifluoride to give a compound of formula (V) or a geometric isomer thereof

(e) treating the compound of formula (V) or a geometric isomer thereof with 2,3-dihydropyran in the presence of an acid to give the compound of formula (I) or a geometric isomer thereof

Each of these stages can be performed using the conditions described above.

In another aspect, the present invention relates to an amorphous form of obetolic acid.

In a particular embodiment, said amorphous form is characterized by comprising a halo (broadband) in the powder X-ray diffractogram having a maximum at about 15 ° 20, in particular the halo ranges from about 5 ° 20 to about 30 ° twenty. Preferably, the amorphous form of the obetolic acid of the present invention has a powder X-ray diffractogram substantially like that of Figure 1. The powder X-ray diffractogram can be obtained by the method described in the examples.

In another particular embodiment, said amorphous form is characterized by presenting a differential scanning calorimetry (DSC) diagram with endothermic peaks at from about 75 ° C to about 90 ° C and from about 260 ° C to about 270 ° C. Preferably, the amorphous form of the obetolic acid of the present invention has a DSC diagram substantially like that of Figure 2. The DSC diagram can be obtained by the method described in the examples.

In the context of the present invention, the term "approximately" refers to the value that characterizes ± 5% of said value.

Examples

Materials and methods

The XRPD analysis was performed on a Siemens D-500 X-ray powder diffractometer equipped with a Copper anode. Scanning parameters: 4-50 degrees 20, continuous scanning, ratio: 1,235 degrees / minute.

DSC analysis was performed on a Mettler Toledo 822e device with STARe SW11.00 software. Parameters: heating range from 25 to 300 ° C with a ramp of 20 ° C / min and N2 flow of 50 ml / min. The measurement is made with a closed perforated capsule.

The purity of the products obtained has been analyzed by means of the High Resolution Liquid Chromatography technique in a Waters Alliance apparatus, equipped with a variable wave detector and a thermostated column furnace. The experimental conditions for obtaining a chromatogram were: XSelect HSS T33.5 ^ m column (150 mm x 3.0 mm, 3.5 ^ m); mobile phase A: water at pH 2.6 corrected with phosphoric acid; mobile phase B: acetonitrile; flow: 0.8 ml / min; column temperature: 40 ° C; injection volume 25 ^ L; detection wavelength: 214 nm; solvent for the samples to be analyzed: acetonitrile / water (70:30); concentration: 1 mg / mL. Time (minutes):

0 min: 50% phase A

3 min: 50% Phase A

23 min: 5% Phase A

30 min: 5% Phase A

32 min: 50% Phase A

35 min: 50% Phase A

Example 1. Obtaining 3a-hydroxy-7-keto-5p-collanic acid (compound of formula (VIII))

250 g (636.8 mmol) of chenodeoxycholic acid (CDCA) and 6.55 g (63.7 mmol, 0.1 molar eq.) Of NaBr were mixed with 1750 mL of methanol under strong stirring to homogenize the mixture. Subsequently, 34 mL (534.9 mmol, 1.05 molar eq.) Of 90% acetic acid were added and the resulting mixture was cooled to a temperature between -5 and 5 ° C. Maintaining this temperature, 371 mL of a 15% NaClO4 solution (titration 164.55 g Cl2 / L, 1.35 molar eq.) Were slowly added. The resulting reaction mixture was kept stirring for approximately 15 h at a temperature between -5 and 5 ° C. After the maintenance, the resulting mixture was heated to an approximate temperature of 25 ° C and 60 mL of a 5% aqueous solution of sodium bisulfite was slowly charged. The obtained mixture was stirred for 30 minutes at the indicated temperature. 250 mL of water was added at the indicated temperature and the mixture obtained was stirred for 30 minutes. The reaction mass was filtered and washed with 125 mL of methanol and two fractions of 250 mL each of water and the solid thus obtained was dried to constant weight yielding 191.4 g (Rd. 76.9%) of 3a-hydroxy-7- acid keto-5p-cholanic.

Example 2. Obtaining 3a-hydroxy-7-keto-5-benzylcolanate (compound of formula (VII))

25 g (64.0 mmol) of 3a-hydroxy-7-keto-5p-collanic acid were mixed with 125 mL of toluene. 13.8 mL (99.0 mmol, 1.55 molar eq) of triethylamine and 11.4 mL (95.98 mmol, 1.5 molar eq) of benzyl bromide were subsequently added to the resulting mixture while maintaining the temperature between 20 and 25 ° C. The resulting mixture was heated to reflux temperature (approximately 111 ° C) and kept under stirring at that temperature for 5 hours. After maintenance, the reaction mass was cooled to the approximate temperature of 25 ° C and a previously prepared solution was slowly added by mixing 45 mL of water and 5 mL of a 30% NaOH aqueous solution. The organic phase was separated and mixed with 45 mL of water. The organic phase was separated again and mixed with 45 mL of water and the mixture obtained was acidified with 37% HCl to a pH value of about 2. The organic phase was separated and the solvent was removed. distilled under vacuum to obtain 30.8 g (Rd. 88%) of a colorless oil corresponding to 3-hydroxy-7-keto-5j3-benzyl colanate.

Example 3. Obtaining of benzyl 3a, 7-trimethylsilyloxy-5-cholan-6-enato (compound of formula (VI))

65.85 g (650 mmol) of disiopropylamine were dissolved in 250 mL of tetrahydrofuran under a nitrogen atmosphere. The resulting mixture was cooled to about -72 ° C and 271.3 mL of a 2.3 M solution of hexyl lithium in hexane was slowly added maintaining the indicated temperature. A previously prepared solution of 50 g (104 mmol) of 3-hydroxy-7-keto-5j3-benzyl acid and 50.84 g (468 mmol, 4.5 molar eq) of TMSCl was slowly added to said temperature (chlorotrimethylsilane)) in 208 mL of tetrahydrofuran. The mixture was kept under stirring under a nitrogen atmosphere at the temperature of about -72 ° C. After the maintenance, a previously prepared solution of 75 g (390 mmol) of citric acid in 200 mL of water was added slowly without the temperature exceeding 5 ° C. After the addition was finished, the mixing temperature was allowed to reach 20 ° C and the organic phase was separated. The solvent was distilled off under vacuum until an oil residue was obtained, which was dissolved in 350 mL of dichloromethane. The resulting organic phase was washed first with 150 mL of a saturated aqueous solution of NaHCO3 and then with 150 mL of water. Finally, the solvent was distilled off under vacuum to obtain 62.80 g of a dense oil corresponding to benzyl 3a, 7-trimethylsilyloxy-5-3-colan-6-enato, which was used in the next synthesis step without further purification.

Example 4. Obtaining of 3a-hydroxy-6-ethyliden-7-keto-5-benzylcolanate (compound of formula (V))

62.80 g (100 mmol) of benzyl 3a, 7-trimethylsilyloxy-5j3-colan-6-enato were dissolved in 470 mL of dichloromethane and the resulting solution was cooled to a temperature between -60 and -65 ° C. 8.85 g (201 mmol, 2 molar eq) of acetaldehyde and subsequently 35.65 g (251 mmol, 2.5 molar eq) of boron diethyl ether trifluoride were added. The reaction mixture was kept under stirring for 2 hours at a temperature between -60 and -65 ° C and subsequently for 3 hours at a temperature between 20 and 25 ° C. After maintenance, 820 mL of an aqueous solution of NaHCO3 was added to the reaction mixture and the resulting mixture was kept under stirring for 45 minutes at a temperature below 30 ° C. The organic phase was separated and initially washed with 250 mL of an aqueous solution. 2N NaCl and subsequently with a saturated aqueous solution of NaCl. Finally, the solvent was distilled off under vacuum to obtain 62.80 g of a dense oil corresponding to benzyl-3-hydroxy-6-ethylidene-7-keto-5j3-colanate.

Example 5. Obtaining 3a-tetrahydropyramloxy-6-ethylidene-7-keto-5-benzyl cholanate (compound of formula (I))

200 g (395 mmol) of benzyl 3ar-hydroxy-6-ethyliden-7-keto-5j3-colanate were mixed with 2000 mL of dichloromethane and 4.58 g (19.7 mmol, 0.05 molar eq) of acid (1S) - (+) - 10-camphorsulfonic under nitrogen atmosphere to obtain a solution at a temperature between 20 and 25 ° C. Maintaining said temperature, 54 ml (592 mmol, 1.5 molar eq) of 2,3-dihydropyran were slowly added and the resulting reaction mixture was kept under stirring at the same temperature for 5 hours. After maintenance, the pH of the reaction mixture was adjusted to an approximate value of 9 by adding 24 mL of triethylamine at a temperature between 20 and 25 ° C. The resulting reaction mixture was concentrated by distilling the solvent in vacuo and a practically colorless very dense oil corresponding to 3a-tetrahydropyranyloxy-6-ethylidene-7-keto-5j3-benzyl colanate was obtained. The purity of the product obtained is 96.68%.

1 H-NMR (CDCl ³ , 400 MHz) 5 (ppm): 7.35 (5H, m), 6.15 (1H, m), 5.30 (1H, s), 5.12 (2H, dd) , 4.72 (1H, dt), 3.88 (1H, m), 3.67 (1H, m), 3.49 (1H, m), 2.56 (1H, m), 2.19- 2.48 (3H, m), 1.05-2.04 (28 H, m), 1.00 (3H, m), 0.91 (3H, d), 0.61 (3H, s).

13C-NMR (CDCl ³ , 400 MHz) 5 (ppm): 205.19, 204.86, 174.15, 143.92, 143.59, 136.25, 129.88, 129.31, 128.67 , 128.30, 96.70, 96.45, 74.31, 66.22, 62.84, 62.59, 54.65, 50.75, 48.86, 45.64, 43.73, 39 , 17, 39.06, 35.54, 35.31, 34.88, 34.54, 33.93, 31.42, 31.26, 31.12, 28.55, 27.98, 26.10 , 25.61, 22.98, 21.45, 19.93, 19.73, 18.55, 12.90, 12.18.

Example 6. Obtaining 3a-tetrahydropyramloxy-6-ethylidene-7-keto-5-benzyl cholanate (compound of formula (I))

200 g (395 mmol) of benzyl 3a-hydroxy-6-ethylidene-7-keto-5j3-colanate were mixed with 2000 mL of dichloromethane and 4.58 g (19.7 mmol) of camphorsulfonic acid under nitrogen atmosphere to obtain a solution at a temperature between 20 and 25 ° C. Maintaining said temperature, 54 ml (592 mmol) of 2,3-dihydropyran was slowly added and the resulting reaction mixture was kept under stirring at the same temperature for 5 hours.

After maintenance, the pH of the reaction mixture was adjusted to approximately 9 by adding 600 mL of a saturated aqueous solution of NaHCO3 at a temperature between 20 and 25 ° C. The obtained phases were allowed to decant and the organic phase was separated from the aqueous phase. 600 mL of water was added over the organic phase and the latter was separated again. The organic phase was concentrated by distilling off the solvent in vacuo and a practically colorless very dense oil corresponding to 3a-tetrahydropyranyloxy-6-ethylidene-7-keto-5j3-benzyl colanate was obtained. The purity of the product obtained is 96.23%.

Example 7. Obtaining 3a-tetrahydropyramloxy-6a-ethyl-7a-hydroxy-5-chlamic acid (compound of formula (III))

52.0 g of the product obtained in example 6 (equivalent to 50 g (84.6 mmol) of 3-tetrahydropyranyloxy-6-ethylidene-7-keto-5j3-benzyl colanate) were dissolved in 500 mL methanol and 23 mL of a 30% (w / v) aqueous solution of sodium hydroxide. 1.6 g of activated carbon type 4S were charged and the resulting mixture was heated to a temperature of approximately 40 ° C, maintaining the stirring of the mixture for 30 minutes at that temperature. The mixture was subsequently cooled to a temperature of approximately 25 ° C. The mixture was filtered through a diatomaceous earth filter, introduced into a pressure reactor and 2.5 mg of Pd / C was added. The reactor was pressurized with hydrogen to an internal pressure of 5 bars and the resulting reaction mixture was maintained at a temperature of approximately 40 ° C for 5 hours. After said maintenance, the reaction mass was cooled to a temperature of approximately 20 ° C and the Pd / C was filtered through a diatomaceous earth filter. The reaction mass was distilled off under reduced temperature without exceeding the temperature of 40 ° C until a dense residue was obtained. 340 mL (8 volumes with respect to the theoretical total mass, 42.5 g, were obtained to obtain the compound of formula (II)) of a 5: 1 mixture of methanol / water on said resultant and heated to a temperature between 75 and 80 ° C. A solution of 8 g (211.5 mmol, 2.5 molar equivalents) of NaBH4 and 0.673 mL of a 50% (w / v) aqueous solution of sodium hydroxide (0.1 molar equivalents) was slowly added to said homogeneous mixture ) in 14.16 mL of water. The resulting reaction mixture was kept under stirring at reflux temperature (approximately 87 ° C) for 3 hours (control by HPLC of the reaction mass reveals the total conversion of the product 3a-tetrahydropyranyloxy-6a-ethyl-7- acid keto-5 ^ -colican). After the maintenance, most of the methanol was distilled at atmospheric pressure and 250 mL of ethyl acetate was added on the resulting mass. The pH of the resulting mixture was adjusted to a value of approximately 5 by the addition of a 85% aqueous solution of phosphoric acid and the phases thus obtained were separated. 250 mL of ethyl acetate were added over the aqueous phase and the resulting phases were separated. The two organic phases thus obtained were combined and mixed with 250 mL of a 10% aqueous solution of sodium chloride. The phases were separated and the resulting organic phase was distilled by vacuum to a maximum temperature of 30 ° C. 55 mL of ethyl acetate was added on the residue obtained and the resulting mixture was heated to a temperature of about 75 ° C. On the resulting solution, 55 mL of n-heptane was added and the mixture was cooled slowly and slowly with stirring to a temperature of approximately 20 ° C, observing the presence of a white solid. The resulting mixture was maintained at that temperature for 2 hours and the solid present was filtered and washed twice with 25 mL of a mixture of ethyl acetate / n-heptane. The soft solid thus obtained yielded after drying 37.0 g (86.6%) corresponding to 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5j3-cholanic acid. The purity of the product was analyzed by HPLC to obtain 99.08%.

1H-NMR (DMSO-d6, 400 MHz) 5 (ppm): 12.07 (1H, broad s), 4.66 (1H, m), 4.05 (1H, s), 3.76 (1H, m), 3.51 (1H, m), 3.38 (1H, m), 3.26 (1H, s), 2.22 (1H, m), 2.09 (1H, m), 1, 89-2.01 (2H, m), 0.94-1.83 (29H, m), 0.8-0.9 (9H, m), 0.61 (3H, s).

13C-NMR (DMSO-d6, 400 MHz) 5 (ppm): 174.95, 96.22, 95.07, 76.38, 75.14, 68.23, 61.46, 55.55, 50, 05, 45.48, 42.02, 41.28, 40.05, 35.31, 35.09, 32.58, 31.15, 30.88, 30.77, 29.69, 28.48, 27.83, 26.20, 25.14, 23.09, 22.97, 22.12, 20.38, 19.42, 18.18, 11.71.

Figure 3 shows the DSC of the product obtained.

Example 8. Obtaining the amorphous form of obetolic acid (compound of formula (IV))

20 g (39.6 mmol) of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5j3-cholanic acid were mixed with 200 mL of acetone. 5 mL (60 mmol, 1.51 eq molars) of a 12N aqueous solution of HCl was added maintaining the temperature between 20 and 25 ° C. The solution thus obtained was kept under stirring at a temperature between 20 and 25 ° C for 8 hours. After the maintenance, the solvent is distilled off under vacuum without exceeding the temperature of 35 ° C and added, maintaining the temperature of approximately 20 ° C, 150 mL of ethyl acetate and a 2N aqueous solution of NaOH up to a pH value of approximately 12. The organic phase is separated and the aqueous phase is acidified to the temperature of about 20 ° C to a pH value of 2-3 by the addition of a 12N aqueous solution of HCl. The resulting mixture is filtered to obtain, after being dried, 14.7 g (Rd. 88%) of a white solid corresponding to obetolic acid. The purity of the product was analyzed by HPLC to obtain 99.58%. Figure 1 shows the XRPD of the product obtained and Figure 2 shows its DSC.

Claims (36)

1. Compound of formula (I):

or a geometric isomer thereof. 2. Use of a compound of formula (I) or a geometric isomer thereof in a process of preparing obetolic acid of formula (IV)

(IV). 3. Use according to claim 2, wherein the process for preparing obetolic acid comprises the following steps: (a) treating the compound of formula (I) or a geometric isomer thereof with a base and hydrogen and in the presence of a catalyst, to give a salt of the compound of formula (II)

(b) treating the salt of the compound of formula (II) with sodium borohydride to give a salt of the compound of formula (III)

(c) optionally treating the salt of the compound of formula (III) with an acid at a pH of 4 to 6 to give the compound of formula (III); Y (d) treating the salt of the compound of formula (III) or the compound of formula (III) with an acid at a pH of 0 to 3 to give the obetolic acid of formula (IV)

(IV). 4. Use according to claim 3, wherein the base of step (a) is sodium hydroxide. 5. Use according to any of claims 3 to 4, wherein in step (a) between 1.5 and 2.5 moles of base are used with respect to each mole of compound of formula (I) or a geometric isomer of the same. 6. Use according to claim 5, wherein in step (a) between 1.9 and 2.1 moles of base are used with respect to each mole of compound of formula (I) or a geometric isomer thereof. 7. Use according to any of claims 3 to 6, wherein step (a) is carried out in the presence of a catalyst selected from the group consisting of palladium on carbon, palladium on calcium carbonate and platinum oxide. 8. Use according to claim 7, wherein the catalyst of step (a) is palladium on carbon. 9. Use according to any of claims 3 to 8, wherein step (a) is carried out at a temperature between 35 ° C and 45 ° C. 10. Use according to any of claims 3 to 9, wherein step (a) is carried out at a pressure between 4.5 and 5.5 bar. 11. Use according to any of claims 3 to 10, wherein step (a) is carried out in the presence of a solvent selected from a C1-C3 alcohol. 12. Use according to claim 11 wherein the C1-C3 alcohol is methanol. 13. Use according to any of claims 11 or 12, wherein between 5 and 15 ml of C1-C3 alcohol are used for each gram of compound of formula (I) or a geometric isomer thereof. 14. Use according to any of claims 3 to 13, wherein step (b) is carried out in the presence of a solvent selected from the group consisting of C1-C3 alcohol, water and mixtures thereof. 15. Use according to claim 14 the solvent is a mixture of methanol and water. 16. Use according to claim 15, wherein the solvent is a mixture of methanol and water with a ratio of between 4 and 6 volumes of methanol per volume of water. 17. Use according to any of claims 14 to 16, wherein between 3.5 and 4.5 ml of solvent is used for each mmol of salt of the compound of formula (II). 18. Use according to any of claims 3 to 17, wherein between 2 and 3.5 moles of sodium borohydride is used with respect to each mole of salt of compound of formula (II). 19. Use according to any of claims 3 to 18, wherein step (b) is carried out at a temperature between 70 ° C and 90 ° C. 20. Use according to any of claims 3 to 19, wherein step (c) is performed. 21. Use according to any of claims 3 to 20, wherein the acid used in step (d) is hydrochloric acid. 22. Use according to any of claims 3 to 21, wherein step (d) is carried out in the presence of a solvent selected from the group consisting of C1-C4 alkyl acetates, ketones, cyclic or linear ethers, acetonitrile and water and mixtures thereof. 23. Use according to claim 22, wherein the solvent is a mixture of acetone and water. 24. Use according to any of claims 3 to 23, wherein step (d) is carried out at a temperature between 15 ° C and 35 ° C. 25. Method of preparing a compound of formula (I) or a geometric isomer thereof which comprises treating a compound of formula (V) or a geometric isomer thereof with 2,3-dihydropyran in the presence of an acid

26. A process according to claim 25, wherein the acid is camforsulfonic acid. 27. A method according to any of claims 25 or 26, wherein between 0.04 and 0.06 moles of acid are used with respect to each mole of compound of formula (V) or a geometric isomer thereof. 28. A method according to any one of claims 25 to 27, wherein between 1 and 3 moles of 2,3-dihydropyran are used with respect to each mole of compound of formula (V) or a geometric isomer thereof. 29. The method according to any of claims 25 to 28, wherein the treatment of the compound of formula (I) or a geometric isomer thereof is carried out in the presence of a solvent selected from the group consisting of dichloromethane, tetrahydrofuran and mixtures thereof. . 30. A process according to claim 29, wherein the solvent is dichloromethane. 31. A method according to any of claims 29 or 30, wherein between 5 and 15 ml of solvent is used with respect to each gram of compound of formula (V) or a geometric isomer thereof. 32. A method according to any one of claims 25 to 31, wherein the treatment of the compound of formula (I) or a geometric isomer thereof is carried out at a temperature between 15 ° C and 35 ° C. 33. A process according to any of claims 25 to 32, wherein the compound of formula (V) or a geometric isomer thereof is obtained by treating a compound of formula (VI) with acetaldehyde in the presence of borodiethyl ether trifluoride

(SAW). 34. A process according to claim 33, wherein the compound of formula (VI) is obtained by treating a compound of formula (VII) with trimethylsilyl chlorotrimethylsilane or trifluoromethanesulfonate in the presence of a base

(VII). 35. A method according to claim 34, wherein the compound of formula (VII) is obtained by treating a compound of formula (VIII) with benzyl bromide in the presence of a base

(VIII). 36. A process according to claim 35, wherein the compound of formula (VIII) is obtained by treating a compound of formula (IX) with sodium bromide and sodium hypochlorite

(IX).