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Method for preparing (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

A technology of hexahydrofuran and furan, which is applied in the field of preparing hexahydrofuro[2,3-b]furan-3-ol, can solve the problems of high cost, long synthesis line and complicated operation, and achieve low production cost, The effect of short reaction route and simple operation

Active Publication Date: 2017-07-07
QINGDAO UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to solve the problems of long synthetic route, complicated operation and high cost in the prior art, the present invention provides a method for preparing (3R, 3aS, 6aR) hexahydrofuro[2,3-b]furan-3-alcohol method

Method used

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  • Method for preparing (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Step (a): Dissolve 2-benzyloxyl-1-iodoethane (31.4g, 0.12mol) and DABCO (16.1g, 0.13mol) in 300mL of dichloromethane, stir at room temperature for 30 minutes and cool to -20°C , add (R)-2,2-dimethyl-1,3-dioxolane-4-acetaldehyde (14.4g, 0.1mol) and tetrahydropyrrole (7.1g, 0.1mol ). The resulting reaction solution was heated up to 25°C and stirred at this temperature for 24 hours, then 100 ml of water and 100 ml of 1N hydrochloric acid were added, stirred for 30 minutes, and the organic phase was separated. The organic phase was washed with saturated brine and then anhydrous sulfuric acid was added. Dried over magnesium, filtered, and the filtrate was concentrated under reduced pressure to obtain II. After separation, 19.5 g of pure product was obtained, with a yield of 70%.

[0033] Step (b): Compound (II) (30 g, 0.11 mol), 3.0 g of 10% Pd / C and 200 mL of methanol were placed in a round bottom flask, and the resulting reaction solution was hydrogenated under 1 atm hydr...

Embodiment 2

[0035]Step (a): Dissolve 2-benzyloxyl-1-iodoethane (52.3g, 0.20mol) and triethylamine (13.1g, 0.13mol) in 300mL dichloromethane, stir at room temperature for 30 minutes and then cool to - 20°C; (R)-2,2-dimethyl-1,3-dioxolane-4-acetaldehyde (14.4g, 0.1mol) and tetrahydropyrrole (1.42g, 0.02mol), the resulting reaction solution was heated to 25°C and stirred at this temperature for 24 hours, then added 100mL of water and 100mL of 1N hydrochloric acid, stirred for 30 minutes, and separated the organic phase, which was washed with saturated brine and anhydrous Dry over magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain II. After separation, 17.5 g of pure product is obtained, yield: 63%.

[0036] Step (b): Compound (II) (35 g, 0.13 mol), 3.5 g of 10% Pd / C and 250 mL of tetrahydrofuran were placed in a round bottom flask, and the resulting reaction solution was hydrogenated under 1 atm hydrogen pressure for 1 hour. After filtration, 100 mL of ...

Embodiment 3

[0038] Step (a): Dissolve 2-(2-iodoethoxy)tetrahydro-2H-pyran (51.2g, 0.20mol) and triethylamine (21.2g, 0.21mol) in 300mL chloroform, stir at room temperature for 30 Minutes later, cool to 0°C; add (14.4g, 0.1mol) (R)-2,2-dimethyl-1,3-dioxolane-4-acetaldehyde and L-proline to the mixture in sequence Amino alcohol derivative L-2-(diphenyl-triphenylsiloxymethyl)tetrahydropyrrole (25.5g, 0.05mol), the resulting reaction solution rose to 40°C and stirred at this temperature for 10 hours, then added 100 mL of water and 100 mL of 1N hydrochloric acid were stirred for 30 minutes, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound II.

[0039] Step (b): 200 mL of tetrahydrofuran and 100 mL of 3N hydrochloric acid were added to the crude product, and the resulting reaction solution was heated to 65° C. for 6 hours. Ad...

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Abstract

The invention belongs to the field of chemical synthesis, and discloses a method for preparing a darunavir intermediate namely (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol. According to the method, (R)-3-hydroxyl-4-acetaldol derivatives (I) are used as raw materials, and under the action of a catalyst, the (R)-3-hydroxyl-4-acetaldol derivatives (I) stereoselectively react with an ethanediol derivative so as to obtain an intermediate (II); and the obtained intermediate (II) is subjected to protecting group removal, and under the acid condition, cyclization is performed, so that the (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is obtained. According to the preparation method, the raw materials are low in cost and easy to obtain, the reaction stereoselectivity is high, the operation is simple, the route is short, the cost is low, and the method is suitable for industrialized production of darunavir.(As shown in the description).

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for preparing (3R, 3aS, 6aR) hexahydrofuro[2,3-b]furan-3-ol. Background technique [0002] Darunavir (structural formula IV), also known as darunavir, is a new non-peptide antiretroviral protease inhibitor for AIDS treatment. Darunavir was successfully developed for the first time by Johnson & Johnson's Tibotec pharmaceutical company. Navir), the most bioavailable of all, inhibits viral proteases by blocking the formation of new, mature virions released from the surface of infected host cells. [0003] [0004] (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol (III) (structure shown in formula III) is one of the key intermediates for the synthesis of darunavir, hexahydrofuran There are three chiral centers in the molecular structure of [2,3-b]furan-3-ol, and there are eight possible stereoisomers in theory. Due to the influence of the double-ring rigid structure, there ar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04
CPCC07D493/04Y02P20/55
Inventor 滕大为仇中选黄龙江龙中柱晏桂刚安娜蔡水洪
Owner QINGDAO UNIV OF SCI & TECH
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