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Preparation method of 4-amino-n-[(2r, 3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide

A technology of isobutylbenzenesulfonamide and phenylbutyl, applied in the field of pharmaceutical synthesis, can solve problems such as high cost and complicated benzenesulfonamide route, and achieve the effects of easy separation, favorable industrial large-scale application, and simple synthesis route

Active Publication Date: 2016-08-17
ASYMCHEM LAB TIANJIN +4
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  • Abstract
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Problems solved by technology

[0011] The present invention aims to provide a preparation method of 4-amino-N-[(2R,3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide to solve the current The preparation of 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide in the prior art is complicated and costly

Method used

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  • Preparation method of 4-amino-n-[(2r, 3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide
  • Preparation method of 4-amino-n-[(2r, 3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide
  • Preparation method of 4-amino-n-[(2r, 3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide

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preparation example Construction

[0041] As introduced in the Background Art section, when preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide in the prior art , there are problems of complicated routes and high costs. In order to solve this problem, the present inventors provide a kind of 4-amino-N-[(2R,3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide The preparation method of the present invention comprises the following steps: S1, reacting L-phenylalanine and diazomethane to obtain the intermediate product of diazomethyl ketone, reacting the intermediate product of diazomethyl ketone with hydrohalic acid to obtain Compound A; S2, the carbonyl group in compound A is reduced to obtain compound B; S3, in the presence of isobutylamine, compound B is sequentially cyclized and ring-opened to obtain compound C; S4, compound C and Reaction of p-nitrobenzenesulfonyl chloride to obtain compound D; and S5, reduction of the nitro group in compound D to obtain 4...

Embodiment 1

[0079] Preparation of 4-amino-N-[(2R,3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide, the specific preparation process is as follows:

[0080] Step S1, preparing compound A

[0081] Methanol / H containing KOH (33.6 g, 0.6 mol) in container A 2 O (1:1 volume ratio) solution, a total of 0.5L; container B is equipped with methanol solution of diazo raw material 1-methyl-1-nitrosourea (3.30g, 32mmol), 54mL; container C is equipped with Boc The THF solution of protected L-phenylalanine (6.4mmol) and triethylamine (6.72mmol) was 20mL in total; the THF solution of ethyl chloroformate (6.4mmol) in container D was filled with 20mL in total. The materials in the reaction vessel C and the reaction vessel D are pumped into the reaction center II through the tetrafluoro pipeline; the solutions in the reaction vessel A and the reaction vessel B are pumped into the reaction center I through the tetrafluoro pipeline (where KOH With the diazo raw material molar ratio is 2:1...

Embodiment 2

[0091] Preparation of 4-amino-N-[(2R,3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonamide, the specific preparation process is as follows:

[0092] Step S1, preparing compound A

[0093] Methanol / H containing NaOH (112 g, 2.8 mol) in vessel A 2 O (1:1 volume ratio) solution, a total of 3L; container B is equipped with methanol solution of diazo raw material 1-methyl-1-nitrosourea (131.9g, 1.28mol), 0.54L; container C is equipped with Boc-protected L-phenylalanine (640mmol) and tri-n-butylamine (672mmol) in 1L THF; container D was filled with ethyl chloroformate (640mmol) in THF, 0.5L in total. Pump the materials in reaction vessel C and reaction vessel D into reaction center II through PTFE pipeline; pump the solutions in reaction vessel A and reaction vessel B into reaction center I through PTFE pipeline, 0°C Reaction (where the molar ratio of KOH to diazo raw material is 2:1), the diazomethane produced in reaction center I enters reaction center III through t...

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Abstract

The invention discloses a method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide. The method comprises the following steps: S1: enabling L-phenylalanine and diazomethane to react to obtain a diazo methyl ketone intermediate product, and enabling the diazo methyl ketone intermediate product and haloid acid to react to obtain a compound A; S2, conducting carbonyl deoxidation on the compound A to obtain a compound B; S3, under the existence of iso-butylamine, conducting cyclization reaction and ring-opening reaction on the compound B in sequence to obtain a compound C; S4, enabling the compound C and nitrobenzenesulfonyl chloride to react to obtain a compound D; S5, conducting nitro reduction on the compound D to obtain the 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide. The method is simple in course, low in cost, mild in condition, and higher in intermediate product stability, and is beneficial for industrial application.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical synthesis, in particular to a 4-amino-N-[(2R,3S)-3-amino-2-hydroxyl-4-phenylbutyl]-N-isobutylbenzenesulfonate Method for the preparation of amides. Background technique [0002] 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide is a very important intermediate in pharmaceutical synthesis, which has The structure is as follows: [0003] [0004] A series of anti-HIV drugs such as Amprenavir, Darunavir, and Fosamprenavir can be prepared from the above-mentioned intermediates. Among them, amprenavir is the fifth generation antiretroviral protein inhibitor developed by Glaxo-Simth Company of the United Kingdom, which was launched in the United States and Japan in May 1999; A non-peptide HIV protein inhibitor, which was launched in the United States in June 2006; the calcium salt of Fusarnavir, a prodrug of the protease inhibitor Amprenavir jointly de...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C303/40C07C311/41
Inventor 洪浩詹姆斯·盖吉陈朝勇李九远陶建李常峰刘志清
Owner ASYMCHEM LAB TIANJIN
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