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Method for preparing (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester

A technology of alkyl carboxylate and azabicyclo, which is applied in the field of drug synthesis, can solve problems such as post-processing difficulties, failure to meet environmental protection requirements, and restrictions on industrial production, and achieve easy scale production, increased yield, and low cost. Effect

Inactive Publication Date: 2014-06-18
SHANGHAI DESANO CHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] Although this route has the advantages of cheap and easy-to-obtain raw materials, short reaction steps, etc., because the cyano addition in this route utilizes potassium cyanide and hydrochloric acid, not only cannot meet the environmental protection requirements, but also the post-treatment is difficult, so this route is limited. industrial production of

Method used

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  • Method for preparing (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester
  • Method for preparing (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester
  • Method for preparing (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]

[0041] Refer to the oxidation reaction operation described on page 31 of the specification of WO2007075790: Add sodium hydroxide (41.4g, 1.04mol) and potassium persulfate (134g, 0.50mol) to 750mL of water and 100mL of acetonitrile at -5°C, and then add the formula Compound III (50g, 0.45mol), react at -5°C for 1 to 3 hours; then add 20mL silver nitrate aqueous solution (3.9g, 0.025mol, 0.05eq) at -5°C to 0°C, the solution becomes dark, and then Raise the temperature to 0-2°C and react for 1-5 hours. Warm up to room temperature, add 360 mL of methyl tert-butyl ether, separate the layers, extract the aqueous phase with 100 mL of methyl tert-butyl ether, combine the organic phases, dry over anhydrous sodium sulfate, and filter.

[0042] The filtrate was first evaporated to remove the solvent at 50 °C under normal pressure, and then fractionated under reduced pressure at 55 °C under a pressure of 0.08 to 0.1 MPa to obtain a colorless oily liquid: 34.6 g of the compound...

Embodiment 2

[0044]

[0045]The compound of formula II (40g, 0.43mol) was dissolved in 100mL of anhydrous tetrahydrofuran, and trimethylsilyl cyanide (64.6g, 0.65mol) was slowly added dropwise. % boron trifluoride ether solution (31.2g, 0.15mol), stirred for 1.0 hours, TLC showed that the reaction was complete (petroleum ether: ethyl acetate = 1:1, V / V); add 80mL methanol, cool down To -30 ~ -25 ℃, dropwise add 376g of hydrochloric acid-methanol solution (the content of HCl is 28.8wt%), after the dropwise addition, stir at room temperature overnight; dropwise add 283mL triethylamine to adjust the pH to 8 ~ 9, filter, filter The cake was washed with 100mL of methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure; 100mL of water was added to the concentrated residue, and then extracted twice with 250mL of methyl tert-butyl ether, and the organic phase was washed with 150mL of saturated brine, anhydrous magnesium sulfate After drying, 51.5 g of the compound of fo...

Embodiment 3

[0047]

[0048] The compound of formula II (40g, 0.43mol) was dissolved in 100mL of anhydrous tetrahydrofuran, and trimethylsilyl cyanide (64.6g, 0.65mol) was slowly added dropwise. Fluoromethanesulfonic acid (30.14g, 0.2mol), stirred and reacted for 1.0 hour, TLC showed that the reaction was complete (the developing solvent was petroleum ether: ethyl acetate=1:1, V / V); add 80mL of ethanol, cool to -25~ -20°C, add dropwise 428g of hydrochloric acid-ethanol solution (the content of HCl is 25.5wt%), after the dropwise addition, stir overnight at room temperature; Methyl tert-butyl ether was washed, and the filtrate was concentrated under reduced pressure; 100 mL of water was added to the concentrated residue, and then extracted twice with 250 mL of methyl tert-butyl ether, the organic phase was washed with 150 mL of saturated brine, and dried over anhydrous magnesium sulfate to obtain The compound of formula I-B was 56.0 g, the molar yield was 83.5%, and the HPLC purity was 9...

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Abstract

The invention discloses a method for preparing (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester. The method is characterized in that a compound shown in the formula II is subjected to cyanation reaction with trimethylsilyl cyanide by adopting a one-pot process to obtain a product, the product is subjected to hydrolysis reaction with acid-ROH solution to obtain the compound shown in the formula I, and the specific reaction formula is shown in the specification, wherein R is selected from C1-C5 alkyls. The compound shown in the formula I prepared by a one-pot reaction can be realized in the invention, and high-purity (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester can be prepared with high yield at low cost by the method disclosed by the invention. The method has advantages of simple process and no special requirement for equipment and can be put into large-scale production easily. The invention has an important significance and a practical value in industrial production of boceprevir.

Description

technical field [0001] The invention relates to a method for preparing (1S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid alkyl ester, which belongs to the technical field of drug synthesis. Background technique [0002] Boceprevir (Boceprevir) is a hepatitis C virus (HCV) protease inhibitor, its specific chemical structural formula is as follows: The phase III SPRINT-2 study showed that compared with standard treatment, 24 weeks of boceprevir standard treatment can improve the SVR rate of HCV genotype 1 treatment-naïve patients. The antiviral efficacy of standard boceprevir treatment for 24 weeks was similar to that of boceprevir standard treatment for 44 weeks. [0003] At present, the synthesis of boceprevir mainly has the following routes: [0004] ①Synthetic route 1 disclosed in US patent US7012066: [0005] [0006] This route is to first amidate compound fragments A and B, then react with fragment C (tert-butyl isocyanate), and finally dock with f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 李金亮赵楠曾振亚
Owner SHANGHAI DESANO CHEM PHARMA
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