CN112142704B

CN112142704B - Preparation method of bimatoprost drug intermediate

Info

Publication number: CN112142704B
Application number: CN202011159374.XA
Authority: CN
Inventors: 陈本顺; 石利平; 叶金星; 李大伟; 徐春涛; 张维冰; 郭炳华; 马骧; 钱若灿; 刘春河; 陆波
Original assignee: Jiangsu Alpha Pharmaceutical Co ltd
Current assignee: Jiangsu Alpha Pharmaceutical Co ltd
Priority date: 2020-10-27
Filing date: 2020-10-27
Publication date: 2022-04-22
Anticipated expiration: 2040-10-27
Also published as: CN112142704A

Abstract

The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of a bimatoprost medical intermediate, which takes a compound I as a raw material to react with a compound II under the action of alkali to obtain the bimatoprost medical intermediate: (3aR,4R,5R,6aS) -5- (benzoyloxy) hexahydro-4- [ (1E) -3-oxo-5-phenyl-1-pentenyl ] -2H-cyclopenta [ b ] furan-2-one. The preparation method has the advantages of easily obtained raw materials, higher stereoselectivity, higher yield and purity, and is easier for the industrial production of the intermediate of the bemepiridine medicine.

Description

Preparation method of bimatoprost drug intermediate

Technical Field

The invention relates to the field of synthesis of medical intermediates, in particular to a synthesis method of a bimatoprost medical intermediate.

Background

Bimatoprost (Bimatoprost) is a prostaglandin analogue used clinically to lower intraocular pressure in open-angle glaucoma patients or in ocular hypertension patients; the bimatoprost has the function of promoting the growth of eyelashes, and is used for promoting the growth of the eyelashes of a patient with thin eyelashes; the bemeprobamate also has the effect of activating a prostasin F2a receptor in hair follicles and promoting hair growth, and the action mechanism is expected to achieve the curative effect in the field of male baldness. The chemical name of the bimatoprost is (Z) -7- [ (1R,2R,5S) -3, 5-dihydroxy-2- [ (1E,3S) -3-hydroxy-5-phenyl-1-pentenyl ] cyclopentyl ] -5-N-ethylheptenamide, and the chemical structural formula is as follows:

(3aR,4R,5R,6aS) -5- (benzoyloxy) hexahydro-4- [ (1E) -3-oxo-5-phenyl-1-pentenyl ] -2H-cyclopenta [ b ] furan-2-one is an important intermediate for preparing bemepiridine medicaments.

Patent WO02/096898 provides a route to the preparation of this intermediate, by the following:

the compound I raw material reacts with a witting reagent IV to obtain a compound III. This route has a partial cis isomer as a by-product, which leads to lower yields after further purification.

In view of the importance of bemesectin in the treatment of glaucoma, it is necessary to develop a new method for preparing the intermediate III, which has higher yield, is more economical and is more beneficial to industrial production.

Disclosure of Invention

The invention aims to provide a method for preparing a bimatoprost drug intermediate with higher stereoselectivity and more economy, so as to solve the problem of cis-trans isomer selectivity in the preparation of the bimatoprost drug intermediate in the prior art.

In order to achieve the purpose, the invention provides the following technical scheme:

a preparation method of a bimatoprost drug intermediate comprises the following steps:

taking a compound I aS a raw material, and reacting with a compound II under the action of alkali to obtain a compound III, namely a bemepiridin drug intermediate (3aR,4R,5R,6aS) -5- (benzoyloxy) hexahydro-4- [ (1E) -3-oxo-5-phenyl-1-pentenyl ] -2H-cyclopenta [ b ] furan-2-one;

wherein the molar ratio of the compound I, the base and the compound II is 1: 2.2-4.5: 1.1.

wherein the base is potassium tert-butoxide or sodium tert-butoxide. Preferably, the base is potassium tert-butoxide.

Wherein the reaction solvent is at least one of dichloromethane and tetrahydrofuran. Preferably, the reaction solvent is dichloromethane.

Wherein the reaction temperature is-80 to-20 ℃.

Compared with the prior art, the invention has the beneficial effects that:

the preparation method takes the compound I aS a raw material, and the compound I reacts with the compound II under the action of alkali to obtain a bimatoprost drug intermediate (3aR,4R,5R,6aS) -5- (benzoyloxy) hexahydro-4- [ (1E) -3-oxo-5-phenyl-1-pentenyl ] -2H-cyclopenta [ b ] furan-2-one. The preparation method has the advantages of easily obtained raw materials, higher stereoselectivity, higher yield and purity, and is easier for the industrial production of the intermediate of the bemepiridine medicine.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

Preparing a solution in advance: under the protection of nitrogen, 2.69g of potassium tert-butoxide (0.024mol) is dissolved in 14g of tert-butanol, stirred until dissolved and sealed for later use. 2.93g (0.0107mol) of the compound I and 4.21g (0.0118mol) of the compound II are sequentially put into a 250ml three-necked flask, and vacuum-replaced with nitrogen for 5 times, then 130g of DCM (dichloromethane) is injected into the flask under the protection of nitrogen, and the temperature is reduced to-60 ℃ under stirring.

And (3) completely injecting the prepared potassium tert-butoxide/tert-butanol solution, controlling the temperature to be not more than-50 ℃, completing the injection within about 10 minutes, keeping the temperature at-60 to-55 ℃ after the injection is completed, reacting for 5-6 hours, and naturally heating to room temperature. The upper reaction solution was transferred to a 250ml single-necked flask and spin-dried. The solid was slurried with 80 g of water at room temperature for 2 hours and filtered. The solid was slurried with 80 g of 10% potassium carbonate solution for 2 hours and filtered. The solid is dried to constant weight in an air drying oven at 50 ℃ to obtain white crystalline powdery solid, the purity of the compound III is 99.84 percent, the weight is 3.87 g, and the yield is 89.43 percent.¹H NMR(400H_Z,CDCl3)：δ2.27-2.32(m,1H),2.44-2.50(m,1H),2.57-2.64(m,1H),2.83-2.96(m,7H),5.07-5.10(m,1H),5.26-5.31(m,1H),6.21(d,J＝16.0Hz,1H),6.62-6.68(m,1H),7.17-7.21(m,3H),7.26-7.29(m,2H),7.45(t,J＝7.8Hz,2H),7.58(t,J＝7.8Hz,1H),7.98(d,J＝7.6Hz,2H)。

Example 2

Preparing a solution in advance: under the protection of nitrogen, 5.38g of potassium tert-butoxide (0.048mol) is dissolved in 14g of tert-butanol, stirred until dissolved, and sealed for later use. 2.93g (0.0107mol) of the compound I and 8.42g (0.0118mol) of the compound II are sequentially put into a 250ml three-necked flask, and vacuum-replaced with nitrogen for 5 times, then 130g of DCM is injected into the flask under the protection of nitrogen, and the temperature is reduced to-60 ℃ under stirring.

And (3) completely injecting the prepared potassium tert-butoxide/tert-butanol solution, controlling the temperature to be not more than-50 ℃, completing the injection within about 10 minutes, keeping the temperature at-60 to-55 ℃ after the injection is completed, reacting for 5-6 hours, and naturally heating to room temperature. The upper reaction solution was transferred to a 250ml single-necked flask and spin-dried. The solid was slurried with 80 g of water at room temperature for 2 hours and filtered. The solid was slurried with 80 g of 10% potassium carbonate solution for 2 hours and filtered. The solid was dried in an air-blast drying oven at 50 ℃ to constant weight to obtain a white crystalline powdery solid, the purity of the compound III was 98.98%, the weight was 3.68 g, and the yield was 85.02%.

Example 3

Preparing a solution in advance: under the protection of nitrogen, 2.31g of sodium tert-butoxide (0.024mol) is dissolved in 14g of tert-butanol, stirred until dissolved and sealed for later use. 2.93g (0.0107mol) of the compound I and 4.21g (0.0118mol) of the compound II are sequentially put into a 250ml three-necked flask, and vacuum-replaced with nitrogen for 5 times, then 130g of DCM (dichloromethane) is injected into the flask under the protection of nitrogen, and the temperature is reduced to-60 ℃ under stirring.

And (3) completely injecting the prepared potassium tert-butoxide/tert-butanol solution, controlling the temperature to be not more than-50 ℃, completing the injection within about 10 minutes, keeping the temperature at-60 to-55 ℃ after the injection is completed, reacting for 5-6 hours, and naturally heating to room temperature. The upper reaction solution was transferred to a 250ml single-necked flask and spin-dried. The solid was slurried with 80 g of water at room temperature for 2 hours and filtered. The solid was slurried with 80 g of 10% potassium carbonate solution for 2 hours and filtered. The solid was dried in an air-blast drying oven at 50 ℃ to constant weight to obtain a white crystalline powdery solid, the purity of the compound III was 97.86%, the weight was 3.65 g, and the yield was 84.33%.

Example 4

Preparing a solution in advance: under the protection of nitrogen, 2.69g of potassium tert-butoxide (0.024mol) is dissolved in 14g of tert-butanol, stirred until dissolved and sealed for later use. 2.93g (0.0107mol) of the compound I and 4.21g (0.0118mol) of the compound II were put into a 250ml three-necked flask in this order, and vacuum-substituted with nitrogen for 5 times, then 130g of THF (tetrahydrofuran) was injected into the flask under the protection of nitrogen, and the mixture was cooled to-60 ℃ with stirring.

And (3) completely injecting the prepared potassium tert-butoxide/tert-butanol solution, controlling the temperature to be not more than-50 ℃, completing the injection within about 10 minutes, keeping the temperature at-60 to-55 ℃ after the injection is completed, reacting for 5-6 hours, and naturally heating to room temperature. The upper reaction solution was transferred to a 250ml single-necked flask and spin-dried. The solid was slurried with 80 g of water at room temperature for 2 hours and filtered. The solid was slurried with 80 g of 10% potassium carbonate solution for 2 hours and filtered. The solid was dried in an air-blast drying oven at 50 ℃ to constant weight to obtain white crystalline powdery solid, the purity of the compound III was 96.41%, the weight was 3.76 g, and the yield was 86.87%.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A preparation method of a bimatoprost drug intermediate is characterized in that: taking a compound I aS a raw material, and reacting with a compound II under the action of alkali to obtain a compound III, namely a bemepiridin drug intermediate (3aR,4R,5R,6aS) -5- (benzoyloxy) hexahydro-4- [ (1E) -3-oxo-5-phenyl-1-pentenyl ] -2H-cyclopenta [ b ] furan-2-one;

2. the method for preparing a bemesedin drug intermediate according to claim 1, wherein: the molar ratio of the compound I to the base to the compound II is 1: 2.2-4.5: 1.1.

3. the method for preparing the intermediate of bemeprostat according to claim 2, which is characterized in that: the alkali is potassium tert-butoxide or sodium tert-butoxide.

4. The method for preparing a bevacizin pharmaceutical intermediate according to claim 3, wherein the intermediate comprises: the base is potassium tert-butoxide.

5. The method for preparing the intermediate of bemeprostat according to claim 2, which is characterized in that: the reaction solvent is at least one of dichloromethane and tetrahydrofuran.

6. The method for preparing a bemesedin drug intermediate according to claim 5, wherein: the reaction solvent was dichloromethane.

7. The method for preparing a bemesedin drug intermediate according to claim 1, wherein: the reaction temperature is-80 to-20 ℃.