CN114349650B

CN114349650B - Method for synthesizing fenoterol intermediate by adopting microfluid technology

Info

Publication number: CN114349650B
Application number: CN202210041913.2A
Authority: CN
Inventors: 方典军; 李彦龙; 孙晓雨; 单志民; 魏克思; 付朋
Original assignee: Beijing Mediking Biopharm Co ltd; Dalian Wanfu Pharmaceutical Co ltd
Current assignee: Beijing Mediking Biopharm Co ltd; Dalian Wanfu Pharmaceutical Co ltd
Priority date: 2022-01-14
Filing date: 2022-01-14
Publication date: 2023-03-10
Anticipated expiration: 2042-01-14
Also published as: CN114349650A

Abstract

A method for synthesizing a fenoterol intermediate by adopting a microfluid technology belongs to the technical field of medical intermediates. When the fenoterol intermediate is prepared by the method, the fenoterol intermediate is efficiently prepared in a short time at 50 to 80 ℃ by adopting a microfluid fixed bed catalyst hydrogenation reduction technology, and the reaction selectivity reaches over 99 percent. The microfluid technology avoids the high pressure danger of the conventional hydrogenation reaction, and reduces the loss of palladium carbon in the post-treatment filtration process and the danger of palladium carbon filtration by using a novel fixed bed catalyst. Because the reaction selectivity is improved, the product does not need secondary recrystallization, the production flow is greatly simplified, and the environmental pollution and the post-treatment difficulty caused by the organic solvent are reduced; and the operation is easy and the treatment is simple. The method has the advantages of high yield, low cost, high safety coefficient, energy conservation and the like, and meets the modern chemical production requirement of green reaction.

Description

Method for synthesizing fenoterol intermediate by adopting microfluid technology

Technical Field

The invention relates to a method for synthesizing a fenoterol intermediate by adopting a microfluid technology, belonging to the technical field of medical intermediates.

Background

Fenoterol is a β 2 adrenergic agonist used to reach the lungs through the respiratory tract, is classified as a sympathetic β 2 agonist and an asthma drug, and has clinically very good efficacy. The hydrobromide of fenoterol ketone is used as an important intermediate of fenoterol, and has good market background.

However, the traditional process method has some problems, the metal catalyst Pd used in the catalytic hydrogenation reaction is greatly influenced by the reaction environment, the catalytic activity is reduced, the multiple circulation cannot be realized, a large amount of Pd catalyst needs to be added, meanwhile, the reaction pressure is high, the temperature is high, the reaction danger coefficient is large, the reaction conversion rate is low, the purity of the obtained fenoterol ketone is low, secondary recrystallization treatment is needed to obtain a qualified product, pollutants such as heavy metal, organic solvent and the like are also generated, the cost is increased by the factors, and inevitable disasters are brought to people and the environment. Therefore, the key steps in the process need to be improved and optimized.

Disclosure of Invention

The invention aims to introduce a fixed bed catalytic hydrogenation technology during hydrogenation debenzylation, wherein the fixed bed is a micro packed bed reactor, and for the hydrogenation mode: the reaction is carried out on a fixed bed reactor by fully mixing, the reaction is rapid under the conditions of high temperature and high pressure, the reaction end point can be reached within 2min, the reaction time is short, the reaction selectivity is high, the conversion rate is high, the reaction risk coefficient is low, the reduction product does not need to be purified, and the reaction yield of the step is improved to more than 99%. By means of the fixed bed technology, the catalyst activity is not significantly reduced after 20 cycles, since the catalyst is always in a closed system. The method can avoid the oxidation of the Pd catalyst, the reduction of the catalytic activity caused by the influence of the reaction environment, and the use of excessive Pd, thereby reducing the problems of environmental pollution, post-treatment difficulty, operation danger and the like caused by heavy metals and organic solvents. The reaction is optimized, the flow is greatly simplified, the production cost is reduced, the experimental safety is greatly improved, and the green modern production requirement is met.

The technical scheme adopted by the invention is as follows: a method for synthesizing a fenoterol intermediate by adopting a microfluid technology, wherein the structural formula of fenoterol ketone hydrobromide is as follows:

the method comprises the following steps:

(1) Sequentially adding toluene and 2-bromo-3 ',5' -diacetoxyacetophenone into a flask, and stirring at room temperature; adding 1- (4-methoxycarbonyl) -2-benzylaminopropane, heating to 80-90 ℃ for reaction, cooling to 25-30 ℃, stirring and filtering; concentrating the filtrate until no fraction is obtained, obtaining a light yellow oily substance, and adding methanol to dissolve the light yellow oily substance for later use;

the molar ratio of the 2-bromo-3 ',5' -diacetoxyacetophenone to the 1- (4-methoxycarbonyl) -2-benzylaminopropane is 1-1.2;

(2) Pumping the methanol solution of the intermediate A into a micro packed bed reactor for hydrogenation reaction, wherein a palladium-carbon catalyst is filled in the micro packed bed, the reaction temperature is 45-55 ℃, and the reaction time is 2-4min, so as to obtain hydrogenation reaction liquid; adding water and hydrochloric acid into the reaction solution, refluxing, concentrating methanol under reduced pressure until no fraction is produced, cooling to 20-25 ℃, stirring, and filtering to obtain an intermediate hydrochloride;

the mass fraction of the methanol solution of the intermediate A is 25.2 percent, and the pumping rate of the methanol solution is 200-220g/min

The flow rate of the introduced hydrogen is 10-12L/min

Pumping the methanol solution into an infusion pump mixer from a raw material bottle through a metering pump, feeding hydrogen into the infusion pump mixer through a gas mass flowmeter, mixing the methanol solution and the hydrogen in the infusion pump mixer, and feeding the mixture into a micro packed bed reactor for reaction, wherein the micro packed bed reactor is filled with a palladium-carbon catalyst; after the reaction is finished, the reaction liquid enters a reaction liquid collecting bottle through a back pressure valve; and carrying out post-treatment on the obtained reaction liquid to obtain the corresponding hydrochloride. (3) Sequentially adding fenoterol ketone hydrochloride, water and 48% hydrobromic acid into a reaction kettle, refluxing, cooling to 0-5 ℃, stirring and filtering to obtain fenoterol ketone hydrobromide;

the mole ratio of the hydrochloride salt of fenoterol to 48% hydrobromic acid is 1. The invention has the beneficial effects that: the fenoterol ketone hydrobromide salt is used as a very important medical intermediate, has a plurality of medical applications, and is in great demand. In the application, when the hydrogenation debenzylation is carried out, a microfluid fixed bed technology is adopted to replace the traditional kettle type heavy metal catalysis method, so that the reaction scheme is optimized, the reaction selectivity is greatly improved, and the recycling times of the reaction catalyst are increased. And because the selectivity is greatly improved, secondary recrystallization is not needed in the reaction, the loss of products is reduced, the yield is improved, and the problems of environmental pollution and operation danger caused by heavy metal generated in the reaction are solved. The optimized reaction scheme has the advantages of improved yield, reduced cost, environmental friendliness and accordance with the requirements of green modern production.

Drawings

FIG. 1 is a schematic work flow diagram of a continuous micro packed bed reactor for hydrogenation deprotection.

FIG. 2 is a liquid phase spectrum of the product of example 3.

Detailed Description

The invention is further illustrated by the following examples, which are intended to provide a better understanding of the contents of the invention. The examples given therefore do not limit the scope of protection of the invention.

Example 1: intermediate 1

Toluene (700 g) and 2-bromo-3 ',5' -diacetoxyacetophenone (90g 0.286 mol) are sequentially added into a 2000mL three-neck flask, stirred at room temperature for 30min, added with 1- (4-methoxycarbonyl) -2-benzylaminopropane (73g 0.286 mol), heated to 80 ℃, reacted for 3h, cooled to 25-30 ℃, stirred for two hours and filtered. The filtrate was concentrated to no fraction to give 135g of a pale yellow oil with a purity of 99.3% and a yield of 96.4%. Adding 400g of methanol to dissolve for standby.

Example 2:3',5' -dihydroxy-2- [ [2- (p-methoxyphenyl) -1-methylethyl ] amino ] acetophenone hydrochloride

And (3) carrying out hydrogenation reaction on 25.2% of the intermediate (containing 135g and 0.276mol of the intermediate A) in the last step through a metering pump and a fixed bed of a novel mesoporous activated carbon-supported palladium catalyst, and finishing the reaction at 50 ℃ for 2min to obtain hydrogenation reaction liquid. 200g of water and concentrated hydrochloric acid (100g, 0.986 mol) are added into the reaction solution, after 1h of reflux, methanol is concentrated under reduced pressure until no fraction is produced, the temperature is reduced to 20-25 ℃, the mixture is stirred for 1h, and 90g of hydrochloride of the intermediate 2 is obtained after filtration and drying, the purity is 99.5 percent, and the yield is 92.7 percent. The mass fraction of the intermediate A in the methanol solution is 25.2%, and the pumping speed of the methanol solution is 220g/min; the flow rate of hydrogen was 12L/min.

Example 3: fenoterol ketone hydrobromide

Adding the hydrochloride of the fenoterol ketone (90g, 0.256 mol), water (180g, 2V) and 48% hydrobromic acid (172.6 g, 1.024mol) into a reaction kettle in sequence, refluxing for 3h, cooling to 0-5 ℃, stirring for 2h, and filtering to obtain the hydrobromide of the fenoterol ketone (92.5 g), wherein the purity is 99.8% and the yield is 94.5%.

Example 4 traditional kettle-type heavy Metal catalysis method

3',5' -dihydroxy-2- [ [2- (p-methoxyphenyl) -1-methylethyl ] amino ] acetophenone hydrochloride

Sequentially adding a methanol solution (25 percent, 535 g) of the intermediate in the last step and 5 percent palladium-carbon (2.7 g) into an autoclave, replacing the autoclave with nitrogen for 3 times and hydrogen for 3 times, controlling the pressure to be 2mPA and the temperature to be below 30 ℃, and reacting for 8 hours to finish the reaction; 200g of water and concentrated hydrochloric acid (100g, 0.986 mol) are added into the reaction solution, after 1 hour of reflux, methanol is concentrated under reduced pressure until no fraction is produced, the temperature is reduced to 20-25 ℃, the mixture is stirred for 1 hour, and the mixture is filtered and dried to obtain 44g of hydrochloride of an intermediate, the purity is 99.5 percent, and the yield is 45.3 percent.

Adding fenoterol hydrochloride (44g, 0.125mol), water (88g, 2V) and 48% hydrobromic acid (84.4 g, 0.500mol) into a reaction kettle in sequence, refluxing for 3h, cooling to 0-5 ℃, stirring for 2h, and filtering to obtain fenoterol hydrobromide 45g with purity of 99.0% and yield of 41.2%.

Table for comparing yield and cost of new process with traditional process

TABLE 1 yield balance of new and conventional processes

As can be seen from Table 1 above, the total yield of depleted product in the conventional process is 41.2%, and the total yield of fenoterol ketone hydrobromide in the new process is 84.7%, which is doubled from 45g to 92.5g. Not only the cost is reduced, but also the yield is improved, the income of a factory is increased, and the profit is improved. 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, relatively easy post-treatment and green and environment-friendly process.

Claims

1. A method for synthesizing a fenoterol intermediate by adopting a microfluid technology is characterized by comprising the following steps of:

700g of toluene and 90g of 0.286mol 2-bromo-3 ',5' -diacetoxyacetophenone are sequentially added into a 2000mL three-neck flask, stirred at room temperature for 30min, added with 73g of 0.286mol 1-4-methoxyphenyl-2-benzylaminopropane, heated to 80 ℃, reacted for 3h, cooled to 25-30 ℃, stirred for two hours and filtered; the filtrate was concentrated to no distillate to give intermediate A135g as a pale yellow oil; adding 400g of methanol for dissolving for later use;

allowing the intermediate solution containing 135g of the intermediate A in the last step 0.276mol to pass through a metering pump, and carrying out hydrogenation reaction on the intermediate solution through a fixed bed of a palladium catalyst loaded by mesoporous activated carbon, wherein the reaction is finished at 50 ℃ for 2min to obtain hydrogenation reaction liquid; adding 200g of water, 100g of concentrated hydrochloric acid and 0.986mol into the reaction solution, refluxing for 1h, concentrating methanol under reduced pressure until no fraction is produced, cooling to 20-25 ℃, stirring for 1h, filtering and drying to obtain 90g of hydrochloride of the intermediate 2; the pumping speed of the intermediate solution is 220g/min; the flow rate of hydrogen is 12L/min;

and sequentially adding 90g of 0.256mol of hydrochloride of the intermediate 2, 180g of water and 172.6g of hydrobromic acid with the concentration of 1.024mol48 into the reaction kettle, refluxing for 3 hours, cooling to 0-5 ℃, stirring for 2 hours, and filtering to obtain hydrobromide of fenoterol ketone.