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Method for preparing optical pure 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

A benzopyran and optical technology, applied in the field of cardiovascular drugs, can solve the problems of high cost, complicated operation of the splitting method, low total yield and the like, and achieve the effects of simple method, high yield and high selectivity

Inactive Publication Date: 2009-08-26
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this splitting method is loaded down with trivial details operation, and total yield is low, and cost is high
"Organic Chemistry" (Volume 25, No. 2, 201-203, 2005) once reported the resolution of racemic 6-fluoro-3,4-dihydro-2H-1-benzopyridine with chiral phenethylamine Fran-2-carboxylic acid, but the resolution yield is only 20% based on single isomer

Method used

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  • Method for preparing optical pure 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid
  • Method for preparing optical pure 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid
  • Method for preparing optical pure 6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0031] 0.98 g of 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid, 1.2 g of optically pure (1R,2S)-N,N-dimethyl 1-p-nitro Add phenyl-2-amino-1,3-propanediolamine and 15mL ethanol into a 25mL round bottom flask, heat to reflux until all solids are dissolved, stir for 5 minutes, slowly lower to 30°C, and filter to obtain diastereoisomeric The solid 0.9 g of body salt, wherein (S) configuration acid is the majority, e.e. value is 89%, and the yield is 41%.

Embodiment 2

[0033] 9.8 grams of 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid, 12 grams of optically pure (1R,2S)-N,N-dimethyl 1-p-nitro Phenyl-2-amino-1,3-propanediol and 130mL ethanol were added to a 250mL round bottom flask, heated to reflux until all the solids were dissolved, stirred for 5 minutes, slowly lowered to 30°C, and filtered to obtain 10 grams of solids, wherein ( The acid in the S) configuration was in the majority, the e.e. value was 84%, and the yield was 46%.

[0034] The obtained solid was recrystallized once with 39 mL of ethanol to obtain 8.2 g of solid, which was dissociated with 50 mL of 1N hydrochloric acid, and then extracted with dichloromethane (100 mL×3). The dichloromethane layers were combined, dried and concentrated to obtain (S)- (+)-6-Fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid 3.65 g, e.e. value 100%, yield 37%.

Embodiment 3

[0036] 58.8 grams of 6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid, 72 grams of optically pure (1R,2S)-N,N-dimethyl 1-p-nitro Phenyl-2-amino-1,3-propanediol and 700mL of ethanol were added to a 1000mL round-bottomed flask, heated to reflux until all the solids were dissolved, stirred for 5 minutes, slowly lowered to 30°C, and filtered to obtain 76 grams of solids, (S ) configuration acid is the majority, e.e. value is 47%, and the yield is 58%.

[0037]The obtained solid was recrystallized once with 370 mL of ethanol to obtain 49.7 grams of solid, which was dissociated with 200 mL of 1N hydrochloric acid, and then extracted with dichloromethane (300 mL×3). The dichloromethane layers were combined, dried and concentrated to obtain (S)- (+)-6-Fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid 22.1 g, e.e. value 99%, yield 37.5%.

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Abstract

The invention discloses a method for preparing optical pure 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid. An optical pure resolving agent shown in a general formula I is adopted to form diastereomer salt with a racemic modification, namely 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid in a solution, the salt is dissociated, and the optical pure 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is obtained, wherein R is equal to H, NO2, CN, and X, R1 and R2 are equal to C1-C4 alkyl, or the H, or any combination of the C1-C4 alkyl and the H, R3 is equal to C1-C4 alkylol, or the C1-C4 alkyl, or Ar, and the X is equal to F, Cl, Br or I.

Description

technical field [0001] The invention relates to a preparation method of an optically pure 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, a key intermediate of the cardiovascular medicine nebivolol. Background technique [0002] Many biologically active molecular structures contain chroman structural units of 3,4-dihydro-2H-1-benzopyran ring, for example, vitamin E and many antihypertensive drugs of β1-receptor antagonists, In particular, (S, R, R, R)-nebivolol and (R, S, S, S)-nebivolol are novel hypotensive drugs with high β1-receptor selectivity and mild vascular It has a dilating effect and is well tolerated by patients with heart failure. [0003] While optically pure 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid is synthesized from (S, R, R, R)-nebivolol and (R, S, S , the key intermediate of S)-nebivolol, its structural formula is: [0004] [0005] There are few literature reports on the preparation of optically pure 6-fluoro-3,4-dihydro-2H-1-c...

Claims

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Application Information

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IPC IPC(8): C07D311/04C07B57/00
Inventor 廖建周宏马海峰邓金根朱槿
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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