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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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  • Abstract
  • Description
  • Claims
  • Application Information

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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 be used, the synthesis process is complicated and the efficiency is low.
In addition, among the amino acids used as raw materials for these resolving agents, although it is relatively easy to obtain a compound with a natural stereo configuration, it is difficult to obtain a compound with an opposite stereo configuration, and it is expensive. In this way, it has the following disadvantages : The stereo configuration of the desired vinyl cyclopropane dicarboxylic acid will lead to a significant increase in the manufacturing cost of the resolving agent
[0007] In addition, as a method of using a vinylcyclopropane carboxylic acid derivative and converting it into a vinyl cyclopropane amino acid derivative, a method using Curtius transformation is known, but this reaction must use Azide compounds that are accompanied by explosion hazards. In addition, this method is difficult to control the amount of nitrogen generated in the reaction, so it is not suitable for industrial production (Patent Document 1, Non-Patent Document 1)

Method used

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

Examples

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Effect test

manufacture example 1

[0149] (Production Example 1) Production method of cis-2-vinyl-1-methoxycarbonylcyclopropanecarboxylic acid

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

manufacture example 2

[0151] (Production Example 2) trans-2-vinyl-1-carbamoylcyclopropanecarboxylic acid {(1S, 2S)-, (1R, 2R)- 1:1 mixture of 2-vinyl-1-carbamoylcyclopropanecarboxylic acid} manufacturing method

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

Embodiment 1

[0153] (Example 1) (1S, 2S)-2-vinyl-1-carbamoylcyclopropanecarboxylic acid (S)-N-benzyl-1-benzene The manufacture method of ethyl ethylamine salt

[0154] A 1:1 mixture of (1S, 2S)-type and (1R, 2R)-type synthesized according to Production Example 2, namely 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (500 mg, 3.22 mmol) was suspended It was mixed in acetonitrile (5 mL), and (S)-N-benzyl-1-phenylethylamine (681 mg, 3.22 mmol) was added thereto at room temperature. Stirring was performed for 1 hour at the same temperature, and precipitated crystals were obtained by filtration. The mixture was washed with acetonitrile (1 mL) cooled to 0° C. and 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), and it was 95.6% ee.

[0156] (HPLC analysis system) column: CHIRALCEL OJ-H, eluent: hexane / isopropanol / trifluoroacetic acid=90 / 10 / 0.1, flow rate: 0...

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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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