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Synthesis process for temsirolimus

A technology for the synthesis of temsirolimus, applied in the direction of organic chemistry, can solve the problems of low yield, lengthy reaction, increased production cost, etc., and achieve the effect of simple process operation, rapid reaction and less by-products

Inactive Publication Date: 2013-12-04
FUJIAN INST OF MICROBIOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The problems in the preparation method of this method are: (1) In the preparation of compound1, triethylamine is used as the base, which will affect the esterification reaction in the next step, so it is necessary to purify and post-process the reaction in this step to remove the triethylamine. Ethylamine, this step is easy to deteriorate the unstable compound1
(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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  • Synthesis process for temsirolimus
  • Synthesis process for temsirolimus
  • Synthesis process for temsirolimus

Examples

Experimental program
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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: The method disclosed in US5362718A, using sirolimus as a starting material, reacts with acid anhydride compound1 to obtain an esterification product, and then hydrolyzes with hydrochloric acid to obtain temsirolimus. [0004] [0005] The problems in the preparation method of this method are: (1) In the preparation of compound1, triethylamine is used as the base, which will affect the esterification reaction in the next step, so it is necessary to purify and post-process the reaction in this step to remove the triethylamine. Ethylamine, this step is easy to deteriorate the unstable compound1. (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 provided by US6277983B1...

Claims

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Application Information

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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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