WO2016045480A1 - Method for preparing obeticholic acid - Google Patents

Abstract

Provided are a compound represented by formula (III) and a preparation method therefor, wherein R¹ is a hydroxyl protective group and preferably is MOM; and also provided is a method for preparing obeticholic acid by using the compound. The preparation method has moderate reaction conditions, few by-products and simple and convenient operation, and is suitable for large-scale production.

Description

Preparation method of oleic acid Technical field

The invention relates to a preparation method of oleic acid.

Background technique

Abecholic acid (as shown in Formula I) is a semi-synthetic chenodeoxycholic acid derivative for the treatment of portal hypertension and liver disease, including primary biliary cirrhosis, bile acid diarrhea, non-alcohol Sexual 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 VI with ethyl iodide under strong basic conditions to obtain compound VII, which is obtained by reduction and decarboxylation of compound VII. 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.

Method for synthesizing oleic acid (WO2002072598)

WO2006122977 has improved the above synthesis process (as shown below) by converting compound IX to a silicon-based protected enol compound X, which is condensed and dehydrated with acetaldehyde to give compound Vb, and compound Vb is subjected to basic conditions. The lower palladium carbon is hydrogenated and reduced to obtain compound XI, and compound XI is reduced by carbonyl to obtain oleic acid.

Method for synthesizing oleic acid (WO2006122977)

Although the synthesis process can achieve amplification synthesis, however, a large amount of by-products are generated during the preparation of compound XI by the hydrogenation reduction of palladium carbon and the high-alkaline high-temperature treatment of compound Vb under strong alkaline conditions, thereby causing the separation of the reaction. The rate is low (about 60%), and the low yield of this step may be due to dehydration of unprotected hydroxyl groups in compounds Vb and XI under strong alkaline (30% NaOH) and high temperature (95-105 ° C) conditions. Caused by side reactions.

Summary of the invention

In view of the shortcomings in the synthetic method of the existing oleic acid, the inventors have discovered through enthusiasm that by protecting the hydroxyl group of the compound V, side reactions such as dehydration under strong alkaline and high temperature conditions can be avoided, and the ozone is greatly improved. The synthesis efficiency of choline acid provides a preparation method of oleic acid which is less suitable for large-scale production, has less by-products, is easy to operate, and has low synthesis cost.

The invention provides a new method for synthesizing oleic acid,

Wherein R ¹ is a hydroxy protecting group and R ² is a carboxy protecting group.

Specifically, the synthesis method includes the following steps:

1) a compound of formula V is protected by a hydroxy group to give a compound of formula IV;

2) Formula IV is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to obtain a compound of formula III;

3) Formula III is reduced to obtain a compound of formula II;

4) Formula II is deprotected by hydroxy groups under acidic conditions to produce oleic acid as shown in Formula I.

Among them, the compound V is synthesized according to the method described in WO2006122977.

In a preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM and the carboxy protecting group R ² is ethyl.

In another preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM and the carboxy protecting group R ² is methyl.

In a particularly preferred embodiment, the present invention provides a synthetic route for oleic acid as follows:

Specifically, the synthesis method includes the following steps:

1) reacting a compound of formula Va with MOMCl to give a compound of formula IVa;

2) Formula IVa is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to obtain a compound of formula IIIa;

3) a compound of formula IIIa is obtained by reduction of sodium borohydride of formula IIIa;

4) Formula IIa is hydrolyzed by hydrochloric acid to remove hydroxy group protection to obtain oleic acid as shown in Formula I.

Among them, the compound Va is synthesized according to the method described in WO2006122977.

The invention also provides a compound of formula IV,

Wherein R ¹ is a hydroxy protecting group and R ² is a carboxy protecting group.

In a preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM and the carboxy protecting group R ² is ethyl.

In another preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM and the carboxy protecting group R ² is methyl.

The invention further provides a process for the preparation of a compound of formula IV, which is prepared by hydroxy protecting a compound of formula V.

Wherein R ¹ is a hydroxy protecting group and R ² is a carboxy protecting group.

The invention also provides a compound of formula III,

Wherein R ¹ is a hydroxy protecting group.

In a preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM.

The invention further provides a process for the preparation of a compound of formula III, which is prepared by catalytic hydrogenation of palladium on carbon under basic conditions by a compound of formula VI.

Wherein R ¹ is a hydroxy protecting group.

In a preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM.

The invention also provides a compound of formula II,

Wherein R ¹ is a hydroxy protecting group.

In a preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM.

The present invention further provides a process for the preparation of a compound of the formula II, which is obtained by subjecting a compound of the formula III to a reduction reaction.

Wherein R ¹ is a hydroxy protecting group.

In a preferred embodiment of the invention, the hydroxy protecting group R ¹ is MOM.

The terminology used in the present invention has the following meanings, unless stated to the contrary:

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, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; may be (C _1-10 alkyl or aryl) acyl, for example: formyl, acetyl, benzoyl An acyl group or the like; may be a (C _1-6 alkyl or C _6-10 aryl)sulfonyl group; or a (C _1-6 alkoxy group or a C _6-10 aryloxy)carbonyl group.

"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. GMWuts), 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.

The English abbreviation used in the present invention has the following meanings:

abbreviation	Full name
		MOMCl	Chloromethyl methyl ether
MOM	Methoxymethyl
		TMS	Trimethylsilyl

The following table shows the structural formula of the compounds involved in the examples.

detailed description

The invention will be explained in detail below with reference to specific examples, which are intended to provide a more complete understanding of the invention.

Example 1: Preparation of Compound IVa

Compound Va (646 g, prepared according to the method of WO2006122977) was dissolved in 7 liters of dichloromethane, 762 ml of diisopropylethylamine was added, cooled to 0 ° C, 166 ml of MOMCl was added, and the reaction system was heated to 20 ° C. After reacting for 16 hours, the reaction was quenched with water, and extracted with 10 liters of ethyl acetate. The organic phase was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered to give 696 g of compound IVa.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.16 (q, 1H), 4.76 - 4.59 (m, 2H), 4.28 - 4.01 (m, 2H), 3.70 - 3.48 (m, 1H), 3.42 - 3.29 (m) , 3H), 2.56 (dd, 1H), 2.46–2.14 (m, 4H), 2.07–1.87 (m, 4H), 1.87–1.68 (m, 5H), 1.55–1.04 (m, 16H), 1.00 (s) , 3H), 0.92 (t, 3H), 0.78–0.62 (m, 3H).

Example 2: Preparation of Compound IIIa

Compound IVa (696g) was dissolved in ethanol (7 liters), palladium on carbon (76 g, 10 wt%) and 500 g of 30% aqueous sodium hydroxide solution were added, and reacted under hydrogen (1.5 atm) and 20 ° C for 16 h, then warmed to After stirring at 95 ° C for 16 hours, cooling to 20 ° C, filtration, the concentrated mother liquor was neutralized with 2N hydrochloric acid, and extracted with 10 liters of ethyl acetate. The extract was concentrated, crystallized, filtered, and dried to give 606 g of compound. IIIa, yield 92%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.74 - 4.55 (m, 2H), 3.52 - 3.39 (m, 1H), 3.38 - 3.30 (m, 3H), 2.68 (dd, 1H), 2.49 - 2.13 (m , 4H), 2.02–1.65 (m, 9H), 1.58–1.02 (m, 15H), 0.95 (dd, 4H), 0.86–0.77 (m, 3H), 0.67 (d, 3H).

Example 3: Preparation of Compound IIa

Compound IIIa (606 g) was dissolved in 7 liters of ethanol, cooled to 0 ° C, 50 g of sodium borohydride was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours. Phosphoric acid was slowly added dropwise until pH = 6, solids were precipitated, filtered, solid After washing with water and drying, 584 g of Compound IVa was obtained in a yield of 96%.

1H NMR (400MHz, CDCl ₃ ) δ 4.66 (s, 2H), 3.72 (m, 2H), 3.35 (m, 4H), 2.25-1.07 (m, 28H), 0.90 (m, 8H), 0.65 (s, 3H).

Example 4: Preparation of oleic acid

The compound IIa (584 g) was dissolved in 6 liters of tetrahydrofuran, cooled to 0 ° C, 5 liters of 4N aqueous hydrochloric acid was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours, and 10 liters of ethyl acetate was added thereto, and the extract was concentrated and analyzed. Crystallization, filtration and drying gave 497 g of oleic acid in a yield of 94%.

1H NMR (400MHz, CD ₃ OD) δ 3.65 (m, 1H), 3.30 (m, 1H), 2.32 (m, 1H), 2.20 (m, 1H), 2.03-1.65 (m, 8H), 1.60-1.06 (m, 18H), 0.90 (m, 9H), 0.67 (s, 3H).

Example 5: Preparation of Compound IVb

Compound Vb (500 g, prepared according to the method of WO2006122977) was dissolved in 5 liters of dichloromethane, 650 ml of diisopropylethylamine was added, cooled to 0 ° C, 147 ml of MOMCl was added, and the reaction system was gradually increased to 20 After reacting for 16 hours, the reaction was quenched with water. EtOAc (EtOAc)EtOAc.

1H NMR (400MHz, CDCl ₃ ) δ 6.16 (m, 1H), 4.65 (s, 2H), 3.66 (s, 3H), 3.55 (m, 1H), 3.34 (s, 3H), 3.08 (m, 1H) , 2.55 (m, 2H), 2.53 (m, 2H), 2.22 (m, 2H), 1.96 (m, 6H), 1.80 (m, 2H), 1.69 (m, 4H), 1.56-1.01 (m, 14H) ), 0.93 (m, 3H), 0.62 (s, 3H).

Example 6: Preparation of Compound IIIa

Compound IVb (70 g) was dissolved in ethanol (750 liters), palladium on carbon (8 g, 10 wt%) and 50 g of 30% aqueous sodium hydroxide solution were added, and reacted under hydrogen (1.5 atm) at 20 ° C for 10 h, then warmed up. After stirring to 100 ° C, stirring for 10 hours, cooling to 20 ° C, filtration, the concentrated mother liquor was neutralized with 2N hydrochloric acid, extracted with 1 liter of ethyl acetate, the extract was concentrated, crystallized, filtered, dried to give 65 g Compound IIIa, yield 95%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ4.62 (m, 2H), 3.43 (m, 1H), 3.34 (m, 3H), 2.68 (m, 1H), 2.25 (m, 4H), 1.82 (m, 9H), 1.58–1.02 (m, 15H), 0.95 (m, 4H), 0.80 (m, 3H), 0.66 (s, 3H).

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 (11)

1. a compound of formula III,

   

   Wherein R ¹ is a hydroxy protecting group, preferably MOM.
2. A process for the preparation of a compound of the formula III, characterized in that the compound IV is obtained by protecting a compound of the formula V by a hydroxyl group, and the compound IV is obtained by hydrogenation to obtain a compound III, preferably under basic conditions. Catalytic hydrogenation of palladium on carbon,

   

   Wherein R ¹ is a hydroxy protecting group, preferably MOM; R ² is a carboxy protecting group, preferably a C _1-10 straight or branched alkyl group, more preferably an ethyl group or a methyl group.
3. A method for preparing a compound as shown in Formula IIIa, which comprises the steps of

   

   1) reacting a compound of formula Va with MOMCl to give a compound of formula IVa;

   2) Formula IVa is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to give a compound of formula IIIa.
4. a compound of formula IV,

   

   Wherein R ¹ and R ^{2 are} as defined in claim 2.
5. A process for the preparation of a compound of the formula IV, which is obtained by protecting a compound of the formula V with a hydroxyl group,

   

   Wherein R ¹ and R ^{2 are} as defined in claim 2.
6. a compound of formula II,

   

   Wherein R ^{1 is} as defined in claim 1.
7. A process for the preparation of a compound of the formula II, which is obtained by reduction of a compound of the formula III after carbonyl reduction, preferably with sodium borohydride,

   

   Wherein R ^{1 is} as defined in claim 1.
8. A method for preparing a compound as shown in Formula IIa, which comprises the steps of

   

   1) reacting a compound of formula Va with MOMCl to give a compound of formula IVa;

   2) Formula IVa is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to obtain a compound of formula IIIa;

   3) The compound of formula IIIa is obtained by reduction of sodium borohydride of formula IIIa.
9. A method for preparing oleic acid, which comprises the steps of preparing a compound of formula II by removing a hydroxy protecting group to prepare oleic acid.

   

   Wherein R ^{1 is} as defined in claim 1.
10. The method for producing oleic acid according to claim 9, which further comprises the step of preparing the compound of the formula II according to claim 7.
11. The method for producing oleic acid according to claim 10, which further comprises the step of preparing a compound of formula III according to claim 2.