WO2010118560A1

WO2010118560A1 - Preparation method for eplerenone

Info

Publication number: WO2010118560A1
Application number: PCT/CN2009/000531
Authority: WO
Inventors: 褚定军; 洪香仙
Original assignee: 浙江省天台县奥锐特药业有限公司; 上海奥锐特国际贸易有限公司
Priority date: 2009-04-15
Filing date: 2009-05-18
Publication date: 2010-10-21
Also published as: CN101863951A; CN101863951B

Abstract

The invention provides a process for preparing eplerenone, which comprises the following steps: (1) in the presence of a side reaction inhibitor, 17α-hydroxyl-3-oxo-γ-lactone-pregn-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester IV is selectively expoxidized on double bond in trichloroacetonitrile, oxidant and phosphate buffer system in solution, to prepare crude eplerenone; (2) the crude eplerenone is recrystallized to yield pure eplerenone. High pure eplerenone can be obtained by the method of the present invention, the purity of eplerenone can reach 99.5% and the yield is as high as 87%. The method of the present invention is suitable for production on an industrial scale.

Description

Preparation method of eplerenone

Technical field

The invention relates to medicinal chemistry, in particular to a novel preparation method of an antihypertensive drug eplerenone. Background technique

Eplerenone, English chemical name:

(7 α, 11 α, 17 α ) - 9, 1 l-epoxy-17- hydroxy- 3 - oxo-pregn

-4~ene-7, 21-dicarboxylic acid, Y-lactone, 7- methyl ester, is an antihypertensive drug. It is mainly used for the treatment of heart failure after myocardial infarction in patients with essential hypertension. The mechanism of action is to block the aldosterone in the renin-angiotensin-aldosterone system by binding to the aldosterone receptor, thereby reducing blood pressure.

The eplerenone preparation method of eplerenone is generally carried out by reacting trienone (formula I) with diethylaluminum cyanide or sodium cyanide to form 7-CN (formula II), and then Reduction oxidation gives 7-C00H (formula 111), which is methylated to give formula IV. The methylating agent can be diazoformin, dimethyl sulfate or iodoformin. As shown in the following reaction formula -

Formula IV is obtained by 9 ( 11 ) epoxidation to give eplerenone,

Patent US4559332 describes the preparation of eplerenone by epoxidation of the starting material of formula IV using a trichloroacetonitrile or hydrogen peroxide system. However, this patent does not describe the quality of the resulting product, including how to perform purification and the like.

The preparation of eplerenone by epoxidation according to the method of US 4,539,332 is reported in U.S. Patent No. 6,688,991 and U.S. Patent Application Publication No. 2008/0234478 A1. The resulting product produces impurities V and impurities VI.

Therefore, there are certain deficiencies in the above methods. The inventors conducted experiments according to the US 4557332 epoxidation method and found that the eplerenone content obtained by the method is low, and the eplerenone content by HPLC is only about 75%, and it is difficult to purify. There is also no mention of how to purify and remove related impurities in US6887991, although US 2008/0234478 A1 gives a clear method of forming a derivative by an acetic anhydride esterification process and then removing impurities by recrystallization, but the yield of the treatment process is only 2%以下。 The content of the individual impurities is only controlled below 0.2%. Not suitable for large-scale production

Therefore, there is a need to find a process for the preparation of eplerenone which is suitable for industrial production and which can obtain high quality and high yield. Summary of the invention

The technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, and to design a preparation method suitable for industrial production and to obtain high quality and high yield of eplerenone.

The inventors conducted a large number of experimental studies, and it was surprisingly found that according to the US 4557332 epoxidation method, a large amount of impurities are generated, mainly because the oxidation system of the reaction system is too strong, resulting in other structures on the reactants. The group destroys or produces various undesirable oxidation side reactions.

In order to reduce the oxidative activity of the above reaction system, the present inventors have conducted research by adding a substance which is reductive or capable of complexing with a peroxide, and as a result, it has been found that urea, thiourea and the like can all have a good inhibitory effect.

At the same time, it was found that the reaction can obtain better results in a certain buffer salt system.

The invention provides a preparation method of eplerenone. The method comprises the following steps - (1) in a solvent, in the presence of a side reaction inhibitor, in a trichloroacetonitrile, an oxidizing agent and a phosphate buffer system, 17α-hydroxy-3-keto-γ-lactone-pregnancy甾-4, 9 (11) -diene-7 α , 21 -dicarboxylic acid methyl ester

IV selective double-bond selective epoxidation to prepare crude eplerenone, the reaction formula is as follows:

(2) Recrystallization of crude eplerenone to obtain eplerenone.

The oxidizing agent used in the present invention is hydrogen peroxide or m-chloroperoxybenzoic acid. The molar ratio of the oxidizing agent to the compound of the formula IV is 10 to 35: 1, and the optimum amount is 27 to 32:1. The side reaction inhibitor is (NH ₂ ) ₂ CX, wherein the urea in which X is 0 or the thiourea in which X is S. 5〜1. 1: 1 The optimum amount of the amount of the reaction is 0. 5~2: 1: 1

The trichloroacetonitrile acts as an oxygen transfer carrier, that is, trichloroacetonitrile and hydrogen peroxide to form an intermediate state oxidant, and then double-bonded selective oxidation with the compound of the formula IV, and the molar ratio of the compound to the compound of the formula IV is 1 to 10: 1, the optimum amount is 6~9: 1. Generally, the molar ratio of the amount of trichloroacetonitrile to the compound of the formula IV is 5 to 6:1 in the initial stage of the reaction, and after the reaction is carried out for 12 hours, it is appropriately added, and the molar ratio of the compounded amount to the compound of the formula IV is 1~ 3: 1.

The buffer salt is one or more combinations of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate or potassium dihydrogen phosphate. The molar ratio of the buffer salt to the compound of the formula IV is 1 to 10: 1, and the optimum amount is 2 to 3: l o

The solvent for the oxidation reaction is dichloromethane or chlorobenzene. The ratio of the amount of the solvent to the compound of the formula IV is 10 to 30:1 (V/W), and the optimum amount thereof is 20 to 25:1 (V/W).

The temperature of the oxidation reaction may be from 0 ° C to 5 (TC, more preferably from 20 to 40 ° C. The oxidation reaction time is from 24 to 48 hours.

The recrystallization of the present invention uses acetone or methyl ethyl ketone as a solvent, and the crude eplerenone is dissolved by refluxing in a solvent, and then the solvent is crystallized to obtain the eplerenone fine, which is 10 times the weight of the crude eplerenone W. /W.

The raw materials described in the present invention are all commercially available.

According to the method of the present invention, high-purity eplerenone can be obtained with a purity of 99.5% and a yield of 87%. The method of the invention is simple and feasible, and provides a high-yield, high-quality product and low production cost for the large-scale industrial production of eplerenone. detailed description

The invention will be understood by the following detailed description, but without restricting the invention. Example 1

In a 250 ml three-necked flask with mechanical stirring, a thermometer, 200 ml of dichloromethane, potassium dihydrogen phosphate 8.5 g, trichloroacetonitrile 15 ml, urea 1. 5 g, 30 g of 30% hydrogen peroxide at room temperature, mixture Heat reflux for 4 hours, cool to 30 ° C, then add 17α-hydroxy-3-keto-γ-lactone-pregnane-4,9(11)-diene-7α,21-dicarboxylic acid methyl ester (form IV) 10 g, the reaction was kept at 35 to 40 ° C, and after 12 hours, 2 ml of trichloroacetonitrile was added, and the reaction was completed by TLC. The organic layer was separated, and the aqueous layer was extracted with 20 ml of dichloromethane. The methylene chloride layer was combined, washed with 3% sodium metabisulfite to be non-oxidative, and then washed with water (100 ml), and the organic layer was evaporated to dryness. The crude product of eplerenone was recrystallized from methyl ethyl ketone to obtain 8.7 g of the finished product of eplerenone with a purity of 99.5%.

Example 2

In a 250 ml three-necked flask with mechanical stirring and a thermometer, 200 ml of dichloromethane, 8.5 g of dipotassium hydrogen phosphate, 15 ml of trichloroacetonitrile, 0.75 g of urea, 75 g of 30% hydrogen peroxide at room temperature, and the mixture was heated under reflux for 4 hours. , cooled to 30 ° C, and then added 17 α -hydroxy-3-keto-γ-lactone-pregnane-4,9(11)-diene-7 α, 21-dicarboxylic acid methyl ester (formula IV) 10 g, the reaction was kept at 35 to 40 ° C, and after 12 hours, 2 ml of trichloroacetonitrile was added, and the reaction was completed by TLC. The organic layer was separated, and the aqueous layer was extracted with 20 ml of dichloromethane. The methylene chloride layer was combined, washed with 3% sodium metabisulfite to be non-oxidative, and then washed with water (100 ml), and the organic layer was evaporated to dryness. The crude product of eplerenone was recrystallized from acetone to obtain 7.6 g of the eplerenone product with a purity of 98.3%.

Example 3

In a 250ml three-necked flask with mechanical stirring and thermometer, add 200ml of dichloromethane, 8.5g of dipotassium hydrogen phosphate, 15ml of trichloroacetonitrile, 1.5g of thiourea, add 75g of 30% hydrogen peroxide at room temperature, and heat the mixture back. 4 hours, cooled to 30 ° C, and then added 17 α-hydroxy-3-keto-y-lactone-pregnane-4,9(11)-diene-7α, 21-dicarboxylic acid methyl ester IV) 10 g, the reaction was kept at 35 to 40 ° C, and after 12 hours, 2 ml of trichloroacetonitrile was added, and the reaction was completed by TLC. The organic layer was separated, and the aqueous layer was extracted with 20 ml of dichloromethane. The methylene chloride layer was combined, washed with 3% sodium sulphite to be oxidized, and then washed with 100 ml of water, and the organic layer was dried under reduced pressure. The crude product of eplerenone was recrystallized from methyl ethyl ketone to obtain 8.2 g of eplerenone, and the purity was 99.13%.

Example 4

In a 250 ml three-necked flask with mechanical stirring and a thermometer, 200 ml of dichloromethane, 8.5 g of dipotassium hydrogen phosphate, 15 ml of trichloroacetonitrile, 1.5 g of urea, and 75 g of 30% hydrogen peroxide at room temperature were added, and the mixture was heated under reflux for 4 hours. , cooled to 30 ° C, and then added 17α-hydroxy-3-keto-γ-lactone-pregnane-4,9(11)-diene-7α, methyl 21-dicarboxylate (formula IV) 10g, The reaction was kept at 10 to 15 ° C, and after 12 hours, 2 ml of trichloroacetonitrile was added, and the reaction was carried out for about 36 hours. The organic layer was separated, and the aqueous layer was extracted with 20 ml of dichloromethane. The chloroform layer was washed with 3% sodium metabisulfite until it was not oxidized, and then washed with 100 ml of water. The organic layer was concentrated under reduced pressure and then filtered, and then filtered, and then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

Example 5

In one with a mechanical stirrer, a thermometer, a three-necked flask 250ml of dichloromethane was added 200ml, dipotassium hydrogen phosphate 8.5g, trichloroacetonitrile 15 ml, urea 1.5g, 30% hydrogen peroxide was added dropwise at room temperature 75 _g, the mixture was heated to reflux 2 hours, cooled to 30 Ό, then add 17 α-hydroxy-3-keto-γ-lactone-pregnane-4, 9 (11)-diene-7 α, 21-dicarboxylic acid methyl ester (formula IV) 10 g, the reaction was kept at 25 to 30 ° C, and after 2 hours, 2 ml of trichloroacetonitrile was added, and the reaction was completed by TLC. The organic layer was separated, and the aqueous layer was extracted with 20 ml of dichloromethane. The methylene chloride layer was combined, washed with 3% sodium metabisulfite to be non-oxidizing, and washed with water (100 ml), and the organic layer was dried under reduced pressure. Filtration, crude eplerenone was obtained, and recrystallized from acetone to give 7.5 g of the product. The purity was 98.5%.

Example 6

In a 250 ml three-necked flask with mechanical stirring and a thermometer, 200 ml of dichloromethane, 8.5 g of dipotassium hydrogen phosphate, 15 ml of trichloroacetonitrile, 1.5 g of urea, 75 g of 30% hydrogen peroxide at room temperature, and 17α-hydroxyl group were added. - 3-keto-oxime-lactone-pregnancy- 4,9(11)-diene- 7α,21-dicarboxylic acid methyl ester (formula IV) 10g, incubated at 25~30°C for 12 hours After adding 2 ml of trichloroacetonitrile, the reaction was confirmed by TLC. The organic layer was separated, and the aqueous layer was extracted with 20 ml of methylene chloride. The methylene chloride layer was combined, washed with 3% sodium metabisulfite to be non-oxidative, and washed with water (100 ml). Filtration gave eplerenone 9.3 g with a purity of 95.2%.

Example 7

In a 250ml three-necked flask with mechanical stirring and thermometer, add 200ml of dichloromethane, 8.5g of dipotassium hydrogen phosphate, 12.5ml of trichloroacetonitrile, 1.5g of urea, 75g of 30% hydrogen peroxide at room temperature, and the mixture is heated to reflux. Hour, cool to 30 ° C and then add 17 α -hydroxy-3-keto-y-lactone-pregnancy-4,9(11)-diene-7α, 21-dicarboxylic acid methyl ester (formula IV) 10 g, the reaction was kept at 25 to 30 ° C, and after 2 hours, 2 ml of trichloroacetonitrile was added, and the reaction was completed by TLC. The organic layer was separated, and the aqueous layer was extracted with 20 ml of methylene chloride. The methylene chloride layer was combined, washed with 3% sodium metabisulfite to be non-oxidative, and washed with water (100 ml). Filtration, crude eplerenone, recrystallization of acetone, 7.9 g of finished product, purity 98.92%.

Claims

Claims, a method for preparing eplerenone, characterized in that the method comprises the following steps:

(1) 17 α-hydroxy-3-keto-γ-lactone-pregnant-4, 9 in the presence of a side reaction inhibitor in a solvent such as trichloroacetonitrile, an oxidizing agent and a phosphate buffer system. 11)-Diene-methyl 7α,21-dicarboxylate IV was subjected to double bond selective epoxidation to prepare crude eplerenone; the reaction formula is as follows:

(2) Resveratization of crude eplerenone to obtain eplerenone.

The method according to claim 1, characterized in that the oxidizing agent is hydrogen peroxide or m-chloroperoxybenzoic acid; the molar ratio of the oxidizing agent to the compound of the formula IV is 10 to 35: 1, and the optimum molar ratio is 27 ~32: 1.

The method according to claim 1, characterized in that said side reaction inhibitor is (NH ₂ ) ₂ CX, urea when X is 0 or thiourea when X is S; side reaction inhibitor and compound of formula IV The molar ratio of the amount is 0.5 to 2: 1, and the molar ratio of the optimum amount is 0.9 to 1.1:1.

The method according to claim 1, characterized in that the molar ratio of the trichloroacetonitrile to the compound of the formula IV is from 1 to 10:1, and the optimum molar ratio is from 6 to 9:1; the trichloroacetonitrile is The molar ratio of the initial amount of the reaction to the compound of the formula IV is 5 to 6: 1, and after the reaction is carried out for 12 hours, the molar ratio of the amount of the compound to the compound of the formula IV is 1 to 3:1.

The method according to claim 1, characterized in that said buffer salt is one or more combinations of disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate or potassium dihydrogen phosphate; a buffer salt and a compound of formula IV Mo The ratio is 1 to 10: 1, and the optimum amount is 2 to 3:1.

The method according to claim 1, characterized in that the solvent for the oxidation reaction is methylene chloride or chlorobenzene; the ratio of the solvent to the compound of the formula IV is 10 to 30: 1 V/, and the optimum amount is 20 to 25 : 1 V/W.

The method according to claim 1, characterized in that the temperature of the oxidation reaction is from 0 ° C to 50 ° C, most preferably from 20 to 40 ° C; and the oxidation reaction time is from 24 to 48 hours.

The method according to claim 1, characterized in that said step (2) is recrystallized using acetone or methyl ethyl ketone as a solvent in an amount of 10 times the weight of the crude eplerenone W/W.