WO2018010651A1

WO2018010651A1 - Method for manufacturing obeticholic acid and intermediate thereof

Info

Publication number: WO2018010651A1
Application number: PCT/CN2017/092554
Authority: WO
Inventors: 张顺吉; 王生; 刘路; 田伟伟
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2016-07-13
Filing date: 2017-07-12
Publication date: 2018-01-18
Also published as: CA3027761A1; CN108602850A; CN108602850B; TW201802103A

Abstract

The present invention relates to a method for manufacturing an obeticholic acid and an intermediate thereof. The invention specifically relates to a method for manufacturing a compound represented by formula V. The method comprises: using a compound represented by formula VI and performing a hydrogenation reaction in the presence of an acidic substance and catalyst to obtain the compound represented by formula V, and using the compound represented by formula V to manufacture the obeticholic acid. The method has the advantages of mild reaction conditions, high yield, little byproducts, ease of operation, and applicability in large scale production.

Description

Method for preparing oleic acid and intermediate thereof

Technical field

The invention relates to a preparation method of oleic acid and an intermediate thereof.

Background technique

Obicholic acid (as shown in formula I), chemical name 6α-ethyl-3α, 7α-dihydroxy-5β-cholanoic acid, is a semi-synthetic chenodeoxycholic acid derivative used to treat the portal vein Hypertension and liver disease, including primary biliary cirrhosis, bile acid diarrhea, nonalcoholic steatohepatitis. Obecholic acid acts by activating FXR receptors, a nuclear receptor that is expressed primarily in the liver, intestines, and kidneys. It regulates the expression of genes involved in bile acids, fats, and glucose metabolism, and regulates immune response. Activation of FXR inhibits bile acid synthesis and prevents toxic reactions caused by excessive accumulation of bile acids.

WO2002072598 discloses for the first time the preparation method of oleic acid (as shown below), which is obtained by direct alkylation of compound XIV with iodoethane under strong basic conditions to obtain compound XV, which is obtained by reduction and carboxyl deprotection of compound XV. Abecholic acid. However, due to the poor selectivity and low yield of direct alkylation with iodoethane, it is difficult to achieve amplification synthesis in this synthesis process.

WO2006122977 has improved the above synthesis process (as shown below) by converting compound VIII into a silicon-based protected enol compound IX, compound IX and acetaldehyde are condensed and dehydrated to obtain compound X, and compound X is first hydrolyzed to obtain XI. Further, the compound XII is obtained by hydrogenation reduction of palladium carbon under basic conditions, and the compound XII is reduced by a carbonyl group to obtain oleic acid. Although the synthesis process can achieve amplification synthesis, the yield of the hydrogenation reduction step is low, resulting in a low yield of the final product.

WO2016045480 discloses a novel synthesis method of oleic acid by finally protecting the hydroxyl group of the compound (XIa) and then hydrogenating the reaction to finally obtain oleic acid. Although the yield of the synthesis process is increased, the reaction has difficulty in the amplification process, the reaction yield is lowered, the impurities are generated, and the separation and purification are difficult, resulting in the presence of a part of impurities in the final product oleic acid which cannot be removed, and the purification is difficult.

Therefore, there is an urgent need for a synthetic process of oleic acid with high yield, low impurity and industrial production to overcome the deficiencies of the prior art.

Summary of the invention

In one aspect, the invention provides a process for the preparation of a compound of formula V, which comprises preparing a compound V by hydrogenation of a compound of formula VI in the presence of an acidic material and a catalyst,

Wherein R ¹ is hydrogen or a carboxy protecting group, preferably hydrogen or C _1-10 alkyl, more preferably hydrogen, methyl or ethyl; R ² is C _1-5 alkyl, preferably methyl; R ³ It is a hydrogen or hydroxy protecting group, preferably hydrogen or methoxymethyl.

The acidic material may be a protic acid or a Lewis acid, preferably an organic or inorganic acid, more preferably a C _1-5 alkyl acid, most preferably acetic acid or formic acid. The catalyst may be a catalyst commonly used in catalytic hydrogenation, preferably palladium carbon, PtO ₂ or Raney nickel. The hydrogenation reaction is preferably carried out at a pressure between 1 and 3 atmospheres.

Another aspect of the present invention provides a process for the preparation of oleic acid comprising the above-described step of preparing a compound of formula V wherein R ² is a methyl group.

In this step, preferably, R ¹ is a carboxy protecting group, preferably a methyl or ethyl group; and R ³ is hydrogen;

Another preferably, R ¹ is hydrogen and R ³ is hydrogen.

When R ¹ is a carboxy protecting group and R ³ is hydrogen, the 3α-hydroxy group of compound V can be further protected to a compound of formula IV wherein R ⁵ is a hydroxy protecting group, preferably a methoxymethyl group.

The compound of formula IV can be further hydrolyzed under basic conditions to give a compound of formula III.

The compound of formula III can be further reduced by a reducing agent to give a compound of formula II, wherein the reducing agent is preferably a borohydride, more preferably sodium borohydride.

The compound of formula II can be further dehydroxylated to give the oleic acid.

Optionally, the method of preparation further comprises the step of heat treating a compound selected from the group consisting of compounds V, IV, III, the heat treatment comprising heating the compound under basic conditions, preferably at a temperature of from 95 to 105 °C. The heat treatment step may be carried out after any one of the steps of preparing the compound V, IV or III, and the heat treatment method is a method disclosed in the prior art, that is, heating the product under alkaline conditions, specifically, reacting The product is heated under the alkaline condition at a temperature of 95-105 ° C for an hour to make the 6-β-ethyl epimerization to 6-α-ethyl. The reaction in this step is stable, the conversion rate is high, and the yield is basically more than 90 percent.

When R ¹ is hydrogen and R ³ is hydrogen, the compound of formula V may be further reduced by a reducing agent to obtain oleic acid, optionally further comprising the step of heat treating the compound of formula V, wherein the reducing agent is preferably a borohydride, more preferably Sodium borohydride, the heat treatment comprising heating the compound under alkaline conditions, preferably at a temperature of from 95 to 105 °C.

Another aspect of the invention also provides a method for preparing oleic acid, comprising the steps of:

1) a compound of the formula VIb is hydrogenated in the presence of an acidic material and a catalyst to produce a compound of the formula Vb;

2) protecting the 3α-hydroxy group of the compound of formula Vb to give a compound of formula IVb;

3) the compound of the formula IVb is hydrolyzed under basic conditions, and optionally the reaction product is obtained to give a compound of the formula IIIb;

4) a compound of formula IIIb is reduced by a borohydride to give a compound of formula IIb;

5) a dehydroxy protecting group of a compound of formula IIb gives oleic acid,

Wherein R ⁴ is a carboxy protecting group, preferably a methyl or ethyl group; R ⁵ is a hydroxy protecting group, preferably a methoxymethyl group; the acidic medium is preferably formic acid or acetic acid; the catalyst is preferably palladium carbon; the borohydride The material is preferably sodium borohydride, and the heat treatment comprises heating the product under basic conditions, preferably at a temperature of from 95 to 105 °C.

1) a compound of the formula IIIc is hydrogenated in the presence of an acidic material and a catalyst to give a compound of the formula IIc;

2) optionally heat treating the compound of formula IIc;

3) the compound of formula IIc is reduced by borohydride to give oleic acid,

Wherein the acidic medium is preferably formic acid or acetic acid; the catalyst is preferably palladium carbon; the borohydride boron hydrogen Sodium, the heat treatment comprising heating the compound of formula IIc under basic conditions, preferably at a temperature of from 95 to 105 °C.

In the chemical structure of the compound of the present invention, a bond

Configuration is not specified, ie key

Can be

or

Or both

with

Two configurations.

In the preparation method of the oleic acid and the intermediate thereof according to the present invention, since the catalytic hydrogenation reaction is carried out under acidic conditions, not only the reaction yield is improved, but also the purity of the product is greatly improved, and the reaction is maintained well after amplification. The reaction effect. Subsequently, the 3α-hydroxy group of the intermediate is protected, the formation of reaction by-products is effectively reduced, the purity of the product is improved, the purification of the final product is greatly reduced, and the efficiency of industrial production is improved.

The hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GM Wuts). As an example, preferably, the hydroxy protecting group may be a (C _1-10 alkyl or aryl) ₃ silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C _1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C _1-6 alkoxy substituted C _{a 1-6} alkyl or phenyl substituted C _1-6 alkyl group, most preferably a C _1-4 alkoxy substituted C _1-4 alkyl group, for example: methyl, tert-butyl, allyl, benzyl , methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; may be (C _1-10 alkyl or aryl) acyl, for example: formyl, acetyl , benzoyl, etc.; may be (C _1-6 alkyl or C _6-10 aryl)sulfonyl; may also be (C _1-6 alkoxy or C _6-10 aryloxy)carbonyl.

"Carboxylic acid protecting group" is a suitable group for carboxylic acid protection known in the art, see the carboxylic acid protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GM Wuts), As an example, preferably, the carboxylic acid protecting group may be a substituted or unsubstituted C _1-10 linear or branched alkyl group, a substituted or unsubstituted C _2-10 linear or branched alkenyl group. Or alkynyl, substituted or unsubstituted C _3-8 cyclic alkyl, substituted or unsubstituted C _5-10 aryl or heteroaryl, or (C _1-8 alkyl or aryl) ₃ silane A straight or branched alkyl group of C _1-6 is preferred, and a linear or branched alkyl group of C _1-4 is more preferred.

"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl groups and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, pentyl, heptyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, Heterocyclic group, aryl group, heteroaryl group, carbonyl group.

The structural formula of the compound involved in the examples is as follows

detailed description

The invention will be explained in detail below with reference to specific examples, which are to be understood by those skilled in the art.

Example 1: Preparation of Compound Va

Compound VIa (6 kg, prepared according to the method of WO2006122977) was dissolved in acetic acid (48 liters), palladium on carbon (0.5 kg, 10 wt%) was added to hydrogen (1.5 atm) and reacted at 20 ° C for 16 hours. The residue was concentrated with ethyl acetate (50 liters), washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and filtered and evaporated. The rate was 96% and the HPLC purity was 97.2%.

1H NMR (400MHz, MeOD) δ 4.14 - 4.07 (m, 2H), 3.54-3.44 (m, 1H), 2.71-2.46 (m, 1H), 2.41-2.32 (m, 1H), 2.28-2.19 (m, 1H), 2.17-0.78 (m, 36H), 0.74-0.68 (m, 3H).

Example 2: Preparation of Compound IVa

Compound Va (5.8 kg) was dissolved in dichloromethane (50 L), diisopropylethylamine (5.6 L) was added, 1.4 L of bromomethyl methyl ether was added dropwise, and the reaction was carried out at room temperature for 16-20 hours. The mixture was washed with dilute aqueous hydrochloric acid, saturated aqueous sodium hydrogen sulfate and brine, dried over anhydrous sodium sulfate and filtered and evaporated to afford 5.8 g of compound IVa, yield 91%, HPLC purity 95.5%.

1H NMR (400MHz, MeOD) δ 4.60-4.54 (m, 2H), 4.08-4.00 (m, 2H), 3.47-3.36 (m, 1H), 3.25 (s, 3H), 2.64-2.40 (m, 1H) , 2.34 - 2.25 (m, 1H), 2.22 - 2.11 (m, 1H), 2.10 - 0.72 (m, 36H), 0.67-0.60 (m, 3H).

Example 3: Preparation of Compound IIIa

Compound IVa (5.8 kg) was dissolved in 40 liters of methanol, cooled to 0 ° C, added 10 liters of 30% sodium hydroxide solution, heated to 90-100 ° C for 15 h, diluted with hydrochloric acid to adjust to weak acidity, concentrated and added 50 Ethyl acetate was added, and the mixture was washed once with brine, dried and concentrated to give 5 g of Compound IIIa, yield 91%, HPLC purity 95.8%.

1H NMR (400MHz, MeOD) δ4.64-4.60 (m, 2H), 3.50-3.40 (m, 1H), 3.31 (s, 3H), 2.86-2.80 (dd, 1H), 2.53-2.47 (dd, 1H) , 2.39-2.29 (m, 1H), 2.25-2.10 (m, 2H), 2.06-0.77 (m, 31H), 0.71 (s, 3H).

Example 4: Preparation of Compound IIa

Compound IIIa (5 kg) was dissolved in 60 liters of ethanol, cooled to 0 ° C, 400 g of sodium borohydride was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours. 1 M hydrochloric acid was slowly added dropwise until pH = 6, solids were precipitated, and filtered. The solid was washed with water and dried to give 4.4 g of Compound IIa.

1H NMR (400MHz, MeOD) δ 4.65 (s, 2H), 3.66 (m, 1H), 3.36-2.27 (m, 4H), 2.38-2.30 (m, 1H), 2.24-2.16 (m, 1H), 2.03 -0.87 (m, 34H), 0.70 (s, 3H).

Example 5: Preparation of oleic acid

The compound IIa (4.4 kg) was dissolved in 50 liters of tetrahydrofuran, cooled to 0 ° C, 40 liters of 4N aqueous hydrochloric acid solution was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours, and 40 liters of ethyl acetate was added thereto, and the extract was concentrated and analyzed. Crystallization, filtration and drying gave 3.8 kg of oleic acid in a yield of 95% and HPLC purity of 98.4%.

1H NMR (400MHz, DMSO-d) δ 11.95 (s, 1H), 4.32-4.28 (d, 1H), 4.07-4.02 (d, 1H), 3.52-3.47 (m, 1H), 3.18-3.07 (m, 1H), 2.28-2.18 (m, 1H), 2.15-2.05 (m, 1H), 1.94-0.79 (m, 34H), 0.61 (s, 3H) ).

Example 6: Preparation of Compound XII

Compound XI (1 kg, prepared according to the method of WO2006122977) was dissolved in acetic acid (10 liters), palladium on carbon (100 g, 10 wt%) was added to hydrogen (1.5 atm) and reacted at 20 ° C for 16 h, filtered and concentrated. The residue was diluted with ethyl acetate (10 L), washed with water, aq. 0 ° C, adding 30 liters of 30% sodium hydroxide solution, heating to 90 ~ 100 ° C reaction for 15h, adding dilute hydrochloric acid to adjust to weakly acidic, concentrated, add 10 liters of ethyl acetate, washed once with saturated brine, concentrated with acetic acid The ester was recrystallized to give 850 g of Compound XII, yield 85%, HPLC purity 98.1%.

Example 7: Preparation of oleic acid

Compound XII (850 g) was dissolved in 10 liters of ethanol, cooled to 0 ° C, 80 g of sodium borohydride was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours. 1 M hydrochloric acid was slowly added dropwise until pH = 6, solids were precipitated, and filtered. The solid was washed with water and then recrystallized from butyl acetate to give 700 g of succinic acid, yield 82%, and HPLC purity 98

Comparative example 1

Compound IVd (3 kg) was dissolved in ethanol (25 liters) according to the method of Example 2 of WO2016045480 Palladium carbon (300 g, 10 wt%), and 2.2 kg of 30% aqueous sodium hydroxide solution were reacted under hydrogen (1.5 atm) and 20 ° C for 20 h, filtered, concentrated under reduced pressure, and the mother liquid was neutralized with 2N hydrochloric acid. The ester was extracted, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 30:1) to yield 2.05 g of Compound IIId, yield 72%, purity 80.5%.

According to the method of Example 3 in WO2016045480, compound IIId (2.05 kg) was dissolved in 25 L of absolute ethanol, 170 g of sodium borohydride was added, and the mixture was heated to 20 ° C for 10 h. Phosphoric acid was slowly added dropwise to adjust pH = 6, concentrated under reduced pressure, and extracted with ethyl acetate. The organic phase was concentrated to give 1.96 g of Compound IId.

According to the method of Example 3 in WO2016045480, the compound IId (1.96 kg) was dissolved in 20 L of tetrahydrofuran, the reaction solution was cooled to 0 ° C, 15 liters of 4N aqueous hydrochloric acid solution was added, and the mixture was heated to 20 to 30 ° C for 8 hours, and TLC showed impurities. The reaction mixture was concentrated under reduced pressure. The residue was evaporated. The yield was 58%, and the HPLC purity was 89.6%.

Since the present invention has been described in terms of its specific embodiments, certain modifications and equivalents are obvious to those skilled in the art and are included within the scope of the invention.

Claims

A process for the preparation of a compound of the formula V, which comprises the steps of preparing a compound V by hydrogenation of a compound of the formula VI in the presence of an acidic substance and a catalyst,

Wherein R 1 is hydrogen or a carboxy protecting group; R 2 is a C 1-5 alkyl group; and R 3 is a hydrogen or a hydroxy protecting group.
The process according to claim 1, wherein R 1 is hydrogen or a C 1-10 alkyl group, preferably hydrogen, methyl or ethyl.
The process according to claim 1, wherein R 2 is a methyl group.
The process according to claim 1, wherein R 3 is hydrogen or methoxymethyl.
The process according to claim 1, wherein the acidic substance is selected from the group consisting of organic acids or inorganic acids, preferably C 1-5 alkyl acids, more preferably acetic acid or formic acid.
The production method according to claim 1, wherein the catalyst is palladium carbon, PtO 2 or Raney nickel.
A process for the preparation of oleic acid characterized by comprising the step of preparing a compound of the formula V according to claims 1 to 6, wherein R 2 is a methyl group.
The process according to claim 7, wherein R 1 is a carboxy protecting group, preferably a methyl group or an ethyl group; and R 3 is hydrogen.
The process according to claim 8, further comprising the step of protecting a compound of formula V by a 3α-hydroxy group, wherein R 5 is a hydroxy protecting group, preferably a methoxymethyl group.

Also included is a step of hydrolyzing a compound of formula IV to a compound of formula III under basic conditions,

Also included is a step of reducing a compound of formula III by a reducing agent to a compound of formula II, preferably a borohydride, more preferably sodium borohydride,

Also included is a step of dehydroxylation of a compound of formula II to give oleic acid,

And, optionally, a step of heat treating a compound selected from the group consisting of compounds V, IV, III, said heat treatment package The compound is heated under alkaline conditions, and the heating temperature is preferably 95-105 °C.
The process according to claim 7, wherein R 1 is hydrogen and R 3 is hydrogen.
The method according to claim 10, further comprising the step of reducing the oleic acid by reduction of the compound of the formula V, and further comprising the step of optionally heat-treating the compound of the formula V, wherein the reducing agent is preferably a borohydride More preferably, sodium borohydride is used, and the heat treatment comprises heating the compound under alkaline conditions at a heating temperature of preferably 95 to 105 °C.
A method for preparing oleic acid comprises the following steps:

1) a compound of the formula VIb is hydrogenated in the presence of an acidic material and a catalyst to produce a compound of the formula Vb;

2) protecting the 3α-hydroxy group of the compound of formula Vb to give a compound of formula IVb;

3) the compound of the formula IVb is hydrolyzed under basic conditions, and optionally the reaction product is obtained to give a compound of the formula IIIb;

4) a compound of formula IIIb is reduced by a borohydride to give a compound of formula IIb;

5) a dehydroxy protecting group of a compound of formula IIb gives oleic acid,

Wherein R 4 is a carboxy protecting group, preferably a methyl or ethyl group; R 5 is a hydroxy protecting group, preferably a methoxymethyl group; the acidic medium is preferably formic acid or acetic acid; the catalyst is preferably palladium carbon; the borohydride The material is preferably sodium borohydride, and the heat treatment comprises heating the product under basic conditions, preferably at a temperature of from 95 to 105 °C.
A method for preparing oleic acid comprises the following steps:

1) a compound of the formula IIIc is hydrogenated in the presence of an acidic material and a catalyst to give a compound of the formula IIc;

2) optionally heat treating the compound of formula IIc;

3) the compound of formula IIc is reduced by borohydride to give oleic acid,

Wherein the acidic medium is preferably formic acid or acetic acid; the catalyst is preferably palladium carbon; the borohydride is preferably sodium borohydride, and the heat treatment comprises heating the compound of the formula IIc under alkaline conditions, preferably at a temperature of 95-105. °C.