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A kind of method for preparing darunavir intermediate

A compound, the technology of butyrolactone, applied in the field of medicine, can solve the problems of poor atom economy and high cost of raw materials

Active Publication Date: 2021-03-05
成都博腾药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] But this synthetic method atom economy is poor, owing to need to use the higher periodic acid and lithium borohydride of price, cause the raw material cost of product higher

Method used

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  • A kind of method for preparing darunavir intermediate
  • A kind of method for preparing darunavir intermediate
  • A kind of method for preparing darunavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Under nitrogen protection, add 270mL of 1.6mol / L n-butyllithium n-hexane solution into a 500mL flask, cool to -78°C, and add 34.4g (2.0eq) of 1,4-butyrolactone dropwise. After the dropwise addition, keep stirring for 2 hours, and then add 31.2g (1.0eq, 0.2mol) of 1,4-dioxaspiro[4,5]decan-2-one (compound of formula IV) in tetrahydrofuran dropwise. After keeping the reaction for 16 hours, the reaction was quenched with saturated ammonium chloride solution, the temperature was raised to room temperature, the layers were separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated to obtain the product with a yield of 38%.

[0047] 1 H NMR (CD 3 OD, 400MHz):δ4.64 (s, 2H), 3.72(t, J=6.3Hz, 2H), 2.42(t, J=6.3Hz, 2H)

[0048] 13 C NMR (CD 3 OD, 400MHz): δ178.77, 177.02, 98.39, 68.48, 61.21, 26.00

[0049] HRMS: M-1=143.0352

[0050] Melting point: 115-117°C.

Embodiment 2

[0052]Under the protection of nitrogen, 160 mL of 2.0 mol / L lithium diisopropylamide solution was added to a 250 mL flask, cooled to -78°C, and 21.5 g (2.5 eq) of 1,4-butyrolactone was added dropwise. After the dropwise addition, keep stirring for 2 hours, and then add dropwise 15.6g (1.0eq, 0.1mol) of 1,4-dioxaspiro[4,5]decan-2-one (compound of formula IV) in tetrahydrofuran. After keeping the reaction for 8 hours, the reaction was quenched with saturated ammonium chloride solution, the temperature was raised to room temperature, the layers were separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated to obtain the product with a yield of 40%.

Embodiment 3

[0054] Under nitrogen protection, add 220mL of 1.0mol / L lithium bis(trimethylsilyl)amide (LHMDS) solution to a 250mL flask, cool to -78°C, and dropwise add 17.2g (2.0eq) of 1,4-butane ester. After the dropwise addition, keep stirring for 2 hours, and then add 15.6g (1.0eq, 0.1mol) of 1,4-dioxaspiro[4,5]decan-2-one (compound of formula IV) in tetrahydrofuran dropwise. After keeping the reaction for 12 hours, the reaction was quenched with saturated ammonium chloride solution, the temperature was raised to room temperature, the layers were separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated to obtain the product with a yield of 35%.

[0055] Synthesis of compounds of formula II

[0056] Embodiment one

[0057] Add 5.04g (0.035mol) of compound III into a 100mL autoclave, add 50mL of methanol, and stir to dissolve. Change the air in the still with high-purity nitrogen three times, then under nitrogen protection, a...

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Abstract

The invention discloses a method for preparing a darunavir intermediate, in particular to a method for preparing a compound of formula I.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an AIDS drug darunavir intermediate. Background technique [0002] Darunavir (Darunavir) is a drug developed by Johnson & Johnson Pharmaceuticals for the treatment of AIDS. Darunavir Ethanolate (Darunavir Ethanolate) was first launched in the United States and Canada in 2006. [0003] Darunavir English name: [0004] [(3R,3AS,6AR)-2,3,3A,4,5,6A-HEXAHYDROFURO[5,4-B]FURAN-3-YL]N-[(2S,3R)-4-[(4- AMINOPHENYL)SULFONYL-(2-METHYLPROPYL)AMINO]-3-HYDROXY-1-PHENYLBUTAN-2-YL]CARBAMATE [0005] Molecular formula: C27H37N3O7S [0006] Molecular weight: 547.66 [0007] [0008] Darunavir is a new non-peptide antiretroviral protease inhibitor for AIDS treatment, which was successfully developed for the first time by Tibotec, an Icelandic branch of Johnson & Johnson Pharmaceuticals. The most bioavailable of navir, indinavir, nalfinavir, amprenavir and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04C07D307/33C07D307/60
CPCC07D307/60
Inventor 林文清郑宏杰刘小波朱剑平
Owner 成都博腾药业有限公司
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