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Improved process for synthesizing valsartan

A process and compound technology, applied in the field of drug synthesis, can solve problems such as difficult control, low yield, and difficult removal of heavy metal tin

Inactive Publication Date: 2012-08-29
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The synthetic method of valsartan has multiple, adopts after reacting with valeryl chloride in US5399578, uses the method for sodium azide and tributyltin chloride reaction, has used expensive and highly toxic organotin halide, and cost is relatively low. High, and the residual heavy metal tin is difficult to remove, and multiple crystallizations are needed to meet the quality requirements, resulting in a decline in yield; improved in CN101270096, canceled the use of tin compounds, but its product optical isomer content is high, quality Difficult to guarantee; In other methods, in the hydrolysis step, alkalis such as sodium hydroxide and potassium hydroxide are easily racemized, and the racemized product reaches 15%, which reduces the yield
[0004] Generally, in the existing process, the acylation reaction mostly adopts a heterogeneous reaction or uses a catalyst DMAP, resulting in an increase in cost; the acylation reaction is carried out in a heterogeneous system, the reaction is not complete and difficult to control, and the yield is likely to decrease

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] In the reaction kettle, add 1.4kg of compound 1, 14L of toluene, 1.58kg of triethylamine, stir, at 5°C, add 0.90kg of n-pentanoyl chloride, after the addition is complete, keep at 5-10°C and continue the reaction for 2 hours. After the reaction is complete, add 10kg water, stirring, standing to separate layers, and washing; the organic layer was dried and filtered to obtain a toluene solution of pentanoylated product 2;

[0023] In the toluene solution of the pentanoylated product 2, add Et 3 N·HCl 1.88kg and NaN 3 0.56kg, after reacting at 100-130°C for 28-32 hours, stop the reaction; after the reaction liquid is cooled to room temperature, filter, and distill under reduced pressure to remove toluene to obtain the cyclization product 3;

[0024] In the cyclization product 3, add 14L methanol, then add 3.69kg barium hydroxide octahydrate and 18L water, react at room temperature for 10-12h, after the reaction is finished, filter, decompress to remove methanol, the solut...

Embodiment 2

[0027] In the reactor, add 1.4kg of compound 1, 14L of toluene, 1.77kg of triethylamine, stir, at 10°C, add 1.18kg of n-pentanoyl chloride, after the addition is complete, keep at 10°C to continue the reaction for 2h, when the reaction is complete, add 10kg of water, Stir, let stand to separate layers, and wash; the organic layer is dried and filtered to obtain a toluene solution of pentanoylated product 2;

[0028] In the toluene solution of the pentanoylated product 2, add Et 3 N·HCl 3.22kg and NaN 3 0.89kg, after reacting at 90-120°C for 28-30 hours, stop the reaction. After the reaction solution was cooled to room temperature, it was filtered, and the toluene was distilled off under reduced pressure to obtain the cyclization product 3;

[0029] In the cyclization product 3, add 21L methanol, then add 5.54kg barium hydroxide octahydrate and 21L water, react at room temperature for 10-12h, after the reaction is completed, filter, distill methanol off under reduced pressure...

Embodiment 3

[0032] In the reaction kettle, add 1.4kg of compound 1, 7L of xylene, 1.38kg of triethylamine, stir at 10°C, add 0.94kg of n-pentanoyl chloride, after the addition is complete, keep at 10-15°C to continue the reaction for 2 hours. After the reaction is complete, add 10kg of water, stirred, allowed to stand to separate layers, and washed; the organic layer was dried and filtered to obtain a xylene solution of pentanoylated product 2;

[0033] In the xylene solution of the pentanoylated product 2, add Et 3 N·HCl 5.36kg and NaN 3 1.52kg, after reacting at 110-130°C for 28-32 hours, stop the reaction. After the reaction solution was cooled to room temperature, it was filtered, and the toluene was distilled off under reduced pressure to obtain the cyclization product 3;

[0034]To the cyclization product 3, add 7L of methanol, then add 1.67kg of barium hydroxide and 15L of water, react at room temperature for 10-12h, after the reaction, filter, distill off methanol under reduced ...

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Abstract

The invention provides an improved process for synthesizing valsartan. According to the method, N-[(2'-cyano-1, 1'-diphenyl-4-yl) methyl]-L-valine methyl ester hydrochloride is used as a starting raw material and is subjected to improved control of acylation reaction, cyclization reaction, hydrolysis reaction and a crystallization process respectively to obtain high-purity valsartan. The process has the advantages of continuous and simple process operation, high yield and purity and suitability for industrial production.

Description

technical field [0001] The invention relates to an improved process for synthesizing valsartan, belonging to the technical field of drug synthesis. Background technique [0002] Valsartan (Valsartan), the Chinese name is (S)-N-(1-pentanoyl)-N-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-L -Valine, an angiotensin II receptor antagonist developed by Novartis, has been marketed in many countries, and its patent in the United States will expire on March 12, 2012. [0003] The synthetic method of valsartan has multiple, adopts after reacting with valeryl chloride in US5399578, uses the method for sodium azide and tributyltin chloride reaction, has used expensive and highly toxic organotin halide, and cost is relatively low. High, and the residual heavy metal tin is difficult to remove, and multiple crystallizations are needed to meet the quality requirements, resulting in a decline in yield; improved in CN101270096, canceled the use of tin compounds, but its product optical isomer con...

Claims

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Application Information

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IPC IPC(8): C07D257/04
Inventor 雷鑫王振国何明祥何明南
Owner SUNSHINE LAKE PHARM CO LTD
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