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Method for preparing temsirolimus

A compound and organic solvent technology, applied in the field of preparation of temsirolimus, can solve the problems of highly toxic compounds, high price, and non-compliance with environmental protection and safety requirements, and achieve the effects of low cost, short preparation route and simple operation

Active Publication Date: 2012-11-28
SHANGHAI SHYNDEC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The disadvantage of this synthetic route is that the reaction needs to use phenylboronic acid, which is expensive and a highly toxic compound, which does not meet the requirements of environmental protection and safety.

Method used

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  • Method for preparing temsirolimus
  • Method for preparing temsirolimus
  • Method for preparing temsirolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 2,2-bis(hydroxymethyl)propionic acid (5.00g, 37.28mmol) and triethylamine (26.41g, 0.26mol) into 50.00ml of N,N-dimethylformamide, ice-water bath, stir and add Tert-butyldimethylsilyl chloride (19.60 g, 0.13 mol) was raised to room temperature and reacted for 5-8 hours to obtain 10.0 g of compound Ⅰ-1.

[0030]

[0031] MS:363.22(M+H), 1 HNMR (CDCl 3 ): δ3.738(dd,4H);1.141(s,3H);0.914(s,18H);0.098(s,12H).

Embodiment 2

[0033] Add compound Ⅰ-1 (5.00g, 13.79mmol) and triethylamine (2.10g, 20.75mmol) into 50.00ml of dichloromethane, stir and add 2,4,6-trichlorobenzoyl chloride (3.30g, 13.53 mmol), after reacting at room temperature for 6 hours, slowly drop into 10.00ml dichloromethane containing rapamycin (4.20g, 4.60mmol) and 4-(N,N-dimethylamino)pyridine (2.25g, 18.38mmol) , and the reaction temperature was controlled at 0°C~5°C, and compound B-1 (3.47g) was obtained after 12 hours of reaction.

[0034]

[0035] MS:363.22(M+H), 1 HNMR (CDCl 3 ): δ4.65(m,1H,C(40)H);

[0036] 4.20((m,1H,C(28)H)4.17(d,2H);3.60(d,2H);1.06(s,3H);0.87(s,18H);0.034(s,12H).

Embodiment 4

[0038] Add compound B-1 (1.00g, 0.79mmol) into a solvent containing 15.00ml of acetone, stir and add 1N hydrochloric acid (2.38ml) in ice-water bath for 1~2h to prepare Tesirolimus (0.75g).

[0039] MS:1052.89(M+23), 1 HNMR was identical to the product described in Example 11 of US5362718.

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Abstract

The invention belongs to the technical field of methods for preparing temsirolimus, and relates to a method for preparing temsirolimus. The method comprises the following steps of: 1) adding 2,2-bis(hydroxymethyl) propionic acid, organic alkali and chlorosilane into an organic solvent, and reacting to obtain a compound I; 2) dissolving the compound I and the alkali in the organic solvent, adding 2,4,6-trichlorobenzene formyl chloride, reacting, adding reaction liquid into an organic solvent of a compound A and 4-(N,N-dimethylamino) pyridine, and reacting to generate a compound B; and 3) reacting the compound B and acid to obtain the temsirolimus. Compared with the prior art, the method has the advantages of short preparation route, high yield, simplicity of operation and low cost, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of temsirolimus. Background technique [0002] Temsirolimus (CCI-779) is the first mTOR inhibitor drug product to be applied for the treatment of cancer, and it is suitable for the treatment of advanced renal cell carcinoma. Temsirolimus is approved as a first-line treatment for patients with advanced renal cell carcinoma who have failed initial therapy, and as a first-line and second-line treatment for metastatic primary renal cell carcinoma (RCC). The results of its phase III clinical trial showed that compared with α-interferon (the current conventional drug for the treatment of renal cell carcinoma) therapy, temsirolimus can prolong the median survival time by 3-6 months (increased by 50%), and its Drugs that can significantly prolong the survival of cancer patients. Studies have also shown that temsirolimus has a significant effect on the treatment of relapsed mantle cell lympho...

Claims

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Application Information

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IPC IPC(8): C07D498/18
CPCY02P20/55
Inventor 杨智亮王国平侯建
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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