阅读说明：本技术 一种腺苷原料药的制备方法 (Preparation method of adenosine bulk drug ) 是由 郑策 徐新盛 于 2020-06-03 设计创作，主要内容包括：本发明公开了一种腺苷原料药的制备方法。该方法首先将肌苷与叔丁基二苯基氯硅烷在催化剂存在的条件下反应,得到的产物纯化后与vilsmeier试剂反应,反应完成后,产物纯化,然后氨解脱保护,精制后得最终产品腺苷。本发明通过采用大分子量并耐酸、耐碱的羟基保护基叔丁基二苯基氯硅烷,使中间产物以固体的形式存在,有利于进一步纯化,提高了中间产物的纯度,同时也提高了反应过程中各中间体的稳定性,加强了对工艺质量控制。同时本发明采用锌粉与氯化锌作为羟基保护反应的催化剂,克服了位阻型羟基保护剂叔丁基二苯基氯硅烷与肌苷反应位阻大,反应时间长,收率低的问题,提高了叔丁基二苯基氯硅烷的反应活性。(The invention discloses a preparation method of an adenosine bulk drug. The method comprises the steps of firstly reacting inosine with tert-butyldiphenylchlorosilane in the presence of a catalyst, purifying an obtained product, reacting the purified product with a vilsmeier reagent, purifying the product after the reaction is finished, then carrying out ammonolysis deprotection, and refining to obtain the final product adenosine. The invention adopts hydroxyl protecting group tert-butyldiphenylchlorosilane with large molecular weight, acid resistance and alkali resistance to ensure that the intermediate product exists in a solid form, thereby being beneficial to further purification, improving the purity of the intermediate product, improving the stability of each intermediate in the reaction process and enhancing the control of process quality. Meanwhile, the zinc powder and the zinc chloride are used as catalysts for hydroxyl protection reaction, so that the problems of large reaction steric hindrance, long reaction time and low yield of steric hindrance type hydroxyl protective agent tert-butyldiphenylchlorosilane and inosine are solved, and the reaction activity of the tert-butyldiphenylchlorosilane is improved.)

1. The preparation method of the adenosine bulk drug is characterized by comprising the following specific steps: firstly, inosine (marked as a compound I) reacts with tert-butyldiphenylchlorosilane in the presence of a catalyst, 9- (((2R, 3R, 4R, 5R) -3, 4-bis ((tert-butyldiphenylsilyl) oxy) -5- (((((tert-butyldiphenylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -9H-purin-6-ol is obtained after the product is purified and is marked as a compound II, secondly, the compound II reacts with a vilsmeier reagent, and the 9- (((2R, 3R, 4R, 5R) -3, 4-bis ((tert-butyldiphenylsilyl) oxy) -5- (((tert-butyldiphenylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -6-chloro-9H-purine is obtained after the product is purified, marking as a compound III; thirdly, carrying out ammonolysis deprotection and refining on the compound III to obtain a final product adenosine;

the reaction formula of the adenosine preparation raw material medicine is as follows:

2. the method for preparing an adenosine bulk drug according to claim 1, wherein the molar ratio of tert-butyldiphenylchlorosilane to inosine in the first step is 3.2 to 6.4, preferably 3.7 to 4.3; the reaction solvent of the first step is dichloromethane, and the reaction temperature is 10-40 ℃, preferably 30-40 ℃.

3. The method for preparing an adenosine bulk drug according to claim 1, wherein the catalyst in the first step is zinc powder and zinc chloride; the molar ratio of the zinc powder to the inosine is 1.1; the molar ratio of zinc chloride to inosine was 0.01.

4. The method for preparing an adenosine bulk drug according to claim 1, wherein the purification solvent of the first step is acetone, and the ratio of acetone to inosine is 10 to 15 mL/g.

5. The method of preparing an adenosine drug substance according to claim 1, wherein the vilsmeier reagent of the second step is prepared by reacting N, N-dimethylformamide with thionyl chloride in a molar ratio of 1: 1.

6. The method of preparing an adenosine drug substance according to claim 1, wherein the reaction solvent of the second step is dichloromethane, chloroform, preferably dichloromethane; the reaction temperature in the second step is 10 to 40 ℃, preferably 30 to 40 ℃.

7. The method for preparing an adenosine bulk drug according to claim 1, wherein the purification solvent of the second step is a mixed solvent of isopropanol and n-hexane in a volume ratio of 5: 1.

8. The method for preparing an adenosine bulk drug according to claim 1, wherein the ammonolysis reagent in the third step is an aqueous ammonia solution; the reaction temperature is 80-150 ℃, preferably 120-130 ℃.

9. The method for producing an adenosine drug substance according to claim 1, wherein the solvent used in the third step is water.

Technical Field

The invention belongs to the technical field of preparation of adenosine bulk drugs, and particularly relates to a chemical synthesis method of an adenosine bulk drug.

Background

Adenosine, chemical name: 9-beta-D-ribofuranosyladenine (Adenosine). It has physiological effects on the cardiovascular system and many other systems and tissues of the body. Adenosine is also an important intermediate for the synthesis of Adenosine Triphosphate (ATP), adenine, adenylate, and vidarabine.

Adenosine is used as antiarrhythmic agent, and can convert paroxysmal supraventricular tachycardia into sinus rhythm, and can be used for treating angina pectoris, myocardial infarction, coronary insufficiency, arteriosclerosis, essential hypertension, cerebrovascular disorder, apoplexy sequelae, progressive muscular atrophy, etc. The structural formula is as follows:

before the eighties, adenosine mainly comes from the degradation of ribonucleic acid and is obtained by dephosphorization; after eighty years, japan began producing adenosine by fermentation; the microbial fermentation method for producing the adenosine has the advantages of complex process, more sewage, low yield and high production cost, and the chemical synthesis method for preparing the adenosine is rapidly developed after the twenty-first century. Adenosine is structurally similar to inosine except that adenosine at the 6-position of the purine ring is-NH₂Inosine is-OH, and the inosine and the adenosine are easy to mutually convert, so that the market price of the inosine is higher than that of adenosine in the past, but the price of the inosine is reduced year by year since the early nineties of the production of the inosine by large-scale industrial fermentation in China. The inosine is used as the raw material to prepare the adenosine, which is beneficial to controlling the production cost.

Chinese patent application CN1408720A discloses a method for obtaining adenosine by reacting hypoxanthine as a starting material with phosphorus oxychloride to obtain 6-chloropurine, condensing the 6-chloropurine with tetraacetyl ribose under the action of a catalyst, and aminolyzing the condensate under the action of a saturated ammonia-methanol solution. The patent has the advantages of expensive raw materials, large using amount, complex process operation and no industrial value.

The method disclosed in the chinese patent application CN1406946A is to take inosine as the starting material, acetylate inosine with excessive acetic anhydride in the presence of excessive pyridine, chloridize inosine with Vilsmeier reagent to obtain chloro-acetylated inosine, deacetylate to obtain chlorinated inosine, add liquid ammonia, and add high pressure (reaction pressure 7479 kg/cm)²) Amination is carried out to obtain adenosine. In the method, the key intermediate, namely the chlorotriethylinosine, is an oily compound, is difficult to further separate and purify, the quality control is difficult, a large amount of impurities are generated in the ammonolysis process of the compound, and the final product is difficult to purify.

In Chinese patent CN100460416C, inosine is used as a raw material, acetonitrile is used as a solvent, triethylamine is used as an acid-binding agent, and acetylation reaction is carried out in the presence of a catalyst to prepare the obtained triacetyl inosine; the chlorotriethylinosine is prepared by chlorination reaction with a Vilsmeier reagent prepared at present, and is aminolyzed with an ammonia-methanol solution under pressure, like CN1406946A, the key intermediate chlorotriethylinosine in the invention is an oily compound, is difficult to further separate and purify, is difficult to control, generates a large amount of impurities in the aminolysis process, and is difficult to purify a final product.

Disclosure of Invention

The invention aims to provide a novel preparation method of an adenosine raw material drug, which overcomes the defects of low product purity, difficult quality control, complex production operation, low safety and the like in the prior art.

The preparation method of the adenosine bulk drug comprises the following steps: firstly, inosine (marked as a compound I) reacts with tert-butyldiphenylchlorosilane in the presence of a catalyst, 9- (((2R, 3R, 4R, 5R) -3, 4-bis ((tert-butyldiphenylsilyl) oxy) -5- (((((tert-butyldiphenylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -9H-purin-6-ol is obtained after the product is purified and is marked as a compound II, secondly, the compound II reacts with a vilsmeier reagent, and the 9- (((2R, 3R, 4R, 5R) -3, 4-bis ((tert-butyldiphenylsilyl) oxy) -5- (((tert-butyldiphenylsilyl) oxy) methyl) tetrahydrofuran-2-yl) -6-chloro-9H-purine is obtained after the product is purified, marking as a compound III; thirdly, carrying out ammonolysis deprotection and refining on the compound III to obtain a final product adenosine;

the reaction formula of the adenosine preparation raw material medicine is as follows:

the molar ratio of tert-butyldiphenylchlorosilane to inosine in the first step is 3.2 to 6.4, preferably 3.7 to 4.3.

The reaction solvent of the first step is dichloromethane, and the reaction temperature is 10-40 ℃, preferably 30-40 ℃.

The catalyst in the first step is zinc powder and zinc chloride; the molar ratio of the zinc powder to the inosine is 1.1; the molar ratio of zinc chloride to inosine was 0.01.

The purification solvent of the first step is acetone, and the ratio of the acetone to the inosine is 10-15 mL/g.

The vilsmeier reagent in the second step is prepared by reacting N, N-dimethylformamide and thionyl chloride in a molar ratio of 1: 1.

The reaction solvent of the second step is dichloromethane and trichloromethane, preferably dichloromethane.

The reaction temperature in the second step is 10 to 40 ℃, preferably 30 to 40 ℃.

The purification solvent of the second step is a mixed solvent of isopropanol and n-hexane in a volume ratio of 5: 1.

The ammonolysis reagent in the third step is ammonia water solution.

The reaction temperature in the third step is 80-150 ℃, preferably 120-130 ℃.

The refined solvent in the third step is water.

The invention has the beneficial effects that: according to the invention, the compound II and the compound III exist in a solid form by adopting hydroxyl protecting group tert-butyldiphenylchlorosilane with large molecular weight, acid resistance and alkali resistance, so that the further purification is facilitated, the purity of the compound II and the compound III is improved, the stability of each intermediate in the reaction process is also improved, and the process quality control is enhanced.

Meanwhile, the zinc powder and the zinc chloride are mixed in proportion and then used as a catalyst for the hydroxyl protection reaction in the first step, so that the reaction activity of the tert-butyldiphenylchlorosilane is improved. The zinc chloride and the tert-butyldiphenylchlorosilane form an electrophilic transition state, so that the activity of the tert-butyldiphenylchlorosilane is improved, and meanwhile, hydrogen chloride generated by the reaction of the electrophilic transition state generated by the reaction and inosine reacts with zinc powder to generate the zinc chloride. The use of the catalyst further overcomes the problems of large reaction steric hindrance, long reaction time and low yield of the steric hindrance type hydroxyl protective agent tert-butyldiphenylchlorosilane and inosine.

The specific implementation mode is as follows:

the present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.