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Preparation method for 4-azaspiro [2.4] heptane hydrochloride

A technology of heptane hydrochloride and azaspiro is applied in the field of synthesis of 4-azaspiro[2.4]heptane hydrochloride, can solve the problems such as no suitable industrial synthesis method, achieves short route, easy reaction, The effect of experimental operation is convenient

Inactive Publication Date: 2013-05-01
上海药明康德新药开发有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Mainly solve the technical problem that there is no suitable industrial synthesis method at present

Method used

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  • Preparation method for 4-azaspiro [2.4] heptane hydrochloride
  • Preparation method for 4-azaspiro [2.4] heptane hydrochloride
  • Preparation method for 4-azaspiro [2.4] heptane hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] Example 1: a. Place ethylmagnesium bromide reagent (4.8 mL, 1.7 mmol) in anhydrous tetrahydrofuran (100 mL), under nitrogen protection, add tetraisopropyl titanate (1.62 g, 5.72 mmol), stirred for 30 minutes, then added 1-benzylpyrrolidin-2-one (1.0 g, 5.72 mmol) into the reaction system at -65 degrees Celsius, and stirred at room temperature for 72 hours. TLC (petroleum ether: ethyl acetate volume ratio = 3:1) tracked the end of the reaction, added water (10 mL) to the reaction system, added potassium carbonate to alkalinize the pH to 8, and then extracted with ethyl acetate, 10 mL each time , extracted three times. After the ethyl acetate extracts were combined, they were washed with saturated brine, 10 mL each time, twice, and the ethyl acetate solution was dried with anhydrous sodium sulfate to 4-benzyl-4-azaspiro[2.4]heptane ( 2 g, yield 93%), the product was directly used in the next step.

[0012] The compound 4-benzyl-4-azaspiro[2.4]heptane (1.0 g, 5.35 mmol) ...

Embodiment 2

[0017] Example 2: Place ethylmagnesium bromide reagent (48 mL, 17 mmol) in anhydrous tetrahydrofuran (1 L), under nitrogen protection, add tetraisopropyl titanate (16.2 g, 57.2 mmol), stirred for 30 minutes, then added 1-benzylpyrrolidin-2-one (10 g, 57.2 mmol) into the reaction system at -65 degrees Celsius, and stirred at room temperature for 72 hours. TLC (petroleum ether: ethyl acetate volume ratio = 3:1) tracked the end of the reaction, added water (100 mL) to the reaction system, added potassium carbonate to alkalinize the pH to 8, and then extracted with ethyl acetate, 200 mL each time , extracted three times. After the ethyl acetate extracts were combined, they were washed with saturated brine, 100 mL each time, twice, and the ethyl acetate solution was dried with anhydrous sodium sulfate to 4-benzyl-4-azaspiro[2.4]heptane ( 19 g, yield 87.4%), the product was directly used in the next step.

[0018] The compound 4-benzyl-4-azaspiro[2.4]heptane (19 g, 0.1 mol) was pl...

Embodiment 3

[0021] Example 3: Place ethylmagnesium bromide reagent (480 mL, 1.7 mol) in anhydrous tetrahydrofuran (1.5 L), under nitrogen protection, add tetraisopropyl titanate (162 g, 572 mmol), stirred for 30 minutes, then added 1-benzylpyrrolidin-2-one (100 g, 572 mmol) into the reaction system at -65 degrees Celsius, and stirred at room temperature for 72 hours. TLC (petroleum ether: ethyl acetate volume ratio = 3:1) tracked the end of the reaction, added water (1.0 L) to the reaction system, added potassium carbonate to alkalinize to pH equal to 8, and then extracted with ethyl acetate, 1.0 L each time L, extracted three times. After the ethyl acetate extracts were combined, they were washed with saturated brine, 1.0 L each time, twice, and the ethyl acetate solution was dried with anhydrous sodium sulfate to 4-benzyl-4-azaspiro[2.4]heptane (200 g, yield 93%), the product was directly used in the next step.

[0022] The compound 4-benzyl-4-azaspiro[2.4]heptane (100 g, 535 mmol) wa...

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Abstract

The invention relates to a preparation method for 4-azaspiro [2.4] heptane hydrochloride and mainly aims to solve the technical problem that a suitable industrial synthesis method does not exist at present. The preparation method comprises the following steps of: firstly, preparing 4-benzyl-4-azaspiro [2.4] heptane by taking 1-benzylpyrrolidine-2-ketone and an ethylmagnesium bromide reagent as raw materials, and then, preparing the 4-azaspiro [2.4] heptane hydrochloride by using chloroethyl chloroformate. The reaction formula is shown as follows: the 4-azaspiro [2.4] heptane hydrochloride obtained by the preparation method is a useful midbody or product used for synthesizing plenty of drugs.

Description

technical field [0001] The invention relates to a synthesis method of 4-azaspiro[2.4]heptane hydrochloride. Background technique [0002] 4-Azaspiro[2.4]heptane hydrochloride and related derivatives are widely used in medicinal chemistry and organic synthesis. Currently, the synthesis of 4-azaspiro[2.4]heptane hydrochloride is difficult. Therefore, it is necessary to develop a synthetic method with readily available raw materials, convenient operation, easy control of the reaction, and suitable overall yield. Contents of the invention [0003] The purpose of the invention is to develop a kind of synthetic method that has raw material easy to get, easy to operate, reaction is easy to control, and yield is higher 4-azaspiro[2.4]heptane hydrochloride. It mainly solves the technical problem that there is no suitable industrial synthesis method at present. [0004] Technical scheme of the present invention: a preparation method of 4-azaspiro[2.4]heptane hydrochloride, compri...

Claims

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Application Information

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IPC IPC(8): C07D209/54
Inventor 安自强任文武徐洋洋毕增梁沈万军邵文庆徐学芹何燕平刘昌平吴明昆于凌波
Owner 上海药明康德新药开发有限公司
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