CN116751196A - Method for efficiently synthesizing maraviroc intermediate N-benzyl tropylamine - Google Patents

Abstract

A method for efficiently synthesizing a maraviroc intermediate N-benzyl tropylamine belongs to the technical field of medical intermediates. During ketoxime reduction reaction, rh660 catalyst is introduced to replace the traditional condition of metal sodium reduction, so that the reaction scheme is optimized, the yield of the reaction is greatly improved, the reaction risk is reduced, and the production cost is not improved due to the cyclic use of the reaction catalyst. Because the reaction conversion rate is improved, the intermediate is not required to be separated and purified in each step, and the direct reaction can be carried out together by controlling the feeding sequence. The pollutants generated in the reaction are improved, and the pollution to the environment is reduced. The optimized reaction scheme has the advantages of improved yield, reduced cost and environmental friendliness, and meets the requirements of green modern production.

Description

Method for efficiently synthesizing maraviroc intermediate N-benzyl tropylamine

Technical Field

The invention relates to a method for developing an efficient synthesis method of a maraviroc intermediate N-benzyl tropine, and belongs to the technical field of medical intermediates.

Background

N-benztropine is a pharmaceutical intermediate, mainly used for the synthesis of maraviroc. Malaevice is an anti-HIV drug, malaevice is a CCR5 receptor antagonist, and CCR5 receptor is a necessary pathway for HIV infection, and therefore it can be used as a broad-spectrum anti-HIV drug. Therefore, the maraviroc has good market prospect.

However, the traditional process method has some problems, particularly when N-benzyl tropamide is synthesized, the reaction uses sodium metal for reduction, the influence on the reaction environment is large, the safety coefficient of the reaction is low, the reaction time is long, the temperature is high, the yield is poor, a large amount of pollutants such as water and a large amount of organic solvents are generated finally, the harm to the environment is large, the reaction selectivity is poor, and the purification of the final product is difficult; the cost is increased, and unavoidable disasters are brought to people and the environment. The steps in the process need to be improved and optimized.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a method for efficiently synthesizing a maraviroc intermediate N-benzyl tropylamine; aims at reducing ketoxime in normal temperature and low pressure hydrogen atmosphere and raising the reaction yield to over 95% via introducing Rh660 ((-) -1, 2-bis ((2R, 5R) -2, 5-diethyl phosphonate) benzene (1, 5-cyclooctadiene) tetrafluoroborate) catalyst. At the same time, the catalyst activity does not significantly decrease after 20 cycles. The improvement of production cost caused by the use of the catalyst can be avoided, and meanwhile, the process reduces environmental pollution and the difficulty of post-treatment; and the operation is easy, and the treatment is simple. The optimized synthetic route has the advantages of greatly improving the yield, reducing the cost, improving the safety, saving energy and the like, and meets the modern chemical production requirements of green reaction.

The catalyst name is Rh660 ((-) -1, 2-bis ((2R, 5R) -2, 5-diethylphosphonate) benzene (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate) CAS 228121-39-9.

The technical scheme adopted by the invention is as follows: a method for synthesizing a maraviroc intermediate N-benzyl tropylamine comprises the following structural formula:

the method comprises the following steps:

2,5 dimethoxy tetrahydrofuran and dilute hydrochloric acid are sequentially added into a reaction bottle, and heating reaction is carried out; after the reaction is finished, the reaction solution is cooled to 0 ℃, acetone dicarboxylic acid, concentrated hydrochloric acid, sodium acetate and benzylamine are sequentially added, then the temperature is raised to room temperature, the temperature is kept for 10 to 14 hours, filtration is carried out, the filtrate is adjusted to be neutral by sodium hydroxide, extraction is carried out twice by ethyl acetate, and N-benzyl tropinone is obtained by concentration;

the concentration of the dilute hydrochloric acid is 0.5-2M; the 2,5 dimethoxy tetrahydrofuran: the dosage ratio of the dilute hydrochloric acid is (6-28) g:100mL;

the acetone dicarboxylic acid: sodium acetate: the molar ratio of the benzylamine is (1.1-1.2): (1.1-1.2): 1, a step of;

sequentially adding N-benzyl tropinone, methanol, hydroxylamine hydrochloride and sodium bicarbonate into a reaction bottle, heating and refluxing for 3-5 hours, concentrating the reaction liquid until no fraction exists, adding water into a reaction kettle, stirring at 20-25 ℃, filtering and drying to obtain N-benzyl tropinone oxime;

the N-benzyl topirane: hydroxylamine hydrochloride: the molar ratio of sodium bicarbonate is 1: (1.05-1.1): (1.05-1.1);

adding N-benzyl tropine oxime, ethanol and a catalyst Rh660 into a reaction bottle, performing hydrogen replacement after nitrogen replacement, reacting for 4-6 hours at 20-25 ℃ under the pressure of 0.5-1.0 Mpa, filtering the reaction solution after the reaction is finished, and concentrating the reaction solution until no fraction exists to obtain N-benzyl tropine;

the dosage of the catalyst Rh660 is 0.2-0.4% of the weight of the N-benzyl tropinone oxime. Further, the method comprises the following steps:

(1) Sequentially adding 2,5 dimethoxy tetrahydrofuran and 1N HCl into a three-mouth bottle, heating the reaction liquid to 70 ℃, preserving heat for 1 hour, reducing the temperature of the reaction liquid to 0 ℃, sequentially adding acetone dicarboxylic acid, concentrated hydrochloric acid, sodium acetate and benzylamine, then heating to room temperature, preserving heat for 12 hours, filtering, adjusting the filtrate to be neutral by sodium hydroxide, extracting the filtrate twice by ethyl acetate, and concentrating to obtain crude N-benzyl tropinone.

(2) Sequentially adding N-benzyl tropinone, methanol, hydroxylamine hydrochloride and sodium bicarbonate into a reaction bottle, heating to reflux for 3-5 hours, concentrating the reaction liquid until no fraction exists, adding water into a reaction kettle, stirring for 2 hours at 20-25 ℃, filtering, and drying to obtain the N-benzyl tropinone oxime.

(3) Adding N-benzyl tropine oxime, ethanol and Rh660 into a reaction bottle, replacing nitrogen for 3 times, replacing hydrogen for 3 times, reacting for 4-6 hours at 20-25 ℃ and hydrogen pressure of 0.5-1.0 mpa, filtering the reaction liquid after the reaction is finished, and concentrating the reaction liquid until no fraction exists, thus obtaining the N-benzyl tropine.

The beneficial effects of the invention are as follows: maraviroc is an important medical product, has important medical application and has a very large demand. When N-benzyl tropine oxime is reduced to prepare N-benzyl tropine amine, a catalyst Rh660 is used to directly and selectively reduce ketoxime to N-benzyl tropine amine, so that the generation of isomers is reduced, and the yield of products is greatly improved. The preparation process has low cost, mild reaction condition, less environmental pollution and high safety coefficient, and the reaction yield of the step can be improved to more than 98% under the normal temperature condition. The process replaces the traditional process of reducing N-benzyl tropinone by sodium metal, reduces the danger of reaction, improves the conversion rate of reaction, simplifies the treatment process, reduces the requirement on equipment, and does not obviously reduce the activity of the catalyst after Rh660 is circulated for 20 times. And after the modified reaction, the final product does not need to be purified, the production flow is greatly simplified, the environmental pollution caused by the organic solvent used for purification is reduced, and the purity of the final product is very high. The process reduces environmental pollution and post-treatment difficulty; and the operation is easy, and the treatment is simple. The optimized synthetic route has the advantages of greatly improving the yield, reducing the cost, improving the safety, saving energy and the like, and meets the modern chemical production requirements of green reaction.

Drawings

FIG. 1 is a liquid phase diagram of N-benztropine.

Detailed Description

The invention is further illustrated by the following examples for a better understanding of the invention. The examples thus set forth do not limit the scope of the invention.

Example 1: n-benzyl topiroxone

2,5 Dimethoxytetrahydrofuran (132.16 g 1.0 mol) in 1N HCl (1000 mL), heating to 70℃and keeping the temperature for 1 hour, cooling the reaction solution to 0℃and sequentially adding acetone dicarboxylic acid (160.71 g,1.1 mol), 110mL concentrated hydrochloric acid, sodium acetate (90.2 g,1.1 mol) and benzylamine (107.16 g,1.0 mol), then heating to room temperature and keeping the temperature for 12 hours, filtering, eluting the filter cake with 200mL water, adjusting the filtrate to neutral with solid sodium hydroxide, extracting the organic layer twice with 500mL ethyl acetate, washing the organic layer twice with 200mL water, and concentrating the organic layer to obtain 215.3g of crude N-benzyl topinone with a purity of 98.5% and a yield of 100%.

Example 2: n-benzyl tropine oxime

215.3g (1.0 mol) of N-benzyl tropinone, methanol (600 mL), hydroxylamine hydrochloride (73.0 g,1.05 eq.) and sodium bicarbonate (88.2 g,1.05 eq.) are sequentially added into a reaction bottle, heated to reflux for 3-5 hours, the reaction is finished, the reaction solution is concentrated until no fraction is generated, water (800 mL) is added dropwise into the reaction kettle, the temperature is reduced to 20-25 ℃, stirring is carried out for 2 hours, filtration and drying are carried out, and 216.3g of N-benzyl tropinone oxime with the purity of 99.2% and the yield of 93.9% is obtained.

Example 3: n-benzyl tropylamine

216.3g (0.939 mol) of N-benzyl tropine oxime, ethanol (600 mL), 0.648g (0.3 percent of N-benzyl tropine oxime dosage) of catalyst are added into a reaction bottle, nitrogen is replaced for 3 times, the reaction bottle is replaced by hydrogen for 3 times, the reaction is finished for 4 to 6 hours under the temperature of 20 to 25 ℃ and the pressure of hydrogen of 0.5 to 1.0Mpa, the reaction liquid is filtered, the catalyst is recycled and reused, the reaction liquid is concentrated until no fraction exists, 199.1g of N-benzyl tropine with the purity of 99.8 percent and the yield of 98.0 percent is obtained; the liquid phase diagram is shown in figure 1.

Table 1 comparison of catalytic effects after 20 cycles of Rh660

Example 4: the yield and cost of the new process are compared with those of the traditional process

TABLE 2 yield balance table for new and traditional processes

As can be seen from Table 2 above, the total yield of N-benztropine in the conventional process was 59.3% and the total yield of N-benztropine in the novel process was 92.0% from 128.2g to 199.1. Not only reduces the cost, but also improves the yield, increases the income of factories and improves the profit. The purity of the final product is also increased, and the product meets the medical requirements. The improved process has obviously improved safety and environmental protection, the post-treatment is relatively easy, and the process is environment-friendly.

Claims (1)

1. A method for efficiently synthesizing a maraviroc intermediate N-benzyl tropylamine is characterized by comprising the following steps of: the method comprises the following steps of

2,5 dimethoxy tetrahydrofuran and dilute hydrochloric acid are sequentially added into a reaction bottle, and heating reaction is carried out; after the reaction is finished, the reaction solution is cooled to 0 ℃, acetone dicarboxylic acid, concentrated hydrochloric acid, sodium acetate and benzylamine are sequentially added, then the temperature is raised to room temperature, the temperature is kept for 10 to 14 hours, filtration is carried out, the filtrate is adjusted to be neutral by sodium hydroxide, extraction is carried out twice by ethyl acetate, and N-benzyl tropinone is obtained by concentration;

the concentration of the dilute hydrochloric acid is 0.5-2M; the 2,5 dimethoxy tetrahydrofuran: the dosage ratio of the dilute hydrochloric acid is (6-28) g:100mL;

the acetone dicarboxylic acid: sodium acetate: the molar ratio of the benzylamine is (1.1-1.2): (1.1-1.2): 1, a step of;

sequentially adding N-benzyl tropinone, methanol, hydroxylamine hydrochloride and sodium bicarbonate into a reaction bottle, heating and refluxing for 3-5 hours, concentrating the reaction liquid until no fraction exists, adding water into a reaction kettle, stirring at 20-25 ℃, filtering and drying to obtain N-benzyl tropinone oxime;

the N-benzyl topirane: hydroxylamine hydrochloride: the molar ratio of sodium bicarbonate is 1: (1.05-1.1): (1.05-1.1);

adding N-benzyl tropine oxime, ethanol and a catalyst Rh660 into a reaction bottle, performing hydrogen replacement after nitrogen replacement, reacting for 4-6 hours at 20-25 ℃ under the pressure of 0.5-1.0 Mpa, filtering the reaction solution after the reaction is finished, and concentrating the reaction solution until no fraction exists to obtain N-benzyl tropine;

the dosage of the catalyst Rh660 is 0.2-0.4% of the weight of the N-benzyl tropinone oxime.