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A method for synthesizing hexahydrofuro[2,3-b]furan-3-alcohol and its enantiomers

A technology of hexahydrofuran and furan, which is applied in the field of drug synthesis, can solve the problems of low reaction yield, difficult realization, uneconomical industrial-scale production and the like, and achieves the effects of simple operation, easy availability of raw materials, and low cost of raw materials

Active Publication Date: 2017-02-22
SHANGHAI DESANO CHEM PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction yield of this method is low, which is uneconomical in industrial scale production, and a low temperature of -78°C is required when using metal catalysts, which is also difficult to achieve in industrial large-scale production

Method used

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  • A method for synthesizing hexahydrofuro[2,3-b]furan-3-alcohol and its enantiomers
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  • A method for synthesizing hexahydrofuro[2,3-b]furan-3-alcohol and its enantiomers

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: Synthesis of 3-(2-benzyloxyacetyl) dihydrofuran-2(3H)-one (compound of formula III-a)

[0028]

[0029] Sodium tert-butoxide (12.0 g, 0.125 mol) was dissolved in 120 mL of methyl tert-butyl ether, and 1,4-butyrolactone (7.2 mL, 0.094 mol) was added under cooling in a dry ice-acetone bath. Reaction at ~-50°C for 0.5-2 hours; dropwise add 2-benzyloxyethyl acetate (15.0g, 0.077mol) in 30mL methyl tert-butyl ether solution, keep the temperature for 3-7 hours; dropwise 4.0M hydrochloric acid to adjust the pH of the reaction system to be 4-5; add 50mL water and 150mL ethyl acetate, separate the liquids, extract the aqueous phase with ethyl acetate (100mL×2), combine the organic phases, and successively wash with saturated sodium bicarbonate solution ( 30mL × 3) and saturated brine (30mL × 2), washed with anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure to obtain 15.78g of the slightly yellow oily compound of formula III...

Embodiment 2

[0030] Embodiment 2: synthetic formula II-a compound

[0031]

[0032] Dissolve (5.0g, 0.021mol) 3-(2-benzyloxyacetyl)dihydrofuran-2(3H)-one (compound of formula III-a) in 50mL tetrahydrofuran, protect with argon, and cool in an ice-water bath Add sodium borohydride (720 mg, 0.019 mol), and keep warm at 0°C for 0.5 to 2 hours after addition; add 1M hydrochloric acid dropwise to adjust the pH of the reaction system to 2 to 3; add 100 mL of ethyl acetate, water (20 mL) and Saturated sodium bicarbonate solution (10 mL) and brine (10 mL) were washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography to obtain 3.2 g of the compound of formula II-a with a molar yield of 63%.

Embodiment 3

[0033] Embodiment 3: Synthesis of 3-(2-ethoxyacetyl) dihydrofuran-2(3H)-one (compound of formula III-b)

[0034]

[0035] Dissolve sodium ethoxide (7.0g, 0.11mol) in 100mL of tetrahydrofuran, add 1,4-butyrolactone (7.2mL, 0.094mol) under cooling in a dry ice-acetone bath, and keep the reaction for 0.5~2 hours; add 2- Ethoxyethyl acetate (10.2g, 0.077mol) in 30mL tetrahydrofuran solution, heat at -78°C~-50°C for 3~7 hours; add 4.0M hydrochloric acid dropwise to adjust the pH of the reaction system to 4~5; add 50mL Water and 120mL ethyl acetate were separated, the aqueous phase was extracted with ethyl acetate (100mL×2), the organic phases were combined, washed successively with saturated sodium bicarbonate solution (30mL×3) and saturated brine (30mL×2), Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 11.8 g of the compound of formula III-b in the form of a light yellow oil, with a molar yield of 89.2% and an HPLC purit...

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Abstract

The invention discloses synthetic methods of hexahydrofuro[2,3-b]furan-3-ol and an enantiomer thereof. The synthetic method of hexahydrofuro[2,3-b]furan-3-ol comprises the step c or the step b to the step c or the step a to the step c in the following synthetic route as shown in the description. The synthetic method of the enantiomer (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol comprises the step c to the step f or the step b to the step f or the step a to the step f in the following synthetic route as shown in the description, wherein R1 is selected from C1 to C4 alkyl or aralkyl, and R2 is selected from C1 to C4 alkyl. The synthetic methods provided by the invention have the advantages of cheap and easily available raw materials, simple operation, low cost and the like, are suitable for large-scale production, and have practical value for realization of industrialized production of darunavir.

Description

technical field [0001] The present invention relates to a synthesis method of hexahydrofuro[2,3-b]furan-3-ol and its enantiomer (3R, 3aS, 6aR) hexahydrofuro[2,3-b]furan-3 A method for synthesizing -alcohol belongs to the technical field of pharmaceutical synthesis. Background technique [0002] The (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-oxyl group is a pharmacologically important moiety present in the structure of protease inhibitors of retroviruses. For example, it is an important synthetic fragment of darunavir, whose chemical structural formula is as follows: [0003] Darunavir is developed by Tibotec Pharmaceuticals Co., Ltd. (Tibotec Pharmaceuticals), also known as TMC114, trade name Prezista, approved by the FDA on June 23, 2006, the drug can selectively inhibit HIV in infected cells Encodes Gag-Pol polyproteins that prevent the formation of mature virions. [0004] An important precursor for the synthesis of the above-described protease inhibitors containing hex...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 李金亮赵楠刘刚
Owner SHANGHAI DESANO CHEM PHARMA
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