3alpha-tetrahydropyranyloxy-6alpha-ethyl-7alpha-hydroxy-5ß-cholanic acid diethylamine salt (Machine-

专利摘要:
3α-tetrahydropyranyloxy-6α-ethyl-7α-hydroxy-5β-cholanic acid diethylamine salt. The present invention relates to the diethylamine salt of 3α-tetrahydropyranyloxy-6α-ethyl-7α-hydroxy-5β-cholanic acid, which is a new intermediate in the synthesis of obeticholic acid, with the use of said diethylamine salt in the synthesis of said obeticholic acid, as well as the procedure for obtaining this new salt. (Machine-translation by Google Translate, not legally binding)
公开号:ES2779985A1
申请号:ES201930143
申请日:2019-02-20
公开日:2020-08-21
发明作者:Martinez María Del Carmen Bernabeu；Alonso Oscar Jimenez；Rodriguez Alicia Dobarro
申请人:Moehs Iberica SL；
IPC主号:

专利说明:

[0002] 3a-Tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt
[0004] Field of the invention
[0006] The present invention relates to the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (compound of formula (I)), which is a new intermediate in the synthesis of obeticholic acid. The present invention also relates to the use of said salt in the synthesis of obeticholic acid, as well as to the procedure for obtaining this new salt.
[0008] Background of the invention
[0010] Obeticholic acid (OCA) or 3a, 7a-dihydroxy-6a-ethyl-5p-cholan-24-oic acid or compound of formula (II) in the present invention, is a 6a-ethylated derivative of chenodeoxycholic bile acid (CDCA) . The chemical structure of obeticholic acid is shown below.
[0015] Obeticholic acid is a farnesoid X receptor (FXR) ligand, which is used in the treatment of primary biliary cholangitis and is under development for the treatment of other liver diseases.
[0017] Obeticholic acid (compound of formula (II)) and its synthesis procedure is disclosed in WO 02/072598 A1. The synthetic route comprises: protecting the hydroxyl group in position C3 of 3a-hydroxy-7-keto-5p-cholan-24-oic acid (IX) with a tetrahydropyranyl group to give 3a-tetrahydroprianyloxy-7-keto-5p- acid cholan-24-oico (XI), alkylation of the carbon in position C6 and esterification of the carboxylic group with bromide ethyl and deprotection of the tetrahydropyranyl group to give ethyl 3a-hydroxy-6a-ethyl-7-keto-5p-cholan-24-oate (XII), reduction of the ketone group at position C7 to hydroxyl with sodium borohydride to give 3a, 7a ethyl-dihydroxy-6a-ethyl-5p-cholan-24-oate (XIII) and, finally, deprotection of the ester group to yield obeticholic acid (II).
[0019]
[0022] The problem with this synthetic route is, on the one hand, the low yield (3%) and, on the other hand, that it involves multiple purification stages by column chromatography, which makes it difficult to implement on an industrial scale.
[0024] Zampella et al. [J. Med. Chem., 2012, 55, 84-93] disclose another route of synthesis of obeticholic acid that comprises the oxidation of chenodeoxycholic acid (compound of formula (X) or CDCA) with a solution of sodium hypochlorite / NaBr and tetrabutylammonium bromide in a mixture of methanol / acetic acid / water / ethyl acetate as solvent, followed by benzylation of the carboxylic acid at the C24 position to give the benzyl ester of 7-ketolitocholic acid (XIV). The silylene ether (XV) is then generated followed by aldol addition with acetaldehyde in the presence of BF3-OEt2 to give benzyl 3a-hydroxy-6a-ethylinden-7-keto-5p-cholan-24-oate. They then carry out the selective reduction of the ketone in position C7 with NaBH4 / CeCh 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 obeticholic acid (II).
[0026]
[0029] The yield of this synthetic route is 32%. Despite improved performance, this synthetic route still involves several purification steps by column chromatography, so it is not suitable for industrial implementation.
[0030] Document US 8,338,628 B2 discloses a process for obtaining obeticholic acid that comprises the steps of oxidizing the hydroxyl in position C7 of CDCA (compound of formula (X)) to a ketone group with pyridinium chlorochromate giving compound (IX), protection of the hydroxyl in position C3 with a tetrahydropyranyl group (yielding compound (XI)), alkylation of the carbon in position C6 with ethyl iodide and deprotection of the tetrahydropyranyl group (yielding compound (XVIII)) and, finally, reduction of the ketone group in C7 position to hydroxyl with sodium borohydride to give obeticholic acid (II), as shown in the scheme below.
[0031] However, this synthetic route also includes several purification steps by column chromatography, so it is not suitable for industrial implementation.
[0033] Document CN 107400154 A discloses the synthesis procedure shown in the scheme below to obtain obeticholic acid, where R is Ci Ca alkyl:
[0035] to
[0036]
[0038] Similar to the above procedure, CN 106589039 A also discloses a procedure for the synthesis of obeticholic acid wherein intermediates having a methyl ester as a carboxylic acid protecting group and / or a tetrahydropyranyl (THP), as a hydroxyl protecting group in position C3.
[0040]
[0043] In the synthetic processes 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 industrially.
[0045] Document CN 107955058 A discloses a process for the synthesis of obeticholic acid that comprises the steps shown in the scheme below, said process comprising a series of steps for obtaining the precursor of formula (Ia). Deprotection of the tetrahydropyranyl group in the precursor of formula (Ia) yields obeticholic acid.
[0046]
[0048] The procedure described in CN 107955058 A mentions the possibility of purifying the compound of formula (V) by formation of an amine salt, in particular of cyclohexylamine, diisopropylamine, or triethylamine. The formation of salts would represent an advantage in terms of the purification of intermediates in processes on an industrial scale. However, in a similar way to the previous processes, in the process described in CN 107955058 A the intermediates obtained in each of the stages are also isolated, which is a disadvantage to carry out the process in an industrial way.
[0050] Therefore, in the state of the art there is a need for alternative procedures for the synthesis of obeticholic acid that present improvements over those already existing, for example improvements in terms of yield, purity, the number of independent steps that involve isolating the intermediates obtained and / or the purity of the obeticholic acid.
[0052] Summary of the invention
[0054] The inventors have discovered a new salt of a synthetic intermediate of obeticholic acid, the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5pcholanic acid, which is obtainable in higher yield and / or purity and / or has greater stability in relation to other salts of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid, relevant in the manufacture of pharmaceutical products. Another advantageous characteristic of the 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt is that, if you want to further increase the purity level of the 3-tetrahydropyranyloxy-6a-ethyl acid salt 7a-hydroxy-5p-cholanic acid, the diethylamine salt of said acid is easily purifiable by recrystallization. Furthermore, the use of the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid makes it possible to obtain obeticholic acid with high yields and levels of purity. Reaching this intermediate salt with high purity allows obeticholic acid to be obtained with the desired purity. Another advantage associated with the new 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt of the present invention is that it can be obtained from 3a-hydroxy-6a-ethylidene-7- acid. keto-5p-cholanic (the compound of formula (V)) 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 steps that involve isolating the intermediates obtained as well as the corresponding purification steps, achieving good yields and high purity.
[0056] Therefore, in a first aspect, the present invention relates to the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid of formula (I).
[0059] In a second aspect, the present invention relates to the use of the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid of formula (I) in a process for preparing obeticholic acid of formula (II), in particular wherein the process for preparing obeticholic acid comprises treating the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid of formula (I) with an acid at a pH of between 0 and 3 to give the obeticholic acid of formula (II).
[0064] In a third aspect, the present invention relates to a process for the preparation of the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5-pcholanic acid of formula (I) that comprises treating 3a-tetrahydropyranyloxy-6a acid -ethyl-7ahydroxy-5p-cholanic of formula (Ia) with diethylamine.
[0067] Description of the drawings
[0069] Figure 1 shows the X-ray powder diffractogram (XRPD) of the diethylamine salt of formula (I) obtained in Example 7.
[0071] Figure 2 shows the differential scanning calorimetry (DSC) diagram of the diethylamine salt of formula (I) obtained in example 7.
[0073] Figure 3 shows the X-ray powder diffractogram (XRPD) of the obeticholic acid of formula (II) obtained in Example 8.
[0075] Figure 4 shows the differential scanning calorimetry (DSC) diagram of the obeticholic acid of formula (II) obtained in example 8.
[0077] Figure 5 shows the differential scanning calorimetry (DSC) diagram of the trometamol salt obtained in Comparative Example 9.2.
[0079] Figure 6 shows the differential scanning calorimetry (DSC) diagram of the glycine salt obtained in Comparative Example 9.3.
[0081] Figure 7 shows the differential scanning calorimetry (DSC) diagram of the taurine salt obtained in comparative example 9.4.
[0083] Figure 8 shows the differential scanning calorimetry (DSC) diagram of the triethylamine salt obtained in Comparative Example 9.5.
[0084] Detailed description of the invention
[0086] Diethylamine salt of formula (I).
[0088] The present invention relates to amine salts of 3a-tetrahydropyranyloxy-6aethyl-7a-hydroxy-5p-cholanic acid, in particular with the diethylamine salt of 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid of formula ( I).
[0090] The first aspect of the present invention relates to the 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt of formula (I).
[0095] In the context of the present invention, the term "salt" is to be understood to mean any form of an acid that assumes an ionic form or is charged (an anion), such as a carboxylic acid or carboxylate anion, and is coupled with a counterion (a cation), such as diethylamine (diethylammonium), triethylamine (triethylammonium), ammonium (NH4 +), sodium (Na +), potassium (K +) cation, among others. "Amine salts" refer to salts wherein the cation comes from a primary amine (+ NH2R), from a secondary amine (+ NHRR ') or from a tertiary amine (+ NRR'R' ').
[0097] In a preferred embodiment, diethylamine and 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid are in an approximate molar ratio of 1: 1, that is, for every mole of diethylamine present in the salt there is one mole of 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid.
[0098] In a preferred embodiment, the 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid diethylamine salt of formula (I) is in solid form.
[0100] In another preferred embodiment, the 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid diethylamine salt of formula (I) of the present invention is characterized by presenting a differential scanning calorimetry (DSC) diagram comprising a endothermic peak presenting a threshold temperature of approximately 202 ° C ± 0.3 ° C, in particular, the diethylamine salt of formula (I) exhibits a differential scanning calorimetry diagram substantially as shown in Figure 2. In In particular, the diethylamine salt of formula (I) of the present invention is characterized by presenting a differential scanning calorimetry diagram comprising an endothermic peak between 170 and 270 ° C. In particular, the diethylamine salt of formula (I) of the present invention is characterized by presenting a differential scanning calorimetry diagram comprising an endothermic peak with a peak temperature between 220 and 230 ° C. The differential scanning calorimetry diagram can be obtained as described in the examples.
[0102] The “threshold temperature” or “T onset” refers to the temperature resulting from extrapolating the baseline before the start of the transition and the baseline during energy absorption (tangent to the energy absorption curve (peak) at the inflection point). It can be calculated as defined in DIN EN ISO 11357-1: 2016 (E).
[0104] The "peak temperature" refers to the temperature where there is a greater distance between the curve of the peak to which it refers and the baseline resulting from extrapolating the baseline before the start of the transition.
[0106] In another preferred embodiment, the 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid diethylamine salt of formula (I) of the present invention is characterized by being in a crystalline form whose powder X-ray diffractogram shows peaks a 5.5, 7.8, 10.1, 11.1, 12.1, 12.8, 13.2, 14.2, 16.4, 16.7, 17.9, 20.3, 20 , 5, 22.1 and 23.3 ° 20 ± 0.2 ° 20. In particular, the 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt of formula (I) of the present invention exhibits an X-ray powder diffractogram substantially as shown in Figure 1. X-ray diffractograms can be recorded using a powder diffraction system with a copper anode emitting CuKa radiation with a wavelength of 1.54 A, in particular, following the method described in the examples.
[0107] Use of the diethylamine salt of formula (I) to obtain obeticholic acid
[0109] The present invention also relates to the use of the amine salts of 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid defined above in a process for the preparation of obeticholic acid, in particular where the amine salt is the diethylamine salt of formula (I).
[0111] The second aspect of the present invention relates to the use of the diethylamine salt of formula (I) in a process for preparing obeticholic acid, preferably where the process for preparing obeticholic acid comprises treating the diethylamine salt of formula ( I) with an acid at a pH of 0 to 3 to give the obeticholic acid of formula (II)
[0116] It is part of the usual routine of those skilled in the art to determine the pH value, for example by using a pH meter.
[0118] Obtaining obeticholic acid (compound of formula (II)) by deprotection of the tetrahydropyranyl group in the diethylamine salt of formula (I) comprises treating the diethylamine salt of formula (I) with an acid at a pH of 0 to 3.
[0120] Any suitable acid can be used for the deprotection of hydroxyl groups protected with a tetrahydropyranyl group.
[0122] Examples of suitable acids are hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid, among others. Preferably the acid is hydrochloric acid.
[0123] In particular, between 2 and 4 moles of acid is used for each mole of diethylamine salt of formula (I), more preferably between 2 and 3 moles, more preferably between 2 and 2.5 moles, even more preferably about 2.25 moles.
[0125] In a preferred embodiment, the acid treatment is carried out in the presence of a solvent selected from the group consisting of C1-C4 alcohols, ketones, C1-C4 alkyl acetates, cyclic or linear ethers, acetonitrile, water, and mixtures thereof. Examples of C1-C4 alcohols are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol and tert-butanol, preferably methanol. Examples of ketones are acetone and methyl / so-butyl ketone. Examples of C1-C4 alkyl acetates are ethyl acetate, n-butyl acetate, and tere-butyl acetate. Examples of cyclic or linear ethers are diethyl ether, tetrahydrofuran, and dioxane. In a more preferred embodiment the solvent is a mixture of methanol and water. Preferably, between 5 and 15 ml of methanol is used for each gram of diethylamine salt of formula (I), more preferably between 8 and 12 ml, still more preferably about 10 ml.
[0127] In another preferred embodiment, the acid treatment is carried out 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.
[0129] In a particular embodiment, the acid treatment lasts between 6 and 10 hours, preferably between 7 and 9 hours, more preferably approximately 8 hours.
[0131] After treatment with acid, obeticholic acid of formula (II) is obtained, except in the case of having used a C1-C4 alcohol as solvent (such as methanol), in which case the corresponding ester of obeticholic acid and the C1-C4 alcohol used (for example obeticholic acid methyl ester). Obeticholic acid can be isolated by standard procedures known to those skilled in the art.
[0133] In a particular embodiment, to isolate the obeticholic acid obtained after the acid treatment, the resulting mixture is basified, preferably to a pH of at least 11, preferably a pH of approximately 12. This step is essential in case of having used as a solvent in the acid treatment of the diethylamine salt (I) a C1-C4 alcohol (for example methanol), to hydrolyze the corresponding ester (for example the methyl ester of obeticholic acid). Any suitable base can be used to achieve the diethylamine in free base form, optionally hydrolyze the ester (if a C1-C4 alcohol, preferably methanol, has been used as solvent in treating the diethylamine salt (I) with acid) and form a salt between the cation of the base and anion of the carboxylate. In particular, it can be treated with a basic aqueous solution of sodium hydroxide or potassium hydroxide, preferably an aqueous solution of sodium hydroxide. In particular, this base treatment is carried out at a temperature between 15 ° C and 60 ° C, more preferably between 30 ° C and 60 ° C, more preferably between 45 ° C and 55 ° C. In a particular embodiment, this base treatment lasts for between 2 and 8 hours, preferably between 4 and 6 hours, more preferably approximately 5 hours. After this basic treatment, at least 70% of the volume of the solvent present in the medium can be removed, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least the 90%, even more preferably at least 95%. This solvent includes the free diethylamine that has formed after the addition of the base, so that the removal of the solvent also involves the removal of the free diethylamine from the mixture obtained. The removal of the solvent (including free diethylamine) is preferably carried out by distillation, in particular by distillation at a temperature below 40 ° C, more preferably around 35 ° C. In particular, said distillation is carried out under reduced pressure, that is, at a pressure lower than 1 atm and capable of removing the solvent at the lower temperature of 40 ° C or 35 ° C. This pressure is easily determined by the person skilled in the art. After removal of the solvent, the mixture obtained, which comprises obeticholic acid in the form of a salt, is acidified. Any suitable acid can be used to form the free obeticholic acid, such as the acids described above, such as hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid and methanesulfonic acid, among others, preferably the acid is hydrochloric acid. . In particular, it can be treated with an acid at a pH less than or equal to 2, more preferably at a pH less than or equal to 1. In particular, it can be treated with an aqueous solution of hydrochloric acid. The treatment can be carried out 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. Preferably the product obtained is isolated by filtration.
[0135] Preparation process of the diethylamine salt of formula ( I)
[0137] The present invention also relates to a process for the preparation of the amine salts of defined 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid above, in particular of the diethylamine salt of formula (I), which comprises treating 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) with the corresponding amine.
[0139] In a third aspect, the present invention relates to a process for the preparation of the diethylamine salt of formula (I) that comprises treating 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) with diethylamine.
[0144] In a preferred embodiment, the treatment of 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid (la) with diethylamine is carried out in the presence of a solvent selected from the group consisting of C1-C4 alkyl acetates, C1- C4, ketones, water, and mixtures thereof, preferably ethyl acetate. Examples of such solvents have been defined above. It is part of the standard practice of those skilled in the art to determine the amount of solvent suitable for the reaction. In particular, a volume of solvent is used in which the 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) is in solution. In a particular embodiment, at least 2 ml of solvent is used for each mmol of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la), preferably between 2 and 3 ml of solvent for each mmol of acid. (the).
[0146] In a particular embodiment, the treatment of 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid (la) with diethylamine is carried out at a temperature between 15 ° C and 80 ° C, more preferably between 20 ° C and 70 ° C, more preferably between 15 ° C and 40 ° C, more preferably between 25 ° C and 45 ° C.
[0148] In a particular embodiment, the treatment of 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid (la) with diethylamine is maintained for 0.5 to 20 hours, preferably between 1 and 10 hours.
[0149] In a particular embodiment, the diethylamine salt of formula (I) obtained is subjected to a purification step, preferably recrystallization. A suitable solvent for recrystallization would be ethyl acetate, preferably 4 ml of ethyl acetate with respect to each gram of diethylamine salt of formula (I).
[0151] 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) and its production process have been described in the state of the art, as for example in documents CN 107400154 A, CN 106589039 A and CN 107955058 A. In the present invention, preferably 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) is obtained by a process comprising:
[0152] (a) treating a compound of formula (111) or a salt thereof with a reducing agent to give 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid or a salt thereof
[0157] (III); and
[0158] (b) optionally treating the 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid salt (Ia) with an acid at a pH of 4 to 6 to give 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy acid -5p-cholanic (Ia);
[0159] wherein the salt of the compound of formula (III) and the 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid salt (Ia) are not diethylamine salts.
[0161] Preferably in step (a) a salt of the compound of formula (III) is treated. The salt of the compound of formula (III) is formed by the carboxylic acid anion (carboxylate) and a cation. In a particular embodiment, the cation is selected from the group consisting of Na +, K + and NH4 +, preferably Na +. In this procedure, the cation of the salt of the compound of formula (III) is not a diethylammonium cation, that is, the salt of the compound of formula (III) is not a diethylamine salt.
[0162] The 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) salt is formed by the carboxylic acid anion of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) and a cation. In a particular embodiment, the cation is selected from the group consisting of Na +, K + and NH4 +, preferably Na +. In this process, the acid salt cation (la) is not a diethylammonium cation, that is, the 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5p-cholanic acid salt is not a diethylamine salt.
[0164] In step (a) the ketone group in position C7 is reduced to a hydroxyl group to give 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) or a salt thereof. Suitable reducing agents for this step are those capable of reducing a ketone to hydroxyl, such as, for example, sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, BH3- (CH3) 2S and cerium trichloride among others, preferably borohydride sodium.
[0166] It is particularly advantageous and preferred to carry out step (a) by treating a salt of the compound of formula (111) with sodium borohydride to give a salt of 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la).
[0168] In a preferred embodiment, step (a) is carried out 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, between 2 and 10 ml of methanol is used for each mmol of compound of formula (IV) or a geometric isomer thereof, more preferably between 3.5 and 6 ml.
[0170] In a preferred embodiment, between 1 and 1.5 moles of reducing agent, preferably sodium borohydride, is used with respect to each mole of salt of compound of formula (II), preferably between 1 and 1.2 moles, more preferably between 1 and 1.1 moles.
[0172] In a preferred embodiment, step (a) is carried out at a temperature between 20 ° C and 60 ° C, preferably between 25 ° C and 50 ° C, more preferably between 30 ° C and 45 ° C, even more preferably between 35 ° C and 45 ° C, even more preferably at about 40 ° 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 approximately 3 hours.
[0173] In a particular embodiment, when the reducing agent in step (a) is sodium borohydride, a solution of sodium hydroxide in water is also added, preferably between 4 and 6 moles of sodium hydroxide are added with respect to each mole of sodium borohydride, preferably between 4 and 5 moles.
[0175] After step (a), the optional step (b) of treating the 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid salt (la) is carried out with an acid at a pH of 4 to 6 to give the 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (free). This stage (b) is carried out when after stage (a) a salt of the acid (la) has been obtained.
[0177] Examples of suitable acids for step (b) are phosphoric acid, hydrochloric acid, acetic acid, sulfurous acid and oxalic acid. Preferably the acid used in step (b) is phosphoric acid, more preferably aqueous solution of the acid, in particular aqueous solution of phosphoric acid.
[0179] In a particular embodiment, the acid treatment of step (b) is carried out at a pH of 4.5 to 5.5, more preferably approximately 5. It is part of the usual routine of those skilled in the art to determine the value of pH, for example by using a pH meter.
[0181] The compound of formula (111) and its procedure for obtaining it have been described in the state of the art, as for example in documents CN 107400154 A, CN 106589039 A and CN 107955058 A. In the present invention, preferably the compound of formula (111) or a salt thereof is obtained by a process comprising:
[0182] (a) treating compound of formula (IV) 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 (111)
[0183] (IV), and
[0184] (b) optionally treating the salt of the compound of formula (111) with an acid at a pH of 4 to 6 to give the compound of formula (III).
[0186] Preferably a salt of the compound of formula (III) is obtained. In this case, step (b) is not performed. As described above, the salt of the compound of formula (III) is formed by the carboxylic acid anion (carboxylate) and a cation. In a particular embodiment, the cation is selected from the group consisting of Na +, K + and NH4 +, preferably Na +. Said cation is not a diethylammonium cation, that is, the salt of the compound of formula (III) is not a diethylamine salt.
[0188] In this preferred embodiment, the exocyclic double bond in position C6 of a compound of formula (IV) or a geometric isomer thereof is reduced and said carbon in position C6 is epimerized to the alpha (a) form, thus obtaining a salt of the compound of formula (III). These transformations are achieved by treating the compound of formula (IV) or a geometric isomer thereof with a base and hydrogen and in the presence of a catalyst.
[0190] The term "geometric isomer" refers to stereoisomers that differ only in the position of the substituents attached to a double bond, in the present case, the exocyclic double bond of the compounds of formula (IV). Possible geometric isomers are cis (E) and the trans (Z).
[0195] In the present invention, the compound of formula (IV) can be the Z isomer, the E isomer or a mixture of said isomers. Preferably it is the E isomer.
[0197] Examples of suitable bases for hydrogen treatment are sodium hydroxide, potassium hydroxide, ammonia, among others, preferably sodium hydroxide. Preferably the base is mixed with water, more preferably the base is an aqueous solution, in particular an aqueous solution of sodium hydroxide.
[0199] In a preferred embodiment, between 1.5 and 2.5 moles of base (preferably sodium hydroxide) are used with respect to each mole of compound of formula (IV) 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.
[0201] In another preferred embodiment, the catalyst is selected from the group consisting of palladium on carbon, palladium on calcium carbonate, and platinum oxide, preferably the catalyst is palladium on carbon.
[0203] In a preferred embodiment, the hydrogen treatment of 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 .
[0204] In another preferred embodiment, the hydrogen treatment of step (a) is carried out 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 bars, even more preferably between 4.8 and 5.0 bars, most preferably about 5 bars.
[0206] 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 approximately 5 hours.
[0208] In a preferred embodiment, the hydrogen treatment of step (a) is carried out in the presence of a solvent selected from a C1-C3 alcohol. Said solvent can also contain mixtures with water, in particular when the base used is in the form of an aqueous solution. Examples of C1-C3 alcohols are methanol, ethanol, n-propanol and isopropanol, preferably methanol. In a preferred embodiment, between 2 and 10 ml of C1-C3 alcohol are used for each mmol of compound of formula (IV) or a geometric isomer thereof, more preferably between 2 and 5 ml, still more between 3 and 4 ml.
[0210] In particular, this hydrogen treatment step of step (a) is carried out by first adding the base and the solvent to the compound of formula (IV) or a geometric isomer thereof, the resulting mixture is treated with active carbon and subsequently filtered the resulting mixture by any conventional method known to the person skilled in the art, for example, by means of a filter with diatomaceous earth, and then the hydrogen is added.
[0212] 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 those skilled in the art, for example, by means of a diatomaceous earth filter. After this procedure, the compound of formula (III) is obtained in the form of a salt. In case the compound of formula (III) is needed in free acid form, the salt obtained from the compound of formula (III) can be treated with an acid at pH 4 to 6, that is to say, the step ( b).
[0214] Examples of suitable acids for this treatment of step (b) are phosphoric acid, hydrochloric acid, acetic acid, sulfurous acid and oxalic acid. Preferably the acid used in step (b) is phosphoric acid, more preferably aqueous solution of the acid, in particular aqueous solution of phosphoric acid.
[0215] In a particular embodiment, this acid treatment of step (b) is carried out at a pH of 4.5 to 5.5, more preferably approximately 5. It is part of the usual routine of those skilled in the art to determine the value of pH, for example by using a pH meter.
[0217] The compound of formula (IV) and its procedure for obtaining it have been described in the state of the art, as for example in documents CN 107400154 A and CN 107955058 A. In the present invention, preferably the compound of formula (IV) or a geometric isomer thereof is obtained by treating a compound of formula (V) or a geometric isomer thereof with 3,4-dihydro-2H-pyran in the presence of an acid.
[0222] As defined with respect to the compound of formula (IV), geometric isomers refer to stereoisomers that differ only in the position of the substituents attached to a double bond, in the present case, the exocyclic double bond of the compound of formula ( V). Possible geometric isomers are cis (Z) and trans (E).
[0227] In the present invention, the compound of formula (V) can be the Z isomer, the E isomer or a mixture of said isomers. Preferably it is the E isomer.
[0228] Any suitable acid can be used for the protection of hydroxyl groups by formation of the tetrahydropyranyl ether, such as camphorsulfonic acid and ptoluenesulfonic acid, among others. Preferably the acid is camphorsulfonic acid, more preferably (1S) - (+) - 10-camphorsulfonic acid.
[0230] 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.
[0232] In another preferred embodiment, between 1 and 2 moles of 3,4-dihydro-2H-pyran are used with respect to each mole of compound of formula (V) or a geometric isomer thereof, preferably between 1 and 2 moles, most preferred about 1.5 moles.
[0234] In another preferred embodiment, the treatment of the compound of formula (V) or a geometric isomer thereof with 3,4-dihydro-2H-pyran is carried out in the presence of a solvent selected from the group consisting of dichloromethane, tetrahydrofuran and mixtures of the themselves, preferably dichloromethane. 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.
[0236] In another preferred embodiment, the treatment of the compound of formula (V) or a geometric isomer thereof with 3,4-dihydro-2H-pyran is carried out at a temperature between 15 ° C and 35 ° C, preferably between 20 ° C and 25 ° C.
[0238] In a particular embodiment, the treatment of the compound of formula (V) or a geometric isomer thereof with 3,4-dihydro-2H-pyran has a duration of between 1.5 and 10 hours, preferably between 1.5 and 3 hours , more preferably about 2 hours.
[0240] In another particular embodiment, said treatment is carried out in an inert atmosphere, for example under a nitrogen or argon atmosphere.
[0242] In another particular embodiment, after the treatment of the compound of formula (V) or a geometric isomer thereof with 3,4-dihydro-2H-pyran, the pH is adjusted to approximately 9.5, for example by adding a suitable base , like 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 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 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.
[0244] In a preferred embodiment of the invention, the treatment of the compound of the compound of formula (V) or a geometric isomer thereof to give the amine salt of formula (I) is carried out one pot, that is, all reaction steps (i.e. treatment of the compound of formula (V) or a geometric isomer thereof with 3,4-dihydro-2H-pyran to give the compound of formula (IV) or a geometric isomer thereof, hydrogenation of said compound of formula (IV) or a geometric isomer thereof to give the salt of the compound of formula (111), treatment of said salt of formula (111) with sodium borohydride to give the 3a-tetrahydropyranyloxy-6a-ethyl acid salt 7a-hydroxy-5p-cholanic (la) and its subsequent treatment with acid to give 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) and, finally, the treatment of said acid (la) with diethylamine to give the diethylamine salt of formula (I)) are carried out in the same reaction vessel without the need for ability to isolate the intermediate products obtained. This embodiment is particularly advantageous for its implementation on an industrial scale and can further reduce the impurity content of the amine salt of formula (I).
[0246] The compound of formula (V) has been described in the state of the art, for example in documents CN 107400154 A and CN 107955058 A. In a preferred embodiment of the present invention, the compound of formula (V) or an isomer It is obtained by treating a compound of formula (VI) or a geometric isomer thereof in the presence of a base and a solvent selected from the group consisting of water, C rC 3 alcohol and a mixture thereof.
[0249] As defined with respect to the compound of formula (IV), geometric isomers refer to stereoisomers that differ only in the position of the substituents attached to a double bond, in the present case, the exocyclic double bond of the compound of formula ( SAW). Possible geometric isomers are cis ( Z) and trans (E).
[0254] In the present invention, the compound of formula (VI) can be the Z isomer, the E isomer or a mixture of said isomers. Preferably it is the E isomer.
[0256] This reaction step corresponds to the deprotection of the methyl ester (or saponification) of the compound of formula (VI) or a geometric isomer thereof. This reaction is widely known to those skilled in the art.
[0258] The base used in this step is any suitable base to carry out the deprotection of the methyl ester, such as for example sodium hydroxide or potassium hydroxide, among others, preferably sodium hydroxide. Preferably the base is mixed with water, more preferably the base is an aqueous solution, in particular an aqueous solution of sodium hydroxide.
[0260] In a preferred embodiment, between 0.5 and 2.5 moles of base (preferably sodium hydroxide) are used with respect to each mole of compound of formula (VI) or a geometric isomer thereof, preferably between 1 and 1.5 moles, more preferably between 1 and 1.1 moles.
[0262] In a preferred embodiment, the solvent used in this deprotection is a mixture of water and C1-C3 alcohol. Examples of C1-C3 alcohols are methanol, ethanol, n-propanol and isopropanol, preferably methanol. In a preferred embodiment, the solvent used in deprotection is a mixture of water and methanol, preferably a mixture of water and methanol in a volumetric ratio of 1: 1 to 1:10. When the base used is in the form of an aqueous solution, part or all of the water in the solvent described herein may come from said aqueous base solution.
[0264] In one embodiment said treatment of the compound of formula (VI) or a geometric isomer thereof is carried out at a temperature between 40 ° C and 60 ° C, more preferably between 45 ° C and 55 ° C, more preferably about 50 ° C.
[0266] In a particular embodiment, after treatment with base, the compound of formula (V) or a geometric isomer thereof can be isolated by removing the solvent from the reaction mixture, in particular by removing at least 70% of the volume of the solvent, preferably by removing less 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 capable of removing the solvent at a temperature below 40 ° C, this pressure is easily determined by the person skilled in the art). The residue obtained can be treated with acid, in particular with aqueous hydrochloric acid, preferably by adjusting the pH of the resulting mixture to approximately 3. In particular, after the acid treatment, one or more washes with an organic solvent, such as for example a C1-C4 alkyl ester, preferably ethyl acetate. Preferably, after the washings 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 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.
[0268] In a preferred embodiment, the compound of formula (VI) or a geometric isomer thereof is obtained by treating a compound of formula (VII) with acetaldehyde in the presence of boron trifluoride diethyl ether.
[0271] In a particular embodiment, between 1.5 and 5 moles of acetaldehyde are used with respect to each mole of compound of formula (VII), preferably between 2 and 4 moles, more preferably between 2.5 and 3.5 moles, even more preferably about 3 moles.
[0273] In another particular embodiment, between 1.5 and 5 moles of borodiethyl ether trifluoride are used with respect to each mole of compound of formula (VII), preferably between 2 and 4 moles, more preferably between 2.5 and 3.5 moles, even more preferably about 3 moles.
[0275] In another particular embodiment, the treatment of the compound of formula (VII) with acetaldehyde in the presence of boron trifluoride-diethyl ether is carried out in dichloromethane. Preferably, between 2 and 15 ml of solvent is used with respect to each gram of compound of formula (VII), more preferably between 7 and 15 ml.
[0277] In another particular embodiment, the treatment of the compound of formula (VII) with acetaldehyde in the presence of boron trifluoride-diethyl ether 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 of between 20 ° C and 25 ° C, in particular for 2 to 5 hours, preferably for about 3 hours.
[0279] In another particular embodiment, after treating the compound of formula (VII) with acetaldehyde in the presence of boron trifluoride-diethyl ether, one or more washes are carried out with an aqueous sodium bicarbonate solution. Preferably, after the washings 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 lower than 1 atm and which is capable of remove 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.
[0281] In a preferred embodiment, the compound of formula (VII) is obtained by treating a compound of formula (VIII) with chlorotrimethylsilane or trimethylsilyl trifluoromethanesulfonate in the presence of a base.
[0286] Suitable bases for this treatment are, for example, lithium diisopropylamide or mixtures of hexyl-lithium or n-butyllithium with diisopropylamine. Preferably, the compound of formula (VII) is obtained by treating a compound of formula (VIII) with chlorotrimethylsilane and lithium diisopropylamide. Preferably between 4 and 5 moles of chlorotrimethylsilane are used for each mole of compound of formula (VIII), 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 25 ml of solvent is used for each gram of compound of formula (VIII), more preferably between 15 and 25 ml. In particular, this treatment is carried out in an inert atmosphere (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 (VIII) with chlorotrimethylsilane or trimethylsilyl trifluoromethanesulfonate in the presence of a base and a solvent, one or more washes are carried out with an aqueous solution of citric acid. 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 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.
[0287] In a preferred embodiment, the compound formula (VIII) is obtained by treating a compound of formula (IX) with methanol in the presence of an acid.
[0292] This step corresponds to the protection of the carboxylic acid group of the compound of formula (IX) in the form of the methyl ester. This protection reaction is widely known to those skilled in the art.
[0294] Suitable acids for this treatment are any acid suitable for the protection of carboxylic acids by formation of the corresponding methyl ester. Preferably the acid is hydrochloric acid. Preferably between 0.5 and 3 moles of acid (preferably hydrochloric acid) are used for each mole of compound of formula (IX), more preferably between 1 and 2.5 moles, still more preferably between 2 and 2.5 moles.
[0296] In a particular embodiment, between 5 and 15 ml of methanol are used for each gram of compound of formula (IX), more preferably approximately 10 ml.
[0298] In particular this treatment is carried out for 1 to 5 hours, preferably for about 2 hours. In particular, the treatment is carried out at a temperature between 20 ° C and 25 ° C. In a particular embodiment, after treatment of the compound of formula (IX) with methanol in the presence of an acid, the pH is adjusted to approximately 7, for example, by adding a suitable base, such as sodium hydroxide, in particular aqueous solution of sodium hydroxide. Preferably, the compound of formula (VIII) is isolated by filtration.
[0300] The compound of formula (IX) and its procedure for obtaining it have been described in the state of the art, such as for example in documents WO 02/072598 A1, US 83386258 B2 and CN 107955058 A. In the present invention, preferably the compound Formula (IX) is obtained by treating a compound of formula (X) with sodium bromide and sodium hypochlorite.
[0303] 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 about 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.
[0305] The compound of formula (X) and its procedure for obtaining it have been described in the state of the art, for example in the documents Zampella et al. [J. Med. Chem., 2012, 55, 84-93], WO 02/072598 A1, US 83386258 B2 and CN 107955058 A.
[0307] In the context of the present invention, the terms "approximate", "approximate" and "approximately" refer to the value that characterizes ± 5% of said value.
[0309] In the context of the present invention, the term "acid" refers to a substance capable of donating a proton (to a base).
[0311] In the context of the present invention, the term "base" refers to a substance capable of accepting a proton (from an acid).
[0313] In order to facilitate the understanding of the foregoing ideas, some examples of the experimental procedures and embodiments of the present invention are described below. These examples are for illustrative purposes only.
[0314] Examples
[0316] Materials and methods
[0318] XRPD analysis was performed on a Siemens D-500 model X-ray powder diffractometer equipped with a Copper anode. Scan parameters: 4-50 degrees 20, continuous scan, ratio: 1,235 degrees / minute.
[0320] DSC analysis was performed on a Mettler Toledo 822e with STARe SW15.00 software. Parameters: heating range of 25 to 300 ° C, except for obeticholic acid where a heating range of 25 to 200 ° C is applied, with a ramp of 5 ° C / min and N2 flow of 50 ml / min . The measurement is made with a closed perforated capsule.
[0322] The purity of the products obtained was analyzed using the High Resolution Liquid Chromatography technique in a Waters Alliance apparatus, equipped with a refractive index detector and a thermostatted oven for the column. The experimental conditions for obtaining a chromatogram were: Kinetex C182.6 ^ m column (150 mm x 4.6 mm); mobile phase 0.1% aqueous solution of phosphoric acid: methanol: acetonitrile (30:30:40); flow: 1.2 ml / min in isocratic mode; column temperature: 40 ° C; injection volume 10 ^ L; solvent for the samples to be analyzed: water / methanol / acetonitrile (12:60:28); concentration: 1 mg / mL. Acquisition time: 45 min
[0324] Example 1. Obtaining 3a-hydroxy-7-keto-5p-collamic acid (compound of formula (IX))
[0326] 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 Ch / 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 was finished, the resulting mixture was heated to the approximate temperature of 25 ° C and 60 mL of a 5% aqueous sodium bisulfite solution were slowly charged. The obtained mixture was stirred for 30 minutes at the indicated temperature. I know 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 in an air oven to constant weight, yielding 191.4 g (Yield 76.9%) of 3a-hydroxy-7-keto-5p-cholanic acid (IX).
[0328] Example 2. Obtaining methyl 3a-hydroxy-7-keto-5p-cholanate (compound of formula (VIII))
[0330] 80 g (0.205 mmol) of 3a-hydroxy-7-keto-5p-cholanic acid (IX) were mixed with 800 mL of methanol. 38 mL (0.471 moles, 2.33 molar eq) of a 37% aqueous HCl solution were subsequently added to the resulting mixture, keeping the temperature between 20 and 25 ° C. The reaction mixture was kept for 2 hours at the mentioned temperature.
[0332] After the maintenance, an aqueous solution of 2N sodium hydroxide was slowly added to a pH value of approximately 7. 1000 mL of water were added at a temperature between 10 and 15 ° C, the mixture obtained was maintained for 30 minutes at the temperature mentioned and subsequently the precipitated solid is filtered to obtain 83.2 g (Yield.
[0333] 99.7%) of a white solid corresponding to methyl 3a-hydroxy-7-keto-5p-cholanate (VIII). The purity of the obtained product analyzed by HPLC is 99.0%.
[0335] Example 3. Obtaining methyl 3a, 7-trimethylsilyloxy-5p-cholan-6-enate (compound of formula (VII))
[0337] 600 mL of tetrahydrofuran were cooled to approximately -65 ° C under a nitrogen atmosphere and 556 mL of a 2M hexane solution of lithium isopropylamide (1.112 mol, 6 eq molar) were slowly added maintaining the indicated temperature. The mixture obtained was cooled to the temperature of approximately -72 ° C and 106 mL (0.834 mol, 4.5 eq molar) of TMSCl (chlorotrimethylsilane) were slowly added. On the mixture obtained, a previously prepared solution of 75 g (0.185 mol) of methyl 3a-hydroxy-7-keto-5p-cholanate (VIII) in 375 mL of tetrahydrofuran was subsequently added. The mixture was kept under stirring under a nitrogen atmosphere at a temperature of about -72 ° C. After the maintenance, 100 mL of a previously prepared solution of 42.739 g (390 mmol) of citric acid in 375 mL of water was slowly added without the temperature exceeding 5 ° C. After the addition was complete, the temperature of the mixture was allowed to reach 20 ° C and the organic phase was separated. The solvent was distilled off under vacuum until an oil residue corresponding to Methyl 3a, 7-trimethylsilyloxy-5p-cholan-6-enate (VII), which was used in the next synthesis step without further purification.
[0339] Example 4. Obtaining methyl 3a-hydroxy-6-ethylidene-7-keto-5p-cholanate (compound of formula (VI))
[0341] 101.5 g (185 mmol) of methyl 3a, 7-trimethylsilyloxy-5p-cholan-6-enate (VII) were dissolved in 914 mL of dichloromethane and the resulting solution was cooled to the temperature between -60 and -65 ° C . 24.45 g (555 mmol, 3 molar eq) of acetaldehyde and subsequently 78.77 g (555 mmol, 3 molar eq) of boron trifluoride-diethyl ether 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 the maintenance, the resulting reaction mixture was added to 1320 mL of an 8% by weight aqueous solution of NaHCO3 and the resulting mixture was kept under stirring for 30 minutes at a temperature between 25 and 30 ° C. The organic phase was separated and the solvent was distilled off by vacuum to obtain a dense oil containing 3a-hydroxy-6-ethylidene-7-keto-5p-methyl cholanate (VI), which was used in the next synthesis step without more purification.
[0343] Example 5. Obtaining 3a-hydroxy-6-ethylidene-7-keto-5p-cholanic acid (compound of formula (V))
[0345] 37.5 g (87 mmol) of 3a-hydroxy-6-ethylidene-7-keto-5p-methyl cholanate (VI) were dissolved in 53 mL of MeOH and 7.5 mL of H2O and 7.5 mL of 50% sodium hydroxide. The mixture thus obtained was heated to a temperature of approximately 50 ° C and was kept under stirring at said temperature for 2 hours.
[0347] Once the maintenance was finished, the reaction solvent was distilled off by vacuum and 150 mL of water were added to the resulting residue. The solution thus obtained was washed 3 times with 50 mL of t-Butylmethyl ether, discarding the organic phases obtained in each wash. A 2N aqueous solution of HCl was added until pH approximately 3. The aqueous phase was washed 3 times with 50 mL of ethyl acetate. The organic wash phases thus obtained were pooled and the solvent was distilled off under vacuum. Two successive series of loading of 100 mL of ethyl acetate and vacuum distillation were made. Finally, 35 ml of ethyl acetate were added to the residue obtained and the suspension obtained. it is filtered to yield after being dried in an air oven 16.53 g of 3a-hydroxy-6-ethylidene-7-keto-5p-cholanic acid (V) with a purity analyzed by HPLC of 95.52%.
[0349] Example 6. Obtaining 3a-tetrahydropyramloxy-6-ethiMden-7-keto-5p-collamic acid (compound of formula (IV))
[0351] 16.0 g (38.4 mmol) of 3a-hydroxy-6-ethylidene-7-keto-5p-cholanic acid (V) and 0.45 g (1.9 mmol, 0.05 molar eq) of acid ( 1S) - (+) - 10-camphorsulfonic acid were mixed with 160 mL of dichloromethane under nitrogen atmosphere to obtain a solution at a temperature between 20 and 25 ° C. Maintaining said temperature, 5.3 mL (57.6 mmol, 1.5 molar eq) of 3,4-dihydro-2H-pyran were added and the resulting reaction mixture was kept under stirring at the same temperature for 2 hours. After the maintenance was finished, the pH of the reaction mixture was adjusted to an approximate value of 9.5 by adding triethylamine at the temperature between 20 and 25 ° C. The resulting reaction mixture was concentrated by distilling off the solvent in vacuo and a very dense, practically colorless oil was obtained corresponding to 3a-tetrahydropyranyloxy-6-ethylidene-7-keto-5p-cholanic acid (IV). The purity of the product obtained analyzed by HPLC is 98.76%.
[0353] Example 7. Obtaining the diethylamine salt of 3a-tetrahydropyramloxy-6a-etN-7a-hydroxy-5p-cholanic acid (compound of formula (I))
[0355] The oil obtained in the previous example corresponding to 3a-tetrahydropyranyloxy-6-ethylidene-7-keto-5p-cholanic acid (IV) (38.4 mmol) was dissolved in 100 mL of methanol and 10.5 mL of an aqueous solution 30% (w / v) of sodium hydroxide (78.75 mmol, 2 molar eq). 0.95 g of activated carbon type 4S were charged and the resulting mixture was heated to a temperature of approximately 40 ° C, maintaining the mixture stirring for 30 minutes at said temperature. Subsequently the mixture was cooled to the temperature of about 25 ° C. The mixture was filtered through a diatomaceous earth filter and the filter was washed with two fractions of 15 mL of methanol each. The whole filtration and washing was introduced into a pressure reactor and 1.73 mg of Pd / C 5% were added. The reactor was pressurized with hydrogen to an internal pressure of 5 bar and the resulting reaction mixture was kept at the temperature of about 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 filter with diatomaceous earth, washing the filter with two fractions of 25 mL of methanol each. It was distilled by pressure reduced the reaction mass without exceeding the temperature of 40 ° C until obtaining a distillate volume of approximately 35 mL.
[0357] 13.3 mL of a 14 M basic solution of sodium hydroxide and 12% of NaBH4 (42.2 mmol of NaBH4, 1.1 molar eq) were slowly added to the obtained reaction mass at a temperature of approximately 40 ° C. The resulting reaction mixture was kept under stirring at reflux temperature for 3 hours (HPLC control of the reaction mass reveals the total conversion of the 3a-tetrahydropyranyloxy-6aethyl-7-keto-5p-cholanic acid product).
[0359] After the maintenance was finished, the reaction solvent was distilled under vacuum and without exceeding the temperature of 45 ° C. 40 mL of water and 40 mL of n-heptane mL were added to the mass obtained and the resulting mixture was heated under stirring to a temperature of approximately 45 ° C. Stirring was stopped, the mixture obtained was kept at rest and the resulting phases were separated. 40 mL of ethyl acetate were added to the aqueous phase obtained and an 85% aqueous solution of phosphoric acid was added until a final pH of the mixture of approximately 5. The mixture was allowed to stand and the phases thus obtained were separated. 40 mL of ethyl acetate were added to the aqueous phase and the resulting phases were separated. The two organic phases thus obtained were combined and mixed with a volume of diethylamine until a final pH of the mixture of approximately 8.5 was achieved. A volume of approximately 75 mL of ethyl acetate was distilled by vacuum and without exceeding the temperature of 45 ° C and two successive series of loading of 15 mL of ethyl acetate and vacuum distillation of approximately 15 mL of ethyl acetate were made. . Finally, 15 mL of ethyl acetate were added and the resulting mixture was slowly cooled to a temperature of approximately 0 ° C. The resulting mixture was kept at said temperature for 2 hours and the solid present was filtered and washed 2 times with 10 mL of ethyl acetate. The white solid thus obtained yielded after drying 17.8 g (80.2%) corresponding to the diethylamine salt of 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (I). The purity of the product was analyzed by HPLC to obtain 99.77%. Figure 1 shows the XRPD of the product obtained and Figure 2 shows its DSC.
[0361] If desired, the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5pcholanic acid (I) can be recrystallized from ethyl acetate (4 volumes of solvent relative to the total mass of salt to be recrystallized). A typical example of purification by Recrystallization enables the product to be obtained with a recrystallization yield of approximately 95% and a purity of the product analyzed by HPLC of 99.97%.
[0363] Table 1 shows the data related to the 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt (I) obtained from the 1H-NMR (DMSO-d6, 400 MHz) and 13C- experiments. NMR (DMSO-d6, 400 MHz). The chemical shifts were referenced to the DMSO-d6 signal (2.49 ppm for proton and 39.5 ppm for carbon).
[0368] Table 1
[0373] Example 8. Obeticholic acid (compound of formula (II)) obtained from the diethylamine salt of 3a-tetrahydropyramloxy-6a-etM-7a-hydroxy-5p-cholanic acid (compound of formula (I))
[0375] 46.2 g (79.9 mmol) of the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (I) were mixed with 462 mL of methanol. 90 mL (180 mmol, 2.25 molar eq) of a 2N aqueous solution of HCl were added, keeping the temperature between 20 and 25 ° C and the mixture thus obtained was kept under stirring at a temperature between 20 and 25 ° C for 8 hours.
[0377] After the maintenance was finished, the pH of the reaction mixture was adjusted to an approximate value of 12 by adding 100 mL of a 30% aqueous solution of sodium hydroxide. The mixture obtained was heated to a temperature of about 50 ° C and kept at that temperature for 5 hours.
[0379] After the maintenance, the solvent was removed by distillation under reduced pressure and water was added to an approximate total volume of 1 L. The mixture obtained was filtered and the filtered solution obtained was slowly added to a 12 N aqueous solution of HCl maintaining the temperature. between 20 and 25 ° C. The final pH resulting from the mixture was approximately 1.
[0381] The mixture obtained was left stirring at a temperature between 20 and 25 ° C for 15 minutes after the addition was completed. The resulting solid was filtered and dried in an air oven at the temperature of 50 ° C. 28.64 g (Yield 85.2%) of a white solid corresponding to obeticholic acid (II) were obtained in this way. The purity of the product was analyzed by HPLC to obtain 99.86%. Figure 3 shows the XRPD of the product obtained and Figure 4 shows its DSC.
[0383] Example 9. Obtaining the salt of different amines of 3a-tetrahydropyranyloxy-6a-etM-7a-hydroxy-5p-collamic acid
[0385] The 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) used in the experiments described below can be obtained following the methodology described in example 7 up to the point of the process in which a solution of 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) in ethyl acetate. On the resulting solution, n-heptane is added and it is slowly cooled to a temperature of approximately 20 ° C, observing the presence of a white solid. The solid can be filtered to isolate in this way the desired product with a purity analyzed by HPLC of 95.48%.
[0387] Recrystallization of the product carried out in 4 volumes of ethyl acetate makes it possible to obtain a product with a purity analyzed by HPLC of 97.04% and a yield of 63.0%.
[0389] Example 9.1. Obtaining the diethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7ahydroxy-5B-cholanic acid ( compound of formula ( I))
[0391] 5 g of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) (9.9 mmol) and 1.2 ml of diethylamine (11.88 mmol) were mixed with 25 ml of ethyl acetate at a temperature between 20 and 25 ° C. The mixture was heated to reflux temperature and was kept at that temperature for 30 minutes.
[0393] The resulting solution was slowly cooled to the temperature of 20 and 25 ° C and the mixture obtained was kept for 16 hours at said temperature. The resulting solid was filtered and dried in an air oven at a temperature of 50 ° C. 4.82 g (Yield.
[0394] 84.2%) of a white solid corresponding to the diethylamine salt of 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (I). The purity of the product was analyzed by HPLC to obtain 98.98%.
[0395] The diethylamine salt (I) is characterized by presenting a differential scanning calorimetry (DSC) diagram with an endothermic peak at a threshold temperature (“7 onset ') of approximately 202 ° C, as shown in Figure 2.
[0397] Comparative Example 9.2. Obtaining the trometamol salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5B-cholanic acid
[0399] 5 g of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) (9.9 mmol) and 1.2 g of trometamol (2-amino-2- (hydroxymethyl) -1,3- propanediol) (9.9 mmol) were mixed with 25 ml of methanol at a temperature between 20-25 ° C. The mixture was heated to reflux temperature and was kept at that temperature for 30 minutes.
[0401] The solvent was distilled off by vacuum and 25 ml of ethyl acetate were added to the resulting residue. The mixture was heated to reflux temperature and was kept at that temperature for 30 minutes. It was slowly cooled to the temperature of 20 and 25 ° C and the mixture obtained was kept for 16 hours at said temperature. The resulting solid was filtered and dried in an air oven at a temperature of 50 ° C. 3.8 g (Yield 61.3%) of a white solid corresponding to the trometamol salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid were thus obtained. The purity of the product was analyzed by HPLC to obtain 96.95%.
[0403] The trometamol salt is characterized by presenting a differential scanning calorimetry (DSC) diagram with an endothermic peak at a threshold temperature (“T onset ') of approximately 174 ° C, as shown in Figure 5.
[0405] Comparative Example 9.3. Obtaining the glycine salt of 3a-tetrahydropyranyloxy-6aethyl-7a-hydroxy-5B-cholanic acid
[0407] 5 g of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) (9.9 mmol) and 0.743 g of glycine (9.9 mmol) were mixed with 25 ml of methanol and 25 ml of water at a temperature between 20 and 25 ° C. The mixture was heated to reflux temperature and was kept at that temperature for 30 minutes.
[0409] The resulting slightly cloudy solution was slowly cooled to the temperature of 20 and 25 ° C and the mixture obtained was kept for 16 hours at that temperature. The resulting solid was filtered and dried in an air oven at a temperature of 50 ° C. They were obtained from this forms 4.4 g (Yield 76.7%) of a white solid corresponding to the glycine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid. The purity of the product was analyzed by HPLC to obtain 98.97%.
[0411] The glycine salt is characterized by presenting a differential scanning calorimetry (DSC) diagram with an endothermic peak at a threshold temperature ("7 onset") of approximately 158 ° C, as shown in Figure 6.
[0413] Comparative Example 9.4. Obtaining the taurine salt of 3a-tetrahydropyranyloxy-6aethyl-7a-hydroxy-5B-cholanic acid
[0415] 5 g of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) (9.9 mmol) and 1.24 g of taurine (9.9 mmol) were mixed with 25 ml of methanol and 25 ml of water at a temperature between 20 and 25 ° C. The mixture was heated to reflux temperature and was kept at that temperature for 30 minutes.
[0417] The resulting slightly cloudy solution was slowly cooled to the temperature of 20 and 25 ° C and the mixture obtained was kept for 16 hours at that temperature. The resulting solid was filtered and dried in an air oven at a temperature of 50 ° C. In this way 5.2 g (Yield 83.9%) of a white solid corresponding to the taurine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid were obtained. The purity of the product was analyzed by HPLC to obtain 97.54%.
[0419] The taurine salt is characterized by presenting a differential scanning calorimetry (DSC) diagram with an endothermic peak at a threshold temperature ("T onset") of approximately 159 ° C, as shown in Figure 7.
[0421] Comparative Example 9.5. Obtaining the triethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5B-cholanic acid
[0423] 5 g of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) (9.9 mmol) and 1.7 g of triethylamine (11.88 mmol) were mixed with 25 ml of acetone and 25 ml of water at a temperature between 20 and 25 ° C. The mixture was heated to reflux temperature and was kept at that temperature for 30 minutes.
[0424] The resulting slightly cloudy solution was slowly cooled to the temperature of 20 and 25 ° C and the mixture obtained was kept for 16 hours at that temperature. The resulting solid was filtered and dried in an air oven at a temperature of 50 ° C. In this way 4.2 g (Yield 70.0%) of a white solid were obtained corresponding to the triethylamine salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid. The purity of the product was analyzed by HPLC to obtain 99.36%.
[0426] The triethylamine salt is characterized by presenting a differential scanning calorimetry (DSC) diagram with an endothermic peak at a threshold temperature ("7 onset") of approximately 179 ° C, as shown in Figure 8.

权利要求:
Claims (46)
[1]
1. 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt of formula (I)

[2]
Diethylamine salt of formula (I) according to claim 1, characterized in that diethylamine and 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid are in a molar ratio of approximately 1: 1.
[3]
3. Diethylamine salt of formula (I) according to any of the preceding claims, characterized in that it is in solid form.
[4]
Diethylamine salt of formula (I) according to any of the preceding claims, characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak that has a threshold temperature of approximately 202 ° C ± 0.3 ° C.
[5]
5. 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid diethylamine salt of formula (I) according to any of the preceding claims, characterized in that it presents a differential scanning calorimetry diagram substantially as shown in Figure 2.
[6]
Diethylamine salt of formula (I) according to any of the preceding claims, characterized in that it has an X-ray powder diffractogram showing peaks at 5.5, 7.8, 10.1, 11.1, 12.1 , 12.8, 13.2, 14.2, 16.4, 16.7, 17.9, 20.3, 20.5, 22.1 and 23.3 ° 20 ± 0.2 ° 20.
[7]
Diethylamine salt of formula (I) according to any of the preceding claims, characterized in that it presents an X-ray powder diffractogram substantially as shown in Figure 1.
[8]
8. Use of the diethylamine salt of formula (I) in a process for preparing obeticholic acid of formula (II)

[9]
9. Use according to claim 8, wherein the process for preparing obeticholic acid of formula (II) comprises treating the diethylamine salt of formula (I) with an acid at a pH of 0 to 3

[10]
10. Use according to claim 9, wherein the acid is hydrochloric acid.
[11]
11. Use according to any of claims 9 or 10, which is carried out in the presence of a solvent selected from the group consisting of C1-C4 alcohols, ketones, C1-C4 alkyl acetates, cyclic or linear ethers, acetonitrile, water and mixtures thereof, preferably a mixture of methanol and water
[12]
12. Use according to any one of claims 9 to 11, which is carried out at a temperature between 15 ° C and 35 ° C.
[13]
13. Process for preparing the diethylamine salt of formula (I) which comprises treating 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) with diethylamine

[14]
14. Process according to claim 13, wherein the treatment of 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) with diethylamine is carried out in the presence of a solvent selected from the group consisting of C1- alkyl acetates C4, C1-C4 alcohols, ketones, water and mixtures thereof, preferably ethyl acetate.
[15]
15. Process according to any of claims 13 or 14, wherein the diethylamine salt of formula (I) obtained is subjected to recrystallization.
[16]
16. Process according to any one of claims 13 to 15, wherein 3-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid (la) is obtained by a process comprising:
(a) treating a compound of formula (111) or a salt thereof with a reducing agent to give 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid or a salt thereof

[17]
17. The process according to claim 16 wherein step (a) comprises treating a salt of a compound of formula (III) with sodium borohydride as a reducing agent to give a salt of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy acid. -5p-cholanic (Ia), and in which stage (b) is carried out.
[18]
18. Process according to any of claims 16 or 17, wherein step (a) is carried out in the presence of a solvent selected from the group consisting of C1-C3 alcohol, water and mixtures thereof, preferably a mixture of methanol and Water.
[19]
19. Process according to any of claims 16 to 18, wherein in step (a) between 1 and 1.5 moles of reducing agent is used with respect to each mole of compound of formula (III) or the salt thereof.
[20]
20. Process according to any of claims 16 to 19, wherein step (a) is carried out at a temperature between 20 ° C and 60 ° C.
[21]
21. Process according to any of claims 16 to 20, wherein the acid used in step (b) is phosphoric acid.
[22]
22. Process according to any one of claims 16 to 21, wherein the salt of the compound of formula (III) is the sodium salt of the compound of formula (III).
[23]
23. Process according to any of claims 16 to 22, wherein the compound of formula (III) or a salt thereof is obtained by a process comprising:
(a) treating a compound of formula (IV) 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 (III)

[24]
24. Process according to claim 23, wherein the compound of formula (III) is in the form of a salt and step (b) is not carried out.
[25]
25. Process according to any of claims 23 or 24, wherein between 1.5 and 2.5 moles of base are used with respect to each mole of compound of formula (IV) or a geometric isomer thereof, preferably between 1, 9 and 2.1 moles of base with respect to each mole of compound of formula (IV) or a geometric isomer thereof.
[26]
26. Process according to any of claims 23 or 25, wherein the base is sodium hydroxide.
[27]
27. The process according to any one of claims 23 to 26, wherein the catalyst is selected from the group consisting of palladium on carbon, palladium on calcium carbonate and platinum oxide, preferably palladium on carbon.
[28]
28. Process according to any of claims 23 to 27, wherein the treatment of step (a) is carried out at a temperature between 35 ° C and 45 ° C.
[29]
29. Process according to any of claims 23 to 28, wherein the treatment of step (a) is carried out at a pressure of between 4.5 and 5.5 bars.
[30]
30. Process according to any of claims 23 to 29, wherein the treatment of step (a) is carried out in the presence of a solvent selected from a C1-C3 alcohol, preferably methanol.
[31]
31. Process according to any of claims 23 to 30, wherein the compound of formula (IV) or a geometric isomer thereof is obtained by treating a compound of formula (V) or a geometric isomer thereof with 3,4- dihydro-2H-pyran in the presence of an acid

[32]
32. Process according to claim 31, wherein the acid is camphorsulfonic acid, preferably (1S) - (+) - 10-camphorsulfonic acid.
[33]
33. Process according to any of claims 31 or 32, 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.
[34]
34. Process according to any of claims 31 to 33, wherein between 1 and 2 moles of 3,4-dihydro-2H-pyran are used with respect to each mole of compound of formula (V) or a geometric isomer thereof.
[35]
35. Process according to any of claims 31 to 34, wherein the treatment of the compound of formula (V) 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 , preferably dichloromethane.
[36]
36. Process according to claim 35, 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.
[37]
37. Process according to any of claims 31 to 36, wherein the treatment of the compound of formula (V) or a geometric isomer thereof is carried out at a temperature between 15 ° C and 35 ° C.
[38]
38. Process according to any of claims 31 to 37 wherein the treatment of the compound of formula (V) or a geometric isomer thereof to give the diethylamine salt of formula (I) is carried out without isolating the intermediate compounds obtained ( one pot ).
[39]
39. Process according to any of claims 31 to 38, wherein the compound of formula (V) or a geometric isomer thereof is obtained by treating a compound of formula (VI) or a geometric isomer thereof in the presence of a base and a solvent selected from the group consisting of water, C1-C3 alcohol, and mixture thereof

[40]
40. Process according to claim 39, wherein the base is sodium hydroxide.
[41]
41. Process according to claim 39 or 40 wherein the solvent is a mixture of water and C1-C3 alcohol, preferably a mixture of water and methanol.
[42]
42. Process according to any of claims 39 to 41, wherein the treatment of the compound of formula (VI) or a geometric isomer thereof is carried out at a temperature between 40 ° C and 60 ° C.
[43]
43. Process according to any of claims 39 to 42, wherein the compound of formula (VI) or a geometric isomer thereof is obtained by treating a compound of formula (VII) with acetaldehyde in the presence of borodiethyl ether trifluoride

[44]
44. Process according to claim 43, wherein the compound of formula (VII) is obtained by treating a compound of formula (VIII) with chlorotrimethylsilane or trimethylsilyl trifluoromethanesulfonate in the presence of a base

[45]
45. Process according to claim 44, wherein the compound of formula (VIII) is obtained by treating a compound of formula (IX) with methanol in the presence of an acid

[46]
46. Process according to claim 45, wherein the compound of formula (IX) is obtained by treating a compound of formula (X) with sodium bromide and sodium hypochlorite

(X).

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公开号 | 公开日

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WO2020169643A1|2020-08-27|

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ES201930143A|ES2779985B2|2019-02-20|2019-02-20|3alpha-tetrahydropyranyloxy-6alpha-ethyl-7alpha-hydroxy-5ß-cholanic acid diethylamine salt|ES201930143A| ES2779985B2|2019-02-20|2019-02-20|3alpha-tetrahydropyranyloxy-6alpha-ethyl-7alpha-hydroxy-5ß-cholanic acid diethylamine salt|

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PCT/EP2019/055033| WO2019170521A1|2018-03-07|2019-02-28|Synthesis of obeticholic acid and synthesis intermediate|

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PCT/EP2020/054308| WO2020169643A1|2019-02-20|2020-02-19|DIETHYLAMINE SALT OF 3α-TETRAHYDROPYRANYLOXY-6α-ETHYL-7α-HYDROXY-5ß-CHOLANIC ACID|

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EP20706678.8A| EP3927719A1|2019-02-20|2020-02-19|Diethylamine salt of 3alpha-tetrahydropyranyloxy-6alpha-ethyl-7alpha-hydroxy-5beta-cholanic acid|