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Preparation method for reducing lactone into hemiacetal

A technology of hemiacetal and lactone, applied in the direction of organic chemistry, etc., can solve the problems of not knowing the synthetic route of red aluminum, no disclosure, etc., and achieve the effects of high application value, low cost and high yield

Active Publication Date: 2020-12-11
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Because the price of red aluminum is relatively expensive, the preparation process of red aluminum is still in the patent protection period and has not been disclosed, so we do not know the synthesis route of red aluminum

Method used

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  • Preparation method for reducing lactone into hemiacetal
  • Preparation method for reducing lactone into hemiacetal
  • Preparation method for reducing lactone into hemiacetal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]

[0039] Drop into ethylene glycol dimethyl ether (50ml) in the 100ml three-necked flask, the ethylene glycol monomethyl ether solution (5.2g, 60mmol) of 50% sodium ethylene glycol monomethyl ether starts magnetic stirring, after stirring and dissolving, cool down to 0 -5°C, add aluminum trichloride (4.0g, 30mmol), stir for 10min, add sodium borohydride (1.1g, 30mmol) at 0-5°C, stir for 10min, then add compound I-1 at 0-5°C ( 5.0g, 20mmol) in 10ml of ethylene glycol dimethyl ether solution, stirred and reacted at 0-5°C for 4 hours; added 7.5g of concentrated sulfuric acid into 45g of water, cooled to 0-5°C, and then added the reaction system dropwise into the sulfuric acid aqueous solution, Extract the aqueous acid phase with 50ml*3 ethyl acetate, combine the organic phases, wash once with 50ml saturated aqueous sodium bicarbonate solution, and wash once with 50ml drinking water, and evaporate the organic phase to dryness under reduced pressure to obtain 4.5g of white...

Embodiment 2

[0041]

[0042] Drop into ethylene glycol dimethyl ether (70ml) in the 100ml three-necked flask, the ethylene glycol monomethyl ether solution (5.2g, 60mmol) of 50% sodium ethylene glycol monomethyl ether starts magnetic stirring, after stirring and dissolving, cool to 0 -5°C, add aluminum trichloride (4.0g, 30mmol), stir for 10min, add sodium borohydride (1.1g, 30mmol) at 0-5°C, stir for 10min, add compound I-2 at 0-5°C ( 7.44g, 20mmol) in 10ml of ethylene glycol dimethyl ether solution, stirred and reacted at 0-5°C for 4 hours; added 7.5g of concentrated sulfuric acid into 70g of water, cooled to 0-5°C, and then added the reaction system dropwise into the sulfuric acid aqueous solution, Extract the aqueous acid phase with 70ml*3 ethyl acetate, combine the organic phases, wash once with 70ml saturated aqueous sodium bicarbonate solution, and wash once with 70ml drinking water, and evaporate the organic phase to dryness under reduced pressure to obtain 6.8g of white solid, w...

Embodiment 3

[0044]

[0045] Put ethylene glycol dimethyl ether (100ml) into a 250ml three-necked flask, ethylene glycol monomethyl ether (4.55g, 60mmol) and start magnetic stirring, after stirring and dissolving, cool down to 0-5°C, add aluminum trichloride (4.0 g, 30mmol), stirred for 10min, triethylamine (6.0g, 60mmol) was added dropwise at 0-5°C, stirred for 10min, sodium borohydride (1.1g, 30mmol) was added at 0-5°C, and after stirring for 10min, 0- Add compound I-1 (5.0g, 20mmol) in 10ml of ethylene glycol dimethyl ether solution at 5°C, stir and react at 0-5°C for 2 hours; add 7.5g of concentrated sulfuric acid into 45g of water, cool to 0-5°C, and then Add the reaction system dropwise into aqueous sulfuric acid solution, extract the aqueous acid phase with 50ml*3 ethyl acetate, combine the organic phases, wash once with 50ml saturated aqueous sodium bicarbonate solution, and wash once with 50ml drinking water, and evaporate the organic phase to dryness under reduced pressure. 4....

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Abstract

The invention relates to the field of medicine synthesis, particularly to a preparation method for reducing a lactone structure into hemiacetal, particularly to a preparation method for a darunavir intermediate. According to the method, a compound shown in a formula I is reduced under the conditions of alkali, aluminum trichloride, a reducing agent and a solvent to prepare a compound shown in a formula II, or the compound shown in the formula I is reduced under the conditions of alcohol, alkali, aluminum trichloride, a reducing agent and a solvent to prepare the compound shown in the formula II, wherein R1, R2, R3, R4, R5 and R7 are hydrogen, hydroxyl, amino, alkyl, aryl, fluorine, chlorine or bromine, R6 and R8 are hydrogen, hydroxyl, amino, benzoyloxy, alkyl, aryl, fluorine, chlorine orbromine, and n is 0 or 1.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method for reducing a lactone structure into a hemiacetal, in particular to a preparation method for a darunavir intermediate. Background technique [0002] Have the compound of following formula II-1 structure: [0003] [0004] It is generally obtained by reducing the lactone structure to hemiacetal under a suitable reducing agent, and it is an intermediate of the anti-AIDS drug darunavir. [0005] We found that the most common method for reducing lactones to hemiacetals is to use DIBAL-H at -78°C. Obviously, this method has harsh conditions and is difficult to produce industrially. Using NaBH 4 Combined with CeCl 3 , LiCl or CuCl can also reduce the lactone to obtain the corresponding hemiacetal, but it is proved by experiments that the yield of the target product II-1 obtained by reduction by these methods is not more than 10%. Buchwald has reporte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/20
CPCC07D307/20Y02P20/55
Inventor 于帅高照波郭雷雷郑辉
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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