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Preparation method for hexahydrofurofuranol derivative, intermediate of hexahydrofurofuranol derivative, and preparation method for intermediate

A technology of hexahydrofuran and body formula, which is applied in the field of preparation of hexahydrofuran and furan alcohol derivatives, can solve the problems that are not suitable for industrialization, and achieve the effect of low cost and mild reaction conditions

Active Publication Date: 2019-09-24
JIANGSU RUIKE MEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Japan's Sumitomo Chemical Co., Ltd. chose to use chiral ligand catalysts for the generation of chiral configurations. Although this is indeed a method for constructing chiral configurations, it is not suitable for industrialization.

Method used

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  • Preparation method for hexahydrofurofuranol derivative, intermediate of hexahydrofurofuranol derivative, and preparation method for intermediate
  • Preparation method for hexahydrofurofuranol derivative, intermediate of hexahydrofurofuranol derivative, and preparation method for intermediate
  • Preparation method for hexahydrofurofuranol derivative, intermediate of hexahydrofurofuranol derivative, and preparation method for intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0088]

[0089] Add the compound of formula A1, dichloromethane, into the reaction flask, cool down, weigh bromine, add dichloromethane to dilute, transfer the diluted bromine to the dropping funnel, add slowly dropwise, and control the internal temperature. After dropping, keep warm for reaction and control internal temperature. Add water, control the temperature, let it stand, and separate the liquid. The lower organic phase was put into another reaction flask, water was added, extracted and separated. The lower organic phase was put into another reaction flask, and 5% NaHCO was added 3 Aqueous solution extraction, liquid separation. The lower organic phase was put into another reaction flask, and the upper aqueous phase was combined and added with dichloromethane for extraction and liquid separation. Discard the aqueous phase and combine the organic phase, add water, extract, separate the liquid, discard the aqueous phase, and the lower organic phase, and place in a r...

Embodiment 2

[0091]

[0092] Put acetone, compound of formula A2 (X is bromine), benzoic acid into the reaction bottle, stir and cool down. Add triethylamine into the dropping tank, start to drop slowly, and control the internal temperature. After dropping, the temperature was raised to room temperature, and the reaction was stirred. After the reaction is finished, filter with suction. After the filter, transfer the filtrate to a distillation bottle for vacuum distillation. Control the temperature at 50-60° C. until the distillation bottle appears solid and becomes a paste, add ethyl acetate and steam. Add ethyl acetate to the distillation bottle and stir until it dissolves evenly, transfer the material liquid in the distillation bottle to the reaction flask, add saturated brine to the reaction flask for washing, let stand, separate the liquids, combine the water layers, and add ethyl acetate Extract, stand still, separate layers, discard the water layer, combine the organic layers, ad...

Embodiment 3

[0094] Preparation of Whole Cells of Genetically Engineered Bacteria with Aldehyde and Keto Reductase

[0095] Recombinant aldehyde and ketone reductase genetically engineered bacteria, the specific preparation method is: select the gene sequence of aldehyde and ketone reductase derived from Saccharomyceskudriavzevii, carry out artificial design, and synthesize the artificially designed sequence through the whole gene (entrusted by KingScript Biotechnology Co., Ltd. Synthetic), cloned into the Nde I and Xho I restriction sites of the expression vector pET28a, transformed host bacteria E.coli BL21 (DE3) competent cells; picked positive transformants and sequenced and identified them to obtain recombinant expression vectors; recombinant The expression vector is transferred into the E. col i BL21 (DE3) strain, and the recombinant aldehyde and ketone reductase genetic engineering bacteria capable of inducing the expression of the recombinant aldehyde and ketone reductase are obtain...

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Abstract

The invention relates to the field of pharmaceutical synthesis, specifically to a preparation method for a hexahydrofurofuranol derivative, an intermediate of the hexahydrofurofuranol derivative, and a preparation method for the intermediate. According to the preparation method provided by the invention, a compound with a formula A1 which is shown in the description is used as a starting raw material; chirality is established through an enzymatic method in the preparation process of the hexahydrofurofuranol derivative; thus, by adoption of the technical means of the invention, a product with high optical purity can be prepared. The preparation method provided by the invention can realize commercial production and preparation of a darunavir key intermediate namely (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-ol, and is an economical route applicable to industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of a hexahydrofuranofuran alcohol derivative, an intermediate thereof and a preparation method thereof. Background technique [0002] The compound with the following formula Z structure is chemically named (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-ol: [0003] [0004] It belongs to a kind of hexahydrofuran and furan alcohol derivatives, and is an intermediate of the anti-AIDS drug darunavir. [0005] The Chinese patent application numbers of Taibotek Pharmaceutical Co., Ltd., the original manufacturer of darunavir, are 02817639.1 (application date: 2002-9-6) and 200580010400.X, which provide the above-mentioned (3R, 3aS, 6aR)-hexahydrofuro[ 2,3-b] the preparation method of-3-alcohol, wherein raw material is following formula (3) compound, [0006] [0007] Compounds of formula (3) are prepared from starting materials of compounds of formula (1). ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33C07D307/20C07D493/04C12P17/04C12P17/16
CPCC07D307/33C07D307/20C07D493/04C12P17/04C12P17/162C07B2200/07C12P41/002Y02P20/55C12Y101/01
Inventor 高照波陈建华万志东何大伟周增乐马晓东向韦林荆鑫梅义将
Owner JIANGSU RUIKE MEDICAL SCI & TECH CO LTD
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