阅读说明：本技术 一种紫杉醇侧链的合成方法 (Synthesis method of paclitaxel side chain ) 是由 杨青春 滕院 赵晓怡 赵泽熙 胡倩 马秋丽 于 2020-07-08 设计创作，主要内容包括：本发明公开了一种紫杉醇侧链的合成方法,该方法以(2R,3S)-3-苯基异丝氨酸盐酸盐为原料,在甲醇、氯化亚砜的参与下发生酯化反应得到(2R,3S)-苯基异丝氨酸甲酯,再通过苯甲酰化反应制得(2R,3S)-N-苯甲酰基-苯基异丝氨酸甲酯,接着通过环化保护反应制得(4S,5R)-5-甲氧基羰基-2-(4-甲氧基苯基)-4-苯基-3-苯甲酰基-1,3-恶唑烷,最后通过水解得到紫杉醇侧链粗品,紫杉醇侧链粗品通过重结晶进一步纯化后得到紫杉醇侧链成品；本发明方法简单易操作、生产周期短,成本低,纯化效率高,适于工业化应用和市场推广。(The invention discloses a synthesis method of a paclitaxel side chain, which takes (2R,3S) -3-phenylisoserine hydrochloride as a raw material, esterification reaction is carried out in the presence of methanol and thionyl chloride to obtain (2R,3S) -phenylisoserine methyl ester, then (2R,3S) -N-benzoyl-phenylisoserine methyl ester is prepared through benzoylation reaction, then preparing (4S, 5R) -5-methoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3-benzoyl-1, 3-oxazolidine through cyclization protection reaction, finally obtaining a taxol side chain crude product through hydrolysis, and further purifying the taxol side chain crude product through recrystallization to obtain a taxol side chain finished product; the method is simple and easy to operate, short in production period, low in cost, high in purification efficiency and suitable for industrial application and market popularization.)

1. The synthesis method of the taxol side chain is characterized by comprising the following steps:

(1) dissolving (2R,3S) -3-phenylisoserine hydrochloride serving as a raw material by using anhydrous methanol, adding thionyl chloride under an ice bath condition, then separating from the ice bath, reacting at room temperature, and inactivating by using a saturated sodium bicarbonate solution after the reaction is finished; concentrating the reaction solution to remove methanol, adding water for dilution, extracting the diluted solution with n-butyl alcohol for 2-3 times, collecting and combining n-butyl alcohol extract, drying by adopting anhydrous sodium sulfate, and then carrying out reduced pressure rotary evaporation and drying at 60-68 ℃ to obtain (2R,3S) -phenylisoserine methyl ester;

(2) dissolving (2R,3S) -phenylisoserine methyl ester in the step (1) by using anhydrous dichloromethane under an ice bath condition, then dropwise adding benzoyl chloride into the solution, removing the ice bath after dropwise adding, reacting at room temperature, inactivating by using a saturated sodium bicarbonate solution after reaction is finished, adding dichloromethane with the volume 0.5 time that of the reaction solution into the inactivated reaction solution, extracting for 2-3 times, collecting and combining dichloromethane extract, adding anhydrous sodium sulfate, drying, filtering, and carrying out reduced pressure rotary evaporation and drying on the filtrate at 50-55 ℃; dissolving the obtained concentrate with ethyl acetate, adding N-hexane, recrystallizing once, and vacuum filtering to obtain (2R,3S) -N-benzoyl-phenylisoserine methyl ester;

(3) dissolving the (2R,3S) -N-benzoyl-phenylisoserine methyl ester in the step (2) by using anhydrous toluene, dropwise adding 4-methoxybenzaldehyde dimethyl acetal, and heating to 60-68 ℃ by using PPTS as a catalyst to perform reflux reaction for 2 hours; concentrating the reaction solution to 1/10 of the original volume, stopping concentrating, diluting the concentrated solution with diethyl ether, and adding saturated sodium bicarbonate solution into the diluted reaction solution for inactivation; separating an organic phase from the inactivated reaction solution, extracting the organic phase with water and a saturated sodium chloride solution for 1-3 times respectively, collecting the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating and draining the filtrate at 40-45 ℃ and under the vacuum degree of 0-minus 0.08MPa to obtain a (4S, 5R) -5-methoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3-benzoyl-1, 3-oxazolidine crude product;

(4) adding anhydrous methanol into the (4S, 5R) -5-methoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3-benzoyl-1, 3-oxazolidine obtained in the step (3) according to the proportion of 1g to 20-30 mL to dissolve, dropwise adding a sodium carbonate solution with the concentration of 0.8-1.5 mol/L into the dissolved solution to adjust the pH value of the dissolved solution to 9-10, and reacting at room temperature; after the reaction is finished, the reaction solution is decompressed, rotary-distilled to remove methanol, then the concentration is stopped, and the reaction solution is cooled to room temperature, and then water is added for dilution; dripping hydrochloric acid solution with the concentration of 0.1-0.3 mol/L into the diluted reaction solution to adjust the pH value to 6.5-7.5, extracting for 3-4 times by using ethyl acetate, separating out an organic phase, drying by using anhydrous sodium sulfate, filtering, concentrating and draining the filtrate to obtain a taxol side chain crude product, dissolving the taxol side chain crude product by using toluene, adding n-hexane for recrystallization for 2-3 times to obtain a taxol side chain finished product;

。

2. the method of synthesizing a paclitaxel side chain according to claim 1, wherein: in the step (1), (2R,3S) -3-phenylisoserine hydrochloride is anhydrous methanol and thionyl chloride =1g, 15-25 mL and 0.3-0.8 mL.

3. The method of synthesizing a paclitaxel side chain according to claim 1, wherein: in the step (2), the ratio of (2R,3S) -phenylisoserine methyl ester to anhydrous dichloromethane to benzoyl chloride =1g, 25-35 mL and 0.5-0.8 mL.

4. The method of synthesizing a paclitaxel side chain according to claim 1, wherein: in the step (2), the volume ratio of the ethyl acetate to the n-hexane is 1: 0.6-1.

5. The method of synthesizing a paclitaxel side chain according to claim 1, wherein: in the step (3), (2R,3S) -N-benzoyl-phenylisoserine methyl ester: PPTS: anhydrous toluene =1g: 8-9 mg: 45-55 mL, (2R,3S) -N-benzoyl-phenylisoserine methyl ester: 4-methoxybenzaldehyde dimethyl acetal =1g: 0.5-0.8 mL).

6. The method of synthesizing a paclitaxel side chain according to claim 1, wherein: the volume ratio of the toluene to the n-hexane is 1: 0.6-1.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis method of a paclitaxel side chain.

Background

Since 1992, paclitaxel is approved by the Food and Drug Administration (FDA) and then is on the market, so that paclitaxel is favored by the research field of international antitumor drugs according to the characteristics of unique action mechanism, definite curative effect and small side effect, and becomes the first-grade drug for treating malignant tumors such as advanced ovarian cancer, breast cancer, non-small cell lung cancer, Kaposi' S sarcoma and the like. The original paclitaxel is mainly derived from bark of natural yew, but has extremely low content, high extraction cost and serious damage to natural resources. In recent years, with the rise of artificial taxus chinensis planting, the method for extracting paclitaxel from taxus chinensis branches and leaves becomes a main method for obtaining natural paclitaxel, natural plant resources are protected, and the yield of the natural paclitaxel is expanded. However, natural paclitaxel still cannot meet the supply requirements of medical and pharmaceutical industries.

The baccatin-III and 10-deacetylbaccatin III (10-DABIII) with very similar structures to paclitaxel parent nucleus are rich in the branches and leaves of the taxus chinensis, and are also found to exist in other plants of taxus, thereby providing a convenient condition for the semi-synthesis of the taxol, and the taxol compounds are obtained by the butt joint of the side chain of the taxol artificially synthesized and the plant extract baccatin-III or 10-deacetylbaccatin III (10-DAB III).

In the existing patents for synthesizing paclitaxel side chains, there are several methods for preparing paclitaxel by resolution, but the disadvantages are low extraction efficiency, low yield, harsh production conditions, and high cost, which results in high product price and is not beneficial to reducing the expense of disease treatment. Some synthesis methods are prepared by ring opening of an epoxy compound by ammonia and an azide compound, but the ring opening regioselectivity of the compound is low, a large amount of impurities and isomers are generated, the subsequent purification difficulty is high, the product yield is low, and meanwhile, due to the dangerous property of the azide compound, huge potential safety hazards exist in production operation, and the method is not suitable for large-scale production.

Therefore, it is necessary to develop a method for preparing a paclitaxel side chain which can avoid the above problems, has a higher reaction yield, is simpler and more convenient to operate, and is more suitable for industrial production.

Disclosure of Invention

The invention aims to provide a synthesis method of a paclitaxel side chain, which takes (2R,3S) -3-phenylisoserine hydrochloride as a raw material, esterification reaction is carried out in the presence of methanol and thionyl chloride to obtain (2R,3S) -phenylisoserine methyl ester, the (2R,3S) -N-benzoyl-phenylisoserine methyl ester is prepared from the (2R,3S) -phenylisoserine methyl ester through benzoylation, and the (2R,3S) -N-benzoyl-phenylisoserine methyl ester is prepared into (4S, 5R) -5-methoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3-benzoyl-1, 3-oxazolidine through cyclization protection reaction; and (4S, 5R) -5-methoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3-benzoyl-1, 3-oxazolidine is further hydrolyzed to obtain a taxol side chain crude product, and the taxol side chain crude product is further purified by recrystallization to obtain a taxol side chain finished product.

The purpose of the invention is realized by the following technical scheme:

1. taking (2R,3S) -3-phenylisoserine hydrochloride as a raw material, adding thionyl chloride under an ice bath condition after the raw material is dissolved by anhydrous methanol according to the proportion of (2R,3S) -3-phenylisoserine hydrochloride to anhydrous methanol to thionyl chloride =1g: 15-25 mL: 0.3-0.8 mL, then removing the ice bath to carry out reaction at room temperature, and inactivating by using a saturated sodium bicarbonate solution after the reaction is finished; concentrating the reaction solution to remove methanol, adding water for dilution, extracting the diluted solution with n-butyl alcohol for 2-3 times, collecting and combining n-butyl alcohol extract, drying by adopting anhydrous sodium sulfate, and then carrying out reduced pressure rotary evaporation and drying at 60-68 ℃ to obtain (2R,3S) -phenylisoserine methyl ester;

concentrating the reaction solution at 60-68 ℃ under vacuum of 0-0.08 MPa to remove methanol;

the water is added for dilution according to the proportion of concentrated solution, namely water =1L: 0.2-0.3L;

in the anhydrous sodium sulfate drying, n-butanol extract is anhydrous sodium sulfate =1L and 100-150 g;

esterification reaction:

；

2. dissolving (2R,3S) -phenylisoserine methyl ester obtained in the step 1 by using anhydrous dichloromethane in an ice bath condition according to a ratio of (2R,3S) -phenylisoserine methyl ester to anhydrous dichloromethane to benzoyl chloride =1g: 25-35 mL: 0.5-0.8 mL, then dropwise adding benzoyl chloride into the solution, removing the ice bath after dropwise adding, reacting at room temperature, inactivating by using a saturated sodium bicarbonate solution after the reaction is finished, adding dichloromethane with 0.5-fold volume of the reaction solution into the inactivated reaction solution, extracting for 2-3 times, collecting and combining dichloromethane extract, adding anhydrous sodium sulfate for drying, filtering, and carrying out reduced pressure rotary evaporation on the filtrate at 50-55 ℃ to dry; dissolving the obtained concentrate with ethyl acetate, adding N-hexane, recrystallizing once, and vacuum filtering to obtain (2R,3S) -N-benzoyl-phenylisoserine methyl ester;

in the anhydrous sodium sulfate drying, the dichloromethane extract solution is anhydrous sodium sulfate =1L and 100-150 g;

the concentrate is ethyl acetate =1g and 2-3 mL; ethyl acetate, namely n-hexane =1mL and 0.6-1 mL;

benzoylation reaction:

；

3. dissolving the (2R,3S) -N-benzoyl-phenylisoserine methyl ester obtained in the step 2 in anhydrous toluene, dropwise adding 4-methoxybenzaldehyde dimethyl acetal, and heating to 60-68 ℃ by taking PPTS as a catalyst to perform reflux reaction for 2 hours; concentrating the reaction solution to 1/10 of the original volume, stopping concentrating, diluting the concentrated solution with diethyl ether, and adding saturated sodium bicarbonate solution into the diluted reaction solution for inactivation; separating an organic phase from the inactivated reaction solution, extracting the organic phase with water and a saturated sodium chloride solution for 1-3 times respectively, collecting the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating and draining the filtrate at 40-45 ℃ and under the vacuum degree of 0-minus 0.08MPa to obtain a (4S, 5R) -5-methoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3-benzoyl-1, 3-oxazolidine crude product;

the (2R,3S) -N-benzoyl-phenylisoserine methyl ester is PPTS anhydrous toluene =1g: 8-9 mg: 45-55 mL, and the (2R,3S) -N-benzoyl-phenylisoserine methyl ester is 4-methoxybenzaldehyde dimethyl acetal =1g: 0.5-0.8 mL;

cyclization protection reaction:

；

4. dissolving (4S, 5R) -5-methoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3-benzoyl-1, 3-oxazolidine obtained in the step 3 in anhydrous methanol according to the proportion of 1g: 20-30 mL, dropwise adding a sodium carbonate solution with the concentration of 0.8-1.5 mol/L into the dissolved solution to adjust the pH value of the dissolved solution to 9-10, carrying out reaction at room temperature, after the reaction is finished, carrying out reduced pressure rotary evaporation on the reaction solution to remove the methanol, stopping concentration, cooling to room temperature, and then adding water according to the proportion of concentrated solution: water =1mL: 3-4 mL for dilution; dripping hydrochloric acid solution with the concentration of 0.1-0.3 mol/L into the diluted reaction solution to adjust the pH value to 6.5-7.5, extracting for 3-4 times by using ethyl acetate, separating out an organic phase, drying by using anhydrous sodium sulfate, filtering, concentrating and draining the filtrate to obtain a taxol side chain crude product, dissolving the taxol side chain crude product by using toluene, adding n-hexane for recrystallization for 2-3 times to obtain a taxol side chain finished product;

extracting 3-4 times by using ethyl acetate according to the proportion of ethyl acetate = 5-6 mL:1mL of acidizing fluid;

drying the ethyl acetate extract phase with anhydrous sodium sulfate in a ratio of anhydrous sodium sulfate =1L to 100-150 g;

the crude product is toluene =1g and 2-3 mL; the volume ratio of the toluene to the n-hexane is 1: 0.6-1;

and (3) hydrolysis reaction:

。

the method has the advantages and the technical effects that:

1. the starting raw materials of the method are conventional products, are easy to purchase and low in price, and are suitable for industrial production and application;

2. the synthesis method does not need inert gas protection, and the production and preparation conditions are not harsh;

3. the method is simple and easy to operate, short in production period, low in cost, high in purification efficiency and suitable for industrial application and market popularization.

Detailed Description

The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to the examples.