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Asymmetric synthesis method of medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate

A technology of tert-butyl dicarbonate and azabicycle, which is applied in the field of 2-azabicyclo[3.1.0]hexane-2, can solve problems such as expensive stability and achieve the effect of simple operation

Inactive Publication Date: 2013-12-18
NANJING UNIV OF TECH
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the stereoselectivity of the cyclopropanating reagent reported by this method is better than that of the previous method, the ICH 2 Cl is relatively expensive and less stable

Method used

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  • Asymmetric synthesis method of medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate
  • Asymmetric synthesis method of medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate
  • Asymmetric synthesis method of medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: (1R, 3R, 5R)-2-azabicyclo[3.1.0]hexane-2,3-tert-butyl dicarbonate (1S, 3R, 5S) 1 and (1S,3R,5S)-2-Azabicyclo[3.1.0]hexane-2,3-dicarbonate tert-butyl ester (1R,3R,5R) 1 Synthesis

[0025]

[0026] Add (25.0g, 92.8mmol) compound (5R) in the four-necked flask of 500mL 2 , Added 75.0 mL of toluene and (99.4 g, 371.2 mmol) of diiodomethane under nitrogen protection, cooled to -20° C., and added dropwise (185.6 mL) of a 1.1 M diethylzinc toluene solution. After reacting for 18 hours, it was added dropwise to (213.0 mL) 0.95 M citric acid aqueous solution, and the organic phase was separated and washed with (75.0 mL×2) saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The solvent was removed to obtain a white solid, which was finally separated by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain 15.7g of compound (1R, 3R, 5R) 1 , mp 130-132°C, and 1.7 g...

Embodiment 2

[0029] Example 2: (1R, 3R, 5R)-2-azabicyclo[3.1.0]hexane-2,3-tert-butyl dicarbonate (1R, 3R, 5R) 1 and (1S,3R,5S)-2-Azabicyclo[3.1.0]hexane-2,3-dicarbonate tert-butyl ester (1S,3R,5S) 1 Synthesis

[0030]Add (20.0g, 74.3mmol) compound (5R) in the four-necked flask of 500mL 2 , Added 70.0 mL of benzene and (79.6 g, 297.2 mmol) of diiodomethane under nitrogen protection, cooled to -22° C., and added dropwise (148.6 mL) of 1.1 M diethylzinc in toluene solution. After reacting for 25 hours, add dropwise to (170.5 mL) 0.95 M citric acid aqueous solution, separate the organic phase and wash with (70.0 mL×2) saturated sodium bicarbonate, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure A white solid was obtained, which was separated by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound (1R, 3R, 5R) 1 (12.6g) and (1S, 3R, 5S) 1 (1.4 g), 67% overall yield.

Embodiment 3

[0031] Example 3: (1R, 3R, 5R)-2-azabicyclo[3.1.0]hexane-2,3-tert-butyl dicarbonate (1R, 3R, 5R) 1 and (1S,3R,5S)-2-Azabicyclo[3.1.0]hexane-2,3-dicarbonate tert-butyl ester (1S,3R,5S) 1 Synthesis

[0032] Add (30.0g, 111.5mmol) compound (5R) in the four-necked flask of 500mL 2 , Added 80.0 mL of trifluorotoluene and (42.8 g, 334.5 mmol) of bromomethane under nitrogen protection, cooled to -17° C., and added dropwise (222.0 mL) 1.1 M diethylzinc toluene solution. After reacting for 18 hours, add dropwise to (255.0 mL) 0.95 M citric acid aqueous solution, separate the organic phase and wash with (80.0 mL×2) saturated sodium bicarbonate, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure A white solid was obtained, which was separated by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound (1R, 3R, 5R) 1 (19.7g) and (1S, 3R, 5S) 1 (2.2 g), 70% overall yield.

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Abstract

The invention belongs to the field of the synthesis of anti-hepatitis C virus medicines by using medical intermediates, and particularly relates to an asymmetric synthesis method of a medical intermediate 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate. The asymmetric synthesis method is mainly characterized in that (2R) or (2S)-1, 2-tert-butyl dicarbonate-2, 3-pyrrole alkene is used as a raw material, methylbenzene, benzene or trihalomethylbenzene is used as a solvent, diiodomethane, chlorobromomethane, dibromomethane or diethylzinc is used as a cyclopropanation reagent, and after reaction, the compound 2-azabicyclo [3. 1. 0] hexane-2, 3-tert-butyl dicarbonate is obtained. The asymmetric synthesis method has the advantages that synthesis steps are simple, the yield is high, the cost is low, the cyclopropanation reagent is wide in selectivity, the synthesis process is simple, convenient and practical, and the like.

Description

technical field [0001] The invention belongs to the field of asymmetrically synthesized pharmaceutical intermediates, in particular to the preparation of pharmaceutical intermediates 2-azabicyclo[3.1.0]hexane-2,3-dicarbonate tert-butyl for synthesizing anti-hepatitis C drugs . technical background [0002] At present, about 200 million people in the world are infected with hepatitis C virus (HCV), and 70% of HCV infected people will eventually lead to chronic liver disease. In western developed countries, hepatitis C has become an important reason for liver transplantation. Drugs for the treatment of hepatitis C have become a research hotspot for medical researchers, and 2-azabicyclo[3.1.0]hexane compounds have become important intermediates of many new drugs of this type (WO2013004290A1, WO2012075439A1, WO2011075439, WO2011079118, WO2010099527, WO2010117635, US20090068140, US20100160403, US20090068140, US6395767, WO2004052850). Patent WO2004052850 discloses a drug struct...

Claims

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Application Information

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IPC IPC(8): C07D209/52
Inventor 朱红军付行花何广科宋广亮刘睿陈凯刘宇剑俞娟樊俭俭
Owner NANJING UNIV OF TECH
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