WO2010111844A1

WO2010111844A1 - The method of preparing optically pure sibutramine and its derivative salts

Info

Publication number: WO2010111844A1
Application number: PCT/CN2009/071508
Authority: WO
Inventors: 胡昱; 孙晓霞; 郭瑛; 周志真; 陈红卫; 杨金诚
Original assignee: 广州辉宏生物医药科技有限公司
Priority date: 2009-04-02
Filing date: 2009-04-28
Publication date: 2010-10-07
Also published as: CN101514163A; CN101514163B

Abstract

An optically pure sibutramine is prepared by using chiral O, O'-diaryl formyl tartaric acid as resolving agent to carry out resolution for sibutramine racemic derivative to obtain diastereomer salt, and separating diastereomer; and extracting after alkalization to obtain optically pure levorotation sibutramine or dextrorotation sibutramine. The method of preparing the derivative salts of optically pure sibutramine comprises combining optically pure sibutramine prepared with acid compound. The resolving agent can be recycled. The method of preparing optically pure sibutramine has high resolution efficiency, simple process, and short resolution period; and can expand application range of the sibutramine.

Description

Process for preparing optically pure sibutramine and its derivative salts

The invention relates to a process for preparing optically pure sibutramine and a derivative salt thereof, and belongs to the field of organic synthesis. Background technique

Sibutramine, chemical name: Ν-{ 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-indole, Ν'-dimethylamine, one in the molecular structure Chiral carbon atoms are the main components of the current new weight-loss drug Qumei. Sibutramine hydrochloride is a new type of weight-loss drug developed by Knoll Pharmaceutical Company of the United States. It has good absorption and exact curative effect. After the listing of sibutramine hydrochloride, about 10 million people have used this product, and sales have grown at an annual rate of 50%, making it the most popular weight-loss drug in Europe and America. However, at present, the drug is clinically used in the form of a racemic form, and there is no chiral tin bromide hydrochloride. Studies have shown that administration of sibutramine hydrochloride as a racemate may cause serious adverse reactions. In 2000, Stanley et al. [Eur. J. Pharm. acol. 397, 93 (2000)] reported the pharmacological activity of two enantiomers of sibutramine hydrochloride, reporting that the two enantiomers are different. Pharmacological activity, wherein the R-isomer has stronger pharmacological activity than the S-isomer and the racemate in the curative effect. In addition, the US patent [US 6,552,087 (2003)] reported that chiral sibutramine also has a good effect in the treatment of depression and Parkinson's disease.

Radhakrishna et al. [J. Pharm. Biomed. Anal. 22, 627 (2000)] Chiral separation of sibutramine by chiral chromatography and capillary electrophoresis can effectively obtain chiral sibutramine, but Chromatography and capillary methods are limited to micro-separation and cannot be used in actual industrial production. Qun K. Fang [Tetrahedron: Asymmetry 10, 4477 (1999)] first reported the use of dibenzoyltartaric acid as a resolving agent for chiral separation of the compound by resolution. Subsequent Chinese patents [CN 1554333A (2003)] also reported a similar method using dibenzoyltartaric acid, di-p-methylbenzoyltartaric acid and tartaric acid as resolving agents (of which dibenzoyltartaric acid is preferred), and the ee value can be It reached 99.5 % and the yield was 28%. Tan Si Shi et al [Fine and Specialty Chemicals, 15, 19 C2007)] also used D-camphor-10-sulfonic acid as a chiral resolving agent to chemically dissociate sibutramine to obtain an optical purity of 97% ee. The chiral sibutramine has a yield of 23.5%. However, the resolving agent used in this method is costly and the separation efficiency is not high. Although the split method is very suitable for the industrial production of optically pure sibutramine, the two methods reported so far do not have good reproducibility and cannot form an effective sibutramine splitting process. Summary of the invention

It is an object of the present invention to provide an effective optically pure sibutramine preparation process which can separate the racemate of sibutramine into optically pure levofloxacin and dextrozamide. And has a good yield. Another object of the present invention is to provide a plurality of optically pure sibutramine-derived salts for extending the useful range of sibutramine.

The preparation process of the optically pure sibutramine according to the invention adopts chiral 0, ο'-diarylformyltartaric acid as a resolving agent to split the racemate of sibutramine, and obtain the non-pair The diastereomeric salt is separated from the diastereomeric salt, and after alkalization, the optically pure levofloxacin or dextrozamide is obtained.

The preparation process of the optically pure sibutramine according to the present invention comprises the following steps:

(1) using a configuration of 0, ο'-diarylformyltartaric acid as a resolving agent to split the sibutramine racemate, and filtering the resolved reaction product;

(2) recrystallizing the filter cake, followed by alkalization, and extracting with an organic solvent to obtain optically pure sibutramine in a configuration;

(3) The mother liquor is alkalized, extracted with an organic solvent, and recrystallized using another configuration of 0,0'-diarylformyltartaric acid to obtain optically pure sibutramine of another configuration.

The preparation process of the optically pure sibutramine according to the present invention further comprises the step of recovering the resolving agent: after alkalizing and extracting the organic solvent, the aqueous phase is acidified, and the resolving agent is precipitated, filtered, and recovered.

In the present invention, the 0,0'-diarylformyl tartaric acid comprises 0,0'-dimonosubstituted benzoyltartaric acid, 0,0'-didisubstituted benzoyltartaric acid and 0,0'- Di-substituted benzoyl tartaric acid, wherein the substituent is a C1-C20 alkyl group, an alkoxy group, a carbonyl group, an ester group, a halogen, a nitro group or a sulfo group.

In the present invention, the 0,0'-diarylformyltartaric acid is preferably 0,0'-di-p-methoxybenzoyltartaric acid, 0, ο'-di-p-nitrobenzoyltartaric acid and 0, ο'-di-o-chlorobenzoyl tartaric acid.

In the present invention, the molar ratio of chiral 0,0'-diarylformyl tartaric acid to sibutramine racemate is 1: 4: 1:

1.

In the present invention, the resolution is in esters (formate, acetate, propionate, butyrate, etc.), alcohols (methanol, ethanol, propanol, isopropanol, etc.), ketones (acetone, butanone, etc.), alkanes (n-hexane, etc.), ethers (petroleum ether, ether, etc.), chlorine (chloroform, methylene chloride, etc.), and aromatics (benzene, toluene, xylene, etc.) It is carried out in one or two or more kinds of mixed solvents.

In the present invention, the alkalization is carried out in a solution of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, and the pH of alkalization is 9-14. .

In the present invention, the acidification is carried out in an inorganic acid solution such as hydrochloric acid, sulfuric acid or nitric acid or an organic acid solution such as acetic acid, and the acidified pH is 1-4.

The optically pure sibutramine-derived salt of the present invention is prepared by combining the optically pure sibutramine prepared by the present invention with an acid compound to form an optically pure sibutramine-derived salt. In the present invention, the combination with the acid compound is carried out in water or an organic solvent selected from one or a mixture of two or more of an ether, an alcohol, an ester, and a ketone solvent. The acid compound includes hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid and the like.

The preparation process of the optically pure sibutramine and the derivative salt thereof according to the invention has the following advantages:

(1) The present invention uses chiral 0, ο'-diarylformyltartaric acid as a resolving agent, and the sibutramine is directly isolated to obtain a single enantiomer salt, which requires only one or two recrystallizations. Obtaining enantiomer salts with high optical purity, high resolution and simple and feasible process;

(2) The solvent system used in the present invention is suitable for the formation and separation of enantiomeric salts, and the crystallization rate is fast, the yield is nearly two times higher than that of the conventional method, and the optimum yield can be more than 40%, which is greatly improved. Splitting efficiency and shortening cycle, the general splitting cycle can be completed within 1 day;

(3) In the present invention, the sibutramine enantiomer solution obtained by isolating the optically active enantiomer of sibutramine and the chiral 0,0'-diarylformyltartaric acid is removed by another configuration. Partitioning crystallization is carried out to obtain another configuration of optically pure sibutramine, and the remaining solution can be recycled to the process;

(4) The chiral 0,0'-diarylformyltartaric acid resolving agent used in the present invention can be conveniently prepared by natural and inexpensive chiral tartaric acid, and can be conveniently separated after obtaining the optically active enantiomer sibutramine. Recycling agent is used again to reduce the cost of using the disintegrator, increase the value of the product, and increase the market competitiveness of the product;

(5) The present invention utilizes a plurality of organic and inorganic acids, and combines with optically pure sibutramine in a mixed solution of water and an organic solvent to conveniently prepare optically pure sibutramine-derived salts having various characteristics, and expands the product. Scope of application. detailed description

In the following examples, the yields of the products were calculated based on the sibutramine racemic material in this example.

Embodiment 1:

Weigh 2.1 g of sibutramine racemate into a 250 mL round bottom flask and dissolve it in 100 mL of ethyl acetate. Add 3.22 g of 0,0'-di-o-chlorobenzoyl-L-tartaric acid resolving agent and stir. After stirring at reflux for half an hour, the crystals gradually dissolved and the solution became transparent. After standing or stirring to cool to room temperature, it was filtered, and the cake was dried to obtain 2.3 g of a white powdery crystal, dextrozilidine, 0,0'-di-o-chlorobenzoyl-L-tartrate. The optical purity was 86.25% e.e., and the yield was 43.98%.

Embodiment 2:

Weigh 2.1 g of sibutramine in a 50 mL round bottom flask and dissolve it in 20 mL of 1,2-dichloroethane. Add 3.22 g of 0,0'-di-o-chlorobenzoyl-L-tartaric acid. The mixture was stirred, heated and refluxed for half an hour, the crystal gradually dissolved, and the solution became transparent. After standing or stirring to cool to room temperature, it was filtered, and the cake was dried to obtain 2.0 g of a white powdery crystal, dextrozilidine, 0,0'-di-o-chlorobenzoyl-L-tartrate. The optical purity was 80.29% e.e., and the yield was 38.28%.

Embodiment 3: Weigh 2.1 g of sibutramine in a 500 mL round bottom flask and dissolve it in 120 mL of acetone. Add 3.38 g of 0,0'-di-p-nitrobenzoyl-L-tartaric acid resolving agent and stir. Dissolved, the solution became transparent. Add 120 mL of n-hexane, mix the solution, heat and reflux for half an hour, let stand to cool to room temperature, filter, and filter the cake to obtain 2.25 g of white powder crystals, 0, 0'-di-pair of dextrozamide. Benzoyl-L-tartrate. The optical purity was 90.09% ee, and the yield was 43.02%.

Embodiment 4:

Weigh 2.1 g of sibutramine in a 250 mL round bottom flask and dissolve it in 60 mL of ethanol. Add 3.13 g of 0,0'-di-p-methoxybenzoyl-L-tartaric acid to remove the crystal. Gradually dissolved, the solution became transparent. Add 60 mL of petroleum ether, mix the solution, heat and reflux for half an hour, let stand to cool to room temperature, filter, filter cake to dry to obtain 2.5 g of white powder crystals, 0, 0'-di-pair of dextrozamide Oxybenzoyl-L-tartrate. The optical purity was 80.88% e.e., and the yield was 47.80%.

Embodiment 5:

Weigh 2.1 g of sibutramine in a 250 mL round bottom flask and dissolve it in 60 mL of ethanol. Add 3.13 g of 0,0'-di-p-methoxybenzoyl-L-tartaric acid to remove the crystal. Gradually dissolved, the solution became transparent. 60 mL of n-hexane was added, the solution was mixed, heated and refluxed for half an hour, allowed to stand to cool to room temperature, filtered, and the filter cake was dried to obtain 2.25 g of white powdery crystals, 0,0'-di-pair of dextrozamide. Oxybenzoyl-L-tartrate. The optical purity was 90.36% e.e., and the yield was 43.02%.

Example 6:

2 g of 0,0'-diarylformyl-L-tartrate of 80% ee - 91% ee of any one of Examples 1 to 5, and recrystallization by adding 100 ml of acetone and 150 ml of petroleum ether. Filtration gave 1.57 g of white crystals, and the yield of recrystallization was 78.5%. Then add sodium hydroxide solution, adjust to pH=9_14, extract with 3×50 ml of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, and dry the solvent to obtain 0.63 g of dextrozamide, optical purity is 99. % ee. The aqueous phase is adjusted to pH = l_2 with an acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%.

Example 7:

Take 80% ee - 91% ee of any of Examples 1 to 5, 2 g of 0,0'-diarylformyl-L-tartrate of dextrozamide, and recrystallize by adding 25 ml of isopropanol. 1.82 g of white crystals were obtained, and the recrystallization yield was 91%. Add sodium hydroxide solution, adjust to pH=9_14, extract with 3×50 ml of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and dry the solvent to obtain 0.72 g of dextrobromide. The optical purity is 99. % ee. The aqueous phase is adjusted to pH = l_2 with an acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%.

Example 8: The solvent was evaporated from the mother liquor in the first to fifth portions, and the solvent was evaporated to dryness. The mixture was adjusted to pH=9_14, and extracted with 3×50 ml of ethyl acetate. The organic phase was combined and dried over anhydrous sodium sulfate. 1.46 g of bucurve, the yield was 55.2%. The aqueous phase is adjusted to pH=l_2 with an acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%.

Example 9:

1.16 g of sibutramine recovered in the experiment example 8 and 1.6 g of 0,0'-diarylformyl-D-tartaric acid were mixed, and recrystallized twice in 40 mL of isopropanol, and filtered to obtain 2.02 g of white crystals. The recrystallization yield was 70%. Add sodium hydroxide solution, adjust to pH=9_14, extract with 3×50 ml of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and dry the solvent to obtain 0.8 g of levozil, and the optical purity is 99%. Ee. The aqueous phase is adjusted to pH=l_2 with an acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%.

Example 10:

Weigh 2.1 g of sibutramine racemate into a 250 mL round bottom flask and dissolve it in 100 mL of ethyl acetate. Add 3.22 g of 0,0'-di-o-chlorobenzoyl-D-tartaric acid resolving agent and stir. After stirring at reflux for half an hour, the crystals gradually dissolved and the solution became transparent. After standing or stirring to cool to room temperature, it was filtered, and the cake was dried to obtain 2.3 g of a white powdery crystal, a succinyl succinyl-D-tartrate. The optical purity was 86.25% e.e., and the yield was 43.98%.

Example ^1:

Weigh 2.1 g of sibutramine in a 50 mL round bottom bottle and dissolve it in 20 mL of 1,2-dichloroethane. Add 3.22 g of 0,0'-di-o-chlorobenzoyl-D-tartaric acid. The mixture was stirred, heated and refluxed for half an hour, the crystal gradually dissolved, and the solution became transparent. After standing or stirring to cool to room temperature, it was filtered, and the cake was dried to obtain 2.0 g of a white powdery crystals of succinimide and 0,0'-di-o-chlorobenzoyl-D-tartrate. The optical purity was 80.29% e.e., and the yield was 38.28%.

Example 12:

Weigh 2.1 g of sibutramine in a 500 mL round bottom flask and dissolve it in 120 mL of acetone. Add 3.38 g of 0,0'-di-p-nitrobenzoyl-D-tartaric acid resolving agent and stir. Dissolved, the solution became transparent. 120 mL of n-hexane was added, the solution was mixed, heated and refluxed for half an hour, allowed to stand to cool to room temperature, filtered, and the filter cake was dried to obtain 2.25 g of white powdery crystals, 0,0'-di-nitro group of levoximezide. Benzoyl-D-tartrate. The optical purity was 90.09% e.e. and the yield was 43.02%.

Example 13:

Weigh 2.1 g of sibutramine in a 250 mL round bottom flask and dissolve it in 60 mL of ethanol. Add 3.13 g of 0,0'-di-p-methoxybenzoyl-D-tartaric acid to remove the crystal. Gradually dissolved, the solution became transparent. Add 60 mL of petroleum ether, mix the solution, heat and reflux for half an hour, let stand to cool to room temperature, filter, and filter the cake to obtain 2.5 g of white powder crystal. O, Ο'-di-p-methoxybenzoyl-D-tartrate of L-Sibutramine. The optical purity was 80.88% ee, and the yield was 47.80%.

Embodiment 14:

Weigh 2.1 g of sibutramine in a 250 mL round bottom flask and dissolve it in 60 mL of ethanol. Add 3.13 g of 0,0'-di-p-methoxybenzoyl-D-tartaric acid to remove the crystal. Gradually dissolved, the solution became transparent. Add 60 mL of n-hexane, mix the solution, heat and reflux for half an hour, let stand to cool to room temperature, filter, and filter the cake to obtain 2.25 g of white powder crystals, 0, 0'-di-methoxy. Benzoyl-D-tartrate. The optical purity was 90.36% e.e., and the yield was 43.02%.

Example 15:

Take 80% ee - 91% ee of any of the tenth to fourteenth examples of 2,0'-diaroyl-D-tartrate 2 g of levozepide, and add 100 ml of acetone and 150 ml of petroleum ether for weight. Crystallization, filtration gave 1.57 g of white crystals, and the yield of recrystallization was 78.5%. Then add sodium hydroxide solution, adjust to pH=9_14, extract with 3 X 50 ml of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, and spin dry the solvent to obtain 0.63 g of levozil, and the optical purity is 99%. Ee. The aqueous phase is adjusted to pH=l_2 with acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%.

Example 16:

Take 80% ee - 91% ee of any of the tenth to fourteenth examples of 2,0'-diaroyl-D-tartrate 2 g of levozepide, and recrystallize by adding 25 ml of isopropanol. After filtration, 1.82 g of a white crystal was obtained, and the yield of recrystallization was 91%. Add sodium hydroxide solution, adjust to pH=9_14, extract with 3×50 ml of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and spin dry the solvent to obtain 0.72 g of levozil, and the optical purity is 99%. Ee. The aqueous phase is adjusted to pH = l_2 with an acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%.

Example 17:

The solvent was evaporated from the mother liquor in the tenth to fourteenth portions, and the solvent was evaporated to dryness with aq. Sibutramine 1.16 g, yield 55.2%. The aqueous phase is adjusted to pH=l_2 with an acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%.

Example 18:

1.16 g of sibutramine recovered in the same manner as in Example 17 and 1.6 g of 0,0'-diarylformyl-L-tartaric acid were mixed, and recrystallized twice in 40 mL of isopropanol, and filtered to obtain white crystals of 2.02 g. The recrystallization yield was 70%. Then add sodium hydroxide solution, adjust to pH=9_14, extract with 3×50 ml of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, and dry the solvent to obtain 0.8 g of dextrobromide. The optical purity is 99. % ee. The aqueous phase is adjusted to pH=l_2 with an acid, and the resolving agent is precipitated, filtered, and recycled for recycling. The recovery rate of the resolving agent is over 90%. Example 19:

Take 0.558 g of optically pure dextrozilidine in Examples 6, 7 and 18, add 5 ml of IN hydrochloric acid diethyl ether solution, stir at room temperature for half an hour, then spin dry the solvent, and dry under reduced pressure to obtain optically pure right-handed Clozamin hydrochloride solid 0.63 g. The salt yield was 100%.

Embodiment 20:

Take 0.558 g of optically pure dextrozilidine in Examples 6, 7 and 18, dissolve into ethyl acetate, add 0.2 mL of acetic acid with stirring, stir at room temperature for half an hour, then spin dry the solvent and dry under reduced pressure. An optically pure 0.6 g of dextrozamide was obtained. The salt yield was 100%.

Embodiment 2 ^一:

Take 0.558 g of optically pure levofloxacin in Examples 9, 15 and 16. Add 5 ml of IN hydrochloric acid in diethyl ether solution, stir at room temperature for half an hour, then spin dry the solvent, and dry under reduced pressure to obtain optically pure levofloxacin. Qu Ming hydrochloride solids 0.63 g. The salt yield was 100%.

Example 22:

Take 0.558 g of optically pure levofloxacin in Examples 9, 15 and 16. Dissolve in ethyl acetate, add 0.2 mL of acetic acid with stirring, stir at room temperature for half an hour, then spin dry the solvent and dry under reduced pressure. Obtained 0.67 g of optically pure levofloxacin acetate solid. The salt yield was 100%.

Claims

Claim

A process for preparing optically pure sibutramine, characterized in that: chiral 0, ο'-diarylformyltartaric acid is used as a resolving agent to split the racemate of sibutramine, and The diastereomeric salt is separated, and the diastereomeric salt is separated, and after alkalization, optically pure levofloxacin or dextrozamide is obtained.

2. The preparation process according to claim 1, comprising the steps of:

(1) using a configuration of 0,0'-diarylformyltartaric acid as a resolving agent to separate the racemate of sibutramine, and filtering the resolved reaction product;

The preparation process according to claim 2, further comprising the step of recovering the resolving agent: after alkalizing and organic solvent extraction, acidifying the aqueous phase to precipitate the resolving agent, filtering, and recovering.

4. The preparation process according to claim 1, 2 or 3, wherein: the 0,0'-diarylformyl tartaric acid comprises 0,0'-dimonosubstituted benzoyltartaric acid, 0,0. '-Di-substituted benzoyltartaric acid and 0,0'-di-substituted benzoyltartaric acid, wherein the substituent is a C1-C20 alkyl group, an alkoxy group, a carbonyl group, an ester group, a halogen, a nitro group or a sulfo group .

The preparation process according to claim 1, 2 or 3, wherein the molar ratio of the 0,0'-diarylformyl tartaric acid to the sibutramine racemate is 1:4. One 1:1.

6. The preparation process according to claim 1, 2 or 3, characterized in that the resolution is in esters, alcohols, ketones, alkanes, ethers, chlorine-containing and aromatic solvents. It is carried out in one kind or two or more kinds of mixed solvents.

7. The preparation process according to claim 1, 2 or 3, wherein the alkalization is in sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or hydrogen carbonate. It is carried out in a potassium solution, and the pH of alkalization is 9-14.

8. The preparation process according to claim 3, wherein the acidification is carried out in a mineral acid solution or an organic acid solution, and the pH of the acidification is 1-4.

9. A process for the preparation of an optically pure sibutramine-derived salt, characterized in that the optically pure sibutramine prepared according to claim 1 is combined with an acid compound to form an optically pure sibutramine-derived salt.

10. The preparation process according to claim 9, wherein: the combination with the acid compound is carried out in water or an organic solvent; the acid compound includes hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, horse. Acid, fumaric acid and tartaric acid.