WO2019170521A1 - Synthèse d'acide obéticholique et intermédiaire de synthèse - Google Patents

Synthèse d'acide obéticholique et intermédiaire de synthèse Download PDF

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WO2019170521A1
WO2019170521A1 PCT/EP2019/055033 EP2019055033W WO2019170521A1 WO 2019170521 A1 WO2019170521 A1 WO 2019170521A1 EP 2019055033 W EP2019055033 W EP 2019055033W WO 2019170521 A1 WO2019170521 A1 WO 2019170521A1
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compound
formula
use according
acid
mol
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PCT/EP2019/055033
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María del Carmen BERNABEU MARTÍNEZ
Oscar Jiménez Alonso
Alicia DOBARRO RODRÍGUEZ
Mauro Gaboardi
Graziano Castaldi
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Moehs Iberica, S.L.
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Priority claimed from ES201830220A external-priority patent/ES2724725B2/es
Priority claimed from ES201930143A external-priority patent/ES2779985B2/es
Application filed by Moehs Iberica, S.L. filed Critical Moehs Iberica, S.L.
Publication of WO2019170521A1 publication Critical patent/WO2019170521A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention relates to a new intermediate for the synthesis of obeticholic acid, the use of said intermediate in the synthesis of said obeticholic acid, as well as the process for obtaining this new intermediate.
  • Obeticholic acid (OCA), or 3a, 7a-dihydroxy- 6a-ethyl-5 b- cholan-24-oic acid or compound of formula (IV) in the present invention is a 6a-ethylated derivative of bile chenodeoxycholic acid (CDCA) .
  • the chemical structure of obeticholic acid is shown below .
  • Obeticholic acid is a farnesoid X receptor (FXR) ligand used in the treatment of primary biliary cholangitis and is under development for the treatment of other liver diseases.
  • FXR farnesoid X receptor
  • Obeticholic acid and its process of synthesis are disclosed in document WO 02/072598 A1.
  • the synthetic route comprises: the protection of the hydroxyl group at position 03 of 3a-hydroxy-7- keto-5 p-cholan-24-oic acid with a tetrahydropyranyl group to yield 3a-tetrahydropyranyloxy-7-keto-5 p-cholan-24-oic acid, alkylation of the carbon at position 06, and esterification of the carboxylic group with ethyl bromide and deprotection of the tetrahydropyranyl group to yield ethyl 3a-hydroxy-6a-ethyl-7- keto-5p-cholan-24-oate, reduction of the ketone group at position C7 to hydroxyl with sodium borohydride to yield ethyl 3a, 7a-dihydroxy-6a-ethyl-5p-cholan-24-oate, and finally deprotection of the ester group to yield obeticholic acid.
  • Zampella et al . disclose another obeticholic acid synthesis route comprising the oxidation of chenodeoxycholic acid (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 position C24, to yield the benzyl ester of 7-ketolitocholic acid.
  • CDCA chenodeoxycholic acid
  • NaBr sodium hypochlorite/NaBr and tetrabutylammonium bromide
  • benzylation of the carboxylic acid at position C24 to yield the benzyl ester of 7-ketolitocholic acid.
  • silyl enol ether is generated followed by aldol addition with acetaldehyde in the presence of BF 3 OEt 2 to yield ethyl 3a- hydroxy-6a-ethylidene-7-keto-5p-cholan-24-oate .
  • selective reduction of ketone at position C7 with NaBIHU/CeCls in a mixture of THF/methanol and after that hydrogenation of the exocyclic double bond, together with the removal of the benzyl protecting group, are carried out to yield obeticholic acid.
  • Document US 8338628 B2 discloses a process for obtaining obeticholic acid comprising the steps of oxidizing the hydroxyl at position C7 of CDCA to a ketone group with pyridinium chlorochromate , protection of the hydroxyl at position C3 with a tetrahydropyranyl group, alkylation of the carbon at position C6 with ethyl iodide and deprotection of the tetrahydropyranyl group, and finally reduction of the ketone group at position C7 to hydroxyl with sodium borohydride to yield obeticholic acid, as shown below.
  • this synthetic route also includes several steps of purification by column chromatography, rendering it unsuitable for industrial implementation.
  • Document CN 107400154 A discloses the following process of synthesis for obtaining obeticholic acid, wherein R is C1-C6 alkyl :
  • CN 106589039 A also discloses a process for synthesis of obeticholic acid in which intermediates having a methyl ester as protecting group of the carboxylic acid and/or a tetrahydropyranyl (THP) as protecting group of the hydroxyl at position C3 are used.
  • THP tetrahydropyranyl
  • the inventors have discovered a new process for synthesis of obeticholic acid which allows obtaining the precursor of obeticholic acid (compound of formula (III)) in a single reaction vessel and without the need to isolate synthesis intermediates.
  • the inventors thereby reduce the number of independent steps which involve isolating the obtained intermediates as well as the corresponding steps of purification, achieving good yields and high purity.
  • This process uses the compound of formula (I) as key intermediate:
  • the present invention relates to the compound of formula (I) or a geometric isomer thereof.
  • the present invention relates to the use of a compound of formula (I) or a geometric isomer thereof in a process for preparing obeticholic acid, particularly wherein the process for preparing obeticholic acid of formula (IV) comprises the following steps:
  • step (d) optionally treating the compound of formula (III) obtained in step (c) with diethylamine to yield the diethylamine salt of compound (III);
  • the present invention relates to a process for preparing a compound of formula (I) or a geometric isomer thereof, which process comprises treating a compound of formula (V) or a geometric isomer thereof with 3, 4-dihydro-2H- pyran in the presence of an acid.
  • Figure 1 shows the x-ray powder diffraction (XRPD) pattern of the amorphous form of obeticholic acid obtained in Example
  • Figure 2 shows the differential scanning calorimetry diagram of the amorphous form of obeticholic acid obtained in Example 10.
  • Figure 3 shows the differential scanning calorimetry diagram of 3a-tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5 b- cholanic acid obtained in Example 8.
  • Figure 4 shows the x-ray powder diffraction (XRPD) pattern of the diethylamine salt of compound (III) obtained in Example
  • Figure 5 shows the differential scanning calorimetry diagram of the diethylamine salt of compound (III) obtained in Example 9.
  • the first aspect of the present invention relates to the compound of formula (I) or a geometric isomer thereof.
  • geometric isomer refers to stereoisomers differing only in the position of the 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) isomers.
  • the compound of formula (I) can be isomer Z, isomer £ or a mixture of said isomers. Preferably it is isomer E.
  • the second aspect of the present invention relates to the use of the compound of formula (I) or a geometric isomer thereof in a process for preparing obeticholic acid of formula (IV), particularly wherein the process for preparing obeticholic acid comprises the following steps:
  • step (d) optionally treating the compound of formula (III) obtained in step (c) with diethylamine to yield the diethylamine salt of compound (III);
  • step (e) treating the salt of the compound of formula (III) obtained in step (b) , the compound of formula (III) obtained in step (c) or the diethylamine salt of compound (III) obtained in step (d) , with an acid at a pH of 0 to 3.
  • steps (a) and (b) can be performed in one and the same reaction vessel without the need to isolate the obtained intermediate products, i.e. one-pot, rendering it particularly suitable for industrial implementation.
  • steps (a) and (b) the compound of formula (III), which is the precursor of obeticholic acid, is obtained.
  • step (a) the benzyl group of the compound of formula
  • bases suitable for step (a) are sodium hydroxide, potassium hydroxide, ammonia, preferably sodium hydroxide .
  • the salt of the compound of formula (II) is formed by the carboxylic acid anion (carboxylate) of the compound of formula
  • the base is sodium hydroxide the salt of the compound of formula (II) is sodium salt
  • the base is hydroxide potassium the salt of the compound of formula (II) is potassium salt
  • the base is ammonia the salt of the compound of formula (II) is ammonium salt.
  • the cation is selected from the group consisting of Na + , K + and NH4 + , preferably Na + .
  • the base is mixed with a solvent selected from water, C1-C3 alcohol, and mixture thereof.
  • a solvent selected from water, C1-C3 alcohol, and mixture thereof.
  • C1-C3 alcohols are methanol, ethanol, n-propanol, and isopropanol.
  • the base is mixed with water, more preferably the base is an aqueous solution, particularly an aqueous solution of sodium hydroxide.
  • step (a) between 1.5 and 2.5 mol of base (preferably of sodium hydroxide) are used with respect to each mol of compound of formula (I) or a geometric isomer thereof, preferably between 1.5 and 2.1 mol, more preferably between 1.8 and 2.1 mol, more preferably between 1.9 and 2.1 mol, most preferably about 2 mol.
  • base preferably of sodium hydroxide
  • 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.
  • step (a) is performed at a temperature of 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 particularly advantageous since the impurity content is reduced.
  • 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 bar, most preferably about 5 bar.
  • 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 bar, most preferably about 5 bar.
  • Working in these pressure ranges is also particularly advantageous since the impurity content is reduced.
  • the treatment with hydrogen 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.
  • step (a) is performed in the presence of a solvent selected from a C1-C3 alcohol.
  • C1-C3 alcohols are methanol, ethanol, n-propanol, and isopropanol.
  • the C1-C3 alcohol of step (a) is methanol.
  • 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.
  • step (a) is performed by first adding the base, the resulting mixture is treated with activated carbon, and then the resulting mixture is filtered by means of any conventional method known to one skilled in the art, for example, by means of a filter with diatomaceous earth, and then hydrogenation is performed.
  • the resulting mixture is filtered to remove the catalyst.
  • Said filtration can be performed by means of any conventional method known to one skilled in the art, for example, by means of a filter with diatomaceous earth.
  • 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%.
  • Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation at a temperature less than 40°C and under reduced pressure (at a pressure less than 1 atm which is able to remove the solvent at a temperature less than 40 °C, which pressure can be readily determined by one skilled in the art) .
  • step (b) for reduction of the ketone group at position C7 to hydroxyl group is performed to yield a salt of the compound of formula (III) .
  • Step (b) comprises the treatment of the salt of the compound of formula (II) with sodium borohydride to yield the salt of the compound of formula (III) .
  • the salt of the compound of formula (III) is formed by the carboxylic acid anion (carboxylate) of the compound of formula (III) and a cation coming from salt of the compound of formula (II), and in the event that there is additionally a base in the reaction medium, the cation can also be from said base, as explained hereinbelow.
  • the cation is selected from the group consisting of Na + , K + , and NH4 + , preferably Na + .
  • between 1 and 3.5 mol of sodium borohydride are used with respect to each mol of salt of compound of formula (II), preferably between 1 and 3 mol, more preferably between 1 and 2.8 mol, even more preferably between 1.1 and 2.5 mol.
  • between 1 and 3.5 mol of sodium borohydride are used with respect to each mol of compound of formula (I) or a geometric isomer thereof, preferably between 1 and 3 mol, more preferably between 1 and 2.8 mol, even more preferably between 1.1 and 2.5 mol.
  • This more preferred particular embodiment is particularly applied when steps (a) and (b) are performed in one and the same reaction vessel without the need to isolate the obtained intermediate products, i.e. one-pot.
  • between 2 and 3.5 mol of sodium borohydride are used with respect to each mol of salt of compound of formula (II), preferably between 2 and 3 mol, more preferably between 2.3 and 2.8 mol, even more preferably about 2.5 mol.
  • between 2 and 3.5 mol of sodium borohydride are used with respect to each mol of compound of formula (I) or a geometric isomer thereof, preferably between 2 and 3 mol, more preferably between 2.3 and 2.8 mol, even more preferably about 2.5 mol.
  • This more preferred embodiment is particularly applied when steps (a) and (b) are performed in one and the same reaction vessel without the need to isolate the obtained intermediate products, i.e. one-pot.
  • step (d) when step (d) is performed (formation of the diethylamine salt of compound (III)), in step (b) between 1 and 1.5 mol of sodium borohydride are used with respect to each mol of salt of compound of formula (II), preferably between 1 and 1.2 mol, more preferably between 1 and
  • steps (a) and (b) are performed in one and the same reaction vessel without the need to isolate the obtained intermediate products, i.e. one-pot.
  • step (b) is performed in the presence of a solvent selected from the group consisting of C 1 -C 3 alcohol, water, and mixtures thereof.
  • a solvent selected from the group consisting of C 1 -C 3 alcohol, water, and mixtures thereof.
  • C1-C3 alcohols are methanol, ethanol, n-propanol, and isopropanol, preferably methanol.
  • the solvent is a mixture of methanol and water, preferably a mixture of methanol and water at a ratio of between 4 and 6 volumes of methanol for each volume of water, more preferably between 4.5 and 5.5 volumes of methanol for each volume of water, even more preferably about 5 volumes of methanol for each volume of water.
  • the solvent is a mixture of methanol and water containing at least 80% by volume of methanol with respect to the total volume of solvent, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%.
  • step (b) between 3.5 and 4.5 ml of solvent are 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 .
  • step (b) between 3.5 and 4.5 ml of solvent are used for each mmol of compound of formula (I), more preferably between 3.75 and 4.25 ml, even more preferably about 4 ml.
  • steps (a) and (b) are performed in one and the same reaction vessel without the need to isolate the obtained intermediate products, i.e. one-pot. Using these volumes of solvent is particularly advantageous since the impurity content is reduced.
  • step (b) is performed at a temperature of between 20°C and 95°C, preferably between 25°C and 90°C, more preferably between 30°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 .
  • step (b) is performed at a temperature of 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.
  • step (b) is performed at a temperature of between 20°C and 60°C, preferably between 25 °C and 50°C, more preferably between 30 °C and 45 °C, more preferably between 35 °C and 45
  • said temperature is maintained between 2.5 and 4 hours, preferably between 2.5 and 3.5 hours, more preferably about 3 hours.
  • step (b) a solution of sodium hydroxide in water is also added, preferably between 0.05 and 0.2 mol of sodium hydroxide are added with respect to each mol of salt of compound of formula (II), preferably between 0.05 and 0.15 mol, more preferably between 0.08 and 0.12 mol, even more preferably about 0.1 mol.
  • a solution of sodium hydroxide in water is also added, preferably between 0.05 and 0.2 mol of sodium hydroxide are added with respect to each mol of salt of compound of formula (II), preferably between 0.05 and 0.15 mol, more preferably between 0.08 and 0.12 mol, even more preferably about 0.1 mol.
  • the salt of the compound of formula (III) is formed by the carboxylic acid anion (carboxylate) of the compound of formula (III) and a sodium cation.
  • step (b) is performed by dissolving the obtained product after step (a) in the solvent of step (b) , preferably by heating the mixture obtained at the temperature described above for step (b) , followed by addition of sodium borohydride and optionally the addition of the solution of sodium hydroxide in water.
  • 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%. Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation at atmospheric pressure, i.e., at about 1 atmosphere.
  • step (c) for treatment of the salt of the compound of formula (III) with an acid at a pH of 4 to 6 can be performed to yield the compound of formula (HI) ⁇
  • Suitable acids for step (c) are phosphoric acid, hydrochloric acid, acetic acid, sulfurous acid, and oxalic acid.
  • the acid used in step (c) is phosphoric acid or hydrochloric acid, more preferably phosphoric acid.
  • the treatment with acid of step (c) is performed at a pH of 4.5 to 5.5, more preferably of about
  • Determining the pH value for example by using a pH-meter, is part of the routine work of one skilled in the art.
  • step (c) is carried out.
  • step (c) comprises one or more washings with aqueous solution of the acid, particularly phosphoric acid or hydrochloric acid, preferably phosphoric acid.
  • aqueous solution of the acid particularly phosphoric acid or hydrochloric acid, preferably phosphoric acid.
  • the product is dissolved in a suitable organic solvent, such as ethyl acetate.
  • a suitable organic solvent such as ethyl acetate.
  • the obtained product is additionally purified by means of crystallization in linear, branched, or cyclic C5-C8 alkane.
  • linear, branched, or cyclic C5- C 8 alkane examples include n-pentane, cyclopentane, isopentane, n-hexane, cyclohexane, n-heptane, cycloheptane, n-octane, isooctane, preferably n-heptane.
  • step (d) Another optional step in step (d) , which comprises treating compound of formula (III) obtained in step (c) with diethylamine to yield the diethylamine salt of compound (III)
  • the formation of the diethylamine salt of compound (III) is particularly advantageous since it allows obtaining compound (III) with high purity and/or high yields and has good stability. Moreover, this diethylamine salt can be easily further purified.
  • the use of the diethylamine salt of compound (III) in the synthesis of obeticholic acid allows obtaining said acid with high purity and yield.
  • the diethylamine salt of compound (III) can be in solid form.
  • the diethylamine salt of compound (III) has a DSC (differential scanning calorimetry) diagram that comprises an endothermic peak having an onset temperature of about 202 ⁇ 0.3 °C, more particularly the DSC diagram is substantially as shown in Figure 5.
  • the diethylamine salt of compound (III) is characterized by a DSC diagram comprising and endothermic peak between 170 and 270 °C. More particularly, the diethylamine salt of compound (III) is characterized by a DSC comprising an endothermic peak having a peak temperature in the range between 220 and 230 °C.
  • the DSC diagrams can be obtained as described in the examples.
  • T onset refers to the temperature resulting from the extrapolation of the baseline before transition starts and baseline during energy absorption (tangent to the curve of energy absorption (peak) at the point of inflection) .
  • peak temperature refers to the temperature that has the greatest distance between the curve of the peak to be characterized and the virtual baseline resulting from the extrapolation of the baseline before transition starts.
  • the diethylamine salt of compound (III) is characterized by being in crystalline form and by having an X- ray powder diffraction (XRPD) pattern with peaks at 5.5, 7.8,
  • XRPD pattern with 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 °2Q + 0.2 °2Q; more particularly substantially as shown in Figure 4.
  • XRPD patterns can be acquired using a powder diffraction system having a copper anode emitting CuKa radiation at a wavelength of 1.54 A, in particular following the method described in the examples.
  • step (d) is performed. In an alternative embodiment, step (d) is not performed.
  • this step is carried out in a solvent selected from the group consisting of C 1 -C 4 alkyl acetates, C 1 -C 4 alcohols, ketones, water, and mixtures thereof, preferably ethyl acetate.
  • a solvent selected from the group consisting of C 1 -C 4 alkyl acetates, C 1 -C 4 alcohols, ketones, water, and mixtures thereof, preferably ethyl acetate.
  • Examples of C 1 -C 4 alkyl acetates are n-butyl acetate and tert-butyl acetate.
  • Examples of C 1 -C 4 alcohols are methanol, ethanol, n-propanol, isopropanol, n- butanol, sec-butanol, isobutanol and tert-butanol .
  • ketones are acetone and methyl isobutyl ketone.
  • the treatment with diethylamine is carried out at a temperature of from 15 °C to 80 °C, preferably from 20 °C to 70 °C, more preferably from 15 °C to 40 °C, more preferably from 25 °C to 45 °C.
  • the treatment with diethylamine is carried out from 0.5 to 20 hours, preferably from 1 to 10 hours .
  • the diethylamine salt of compound (III) is subjected to a purification step, preferably recrystallization.
  • a suitable solvent for recrystallizing said salt is ethyl acetate, preferably in a ratio of 4 ml of ethyl acetate with respect to 1 g of diethylamine salt of compound (HI) ⁇
  • step (e) which involves deprotection of the tetrahydropyranyl group in the compound of formula (III) or in the salt of the compound of formula (III), including the diethylamine salt of compound (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.
  • Any suitable acid can be used for the deprotection of hydroxyl groups protected with a tetrahydropyranyl group.
  • Suitable acids for step (e) are hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid, among others.
  • the acid of step (e) is hydrochloric acid.
  • step (e) when step (c) is performed and step (d) is not performed, in step (e) between 1 and 2 mol of hydrochloric acid are used for each mol of compound of formula (III), more preferably between 1.2 and 2 mol, more preferably between 1.4 and 1.8 mol, even more preferably about 1.5 mol.
  • step (e) when step (d) is performed, in step (e) between 2 and 4 mol of hydrochloric acid are used for each mol of the diethylamine salt of compound (III), more preferably between 2 and 3 mol, more preferably between 2 and 2.5 mol, even more preferably about 2.25 mol.
  • step (e) is performed in the presence of a solvent selected from the group consisting of C1-C4 alkyl acetates, ketones, C1-C4 alcohols, cyclic or linear ethers, acetonitrile, water, and mixtures thereof.
  • a solvent selected from the group consisting of C1-C4 alkyl acetates, ketones, C1-C4 alcohols, cyclic or linear ethers, acetonitrile, water, and mixtures thereof.
  • C1-C4 alkyl acetates are ethyl acetate, n-butyl acetate, and tert- butyl acetate.
  • ketones are acetone and methyl-iso- butylketone.
  • C1-C4 alcohols are methanol, ethanol, n- propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol , preferably methanol.
  • cyclic or linear ethers are diethyl ether, tetrahydrofuran, and dioxane.
  • the solvent is selected from the group consisting of acetone, methanol, water and mixtures thereof.
  • the solvent comprises acetone, preferably it is a mixture of acetone and water.
  • the solvent comprises methanol, preferably it is a mixture of methanol and water.
  • acetone between 2.5 and 7.5 ml of acetone are used for each mmol of compound of formula (III) or salt of the compound of formula (III), more preferably between 4 and 6 ml, even more preferably about 5 ml.
  • methanol Preferably, between 2 and 10 ml of methanol are used for each gram (g) of compound of formula (III) or salt of the compound of formula (III), more preferably between 4 and 8 ml, even more preferably about 6 ml.
  • step (e) is performed at a temperature of between 15°C and 35°C, more preferably between 15°C and 30°C, more preferably between 20°C and 25°C.
  • the treatment with acid of step (e) has a duration of between 6 and 10 hours, preferably between 7 and 9 hours, more preferably about 8 hours.
  • 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%.
  • Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation at a temperature less than 40°C, more preferably of about 35°C.
  • said distillation is performed under reduced pressure, i.e., at a pressure less than 1 atm which is able to remove the solvent at a temperature less than 40°C or 35°C. This pressure can be readily determined by one skilled in the art.
  • the product obtained after removal of the solvent is purified by means of one or more washings with basic aqueous solution, particularly of sodium hydroxide, until obtaining a pH of about 12.
  • basic aqueous solution particularly of sodium hydroxide
  • the product is dissolved in a suitable organic solvent such as ethyl acetate.
  • the basic aqueous phase obtained after the washings is taken to pH of between 2 and 3, particularly by means of the addition of hydrochloric acid. Even more preferably the obtained product is isolated by means of filtration.
  • step (d) is performed and step (e) is carried out in a C1-C4 alcohol (such as methanol), instead of directly obtaining obeticholic acid, the corresponding ester of obeticholic acid and the C1-C4 alcohol (such as the methyl ester of obeticholic acid) is obtained.
  • step (d) is performed (i.e. formation of the diethylamine salt of compound (III))
  • step (e) after the treatment with an acid in the presence of a solvent, the resulting mixture is basified, preferably to a pH of at least 11, more preferably to a pH of at least 12.
  • This step needs to be performed when the solvent used in step (e) is a C1-C4 alcohol (such as methanol), in order to hydrolyze the corresponding ester of obeticholic acid and the C1-C4 alcohol.
  • a C1-C4 alcohol such as methanol
  • Any suitable base capable of hydrolyzing said ester and also capable of providing diethylamine as a free base and forming a salt between the cation of said base and the carboxylate anion can be used.
  • bases are aqueous solutions of sodium hydroxide or potassium hydroxide, preferable aqueous solution of sodium hydroxide.
  • this treatment with base is carried out at a temperature of from 15 °C to 60 °C, preferably from 30 °C to 60 °C, more preferably from 45 °C to 55 °C.
  • this treatment with base is carried out for 2 to 8 hours, preferably from 4 to 6 hours, more preferably about 5 hours.
  • 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%.
  • This solvent includes the diethylamine (free base) released with the basic treatment.
  • Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation at a temperature less than 40°C, more preferably of about 35°C. Particularly, said distillation is performed under reduced pressure, i.e., at a pressure less than 1 atm which is able to remove the solvent at a temperature less than 40°C or 35°C. This pressure can be readily determined by one skilled in the art.
  • the resulting mixture (which comprises obeticholic acid in the form of a salt) is acidified.
  • Any acid suitable for forming obeticholic free acid may be used, such as hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid and methanesulfonic acid, preferably hydrochloric acid, more preferably aqueous solution of hydrochloric acid.
  • the mixture is acidified to a pH less than or equal to 2, preferably less than or equal to 1.
  • the treatment with acid is carried out at from 15 °C to 35 °C, preferably from 15 °C to 30 °C, more preferably from 20 °C to 25 °C.
  • the product obtained after said treatment, i.e. obeticholic acid is preferably isolated by filtration.
  • the present invention relates to a process for preparing a compound of formula (I) or a geometric isomer thereof, which process comprises treating a compound of formula (V) or a geometric isomer thereof with 3, 4-dihydro-2H- pyran in the presence of an acid.
  • geometric isomers refer to stereoisomers differing only in the position of the substituents linked 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) isomers.
  • the compound of formula (V) can be isomer Z, isomer E, or a mixture of said isomers. Preferably it is isomer E.
  • Any suitable acid can be used for the protection of hydroxyl groups by formation of the tetrahydropyranyl ether, such as camphorsulfonic acid and p-toluenesulfonic acid, among others.
  • the acid is camphorsulfonic acid, more preferably (IS) - (+ ) -10-camphorsulfonic acid.
  • treatment of the compound of formula (V) with 3 , 4-dihydro-2H-pyran is performed at a temperature of between 15°C and 35°C, preferably between 20°C and 25°C.
  • treatment of the compound of formula (V) with 3 , 4-dihydro-2H-pyran has a duration of between 4 and 10 hours, preferably between 4 and 7 hours, more preferably about 5 hours .
  • said treatment is performed in inert atmosphere, for example in nitrogen or argon atmosphere .
  • the pH is adjusted to about 9, for example by means of the addition of triethylamine .
  • 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%.
  • Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation under reduced pressure, i.e., at a pressure less than 1 atm which is able to remove the solvent at the temperature used (which pressure can be readily determined by one skilled in the art) , and preferably at a temperature less than 40 °C .
  • treatment of compound (V) or a geometric isomer thereof to give the diethylamine salt of compound (III) is performed one-pot, i.e. in the same reaction vessel and without isolating the intermediate compounds obtained in the process. This is particularly advantageous for industrial implementation of the process.
  • the compound of formula (V) or a geometric isomer thereof is obtained by treatment of a compound of formula (VI) with acetaldehyde in the presence of boron trifluoride-diethyl ether.
  • acetaldehyde between 1.5 and 2.5 mol are used with respect to each mol of compound of formula (VI), preferably between 1.8 and 2.2 mol, more preferably about 2 mol .
  • boron trifluoride-diethyl ether are used with respect to each mol of compound of formula (VI), preferably between 2 and 3 mol, most preferably about 2.5 mol.
  • treatment of the compound of formula (VI) with acetaldehyde in the presence of boron trifluoride-diethyl ether is performed in dichloromethane .
  • boron trifluoride-diethyl ether is used in dichloromethane .
  • between 2 and 15 ml of solvent are used with respect to each gram of compound of formula (VI), more preferably between 5 and 10 ml.
  • treatment of the compound of formula (VI) with acetaldehyde in the presence of boron trifluoride-diethyl ether is performed at a temperature of between -60°C and -65°C, particularly for 1.5 to 3 hours, preferably for about 2 hours, followed by a temperature of between 20°C and 25°C, particularly for 2 to 5 hours, preferably for about 3 hours.
  • one or more washings are performed with an aqueous solution of sodium bicarbonate.
  • 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%.
  • Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation under reduced pressure, i.e., at a pressure less than 1 atm which is able to remove the solvent at the temperature used (which pressure can be readily determined by one skilled in the art) and preferably at a temperature less than 40°C.
  • the compound of formula (VI) is obtained by treatment of a compound of formula (VII) with chlorotrimethylsilane or trimethylsilyl trifluoromethane- sulfonate in the presence of a base.
  • Bases suitable for this treatment are, for example, hexyl- lithium and n-butyl-lithium, preferably further comprising diisopropylamine.
  • the compound of formula (VI) is obtained by treatment of a compound of formula (VII) with chlorotrimethylsilane and hexyl-lithium in the presence of diisopropylamine.
  • chlorotrimethylsilane Preferably between 4 and 5 mol of chlorotrimethylsilane are used for each mol of compound of formula (VII), more preferably about 4.5 mol.
  • the treatment is performed in a suitable solvent, such as, for example, tetrahydrofuran, hexane, and mixtures thereof, preferably in a mixture of tetrahydrofuran and hexane.
  • a suitable solvent such as, for example, tetrahydrofuran, hexane, and mixtures thereof, preferably in a mixture of tetrahydrofuran and hexane.
  • a suitable solvent such as, for example, tetrahydrofuran, hexane, and mixtures thereof, preferably in a mixture of tetrahydrofuran and hexane.
  • a suitable solvent such as, for example, tetrahydrofuran, hexane, and mixtures thereof, preferably in a mixture of tetrahydrofuran and hexane.
  • this treatment is performed in inert atmosphere (for example, nitrogen or argon atmosphere) and preferably at a temperature of between -70
  • one or more washings with aqueous solution of citric acid and optionally one or more washings with aqueous solution of bicarbonate are performed.
  • 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%.
  • Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation under reduced pressure, i.e., at a pressure less than 1 atm which is able to remove the solvent at the temperature used (which pressure can be readily determined by one skilled in the art) and preferably at a temperature less than 40°C.
  • the compound of formula (VII) is obtained by treatment of a compound of formula (VIII) with benzyl bromide in the presence of a base.
  • Bases suitable for this treatment are any base suitable for the protection of carboxylic acids by formation of the corresponding benzyl ester, such as, for example, tertiary amines containing three C1-C4 alkyl groups that are the same or different, such as, for example, triethylamine, and cesium carbonate, among others.
  • the base is triethylamine.
  • benzyl bromide are used for each mol of compound of formula (VIII), more preferably about 1.5 mol.
  • the treatment is performed in a suitable solvent, such as, for example, toluene.
  • a suitable solvent such as, for example, toluene.
  • 2 and 8 ml of solvent are used for each gram of compound of formula (VII), more preferably about 5 ml.
  • this treatment is performed for 4 to 6 hours, preferably for about 5 hours.
  • treatment is performed at a temperature of between 90°C and 120°C, preferably of between 105°C and 115°C.
  • one or more washings with water and one or more washings with aqueous solution of sodium hydroxide, and one or more washings with aqueous solution of hydrochloric acid are performed.
  • 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%.
  • Removal of the solvent is preferably performed by means of distillation, particularly by means of distillation under reduced pressure, i.e., at a pressure less than 1 atm which is able to remove the solvent at the temperature used (which pressure can be readily determined by one skilled in the art) and preferably at a temperature less than 40°C.
  • the obtained product can be purified by means of crystallization, particularly of a mixture of ethyl acetate and hexane .
  • the compound of formula (VIII) is obtained by treatment of a compound of formula (IX) with sodium bromide and sodium hypochlorite.
  • treatment of the compound of formula (IX) with sodium bromide and sodium hypochlorite is performed in the presence of acetic acid.
  • this treatment is performed for 10 to 20 hours, preferably for about 15 hours.
  • the treatment is performed at a temperature of between -5°C and 5°C.
  • water and sodium bisulfite are added.
  • compound of formula (VIII) is isolated by means of filtration.
  • the compound of formula (I) or a geometric isomer thereof is obtained by means of a process comprising the steps of:
  • the present invention relates to an amorphous form of obeticholic acid.
  • said amorphous form is characterized by comprising a halo (broad band) in the x-ray powder diffraction pattern which has a maximum at about 15 °2Q, particularly the halo goes from about 5 °2Q to about 30 °2Q.
  • a halo broad band
  • the amorphous form of obeticholic acid of the present invention has an x-ray powder diffraction pattern substantially similar to that of Figure 1.
  • the x-ray powder diffraction pattern can be obtained by means of the method described in the examples.
  • said amorphous form is characterized by having a differential scanning calorimetry (DSC) diagram with endothermic peaks at from about 75°C to about 90°C and at from about 260°C to about 270°C.
  • the amorphous form of obeticholic acid of the present invention has a DSC diagram substantially similar to that of Figure 2.
  • the DSC diagram can be obtained by means of the method described in the examples .
  • XRPD analysis was performed in a Siemens D-500 x-ray powder diffractometer equipped with a copper anode with a wavelength of 1.54 A. Scanning parameters: 4-50 degrees 2Q, continuous scanning, ratio: 1.2 35 degrees/minute.
  • DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW11.00 software for obeticholic acid and 3a-tetrahydropyranyloxy- 6a-ethyl-7a-hydroxy-5 b-cholanic acid or STARe SW15.00 software for the diethylamine salt of compound (III) .
  • Parameters heating range of 25 to 300°C with a ramp of 20°C/min and N2 flow of 50 ml/min. The measurement is taken with a pierced closed crucible.
  • the resulting reaction mixture was maintained under stirring for about 15 h at the temperature of between -5 and 5°C. After maintenance ended, the resulting mixture was heated at the approximate temperature of 25°C and 60 mL of an aqueous solution of 5% sodium bisulfite were slowly loaded. The obtained mixture was stirred for 30 minutes at the indicated temperature. 250 mL of water were added at the indicated temperature and the obtained mixture 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 (yield 76.9%) of 3a-hydroxy-7-keto-5 b-cholanic acid .
  • reaction mass was cooled at the approximate temperature of 25°C and a solution previously prepared by mixing 45 mL of water and 5 mL of an aqueous solution of NaOH 30% was slowly added.
  • 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 obtained mixture was acidified with HC1 37% to a pH value of about 2.
  • the organic phase was separated and the solvent was vacuum-distilled to obtain 30.8 g (yield 88%) of a colorless oil corresponding to benzyl 3a-hydroxy-7-keto-5b-cholanate .
  • the mixture was maintained under stirring under nitrogen atmosphere at the temperature of about - 72°C. Once maintenance ended, a previously prepared solution of 75 g (390 mmol) of citric acid in 200 mL of water was slowly added without the temperature exceeding 5°C. Once the addition ended, the mixture temperature was left to reach 20°C and the organic phase was separated. The solvent was distilled by means of vacuum until obtaining an oil residue, which was dissolved in 350 mL of dichloromethane . The resulting organic phase was first washed with 150 mL of a saturated aqueous solution of NaHC0 3 and then with 150 mL of water.
  • the pH of the reaction mixture was adjusted to an approximate value of 9 by means of the addition of 24 mL of triethylamine at the temperature of between 20 and 25°C.
  • the resulting reaction mixture was concentrated by vacuum distilling the solvent, and a very dense and virtually colorless oil corresponding to benzyl 3a-tetrahydropyranyloxy-6-ethylidene-7-keto-5p-cholanate was obtained.
  • the purity of the obtained product is 96.68%.
  • the obtained phases were allowed to decant, and the organic phase was separated from the aqueous phase. 600 mL of water were added to the organic phase, and the organic phase was separated again. The organic phase was concentrated by vacuum-distilling the solvent, and a very dense and virtually colorless oil corresponding to benzyl 3a-tetrahydropyranyloxy- 6-ethylidene-7-keto-5 b-cholanate was obtained. The purity of the obtained product is 96.23%.
  • the pH of the reaction mixture was adjusted to an approximate value of 9.5 by means of the addition of 1.5 L of triethylamine at the temperature of between 20 and 25°C.
  • the resulting reaction mixture was concentrated by vacuum distilling the solvent, and a very dense and virtually colorless oil corresponding to benzyl 3a-tetrahydropyranyloxy- 6- ethylidene-7-keto-5b-cholanate was obtained.
  • the purity of the obtained product as determined by HPLC is 98.35%.
  • the mixture was filtered through a diatomaceous earth filter, was introduced in a pressure reactor, and 2.5 mg of Pd/C were added.
  • the reactor was pressurized with hydrogen to an internal pressure of 5 bar, and the resulting reaction mixture was maintained at the temperature of about 40°C for 5 hours. Once said maintenance ended, the reaction mass was cooled at the temperature of about 20°C, and the Pd/C was filtered by means of a filter with diatomaceous earth.
  • the reaction mass was distilled by means of reduced pressure without exceeding the temperature of 40°C until obtaining a dense residue.
  • the resulting reaction mixture was maintained under stirring at the reflux temperature (about 87 °C) for 3 hours (control of the reaction mass by means of HPLC shows complete conversion of the product 3a-tetrahydropyranyloxy- 6a- ethyl-7-keto-5/3-cholanic acid) .
  • control of the reaction mass by means of HPLC shows complete conversion of the product 3a-tetrahydropyranyloxy- 6a- ethyl-7-keto-5/3-cholanic acid.
  • most of the methanol was distilled at atmospheric pressure and 250 mL of ethyl acetate were added to the resulting mass.
  • the pH of the resulting mixture was adjusted to a value of about 5 by means of the addition of an 85% aqueous solution of phosphoric acid and the phases thus obtained were separated. 250 mL of ethyl acetate were added to the aqueous phase and the resulting phases were separated.
  • the two organic phases thus obtained were pooled and mixed with 250 mL of a 10% aqueous solution of sodium chloride.
  • the phases were separated and the resulting organic phase was vacuum-distilled to a maximum temperature of 30°C.
  • 55 mL of ethyl acetate were added to the obtained residue and the resulting mixture was heated at a temperature of about 75°C.
  • 55 mL of n-heptane were added to the resulting solution and the mixture was slowly cooled under gentle stirring until the temperature of about 20°C, the presence of a white solid being observed.
  • the resulting mixture was maintained at said 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 white solid thus obtained yielded, after being dried, 37.0 g (86.6%) corresponding to 3a-tetrahydropyranyloxy- 6a-ethyl-7a- hydroxy-5 b-cholanic acid.
  • the purity of the product was analyzed by means of HPLC to obtain 99.08%.
  • Figure 3 shows the DSC of the obtained product.
  • Example 7 The product obtained in Example 7 was dissolved in 30 L of methanol. The resulting reaction mixture was concentrated by means of solvent vacuum distillation and 45 L of methanol and 0.96 L of a 30% (w/v) aqueous solution of sodium hydroxide were added. The solution thus obtained was heated to the temperature of about 40 °C and recirculated for 1 hour and 15 minutes through a filter containing 4S-type activated carbon and diatomaceous earth. The filtered solution was introduced in a pressure reactor, the filtering system was washed with 2 fractions of 16 L each of methanol and 4.3 L of a 30% (w/v) aqueous solution of sodium hydroxide and 0.6 kg of 5% Pd/C were added.
  • the reactor was pressurized with hydrogen to an internal pressure of 5 bar, and the resulting reaction mixture was maintained at the temperature of about 40°C for 5 hours. Once said maintenance ended, the reaction mass was cooled at the temperature of about 20°C, and the 5% Pd/C was filtered by means of a filter with diatomaceous earth. The filter was washed with 3 fractions of 20 L each of methanol. The reaction mass was distilled by means of reduced pressure without exceeding the temperature of 40°C until obtaining a distillate volume of about 50 L. 6 L of a 14 M solution of sodium hydroxide and 12% of NaBH4 (38.09 mol NaBIHU, 1.1 molar equivalents) were slowly added at a temperature of about 40 °C.
  • the resulting reaction mixture was maintained under stirring at the reflux temperature for 3 hours (control of the reaction mass by means of HPLC shows complete conversion of the product 3a-tetrahydropyranyloxy- 6a- ethyl-7-keto-5/3-cholanic acid) .
  • the reaction solvent was distilled at atmospheric pressure and 48 L of water and 38 L of n-heptane were added to the obtained residue.
  • the resulting mixture was heated under stirring to the temperature of about 45 °C. Stirring was stopped and the obtained mixture was allowed to stand and the resulting phases were separated. 25 L of ethyl acetate and an aqueous solution of 85% phosphoric acid were added to a final pH of the mixture of about 5. The phases thus obtained were separated.
  • the diethylamine salt of 3a- tetrahydropyranyloxy-6a-ethyl-7a-hydroxy-5p-cholanic acid can be recrystallized from ethyl acetate (4 volumes of solvent per mass of salt to recrystallize) .
  • a typical example of purification by recrystallization allows obtaining the product with a recrystallization yield of about 95% and a product purity as analyzed by means of HPLC of 99.87%.
  • the organic phase is separated and the aqueous phase is acidified at the temperature of about 20°C to a pH value of 2-3 by means of the addition of a 12N aqueous solution of HC1.
  • the resulting mixture is filtered to obtain, after being dried, 14.7 g (yield 88%) of a white solid corresponding to obeticholic acid.
  • the purity of the product was analyzed by means of HPLC to obtain 99.58%.
  • Figure 1 shows the XRPD of the obtained product and Figure 2 shows its DSC.
  • the mixture thus obtained was heated to about 50 °C and was maintained at said temperature for 5 hours . Once maintenance ended, the solvent was distilled under reduced pressure and water was added to a total volume of about 1 L. The mixture thus obtained was filtered and the filtered solution was slowly added to a 12 N HC1 aqueous solution maintaining the temperature between 20 and 25 °C. The final pH of the resulting mixture as about 1. Once the addition had ended, the resulting mixture was stirred at a temperature of between 20 and 25 °C for 15 minutes. The resulting solid was filtered and dried in an air oven at a temperature of about 50 °C. 28.64 g (yield 85.2%) of a white solid corresponding to obeticholic acid were thus obtained. The purity of the product was analyzed by means of HPLC to obtain 99.81%. The XRPD and DSC of the obtained product correspond to those of amorphous obeticholic acid according to Figure 1 and Figure 2.

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Abstract

La présente invention concerne un nouvel intermédiaire pour la synthèse de l'acide obéticholique, composé de formule (I) ou un isomère géométrique de celui-ci, son procédé d'obtention, ainsi que l'utilisation dudit intermédiaire dans la synthèse de l'acide obéticholique.
PCT/EP2019/055033 2018-03-07 2019-02-28 Synthèse d'acide obéticholique et intermédiaire de synthèse WO2019170521A1 (fr)

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ES201830220A ES2724725B2 (es) 2018-03-07 2018-03-07 Síntesis de ácido obeticólico e intermedio de síntesis
ESP201830220 2018-03-07
ES201930143A ES2779985B2 (es) 2019-02-20 2019-02-20 Sal de dietilamina del ácido 3alfa-tetrahidropiraniloxi-6alfa-etil-7alfa-hidroxi-5ß-colánico
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020169643A1 (fr) * 2019-02-20 2020-08-27 Moehs Iberica, S.L. Sel de diéthylamine de l'acide 3 alpha-tétrahydropyranyloxy-6 alpha-éthyl-7 alpha-hydroxy-5 bêta-cholanique
EP3943502A4 (fr) * 2019-03-19 2022-11-23 Suzhou Zelgen Biopharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'acide chénodésoxycholique

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020169643A1 (fr) * 2019-02-20 2020-08-27 Moehs Iberica, S.L. Sel de diéthylamine de l'acide 3 alpha-tétrahydropyranyloxy-6 alpha-éthyl-7 alpha-hydroxy-5 bêta-cholanique
EP3943502A4 (fr) * 2019-03-19 2022-11-23 Suzhou Zelgen Biopharmaceutical Co., Ltd. Procédé de préparation d'un dérivé d'acide chénodésoxycholique

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