Synthetic method for sartan drug intermediate and application of intermediate

A synthetic method and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of mediocre effect and high toxicity of organotin compounds

Active Publication Date: 2015-03-25
苏州天绿生物制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] There are many existing valsartan synthesis methods, and tributyl tin chloride is used to assist in the synthesis of valsartan intermediate N-[(2'-tetrazolylbiphenyl-4-yl)methyl]-N- N-valeryl-(L)-valine methyl ester works best, but organotin compounds are highly toxic
In addition, metal zinc compounds and tungstic acid compounds are used to assist the reaction, but the effect is average, and the yield is only 40~60%.

Method used

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  • Synthetic method for sartan drug intermediate and application of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 40.6g (0.10mol) of N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester was dissolved in 400mL of dried xylene In addition to water and oxygen, and nitrogen protection, 37.8g (0.11mol) of bis(methylcyclopentadiene)samarium chloride and 7.2g (0.11mol) of sodium azide were added to the reaction solution, and the temperature was raised to 130℃ React until the reaction is complete (reaction time 1.8 hours). After the reaction was completed, the temperature was lowered to room temperature, 200 mL of purified water was added for washing and extraction, and the mixture was separated by standing. The organic layer was extracted twice with saturated brine, the organic phase was separated, 350 mL of 13% potassium hydroxide aqueous solution was added, and the temperature was raised to 40°C for reaction. After the reaction is over (reaction time 3 hours), the organic phase is separated and the organic phase is washed with 80 mL of 13% potassium hydroxide aqueous solu...

Embodiment 2

[0041] Dissolve 60.9g (0.15mol) of N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester in 600mL of dried xylene In addition to water and oxygen, protected by nitrogen, 56.8g (0.165mol) of bis(methylcyclopentadiene)samarium chloride and 10.8g (0.166mol) of sodium azide were added to the reaction solution, and the temperature was raised to 130°C React until the reaction is complete (reaction time 2 hours). After the reaction was completed, the temperature was lowered to room temperature, 300 mL of purified water was added for washing and extraction, and the mixture was separated by standing. The organic layer was extracted twice with saturated brine, the organic phase was separated, 530 mL of 13% potassium hydroxide aqueous solution was added, and the temperature was raised to 40° C. for reaction. After the completion of the reaction (reaction time 3.5 hours), the organic phase was allowed to stand and separate into layers. The organic phase was washed with 120 m...

Embodiment 3

[0045] Other conditions are the same as in Example 1, the difference is that in the synthesis of the intermediate: the organic solvent used is DMF; the molar ratio, the amount of bis(methylcyclopentadiene)samarium chloride is N-[(2′ -Cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester 1.2 times; N-[(2′-cyanobiphenyl-4-yl)methyl The molar ratio of N-N-pentanoyl-(L)-valine methyl ester to sodium azide is 1:0.8; N-[(2′-cyanobiphenyl-4-yl)methyl] The ratio of -N-valeryl-(L)-valine methyl ester to organic solvent DMF is 1:10 (g:mL); the reaction temperature is 120°C, and the reaction time is 2 hours.

[0046] In the hydrolysis reaction for the synthesis of valsartan: the alkaline hydrolysis reagent is potassium hydroxide, the hydrolysis temperature is 50°C, and the volume (mL) of potassium hydroxide is N-[(2′-cyanobiphenyl-4-yl) 9 times the mass (g) of methyl]-N-valeryl-(L)-valine methyl ester, and the reaction time is 4 hours.

[0047] The yield of the crude valsartan is 90%...

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Abstract

The invention relates to a synthetic method for a sartan drug intermediate. The method includes: dissolving N-[(2'-cyanobiphenyl-4-base) methyl]-N-amyl acyl-(L)-valine methyl ester and sodium azide in an organic solvent, reacting under the catalytic action of catalyst, and obtaining the drug intermediate N-[(2'-tetra-nitrogen imidazolyl biphenyl-4-base]-N-amyl acyl-(L)-valine methyl ester. Rare-earth metal organic chloride is applied to the preparation process of the sartan drug intermediate, the fact that tributyl tin chloride can be substituted, better effect is obtained, product yield and quality are improved to some extent, reaction time is short, toxicity does not exist, a new assistant catalyst which is economical and environment-friendly is provided for synthesis of the sartan drug intermediate, and the sartan drug intermediate has quite high application value and economic value.

Description

Technical field [0001] The present invention relates to the field of pharmaceutical synthesis, in particular, to a method for synthesizing a drug intermediate and the application of the intermediate in the synthesis of sartan drugs. Background technique [0002] Sartan drugs, as one of the representative valsartans, are orally effective and specific angiotensin II (AT1) receptor antagonists, which selectively act on the AT1 receptor subtype and block Cut off the binding of AngⅡ and AT1 receptor (its specific antagonistic effect on AT1 receptor is about 20,000 times greater than AT2 receptor), thereby inhibiting vasoconstriction and the release of aldosterone, resulting in a hypotensive effect. The synthetic drug does not act on angiotensin converting enzyme (ACE), renin and other receptors, and does not inhibit ion channels related to blood pressure and sodium balance; the synthetic drug has no inhibitory effect on angiotensin converting enzyme and does not affect the body The l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D257/04C07D403/10
Inventor 陆其华秦笃伟
Owner 苏州天绿生物制药有限公司
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