CN111072593B

CN111072593B - Preparation method of pramipexole dihydrochloride

Info

Publication number: CN111072593B
Application number: CN201911406476.4A
Authority: CN
Inventors: 刘磊; 赵云德; 张来平; 魏莉; 薛晨
Original assignee: Jiangsu Tianhe Pharmaceutical Co ltd
Current assignee: Jiangsu Tianhe Pharmaceutical Co ltd
Priority date: 2019-12-31
Filing date: 2019-12-31
Publication date: 2022-11-08
Anticipated expiration: 2039-12-31
Also published as: CN111072593A

Abstract

The invention relates to a preparation method of pramipexole dihydrochloride in the technical field of medicine preparation, which takes (S) -2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as a starting material I, adds the starting material I and N-propyl p-toluenesulfonate into a toluene solvent together, performs N-alkylation reaction on the N-propyl p-toluenesulfonate under the action of alkali and a phase transfer catalyst to generate (S) -2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole (II), and adds hydrochloric acid into toluene to form salt, thereby obtaining the pramipexole dihydrochloride. According to the synthesis method, n-propyl p-toluenesulfonate is used as an alkylating reagent, the alkylation reaction of amino groups is completed in one step to obtain pramipexole, and hydrochloric acid is directly added dropwise to form salt without separation of pramipexole, so that the reaction steps are shortened, and the economic benefit of the product is improved.

Description

Preparation method of pramipexole dihydrochloride

Technical Field

The invention relates to a preparation method of pramipexole dihydrochloride, belonging to the technical field of medicines.

Background

Pramipexole dihydrochloride is a drug developed by Boehringer Ingelheim, germany for the treatment of parkinson's disease and approved by the FDA for marketing on 5, 10 days in 1997. The pramipexole dihydrochloride has the action target spots of D2 and D3 receptor subtypes of a dopamine system, has the common characteristics of non-ergot anti-Parkinson drugs, has fewer side effects, has a good protection effect on dopamine nerves, is the best choice for treating early stages, and can also be used for later-stage combined medication. The treatment of hypotherapy, switching phenomenon and dyskinesia by using the pramipexole and the levodopa together is better than that by combining the carbidopa and the levodopa.

The literature reports more synthetic routes of pramipexole, most of the synthetic routes involve a key intermediate (S) -2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (I), and the synthesis of pramipexole from the intermediate has three routes. The method comprises the following steps: taking I as a starting material, taking anhydrous THF as a solvent, adding propionic anhydride for reaction to prepare (S) -2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole, then reacting with NaBH4/BF3 ether solution or THF solution of borane to obtain pramipexole alkali, and finally introducing hydrogen chloride gas for salt formation to prepare pramipexole hydrochloride, wherein the total yield is about 45%. The second method comprises the following steps: taking I as a starting material, reacting with n-propionaldehyde in a DMF solvent to generate an oxifu product, adding triacetoxy sodium borohydride into a reaction product without separation for reduction, and preparing pramipexole by a one-pot method, wherein the method has the advantages that an intermediate product does not need to be separated, the intermediate steps are few, the operation is simple, and the defects that the triacetoxy sodium borohydride is expensive, the production cost is high, and the reduction yield is low; the third method comprises the following steps: the method comprises the steps of taking I as a starting material to react with n-propionaldehyde in a DMF solvent to produce Schiff base, reducing with sodium borohydride to obtain pramipexole, and finally adding an ether solution of hydrogen chloride to prepare pramipexole hydrochloride, wherein the total yield is about 42%.

Disclosure of Invention

The invention aims to provide a preparation method of pramipexole dihydrochloride, which is used for reducing the production cost and improving the economic benefit of products.

In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a preparation method of pramipexole dihydrochloride comprises the following steps:

(1) N-alkylation reaction: taking (S) -2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as a starting material I, putting the starting material I and n-propyl p-toluenesulfonate into toluene which is 6 to 10 times of the weight of the starting material I according to a molar ratio of 1 (1.2 to 1.8), adding 3 to 6 times of caustic soda flakes and a phase transfer catalyst which is 4 to 6 percent of the weight of the starting material I, stirring, heating, refluxing and dehydrating until no water is separated out, cooling to below 60 ℃ after the reaction is finished, washing until the pH of a water phase is neutral, then heating, refluxing and carrying out water on a toluene layer until no water is separated out, and cooling to obtain a toluene solution of pramipexole;

(2) Salt forming reaction: and (3) dropwise adding hydrochloric acid into the toluene solution of the pramipexole to separate out crystals, filtering, washing with toluene, and drying the solid to obtain pramipexole dihydrochloride.

Further, in the step (1), when the temperature rise reflux dehydration reaction is finished, the material temperature is more than or equal to 110 ℃.

Further, in the step (1), the phase transfer catalyst is one of tetrabutylammonium bromide, benzyltriethylammonium chloride and tetrabutylammonium chloride.

Further, in step (1), the phase transfer catalyst was added in an amount of 5% by weight based on the starting material I.

Further, in the step (1), drinking water is adopted for washing for a plurality of times.

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

the method comprises the steps of taking (S) -2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as an initial raw material I, adding the initial raw material I and N-propyl p-toluenesulfonate into a toluene solvent together, carrying out N-alkylation reaction on the N-propyl p-toluenesulfonate under the action of alkali and a phase transfer catalyst to generate (S) -2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole (II), and dropwise adding hydrochloric acid into toluene to form salt so as to obtain pramipexole hydrochloride. The method adopts n-propyl p-toluenesulfonate as an alkylating reagent, and the intermediate does not need to be separated from alkylation to salt formation. The excessive n-propyl p-toluenesulfonate can promote the complete reaction of the initial material I and reduce the reverse reaction. The method does not adopt a common method of firstly acylating propionaldehyde, propionic anhydride and the like and then reducing in literature reports, so that the reaction steps are reduced, and the operation procedures are simplified; and common alkylating reagents such as halogenated n-propane and the like are not adopted, so that the reaction time is shortened, and the production efficiency is improved.

Drawings

Fig. 1 is a nuclear magnetic hydrogen spectrum of pramipexole dihydrochloride prepared by the method of the present invention.

Fig. 2 is a nuclear magnetic carbon spectrum of pramipexole dihydrochloride prepared by the method of the present invention.

Fig. 3 is a mass spectrum of pramipexole dihydrochloride prepared by the method of the present invention.

Detailed Description

Example 1

Adding 300g of toluene, 50g of starting material I, 76g of n-propyl p-toluenesulfonate, 35.5g of caustic soda flakes and 2.5g of tetrabutylammonium bromide into a 500mL four-mouth reaction bottle, heating, refluxing and carrying out water carrying till no water is separated out, wherein the temperature of the feed liquid reaches more than 110 ℃, cooling to room temperature after the reaction is finished, putting the feed liquid into a 1L separating funnel, washing with 3 x 300ml of drinking water, finally, basically neutralizing the water phase, separating out the water layer, heating, refluxing and carrying out water separation on the toluene layer till no water is separated out, cooling to room temperature to obtain a toluene solution of pramipexole, dropwise adding 60g of hydrochloric acid with the mass concentration of 36% into the toluene solution into a 500mL four-mouth reaction bottle, stirring and crystallizing, filtering, washing the toluene, and drying the solid to obtain 83.4g of pramipexole hydrochloride.

The reaction equation is as follows:

the method is characterized in that (S) -2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (I) is used as an initial raw material, toluene is used as a solvent, N-propyl tosylate is subjected to N-alkylation reaction under the action of alkali and a phase transfer catalyst to generate (S) -2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole (II), and the II is salified in toluene by hydrochloric acid to obtain pramipexole hydrochloride. According to the synthesis method, n-propyl p-toluenesulfonate is used as an alkylating reagent, the alkylation reaction of amino groups is completed in one step to obtain pramipexole, and hydrochloric acid is directly added dropwise to form salt without separation of pramipexole, so that the reaction steps are shortened, and the economic benefit of the product is improved.

Example 2

Adding 300g of toluene, 30g of starting material I, 68g of n-propyl p-toluenesulfonate, 42.6g of caustic soda flakes and 1.8g of tetrabutylammonium chloride into a 500mL four-mouth reaction bottle, heating, refluxing and carrying out water carrying, reducing the temperature of the feed liquid to be above 110 ℃, reducing the temperature to be below 60 ℃ after the reaction is finished, putting the feed liquid into a 1L separating funnel, washing the feed liquid with 4 x 300mL of drinking water, finally, enabling the water phase to be basically neutral, separating out the water layer, heating, refluxing and carrying out water separation on the toluene layer, reducing the temperature to room temperature to obtain a toluene solution of pramipexole, dropwise adding 36g of hydrochloric acid with the mass concentration of 36% into the toluene solution into a 500mL four-mouth reaction bottle, stirring and crystallizing, filtering, washing the toluene, and drying the solid, wherein 48.9g of pramipexole hydrochloride is obtained.

Example 3

Adding 400g of toluene, 50g of starting material I, 95g of n-propyl p-toluenesulfonate, 40g of caustic soda flakes and 2g of benzyltriethylammonium chloride into a 500mL four-mouth reaction bottle, heating, refluxing and carrying out water carrying until no water is separated out, cooling the feed liquid to room temperature when the temperature of the feed liquid reaches more than 110 ℃, washing the feed liquid in a 1L separating funnel by using 4 x 300ml of drinking water, finally, removing a water layer when the water phase is basically neutral, heating, refluxing and carrying out water carrying out until no water is separated out, cooling to room temperature to obtain a toluene solution of pramipexole, dropwise adding 60g of hydrochloric acid with the mass concentration of 36% into the toluene solution in a 500mL four-mouth reaction bottle, stirring, crystallizing, filtering, washing the toluene, and drying solid to obtain 84.2g of pramipexole hydrochloride.

Fig. 1 is a nuclear magnetic hydrogen spectrum of pramipexole dihydrochloride prepared by the method of the present invention, which is analyzed as follows:

fig. 2 is a nuclear magnetic carbon spectrum of pramipexole dihydrochloride prepared by the method of the present invention, which is analyzed as follows:

fig. 3 is a mass spectrum of pramipexole dihydrochloride prepared by the method of the present invention, from which it can be determined that [ M + H ] is 212 and the molecular weight of pramipexole is 211.

The present invention is not limited to the above-mentioned embodiments, and based on the technical solutions disclosed in the present invention, those skilled in the art can make some substitutions and modifications to some technical features without creative efforts according to the disclosed technical contents, and these substitutions and modifications are all within the protection scope of the present invention.

Claims

1. The preparation method of pramipexole dihydrochloride is characterized by comprising the following steps:

(1) N-alkylation reaction: taking (S) -2,6-diamino-4,5,6,7-tetrahydrobenzothiazole as a starting material I, putting the starting material I and n-propyl p-toluenesulfonate into toluene which is 6 to 10 times of the weight of the starting material I according to a molar ratio of 1 (1.2 to 1.8), adding 3 to 6 times of caustic soda flakes and a phase transfer catalyst which is 4 to 6 percent of the weight of the starting material I, stirring, heating, refluxing and dehydrating until no water is separated out, cooling to below 60 ℃ after the reaction is finished, washing until the pH of a water phase is neutral, then heating, refluxing and carrying out water on a toluene layer until no water is separated out, and cooling to obtain a toluene solution of pramipexole; the phase transfer catalyst is one of tetrabutylammonium bromide, benzyltriethylammonium chloride and tetrabutylammonium chloride;

2. The method for preparing pramipexole dihydrochloride according to claim 1, characterized in that: in the step (1), when the temperature rise reflux dehydration reaction is finished, the material temperature is more than or equal to 110 ℃.

3. The method for preparing pramipexole dihydrochloride according to claim 1, characterized in that: in the step (1), the step (c),

the phase transfer catalyst was added in an amount of 5% by weight of the starting material I.

4. The method for preparing pramipexole dihydrochloride according to claim 1, characterized in that: and (2) washing for a plurality of times by using drinking water in the step (1).