阅读说明：本技术 生物酶拆分前列腺素类药物关键中间体（1S,5R）-Corey内酯的方法 (Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme ) 是由 吴�荣 于 2020-12-31 设计创作，主要内容包括：本发明提供了一种生物酶拆分前列腺素类药物关键中间体(1S,5R)-Corey内酯的方法,首先往消旋的Corey内酯的乙腈水溶液加入水解酶,常温搅拌后,反应液用水淬灭,然后用乙酸乙酯萃取、干燥、纯化,得到手性环戊烯醇；往环戊烯醇的乙醇溶液中缓慢加入稀HCl,反应产物后处理纯化后即得。本发明方法适用底物范围广,反应选择性好,无需金属催化剂,且反应条件温和；合成的(1S,5R)-Corey内酯可以用于多种药用功能,与传统化学手性拆分路线相比,缩短了合成步骤,同时得到的副产物也可以利用,增加了原子利用率。本发明的合成方法原料便宜易得步骤短,通过生物酶进行手性拆分,原料易得,反应条件温和,产率高；本发明合成的(1S,5R)-Corey内酯,可以轻松地转换成各种有用的合成结构。(The invention provides a method for splitting prostaglandin drug key intermediate (1S,5R) -Corey lactone by biological enzyme, firstly adding hydrolase into acetonitrile aqueous solution of racemic Corey lactone, stirring at normal temperature, quenching reaction liquid by using water, then extracting by using ethyl acetate, drying and purifying to obtain chiral cyclopentenol; and (3) slowly adding dilute HCl into the ethanol solution of the cyclopentenol, and carrying out post-treatment and purification on a reaction product to obtain the cyclopentenol. The method has the advantages of wide substrate application range, good reaction selectivity, no need of metal catalyst and mild reaction conditions; the synthesized (1S,5R) -Corey lactone can be used for various medicinal functions, compared with the traditional chemical chiral resolution route, the synthetic steps are shortened, meanwhile, the obtained by-products can also be utilized, and the atom utilization rate is increased. The synthetic method has the advantages of cheap and easily-obtained raw materials, short steps, easy acquisition of raw materials, mild reaction conditions and high yield, and chiral resolution is carried out by using the biological enzyme; the (1S,5R) -Corey lactone synthesized by the present invention can be easily converted into various useful synthetic structures.)

1. A method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme comprises the following steps: step 1: firstly, adding hydrolase into a water solution of acetonitrile of racemic Corey lactone, stirring for 24-48 hours, quenching a reaction solution by using water, and then extracting, drying, purifying and drying to obtain a mixture; step 2: purifying the mixture obtained in the step 1 by a column chromatography method to obtain an intermediate product chiral cyclopentenol; and step 3: adding the chiral cyclopentenol obtained in the step 2 into an ethanol solution to obtain an ethanol solution of the cyclopentenol; and 4, step 4: adding dilute HCl into the ethanol solution of the chiral cyclopentenol obtained in the step (3), and reacting for 2-4 hours at normal temperature; extracting, drying, purifying, concentrating under reduced pressure to remove solvent, and purifying by column chromatography to obtain (1S,5R) -Corey lactone.

2. The method of claim 1, wherein: in the step 1, the mass ratio of the racemic Corey lactone to the hydrolase is 90-110: 1.

3. the method of claim 1, wherein: the concentration of the racemic Corey lactone in acetonitrile water solution is 0.8-1.2 mol/L.

4. The method of claim 1, wherein: in step 2, when column chromatography is used for purification, the developing solvent ratio is ethyl acetate: petroleum ether = 1: 3.6-4.4.

5. The method of claim 1, wherein: in step 3, the concentration of the ethanol solution of the cyclopentenol is 0.8-1.2 mol/L.

6. The method of any one of claims 1-5, wherein: the steps 1 to 4 are all carried out at normal temperature.

7. The method of any one of claims 1-5, wherein: in step 4, the ratio of chiral cyclopentenol: the molar ratio of HCl is 1: 1.8-2.2.

8. A method for searching foxes, in accordance with claim 7, characterized by: the molar concentration of HCl is 1M.

Technical Field

The invention belongs to the technical field of bio-organic synthesis, relates to a synthesis method of Corey lactone, and particularly relates to a method for splitting a key intermediate (1S,5R) -Corey lactone of a prostaglandin medicament by using biological enzyme.

Background

Prostaglandin (PGs) drugs are widely used for contraception, induction of labor, treatment of asthma, peptic ulcer, hypertension, thrombosis, glaucoma, induction of labor by veterinary drugs, and the like.

Corey lactone is a general intermediate for synthesizing prostaglandin drugs, and at present, dicyclopentadiene is mainly used as a raw material in a general synthesis method, and is subjected to steps of depolymerization, cyclization, dechlorination, resolution, oxidation, Prins reaction, hydrolysis and the like to synthesize the Corey lactone, and then various PGs are further synthesized. The synthetic route is shown in figure 1.

Wherein, the compound 5 is a racemate, and the pure (1S,5R) configuration is obtained by repeated recrystallization in an organic solvent through a chiral resolving reagent such as phenylethylamine and the like, and the yield is only 15-20%. There are major problems: the chemical resolution efficiency is very low, the (1R,5S) configuration in the resolved mother liquor is not effectively utilized, the total utilization rate of the compound is only about 15 to 20 percent, a large amount of organic waste liquid and waste residue are generated, and the cost is very high. Thus resulting in high cost of the finished prostaglandin drug product.

Disclosure of Invention

1. The technical problem to be solved is as follows:

in the prior art, the resolution efficiency is low, the total utilization rate of the compound is not high (15-20%), a large amount of organic waste liquid and waste residue are generated, and the cost is high.

2. The technical scheme is as follows:

in order to solve the problems, the invention provides a method for separating a key intermediate (1S,5R) -Corey lactone of a prostanoid drug by using biological enzyme, which comprises the following steps: step 1: firstly, adding hydrolase into a water solution of acetonitrile of racemic Corey lactone, stirring for 24-48 hours, quenching a reaction solution by using water, and then extracting, drying, purifying and drying to obtain a mixture; step 2: purifying the mixture obtained in the step 1 by a column chromatography method to obtain an intermediate product chiral cyclopentenol; and step 3: adding the chiral cyclopentenol obtained in the step 2 into an ethanol solution to obtain an ethanol solution of the cyclopentenol; and 4, step 4: adding dilute HCl (dilute hydrochloric acid) into the ethanol solution of the chiral cyclopentenol obtained in the step (3), and reacting for 2-4 hours at normal temperature; extracting, drying, purifying, concentrating under reduced pressure to remove solvent, and purifying by column chromatography to obtain (1S,5R) -Corey lactone.

In the step 1, the mass ratio of the racemic Corey lactone to the hydrolase is 90-110: 1.

the concentration of the racemic Corey lactone in acetonitrile water solution is 0.8-1.2 mol/L.

In step 2, when column chromatography is used for purification, the developing solvent ratio is ethyl acetate: petroleum ether = 1: 3.6-4.4.

In step 3, the concentration of the ethanol solution of the cyclopentenol is 0.8-1.2 mol/L.

The steps 1 to 4 are all carried out at normal temperature.

In step 4, the ratio of chiral cyclopentenol: the molar ratio of HCl is 1: 1.8-2.2.

The molar concentration of HCl is 1M.

3. Has the advantages that:

the synthetic method has the advantages of cheap and easily-obtained raw materials, short steps, easy acquisition of raw materials, mild reaction conditions and high yield, and chiral resolution is carried out by using the biological enzyme; the (1S,5R) -Corey lactone synthesized by the present invention can be easily converted into various useful synthetic structures.

Drawings

FIG. 1 is a synthetic route of the prior art.

FIG. 2 is a schematic diagram of the resolution of the biological enzyme of the present invention.

FIG. 3 is a nuclear magnetic hydrogen spectrum of (1S,5R) -Corey lactone obtained in example 1.

FIG. 4 is a nuclear magnetic hydrogen spectrum of (1S,5R) -Corey lactone obtained in example 1.

Detailed Description

The present invention will be described in detail with reference to examples.

Example 1

As shown in figure 2, the method for separating the key intermediate (1S,5R) -Corey lactone of the prostanoid drug by using the biological enzyme comprises the following steps: firstly, adding hydrolase into a water solution of acetonitrile of racemized Corey lactone, stirring for 24-48 hours at normal temperature, quenching a reaction solution by using water, extracting, drying, purifying to obtain a mixture, and purifying the mixture by using a column chromatography to obtain an intermediate product chiral cyclopentenol; the yield was 38%.

Slowly adding dilute HCl (dilute hydrochloric acid) into an ethanol solution of chiral cyclopentenol, reacting for 2-4 hours at normal temperature, extracting, drying, purifying, concentrating the dried mixture under reduced pressure to remove the solvent, and purifying by column chromatography to obtain the product (1S,5R) -Corey lactone with a yield of 95%.

The molar concentration of HCl is 1M.

FIG. 2 is a nuclear magnetic hydrogen spectrum of (1S,5R) -Corey lactone obtained in example 1; FIG. 3 is a nuclear magnetic carbon spectrum of (1S,5R) -Corey lactone obtained in example 1. From FIGS. 1 and 2, it can be confirmed that the product was (1S,5R) -Corey lactone.

Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.