阅读说明：本技术 一种生物酶催化制备托品醇的方法 (Method for preparing tropine through biological enzyme catalysis ) 是由 潘刚 方典军 倪妮 于 2021-10-21 设计创作，主要内容包括：一种生物酶催化制备托品醇的方法,其属于医药中间体制备的技术领域。该反应以水做溶剂采用生物酶TR-I代替传统用Pd重金属催化剂,优化了反应方案,使得反应的选择性得到了大幅度提高,反应催化剂循环使用次数得到增加。且选择性大幅度的提高,不需要进行二次重结晶,减少了产品的损失,提高了收率；同时改善了反应中产生的重金属,造成的环境污染和操作危险性问题。采用这种优化后的合成路线,产率高,成本低,安全系数高,节省能源等诸多优点,符合绿色反应的现代化工生产要求。(A method for preparing tropine by using biological enzyme catalysis, which belongs to the technical field of preparation of medical intermediates. According to the reaction, water is used as a solvent, and the conventional Pd heavy metal catalyst is replaced by the biological enzyme TR-I, so that the reaction scheme is optimized, the reaction selectivity is greatly improved, and the recycling times of the reaction catalyst are increased. The selectivity is greatly improved, secondary recrystallization is not needed, the product loss is reduced, and the yield is improved; meanwhile, the problems of environmental pollution and operation danger caused by heavy metal generated in the reaction are solved. The optimized synthesis route has the advantages of high yield, low cost, high safety factor, energy saving and the like, and meets the requirements of modern chemical production of green reaction.)

1. A method for preparing tropine by bio-enzyme catalysis is characterized in that: the method comprises the following steps:

(1) adding 2, 5-dimethoxy tetrahydrofuran and hydrochloric acid into a three-neck flask, and stirring at room temperature; adding acetone dicarboxylic acid and sodium acetate, and stirring; cooling to 0-5 ℃, then dropwise adding a methylamine water solution, and reacting for 4-8h at 40 ℃ after dropwise adding; cooling the reaction liquid to room temperature, adding a sodium hydroxide aqueous solution to adjust the pH value to 9-10, extracting with dichloromethane, and distilling to obtain tropinone;

the content of the 2, 5-dimethoxy tetrahydrofuran: acetone dicarboxylic acid: the molar ratio of the methylamine water solution is 1.2:1.2: 0.8-1;

(2) adding the biological enzyme TR-I, tropinone and water into a three-necked bottle, and reacting for 8 hours at room temperature; the mass ratio of the biological enzyme TR-I to the tropinone is 1: 10-15;

after the reaction is finished, dichloromethane is added to extract reaction liquid, an organic layer is concentrated to obtain a crude product, methanol is added to the crude product, the crude product is pulped, and the crude product is filtered to obtain the product tropine.

Technical Field

The invention relates to a method for preparing tropine through biological enzyme catalysis, and belongs to the technical field of preparation of medical intermediates.

Background

Tropine, α -tropine, is a naturally occurring tropane alkaloid, a synthetic intermediate for a variety of biologically active alkaloids, most of which have potent neurological effects. Atropine is a representative drug, and is a parasympathetic nerve inhibitor, and can be used as a pupil expanding drug and a laxative in ophthalmology.

However, the traditional process method has some problems, the catalytic hydrogenation reaction uses a metal catalyst Pd, the metal catalyst Pd 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, the reaction pressure is high, the temperature is high, the reaction danger coefficient is large, a certain amount of beta-tropine alcohol is contained in the tropine alcohol obtained by the reaction, the qualified product can be obtained only by performing secondary recrystallization treatment, and pollutants such as heavy metal, organic solvent and the like are also generated, and the factors not only increase the cost, but also bring unavoidable disasters 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 biological enzyme TR-I as a catalyst when carbonyl is hydrogenated and reduced into hydroxyl, and for the enzyme catalyst of the biological enzyme TR-I, water is directly used as a solvent, and the reaction is carried out at normal temperature, so that the reaction risk coefficient is low, the reduction selectivity is high, a reduction product does not need to be purified, and the reaction yield of the step is improved to more than 99 percent. The biological enzyme TR-I catalyst replaces the traditional Pd metal catalyst, and the biological enzyme TR-I is tropinone reductase I and is used for autonomous fermentation and cultivation. After 20 cycles, no significant reduction in enzyme activity occurred. The method can avoid the oxidation of the Pd catalyst, the reduction of the catalytic activity caused by 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 preparing tropine by bio-enzyme catalysis, wherein the tropine has the following structural formula:

the method comprises the following steps:

(1) sequentially adding water, 2, 5-dimethoxy tetrahydrofuran and hydrochloric acid into a three-necked bottle, uniformly stirring, adding acetone dicarboxylic acid and sodium acetate, stirring for 30 minutes, dropwise adding a methylamine water solution, keeping the temperature at 40 ℃ for 6 hours after dropwise adding, reacting, adjusting the pH to 10, extracting by using dichloromethane, and concentrating the dichloromethane to obtain the tropinone. The content of the 2, 5-dimethoxy tetrahydrofuran: acetone dicarboxylic acid: the molar ratio of the methylamine water solution is 1.2:1.2: 0.8-1.

(2) Adding the biological enzyme TR-I, tropinone and water into a three-neck flask, reacting for 8 hours at room temperature, adding dichloromethane to extract reaction liquid after the reaction is finished, concentrating an organic layer to obtain a crude product, adding methanol, pulping, and filtering to obtain the tropine product. The mass ratio of the biological enzyme TR-I to the tropinone is 1: 10-15.

The invention has the beneficial effects that: the tropine has a plurality of medical purposes as a very important medical intermediate, and the demand is very large. (1) When carbonyl is reduced into hydroxyl, the biological enzyme TR-I is introduced to directly reduce tropinone in normal temperature water solution and to raise the reaction selectivity to over 99%.

(2) The biological enzyme TR-I replaces the traditional Pd metal catalyst, so that the oxidation of the Pd catalyst can be avoided, the catalytic activity is reduced, and the high-pressure hydrogenation reduction of dangerous reaction can also be avoided; after 20 cycles of the novel biological enzyme catalyst, the activity of the catalyst is not obviously reduced.

(3) Because of the improvement of the biocatalysis selectivity, the product does not need to be recrystallized for the second time, the production flow is greatly simplified, the environmental pollution caused by organic solvent is reduced, and the final product is offwhite powder, has no odor, slightly bitter taste, hygroscopicity and very high purity.

(4) The biological enzyme TR-I is applied to reduce the environmental pollution and the difficulty of post-treatment; and the operation is easy and the treatment is simple. The optimized synthesis route has the advantages of high yield, low cost, high safety factor, energy saving and the like, and meets the requirements of modern chemical production of green reaction.

According to the reaction, water is used as a solvent, and the conventional Pd heavy metal catalyst is replaced by the biological enzyme TR-I, so that the reaction scheme is optimized, the reaction selectivity is greatly improved, and the recycling times of the reaction catalyst are increased. The selectivity is greatly improved, secondary recrystallization is not needed, the product loss is reduced, and the yield is improved; meanwhile, the problems of environmental pollution and operation danger caused by heavy metal generated in the reaction are solved.

Drawings

FIG. 1 is a gas phase diagram for purity analysis of the product tropine in example 2.

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: tropinone

Adding 600mL of water, 2, 5-dimethoxy tetrahydrofuran (90g, 0.68mol) and hydrochloric acid (8g) into a 1000mL three-necked bottle in sequence, stirring uniformly, adding acetonedicarboxylic acid (100.8g, 0.69mol) and sodium acetate (200g), stirring for 30 minutes, dropwise adding a methylamine water solution (44g, 0.56mol), and preserving heat for 6 hours at 40 ℃ after dropwise adding; after the reaction, the pH was adjusted to 10, and methylene chloride was extracted and concentrated to obtain 70g of tropinone, yield 90% and purity 99.5%.

Example 2: tropine alcohol

To tropinone (70g, 0.5mol), water (200ml) was added in a three-necked flask, and the biological enzyme TR-I (7g) was added, stirred, and reacted at room temperature for 8 hours. And after the reaction is finished, 140ml of dichloromethane is added to extract the reaction solution, the organic layer is concentrated to obtain a crude product, methanol is added to the crude product, the crude product is pulped and filtered, and the product tropine alcohol 70g with the purity of 99.8 percent and the yield of 99 percent is obtained.

Example 3: the yield and cost of the new process are compared with those of the traditional process

As can be seen from Table 1, the total yield of the depleted product in the conventional process is 45%, and the total yield of the tropine in the new process is 89%, which is doubled from 35g to 70 g. 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.