A kind of synthetic technique of temsirolimus

A technology of temsirolimus and synthesis process, applied in the direction of organic chemistry and the like, can solve the problems of low yield, lengthy reaction, increase production cost and the like, and achieve the effects of simple process operation, rapid reaction and few by-products

Inactive Publication Date: 2015-09-23
FUJIAN INST OF MICROBIOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The problem that this method preparation method exists is: (1) in the preparation of compound 1, with triethylamine as base, this base has influence on the reaction esterification reaction of next step, therefore needs to carry out purification post-treatment to this step reaction, removes Triethylamine, this step is easy to deteriorate the unstable compound 1
(2) There are many by-products of diesterification, and the hydrolysis reaction time is long
(3) The yield is low
[0008] The problems in the preparation method of this document are: 1. The protection and selective deprotection of silyl ether used in the reaction increase the reaction steps, make the reaction more tedious, and increase the production cost

Method used

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  • A kind of synthetic technique of temsirolimus
  • A kind of synthetic technique of temsirolimus
  • A kind of synthetic technique of temsirolimus

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Embodiment

[0059] Step 1: Preparation of 2,2,5-trimethyl-5-carboxy-1,3-dioxane

[0060] In a 1L round bottom flask, add 100g of 2,2-dimethylhydroxy-propionic acid, 150g of 2,2-dimethoxypropane and 1.5g of p-toluenesulfonic acid in 400ml of anhydrous acetone and stir at room temperature After 5 hours, after adding 2ml of DIPEA, concentrated to dryness by rotary evaporation under reduced pressure to obtain a white solid, the resulting white solid was poured into 1L of dichloromethane and stirred mechanically for 30mins, filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure to obtain 140g target product.

[0061] The second step: the preparation of acid anhydride

[0062] Put 48g of 2,2,5-trimethyl-5-carboxy-1,3-dioxane and 200ml of dichloromethane into a 1L three-necked bottle, and cool down to 0-5°C under nitrogen protection. Stir to dissolve, add 52g of DIPEA after dissolving, and dropwise add 63g of 2,4,6-trichlorobenzoyl chloride for 50-70...

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Abstract

The invention provides a synthesis process for temsirolimus. The synthesis process comprises the following steps: step 1, preparing 2,2,5-trimethyl-5-carboxyl-1, 3-dioxane; step 2, preparing anhydride; step 3, carrying out esterification reaction; step 4, carrying out hydrolysis reaction and finally obtaining the target product, temsirolimus. According to the invention, in the reaction of the step 2, DIPEA (diisopropanolamine) is selected as alkali and methylene chloride is selected as solvent so that anhydride reaction liquid obtained directly can be directly used in the reaction in the step 3, and technological operation is reduced; the selectivity of the esterification reaction is directly achieved by lowering the temperature and controlling the usage amount of DMAP (dimethylaminopyridine) and the usage amount of anhydride, and the by-products of 31-esterification are reduced; esterification selectivity is improved greatly, and the reaction route is simplified; by selecting an ethylene-glycol, para-toluenesulfonic acid and tetrahydrofuran deprotection system, the reaction time is reduced greatly, and the productivity is improved.

Description

【Technical field】 [0001] The invention relates to a synthesis process of temsirolimus. 【Background technique】 [0002] The synthetic method of existing temsirolimus has following several kinds: [0003] Method 1: In the method disclosed in US5362718A, sirolimus is used as a starting material to react with acid anhydride compound 1 to obtain an esterified product, which is then hydrolyzed with hydrochloric acid to obtain temsirolimus. [0004] [0005] The problem that this method preparation method exists is: (1) in the preparation of compound 1, with triethylamine as base, this base has influence on the reaction esterification reaction of next step, therefore needs to carry out purification post-treatment to this step reaction, removes Triethylamine, this step is easy to deteriorate the unstable compound 1. (2) There are many by-products of diesterification, and the hydrolysis reaction time is long. (3) The yield is low. [0006] Method 2: The method disclosed in US6...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/18
Inventor 郑从燊程元荣黄捷杨国新余辉陈夏琴
Owner FUJIAN INST OF MICROBIOLOGY
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