Optically active vinyl-cyclopropane carboxylic acid derivative and optically active vinyl-cyclopropane amino acid derivative manufacturing method

A technology of vinyl cyclopropane carboxylic acid and vinyl cyclopropane amide carboxylic acid, which is applied in the preparation of carbamic acid derivatives, carboxylic acid amide optical isomers, carboxylate esters, etc., and can solve the complex and efficient synthesis process. Low, low productivity and other issues

Inactive Publication Date: 2011-09-07
KANEKA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, in the method of 1), since the selectivity at the time of enzymatic resolution is low and the reactivity is also low, a large amount of enzyme must be used
In addition, pig-derived enzymes and the like are required, so this method is not preferable as an industrial production method
In addition, as the method of 2), since vinylcyclopropanedicarboxylic acid is a highly water-soluble compound, there are problems that a large amount of organic solvent is required for the extraction operation, and productivity is low.
In addition, when the racemate of vinylcyclopropanedicarboxylic acid is optically resolved, the resolution efficiency is as low as 78% ee or less, so there is also the following problem: usually in order to meet the requirements of pharmaceutical intermediates of high optical purity quality specifications, which will lead to an increase in the purification load of subsequent steps
[0006] In addition, as an amine resolving agent, although amino acid derivatives and amino alcohol derivatives can b

Method used

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  • Optically active vinyl-cyclopropane carboxylic acid derivative and optically active vinyl-cyclopropane amino acid derivative manufacturing method
  • Optically active vinyl-cyclopropane carboxylic acid derivative and optically active vinyl-cyclopropane amino acid derivative manufacturing method
  • Optically active vinyl-cyclopropane carboxylic acid derivative and optically active vinyl-cyclopropane amino acid derivative manufacturing method

Examples

Experimental program
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Effect test

Example Embodiment

[0149] (Production Example 1) Method for producing cis-2-vinyl-1-methoxycarbonylcyclopropane carboxylic acid

[0150] While keeping the internal temperature at 1~5°C, 28wt% sodium methoxide / methanol solution was added dropwise to trans-1,4-dibromo-2-butene (25.00g, 0.144mol), propylene over 30 minutes Dimethyl diacid (15.06g, 0.144mol) in methanol (150mL) solution. After the dripping was completed, stirring was performed for 5 hours under the condition that the internal temperature was 24°C. Then, the reaction liquid was cooled, and while maintaining the internal temperature at 1 to 5°C, a 14% potassium hydroxide aqueous solution (36.02 g, 0.091 mol) was added dropwise over 30 minutes. After the dropwise addition, under the condition of an internal temperature of 24° C., stirring was performed for another 21 hours, and then concentrated by a rotary evaporator until the total amount was about 70 g. Water (45 mL) and tert-butyl methyl ether (75 mL) were added to the concentrated ...

Example Embodiment

[0151] (Production Example 2) trans-2-vinyl-1-carbamoyl cyclopropane carboxylic acid {(1S, 2S)-, (1R, 2R)- 1:1 mixture of 2-vinyl-1-carbamoyl cyclopropane carboxylic acid)

[0152] While keeping the internal temperature at 1~5°C, 28wt% sodium methoxide / methanol solution was added dropwise to trans-1,4-dibromo-2-butene (25.00g, 0.144mol), propylene over 30 minutes Dimethyl diacid (15.06g, 0.144mol) in methanol (150mL) solution. After the dripping is completed, stir for 5 hours at an internal temperature of 24°C, and then, while maintaining the internal temperature at 15-25°C, introduce ammonia gas (about 15g, 0.88mol) into the reaction solution for 1 hour . Under the condition of an internal temperature of 25°C, stirring was performed for 15 hours, and then concentrated using a rotary evaporator until the total amount was approximately 142 g. Water (17.44 g) and a 30 wt% sodium hydroxide aqueous solution (12.17 g, 0.09 mmol) were added to the concentrated solution, and stirrin...

Example Embodiment

[0153] (Example 1) (1S, 2S)-2-vinyl-1-carbamoylcyclopropanecarboxylic acid (S)-N-benzyl-1-benzene Method for producing phenylethylamine salt

[0154] Suspend the 1:1 mixture of (1S, 2S)-type and (1R, 2R)-type synthesized in accordance with Production Example 2, namely 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (500 mg, 3.22 mmol) It was mixed in acetonitrile (5 mL), and (S)-N-benzyl-1-phenylethylamine (681 mg, 3.22 mmol) was added thereto at room temperature. At the same temperature, stirring was performed for 1 hour, and the precipitated crystals were obtained through filtration operation. It was washed with acetonitrile (1 mL) cooled to 0°C and then dried to obtain the title compound (yield: 416.9 mg, yield: 35.3%).

[0155] The optical purity of the obtained compound was measured by high performance liquid chromatography (HPLC) analysis, and the result was 95.6%ee.

[0156] (HPLC analysis system) Column: CHIRALCEL OJ-H, eluent: hexane / isopropanol / trifluoroacetic acid = 90 / ...

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Abstract

The issue is to provide a method to obtain optically active vinyl-cyclopropane carboxylic acid derivatives with high yield and high optical purity using starting materials that are safe and easily acquired at a low cost. An additional issue is to provide a method to obtain vinyl-cyclopropane amino acids with high optical purity inexpensively and safely. The issues are resolved by obtaining optically active vinyl-cyclopropane carboxylic acid derivatives with a method comprising a process to allow an optically active amine to act on a racemic vinyl-cyclopropane carboxylic acid derivative and produce an optically active vinyl-cyclopropane carboxylic acid derivative-amine diastereomer salt. Vinyl-cyclopropane amino acids can also be obtained by deriving a vinyl-cyclopropane amino acid from the optically active vinyl-cyclopropane carboxylic acid derivative-amine diastereomer salt obtained in this way.

Description

technical field [0001] The present invention relates to a method for producing an optically active vinylcyclopropanecarboxylic acid derivative and an optically active vinylcyclopropane amino acid derivative useful as a drug, especially as an intermediate of a hepatitis C drug. Background technique [0002] Known methods for producing optically active vinylcyclopropanecarboxylic acid derivatives include: [0003] 1) by the reaction of malonate diester and 1,4-dibromo-2-butene, the racemate of vinylcyclopropane malonate diester is synthesized, and then the method of utilizing lipase to resolve it ( Non-patent literature 1); [0004] 2) A method of reacting a racemate of vinylcyclopropanedicarboxylic acid with an optically active amine to form a diastereoisomeric salt, followed by optical resolution (Patent Document 1), etc. [0005] However, in the method of 1), since the selectivity of enzyme resolution is low and the reactivity is also low, it is necessary to use a large a...

Claims

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Application Information

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IPC IPC(8): C07C69/757C07C67/52C07C211/27C07C211/29C07C211/30C07C227/32C07C229/28C07C231/20C07C235/82C07C269/04C07C271/24
CPCC07C67/347C07C2101/02C07C227/32C07C233/58C07C271/24C07C2601/02C07C69/743C07C229/48
Inventor 田中辰佳大黑一美
Owner KANEKA CORP
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