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Preparing method of 3-N-bicyclo[4,1,0]heptane-1-carboxylic acid,3-tertiary butyl ester

A technology of tert-butyl ester and carboxylic acid, applied in the field of preparation of 3-nitro-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester, can solve the problem of expensive raw materials, Long synthetic route, difficult post-processing and other problems, to achieve the effect of simple post-processing, short steps, and shortened synthesis steps

Inactive Publication Date: 2013-06-05
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention: to effectively prepare the synthetic method of 3-nitrogen-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester, which mainly solves the expensive reaction of raw materials in the known synthetic method, and synthesizes Long route, inconvenient operation, difficult post-processing, low total yield and other technical problems

Method used

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  • Preparing method of 3-N-bicyclo[4,1,0]heptane-1-carboxylic acid,3-tertiary butyl ester

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Embodiment 1

[0017] Example 1: 10.6 g of sodium hydrogen and 58.4 g of iodotrimethylsilane were added to 150 ml of dimethyl sulfoxide solvent, under nitrogen protection and stirred at room temperature (20-30° C.) for 30 minutes. Dissolve 5,6-dihydro-2H-pyrimidine-1-carboxylic acid 1-tert-butyl ester 3-ethyl ester (50 g) in 150 ml of dimethyl sulfoxide, and add dropwise to the above reaction solution at room temperature , and then react at 110°C for 3 hours. After the raw materials reacted completely, the system was cooled to room temperature, and a large amount of water was added to quench the sodium hydrogen, then extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with water (100 mL*3). Then dry with anhydrous sodium sulfate, filter, spin dry under reduced pressure, obtain gram 3-nitrogen-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester 1-ethane through column chromatography ester (3.9 g, yield: 7.5%).

[0018] Dissolve 15.6 grams of lithium ...

Embodiment 2

[0019] Example 2: 10.6 g of sodium hydrogen and 58.4 g of iodotrimethylsilane were added to 150 ml of dimethyl sulfoxide solvent, under nitrogen protection and stirred at room temperature (20-30° C.) for 3 hours. Dissolve 5,6-dihydro-2H-pyrimidine-1-carboxylic acid 1-tert-butyl ester 3-ethyl ester (50 g) in 150 ml of dimethyl sulfoxide, and add dropwise to the above reaction solution at room temperature , and then react at 110°C for 3 hours. After the raw materials reacted completely, the system was cooled to room temperature, and a large amount of water was added to quench the sodium hydrogen, then extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with water (100 mL*3). Then dry with anhydrous sodium sulfate, filter, spin dry under reduced pressure, obtain 3.5 grams of 3-nitrogen-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester 1- ethyl ester (17.5 g, yield: 33.3%).

[0020] Dissolve 15.6 grams of lithium hydroxide in 100 millil...

Embodiment 3

[0021] Example 3: 10.6 g of sodium hydrogen and 58.4 g of iodotrimethylsilane were added to dimethyl sulfoxide solvent, under nitrogen protection and stirred at room temperature (20-30° C.) for 2 hours. Dissolve 5,6-dihydro-2H-pyrimidine-1-carboxylic acid 1-tert-butyl ester 3-ethyl ester (50 g) in 150 ml dimethyl sulfoxide, and add dropwise to the above reaction solution at room temperature , and then reacted at 110°C for 4 hours. After the reaction of raw materials was complete, the system was cooled to room temperature, sodium hydrogen was quenched by adding elephant water, and then extracted with ethyl acetate (100 mL*3), and the combined organic phases were washed with water (100 mL*3). Then dry with anhydrous sodium sulfate, filter, spin dry under reduced pressure, obtain 4.2 grams of 3-nitrogen-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester 1- Ethyl ester (24.14 g, yield: 45.8%).

[0022] Dissolve 15.6 grams of lithium hydroxide in 100 milliliters of water...

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Abstract

The invention relates to a preparing method of 3-N-bicyclo[4,1,0]heptane-1-carboxylic acid,3-tertiary butyl ester. The preparing method solves the technical problems that according to an existing method, the preparing route is long, total yield is low, and cost of raw material is high. The preparing method of the 3-N-bicyclo[4,1,0]heptane-1-carboxylic acid,3-tertiary butyl ester is characterized by comprising the steps that 5,6-dihydro-2H-pyrimidine-1-carboxylic acid 1-tertiary butyl ester 3-ethyl ester is taken as the precursor, the 5,6-dihydro-2H-pyrimidine-1-carboxylic acid 1-tertiary butyl ester 3-ethyl ester reacts with trimethyl iodide silane, sodium and hydrogen to produce corresponding 3-N-bicyclo[4,1,0]heptane-1-carboxylic acid,3-tertiary butyl ester 1- ethyl ester, and then the 3-N-bicyclo[4,1,0]heptane-1-carboxylic acid,3-tertiary butyl ester is obtained through lithium hydroxide hydrolysis.

Description

technical field [0001] The present invention relates to a practical synthesis method of 3-nitro-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester. Background technique [0002] 3-Aza-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester is an important intermediate in the synthesis of drugs with norepinephrine reuptake inhibitors. For the preparation of 3-nitro-bicyclo[4,1,0]heptane-1-carboxylic acid, 3-tert-butyl ester, there are few literature reports. Tetrahedron Journal [Tetrahedron, 5492-5497; 2010] reported that N-1,2-dibutene phthalamide was used as raw material to obtain 3-nitrogen-bicyclo[4,1,0] through 9-step reaction Heptane-1-carboxylic acid and 5,6-dihydro-2H-pyrimidine-1-carboxylic acid 1-tert-butyl ester 3-ethyl ester obtained 3-nitro-bicyclo[4,1 ,0]heptane-1-carboxylic acid. The synthesis methods in the literature mainly have the following problems: (1) The reaction route is long and the overall yield is not high; (2) The cost is high, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/04
Inventor 于凌波周强张明亮龙治丞王瑞乐刘月领沈万军邵文庆张英杨旭张永丽付新雨王琏毕增梁唐立强牛彦霞徐洋洋刘鹏哈维杰马汝建
Owner 上海药明康德新药开发有限公司