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Method used for preparing temsirolimus and suitable for industrial production

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

Inactive Publication Date: 2012-12-05
SHANGHAI SHYNDEC PHARMA CO LTD +1
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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 used for preparing temsirolimus and suitable for industrial production
  • Method used for preparing temsirolimus and suitable for industrial production
  • Method used for preparing temsirolimus and suitable for industrial production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 2,2-bis(hydroxymethyl)propionic acid (5 g, 37.3 mmol) and 4-methoxybenzaldehyde dimethyl acetal (8.2 g, 45 mmol) to 50 ml N,N-dimethylformamide , stirred and added p-toluenesulfonic acid monohydrate (1.8g, 9.4mmol), reacted at room temperature for 3~5h, then poured the reaction solution into 500ml of ice water and stirred for 5~10min, then directly suction filtered, and the filter cake was washed with a small amount of water and drained After that, it was directly dried in a vacuum oven at 50°C to 60°C to obtain 7.6g of compound II-1.

[0030]

[0031] MS: 253.14 (M+H), 1 HNMR (CDCl 3 ): δ7.397-7.375, 6.882-6.861 (dd, 4H); 7.257 (s, 1H, COOH); 5.443 (s, 1H); 4.589-4.560, 3.740-3.675 (dd, 4H, Ar-H); 3.791(s, 3H); 1.095(s, 3H).

Embodiment 2

[0033] Add 2,2-bis(hydroxymethyl)propionic acid (5 g, 37.3 mmol) and 4-methoxybenzaldehyde dimethyl acetal (8.2 g, 45 mmol) to 50 ml N,N-dimethylformamide , stirred and added zinc chloride (1.28g, 9.4mmol), reacted at room temperature for 3~5h, poured the reaction solution into 500ml of ice water and stirred for 5~10min, then directly sucked and filtered, washed the filter cake with a small amount of water and drained, and directly used Dry in a vacuum oven at 50°C~60°C to obtain 7.0 g of compound Ⅱ-1.

Embodiment 3

[0035] Add compound Ⅱ-1 (0.56g, 2.2mmol) and triethylamine (0.34g, 3.4mmol) into 5ml of dichloromethane, stir and add 2,4,6-trichlorobenzoyl chloride (0.54g, 2.2mmol ), after reacting at room temperature for 6 hours, add rapamycin (1g, 1.1mmol) and 4-(N,N-dimethylamino)pyridine (0.53g, 4.3mmol) in 5ml dichloromethane, and control the reaction temperature Compound B-1 (1.1 g) was obtained after reacting for 3 hours at 0°C to 5°C.

[0036]

[0037] MS: 1170.72 (M+Na), 13 CNMR (CDCl 3 ): δ17.74 & 19.20(CH3), 41.99 & 42.40(C), 57.53 & 57.88(OCH3), 101.66 & 101.77(CH), 113.51 & 113.68(ArCH), 127.39 & 127.60(ArCH), 173.56 &177. 47 (C=O).

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Abstract

The invention belongs to the technical field of methods for preparing temsirolimus. The method for preparing the temsirolimus comprises the following steps of: 1) performing catalytic reaction on 2,2-bis(hydroxymethyl)propionic acid and 4-methoxybenzaldehyde dimethylacetal in the presence of an organic solvent; 2) reacting a compound II with 2,4,6-trichlorobenzoyl chloride at normal temperature in the presence of an organic solvent under the alkaline condition, adding an organic solvent containing a compound A and 4-(N,N-dimethylamino)pyridine into the reaction solution, and reacting to obtain a compound B, wherein P is a protecting group; and 3) reacting the compound B with acid in the presence of a solvent to obtain the temsirolimus. The method is easy to operate, low in cost and suitable for industrial production, the synthetic route is short, and yield is high.

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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Patent Type & Authority Applications(China)
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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