Synthetic method of boceprevir intermediate

A synthesis method and compound technology, applied in the field of synthesis of boceprevir intermediates, can solve the problems of increasing production cost and post-processing cost, affecting product yield and production efficiency, long reaction time, etc., achieving low production cost, The effect of less reaction steps and simple reaction conditions

Active Publication Date: 2015-07-08
SUZHOU UUGENE BIOPHARMA
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Problems solved by technology

[0013] Although this method also finally synthesized boceprevir intermediate (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride salt, but expensive catalysts Pd-C / Pt-C and AgNO are also used in this synthesis 3 , and a flammable K 2 S 2 o 8 , there are special requirements for the equipment during the reaction. In addition, the steps of the synthesis method are cumbersome and the reaction time is long. For example, the last step needs to be processed in a drying box for about 3 days, and it is easy to generate different hand compounds in the last four-step reaction. Sexual by-products that need to be removed for the synthesis of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride, in a large While increasing production cost and post-processing cost, it also seriously affects product yield and production efficiency

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  • Synthetic method of boceprevir intermediate

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Embodiment 1

[0051] Add 300g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride into a 1L reaction flask and dissolve it in 200mL of methyl tert-butyl ether to form a reaction solution. Stir to dissolve and ice The salt bath was cooled to 5°C, and then 200 mL of water and 60 g of potassium carbonate were added. 112 g of di-tert-butyl dicarbonate dissolved in 150 mL of methyl tert-butyl ether was added to the reaction liquid, and the reaction was incubated at 20° C. for 3 hours until the reaction was complete. The reaction solution after the complete reaction was left to stand for liquid separation, and the organic phase was washed once with 300mL aqueous solution containing 15g of sodium bisulfate, left for liquid separation, and the organic phase was washed once with 300mL of water, and left for liquid separation again, and the organic phase was washed with 200g of sodium bisulfate Dry over sodium sulfate for 2 hours, concentrate methyl tert-butyl ether to dryness under vacuum at 40°...

Embodiment 2

[0055]Add 300g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride into a 1L reaction flask and dissolve it in 200mL of ethyl acetate to form a reaction solution. Stir to dissolve and cool down in an ice-salt bath to 0°C, then 200 mL of water and 46 g of potassium carbonate were added. 112 g of di-tert-butyl dicarbonate dissolved in 150 mL of ethyl acetate was added to the reaction liquid, and the reaction was incubated at 10° C. for 3 hours until the reaction was complete. The reaction solution after the complete reaction was left to stand for liquid separation, and the organic phase was washed once with 300mL aqueous solution containing 15g of sodium bisulfate, left for liquid separation, and the organic phase was washed once with 300mL of water, and left for liquid separation again, and the organic phase was washed with 200g of sodium bisulfate Dry over sodium sulfate for 2 hours, concentrate ethyl acetate to dryness under vacuum at 35°C, add 200 mL of n-heptane and con...

Embodiment 3

[0059] Add 300g of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride into a 1L reaction flask and dissolve it in 200mL of dichloromethane to form a reaction solution. Stir to dissolve and cool down in an ice-salt bath to 0°C, then 200 mL of water and 36.6 g of potassium carbonate were added. 112 g of di-tert-butyl dicarbonate dissolved in 150 mL of dichloromethane was added to the reaction liquid, and the reaction was maintained at 10° C. for 3 hours until the reaction was complete. The reaction solution after the complete reaction was left to stand for liquid separation, and the organic phase was washed once with 300mL aqueous solution containing 15g of sodium bisulfate, left for liquid separation, and the organic phase was washed once with 300mL of water, and left for liquid separation again, and the organic phase was washed with 200g of sodium bisulfate Dry over sodium sulfate for 2 hours, concentrate dichloromethane to dryness under vacuum at 35°C, add 200 mL of n-hepta...

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Abstract

The invention relates to a synthetic method of a boceprevir intermediate, namely (1R, 2S, 5S)-6, 6-dimethyl-3-aza-bicyclo-[3. 1. 0] hexane-2-carboxylic acid methyl ester hydrochloride, belonging to the technical field of drug synthesis. The synthetic method solves the problems of high cost, complex reaction, low yield, and the like of the synthesis of the boceprevir intermediate in the prior art. The synthetic method comprises the following steps of carrying out amino protection on 6, 6-dimethyl-3-aza-bicyclo-[3. 1. 0] hexane hydrochloride which is taken as an original raw material; then reacting 6, 6-dimethyl-3-aza-bicyclo-[3. 1. 0] hexane hydrochloride with 1, 2, 3, 4-tetralin-1-naphthylamine for 3-4 hours at 30-35 DEG C under the action of a hydrogen drawing reagent by taking 4, 4'-difluoro benzophenone as a chiral inductive agent; finally removing an amino protecting group, and adding acid to form salt to directly obtain a final product. The synthetic method disclosed by the invention has the advantages of low cost, simple reaction condition, few reaction steps, short time and high purity and yield of the final product, namely the boceprevir intermediate.

Description

technical field [0001] The present invention relates to a synthetic method of a boceprevir intermediate, in particular to a boceprevir intermediate (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0 The invention discloses a synthesis method of hexane-2-carboxylic acid methyl ester hydrochloride, which belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Hepatitis C protease inhibitor Boceprevir (Boceprevir), its Chinese name: (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutane-2 -yl)-3-[(2S)-2-(tert-butylcarbamoylamino)-3,3-dimethylbutyryl]-6,6-dimethyl-3-azabicyclo[3.1. 0] Hexane-2-carboxamide; English chemical name: (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-[(2S) -2-(tert-butylcarbamoylamino)-3,3-dimethylbutanonyl]-6,6-dimethyl-3-azabicylo[3.1.0]hexane-2-carboxamide; Molecular formula: C 27 h 45 N 5 o 5 ; Molecular Weight: 519.68; CAS Registry Number: 394730-60-0. Its structural formula is as follows: [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/52
CPCY02P20/55
Inventor 肖坤福江锋王伸勇王晓俊胡长春
Owner SUZHOU UUGENE BIOPHARMA
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