阅读说明：本技术 一种手性盐酸舍曲林的制备方法 (Preparation method of chiral sertraline hydrochloride ) 是由 范锦敏 汪平中 顾晋文 袁豹 于 2019-12-27 设计创作，主要内容包括：本发明涉及一种手性盐酸舍曲林的制备方法,包括以下步骤：1)将cis-盐酸舍曲林与无机碱在甲苯与水的混合液中反应,油层浓缩除去溶剂,残留物加醇类与水的混合溶剂溶解,加L-谷氨酸拆分,得粗品谷氨酸舍曲林；2)将粗品谷氨酸舍曲林进行重结晶,得到精制谷氨酸舍曲林；3)将精制谷氨酸舍曲林在水与甲苯的混合液中与无机碱反应,油层浓缩除去溶剂,残留物加乙醇溶解,然后加氯化氢乙醇溶液结晶,得cis-(1S,4S)-盐酸舍曲林。本发明的方法收率高,得到的cis-(1S,4S)-盐酸舍曲林纯度高,成本低,适于工业化生产。(The invention relates to a preparation method of chiral sertraline hydrochloride, which comprises the following steps: 1) reacting cis-sertraline hydrochloride with inorganic base in a mixed solution of toluene and water, concentrating an oil layer to remove a solvent, adding a mixed solvent of alcohol and water into residues to dissolve, and adding L-glutamic acid to split to obtain a crude sertraline glutamate product; 2) recrystallizing the crude sertraline glutamate to obtain refined sertraline glutamate; 3) reacting refined sertraline glutamate with inorganic base in a mixed solution of water and toluene, concentrating an oil layer to remove the solvent, adding ethanol into residues to dissolve the residues, and then adding a hydrogen chloride ethanol solution to crystallize to obtain cis- (1S,4S) -sertraline hydrochloride. The method has high yield, and the obtained cis- (1S,4S) -sertraline hydrochloride has high purity and low cost, and is suitable for industrial production.)

1. A preparation method of chiral sertraline hydrochloride is characterized by comprising the following steps:

1) reacting cis-sertraline hydrochloride with a first inorganic base in a mixed solution of a first organic solvent and water, layering, extracting a water layer by using the first organic solvent, combining oil layers, washing the oil layer by using water, concentrating the oil layer to remove the solvent, dissolving residues by using a mixed solvent of alcohol and water, and adding a resolving agent L-glutamic acid for resolution to obtain a crude product sertraline glutamate;

2) recrystallizing the crude sertraline glutamate obtained in the step 1), and carrying out solid-liquid separation to obtain refined sertraline glutamate;

3) reacting the refined sertraline glutamate obtained in the step 2) with a second inorganic base in a mixed solution of a second organic solvent and water, layering, extracting an aqueous layer with the second organic solvent, combining oil layers, washing the oil layers with water, concentrating the oil layers to remove the solvent, adding alcohol to dissolve residues, adding an alcoholic solution of hydrogen chloride to crystallize, carrying out solid-liquid separation, and drying to obtain cis- (1S,4S) -sertraline hydrochloride.

2. The method of claim 1, wherein the first inorganic base and the second inorganic base are each independently selected from sodium hydroxide, potassium hydroxide, or a combination thereof.

3. The method of claim 1, wherein the first organic solvent and the second organic solvent are each independently selected from the group consisting of benzene, toluene, xylene, isoamyl propionate, ethyl acetate, methylene chloride, and mixtures of two or more thereof.

4. The method of claim 3, wherein the first organic solvent and the second organic solvent are both toluene.

5. The method of claim 1, wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol, and n-butanol.

6. The method of claim 1, wherein the ratio of L-glutamic acid: the molar ratio of cis-sertraline hydrochloride is 1-2: 1.

7. the process according to claim 1, wherein the solvent used for recrystallization in step 2) is an aqueous ethanol solution.

8. The method of claim 7, wherein the aqueous ethanol solution has a water content of 3 to 15 wt%.

9. The process according to claim 1, wherein the cis- (1S,4S) -sertraline hydrochloride obtained in step 3) has a cis- (1R,4R) -sertraline hydrochloride content not higher than 0.08%.

10. The process according to claim 1, wherein trans-sertraline hydrochloride is not detected in cis- (1S,4S) -sertraline hydrochloride obtained in step 3).

Technical Field

The invention belongs to the field of chemical medicines, relates to a preparation method of chiral sertraline hydrochloride, and particularly relates to a method for preparing cis- (1S,4S) -sertraline hydrochloride.

Background

Sertraline (Sertraline), CAS number: 79617-96-2, chemically (1S,4S) -4- (3, 4-dichlorophenyl) -1,2,3, 4-tetrahydro-N-methyl-1-naphthalenamine, is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI). The structural formulae of several isomers of sertraline are shown below:

wherein, the racemate formed by the 1S-cis-sertraline and the 1R-cis-sertraline is cis- (+/-) -sertraline (or racemic cis-sertraline); the racemate formed by 1S-trans-sertraline and 1R-trans-sertraline is trans- (+/-) -sertraline (or racemic trans-sertraline).

Sertraline hydrochloride is the hydrochloride of sertraline, has CAS number 79559-97-0, is an antidepressant developed and marketed by the American pfeizu company in the early 90 s of the 20 th century, has been marketed in 96 national regions of the world so far, and still occupies an irreplaceable position in the market of antidepressant at present.

Resolution of the chiral drug sertraline hydrochloride is mainly carried out by a chemical resolution method, and D-mandelic acid is generally used as a resolving agent, and the resolution method can be seen in CN1891681A, US20070054960A1, WO2005121074A3, CN103524354A and the like. The general disadvantage of these processes is that the recovery of the relatively expensive D-mandelic acid is not high (currently only about 70%), which leads to high production costs.

Disclosure of Invention

In order to produce high-purity chiral sertraline hydrochloride bulk drug by adopting a more economic process, the inventor innovates a chemical resolution method of sertraline through a large number of research experiments, thereby preparing cis- (1S,4S) -sertraline hydrochloride with high purity. Specifically, the present invention includes the following technical means.

1. A preparation method of chiral sertraline hydrochloride is characterized by comprising the following steps:

1) mixing cis-sertraline hydrochloride and a first inorganic base in a mixed solution of a first organic solvent and water, stirring for reaction, layering, extracting a water layer by using the first organic solvent, combining oil layers, washing the oil layer with water, concentrating the oil layer to remove the solvent, dissolving residues by using a mixed solvent of alcohol and water, and adding a resolving agent L-glutamic acid for resolution to obtain a crude product sertraline glutamate;

2) recrystallizing the crude sertraline glutamate obtained in the step 1), and carrying out solid-liquid separation to obtain refined sertraline glutamate;

3) reacting the refined sertraline glutamate obtained in the step 2) with a second inorganic base in a mixed solution of a second organic solvent and water, layering, extracting an aqueous layer with the second organic solvent, combining oil layers, washing the oil layers with water, concentrating the oil layers to remove the solvent, adding alcohol to dissolve residues, adding an alcoholic solution of hydrogen chloride to crystallize, carrying out solid-liquid separation, and drying to obtain cis- (1S,4S) -sertraline hydrochloride.

The purity of the crude sertraline glutamate obtained in step 1) is preferably about 97.84 wt% or more, and the purity of the refined sertraline glutamate obtained in step 2) is preferably about 99.54 wt% or more.

The first inorganic base and the second inorganic base are each independently selected from sodium hydroxide, potassium hydroxide, or a combination thereof. Preferably, the first inorganic base and the second inorganic base are both sodium hydroxide.

The first organic solvent and the second organic solvent are respectively and independently selected from benzene, toluene, xylene, isoamyl propionate, ethyl acetate, dichloromethane or a mixture of more than two of the benzene, the toluene, the xylene, the isoamyl propionate and the dichloromethane.

Preferably, the first organic solvent and the second organic solvent are both toluene.

Optionally, the alcohol in step 1) is selected from methanol, ethanol, propanol, n-butanol, preferably ethanol. Preferably, the ratio of L-glutamic acid in the above step 1): the molar ratio of cis-sertraline hydrochloride is preferably 1-2: 1.

the reaction time in the step 1) is more than 1 hour, so that the resolving agent L-glutamic acid can fully react with cis-sertraline hydrochloride.

The operation temperature of the solid-liquid separation in the step 2) and the step 3) is preferably 10-30 ℃, so that racemization of the product caused by high temperature is avoided.

The solvent used for recrystallization in step 2) is preferably an aqueous ethanol solution. Preferably, the aqueous ethanol solution has a water content of 3 to 15 wt.%, preferably 4 to 13 wt.%, 4.5 to 12 wt.%, 5 to 11 wt.%, more preferably 5 to 10 wt.%.

In a preferred embodiment, the cis- (1S,4S) -sertraline hydrochloride obtained in step 3) has a cis- (1R,4R) -sertraline hydrochloride content not higher than 0.08%, preferably not higher than 0.07%, not higher than 0.06%, more preferably not higher than 0.05%.

Preferably, trans-sertraline hydrochloride is not detected in cis- (1S,4S) -sertraline hydrochloride obtained in the step 3) above.

The preparation method of the invention adopts the L-glutamic acid with low price as the resolving agent, improves the yield of cis- (1S,4S) -sertraline hydrochloride, can recycle the L-glutamic acid, reduces the production cost, and is suitable for large-scale production.

Detailed Description

The invention adopts a chemical resolution method to prepare the chiral sertraline hydrochloride, namely cis- (1S,4S) -sertraline hydrochloride, and the adopted resolving agent L-glutamic acid belongs to a large number of commodities and is cheap and easy to obtain. Glutamic acid is an acidic amino acid, has an isoelectric point of 3.22, and has a structural formula:

the salt formed by combining L-glutamic acid with cis- (1S,4S) -sertraline (or 1S-cis-sertraline) has high stability, but the L-glutamic acid is not combined with 1R-cis-sertraline, and the 1S-cis-sertraline and 1R-cis-sertraline can be separated by virtue of the stereoisomer difference, so that cis- (1S,4S) -sertraline hydrochloride is finally obtained.

Herein, the term "cis" is expressed as "cis" and "trans" is expressed as "trans", as will be understood by those skilled in the art.

Compared with the resolving agent D-mandelic acid with higher price, the production cost of cis- (1S,4S) -sertraline hydrochloride can be obviously reduced by adopting L-glutamic acid as the resolving agent.

In a preferred embodiment, the L-glutamic acid after the treatment of step 3) can be recycled, thereby further reducing the production cost of cis- (1S,4S) -sertraline hydrochloride. Production tests show that the recovery rate of the L-glutamic acid can reach above 87.26%.

The invention has the advantages that:

1. the price of the resolving agent L-glutamic acid is much lower than that of D-mandelic acid; and the recovery rate can reach above 87.26 percent and is far higher than 70 percent of the prior D-mandelic acid, so the production cost of cis- (1S,4S) -sertraline hydrochloride can be obviously reduced.

2. The preparation process is simple, economical, practical and environment-friendly.

The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.

The addition amount, content and concentration of various substances are referred to herein, wherein the percentage refers to the mass percentage unless otherwise specified.

In the examples herein, if no specific description is made about the reaction temperature or the operation temperature, the temperature is usually referred to as room temperature (15 to 30 ℃).