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2,2'-[iminodi(methylene)di-(6-fluoro-3,4-dihydro-2h-1-benzenepyran-2- methanol) methane sulfosalt

A technology of benzopyran and mesylate, which is applied in the field of medicinal chemistry and can solve problems such as harsh conditions, difficulties in mass production, and expensive raw material reagents

Inactive Publication Date: 2006-03-08
TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The purpose of the present invention is to overcome the existing problems in the prior art, such as complex reaction operation, harsh conditions, low product purity, expensive raw material reagents, high production cost, low yield, and difficulty in mass production, and provides a reaction condition Mild, easy to operate, low synthesis cost, high yield, high product purity, suitable for mass production of NBL methanesulfonate synthesis method

Method used

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  • 2,2'-[iminodi(methylene)di-(6-fluoro-3,4-dihydro-2h-1-benzenepyran-2- methanol) methane sulfosalt
  • 2,2'-[iminodi(methylene)di-(6-fluoro-3,4-dihydro-2h-1-benzenepyran-2- methanol) methane sulfosalt

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] (1).6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (shown in scheme 2 1) (3.0 grams, 0.016mol), benzylamine (8.3 gram, 0.08mol), isopropanol 100ml, add in the reaction vessel, reflux reaction 2 hours. After stopping the reaction, the solvent was distilled off to obtain a white solid. Recrystallization gave pure white solid 6-fluoro-3,4-dihydro-1-[benzylamino (methylene)]-2H-1-benzopyran-2-methanol] (shown in scheme 2 ) (85% yield), mp 117-118°C.

[0029] (2).6-fluoro-3,4-dihydro-2-oxirane group-2H-1-benzopyran (1 shown in scheme 2) (8.0 grams, 40mmol), the ammoniacal liquor of 15wt% ( 0.27 grams, 4.0mmol), methanol 800ml, after reflux reaction for 2 hours. The solvent was evaporated to obtain a yellow thick substance. Silica gel column purification, using dichloromethane and methanol as eluent. After distilling off the solvent, the white solid 6-fluoro-3,4-dihydro-1-[amino(methylene)]-2H-1-benzopyran-2-methanol (shown in scheme 2) (Yield 78%), mp 119-112°C.

[0...

Embodiment 2

[0035] (1).6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (shown in Scheme 2) (7.5 grams, 0.04mol), benzylamine (0.83 gram, 0.008mol), tetrahydrofuran 20ml, add in the reaction container, reflux reaction 2 hours. After stopping the reaction, the solvent was distilled off to obtain a white solid. Recrystallization gave pure white solid 6-fluoro-3,4-dihydro-1-[benzylamino (methylene)]-2H-1-benzopyran-2-methanol] (shown in scheme 2 ) (85% yield), mp 117-118°C.

[0036] (2).6-Fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (1 shown in scheme 2) (1.6 g, 8.0 mmol), 25% ammonia water (0.54 g, 8.0 mmol), butanol 70 ml, after reflux reaction for 2 hours. The solvent was evaporated to obtain a yellow thick substance. Silica gel column purification, using dichloromethane and methanol as eluent. After distilling off the solvent, the white solid 6-fluoro-3,4-dihydro-1-[amino(methylene)]-2H-1-benzopyran-2-methanol (shown in scheme 2) (Yield 78%), mp 119-112°C.

[0037] or

[0038] Th...

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Abstract

This invention relates to a synthetic method for beta1-receptor blocking agent and 2, 2'-[imino di(methylene)]-di-(6-fluorine-3, 4-dihydro-2H-1-benzopyrane-2-methanol) methanesulfonate. First, prepare 6-fluorine-3, 4-dihydro-1-[amino (methylene)]-2H-1-benzopyrane-2-methanol using 6-fluorine-3, 4-dihydro-2- oxirane group -2H-1- benzopyrane as raw material; then, use LiAlH4 to dispose and get the compound Li-Al amidate; finally, enable Li-Al amide to react with 6-fluorine-3, 4-dihydro-2-oxirane group-2H-1- benzopyrane to get NBL. Advantages:low cost, simple operation and high purity of NBL methanesulfonate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to β1-receptor blocker 2,2'-[iminobis(methylene)]bis-(6-fluoro-3,4-dihydro-2H-1- The synthetic method of benzopyran-2-methanol) (hereinafter referred to as NBL) methanesulfonate. Background technique [0002] NBL, the chemical name is 2,2'-[iminobis(methylene)]bis-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol). Is a selective β with vasodilator effect 1 - Receptor blockers, clinically used to lower blood pressure, pharmacodynamically classified as selective angiotensin II receptor antagonists, which are pseudosymmetric compounds with a β-aminoalcohol structure in chemical structure, There are four chiral carbon centers in the molecule, so theoretically it has 16 isomers. [0003] Regarding the synthesis of NBL, there have been reports in the literature, but in terms of route design, they are all synthesized by docking of A unit and B unit according to its pseudosymmetric mol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/58
Inventor 王乃兴杨运旭
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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