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Method for preparing 2S,3R-2-benzyloxy-3-pentanol

A technology of benzyloxyl and amyl alcohol, which is applied in the field of intermediates for the synthesis of posaconazole, can solve the problems of not easy access to chiral inducers, poor atom economy, and difficult control, and achieve less impurities, less pollution, and better reaction mild temperature effect

Inactive Publication Date: 2012-11-28
成都费歇尔医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above two approaches can achieve highly selective asymmetric addition of Grignard reagents to aldehydes, but they also have significant disadvantages
The chiral inducer required by the first route is not easy to obtain, so the price is quite expensive, and its source has become the biggest defect; the second route requires the metal compound and the Grignard reagent to react with the Grignard reagent. Swap, quite cumbersome to operate, difficult to control, and poor atom economy

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0019] 16.4 g (0.1 mol) of 2S-benzyloxy-propionaldehyde was put into a three-necked flask, 200 ml of anhydrous tetrahydrofuran was added, 51.5 g of bis(trimethylsilyl)trifluoroacetamide (0.2 mol) was added, and stirred for 1 hour, Cool in an ice-salt bath, add the pre-prepared tetrahydrofuran solution of ethylmagnesium bromide (3M, 267ml) dropwise at -10°C to -5°C, and keep the temperature at -10°C to -5°C. , continue to maintain this temperature for 8 hours, stop the reaction, extract with water, extract the product with dichloromethane, wash the organic phase with brine and water respectively, dry over anhydrous magnesium sulfate, filter, concentrate, and beat with isopropyl ether to obtain the target product 16.3 g, yield: 84.9%, ee value: 99.2%.

[0020] 1 H-NMR (CD 3 Cl, 400MZ): 0.96(3H)1.20-1.24(3H)1.46-1.48(2H)1.97-2.04(2H)3.07-3.09(1H)4.65-4.67(2H)7.10-7.22(5H)

[0021] MS(H + ): 195

[0022] Wherein, the preparation of 2S-benzyloxy-propionaldehyde can refer to th...

example 2

[0024] 16.4g (0.1mol) of 2S-benzyloxy-propionaldehyde was put into a three-necked flask, 200ml of anhydrous tetrahydrofuran was added, 103g of bis(trimethylsilyl)trifluoroacetamide (0.4mol) was added, stirred for 1 hour, and placed on ice Cool in a salt bath, add a pre-prepared tetrahydrofuran solution of ethylmagnesium bromide (3M, 267ml) dropwise at -10°C to -5°C, and keep the temperature at -10°C to -5°C, and the addition is completed in about 1 hour. Continue to react at this temperature for 8 hours, stop the reaction, extract with water, extract the product with dichloromethane, wash the organic phase with brine and water respectively, dry over anhydrous magnesium sulfate, filter, concentrate, and beat with isopropyl ether to obtain the target product 15.9 g, yield: 82.8%, ee value: 99.1%.

example 3

[0026] 16.4 g (0.1 mol) of 2S-benzyloxy-propionaldehyde was put into a three-necked flask, 200 ml of anhydrous tetrahydrofuran was added, 25.8 g of bis(trimethylsilyl)trifluoroacetamide (0.1 mol) was added, and stirred for 1 hour, Cool in an ice-salt bath, add the pre-prepared tetrahydrofuran solution of ethylmagnesium bromide (3M, 267ml) dropwise at -10°C to -5°C, and keep the temperature at -10°C to -5°C. , continue to maintain this temperature for 8 hours, stop the reaction, extract with water, extract the product with dichloromethane, wash the organic phase with brine and water respectively, dry over anhydrous magnesium sulfate, filter, concentrate, and beat with isopropyl ether to obtain the target product 15.2 g, yield: 79.2%, ee value: 99.0%.

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Abstract

The invention discloses a method for preparing a 2S,3R-2-benzyloxy-3-pentanol intermediate for preparing posaconazole. The method comprises the following steps of: performing addition on 2S-benzyloxy-propanal and ethyl magnesium bromide at the temperature of 60 DEG C below zero to 5 DEG C under induction of a chiral aid, and performing post treatment on the reactants to obtain a crude 2S,3R-2-benzyloxy-3-pentanol product of which the enantiomeric excess (ee) value is more than 99 percent, wherein the crude product is directly used for synthesizing the posaconazole without refining. The preparation method is environment-friendly, high in optical selectivity and high in yield, and greatly reduces the cost.

Description

technical field [0001] The present invention relates to a kind of intermediate used in the synthesis of drug posaconazole, more specifically, relates to a kind of intermediate 2S, 3R-2-benzyloxy-3-pentanol used in the synthesis of posaconazole synthetic method. Background technique [0002] Posaconazole (trade name: Noxafil) is the third-generation antifungal drug developed by Schering-Plough Pharmaceutical Co., Ltd. It was first launched in Germany in December 2005, and in the UK in March 2006. It was launched on September 18, 2006. , has been approved by the FDA. Posaconazole has a broad antibacterial spectrum against Candida, Histoplasma capsulata, Seidosporium, Bipolar zygomycetes, Fusarium, and yeasts. Including fluconazole-resistant non-albicans strains, Cryptococcus neoformans and Aspergillus have strong inhibitory activity; especially against relatively rare but life-threatening fungal diseases (zygomycosis, fusarium and coccidioidomycosis, etc. ) also works. [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/178C07C41/30
Inventor 余长杰万小娟
Owner 成都费歇尔医药科技有限公司
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