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Method for preparing N-amino-3-azabicyclo[3,3,0]octane hydrochloride

A technology of octane hydrochloride and azabicycle, applied in the field of organic synthesis, can solve the problems of large environmental pollution, complicated operation, high difficulty and the like, and achieve the effect of reducing environmental pollution

Active Publication Date: 2008-11-19
NINGBO CHEMGOO PHAMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 1) The preparation steps are long and the total yield is low;
[0006] 2) The operation is complex and requires multiple extractions of organic substances from water;
[0007] 3) Large environmental pollution, especially the intermediate N-nitroso-3-azabicyclo[3,3,0]octane is a carcinogenic substance
[0010] Another method uses azabicyclo[3,3,0]octane to react with chloramine to prepare N-amino-3-azabicyclo[3,3,0]octane hydrochloride, which shortens the reaction step, also avoids the generation of highly toxic substance N-nitroso-3-azabicyclo[3,3,0]octane, but it is very difficult to prepare high-purity chloramine

Method used

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  • Method for preparing N-amino-3-azabicyclo[3,3,0]octane hydrochloride
  • Method for preparing N-amino-3-azabicyclo[3,3,0]octane hydrochloride
  • Method for preparing N-amino-3-azabicyclo[3,3,0]octane hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 68.5g (1.0mol) hydrazine monohydrochloride, 33.8g (0.33mol) concentrated hydrochloric acid, 43.4g (0.33mol) cis-cyclopentane-1,2-dimethanol, 100.0g water into a 500mL autoclave, 140 °C, react for 5 hours under the pressure of 2.2-5.6 atm. The reaction solution (containing hydrazine monohydrochloride and hydrazine dihydrochloride) was concentrated under reduced pressure, filtered, washed with methanol, and 54.2 g of crystals were precipitated. The mixture was titrated with 1N sodium hydroxide, and 42.2 g of hydrazine monohydrochloride was detected, with a recovery rate of 92.3%. The amount of water added is estimated in real time based on the viscosity of the feed.

[0033] The filtrate was concentrated, 6.1g of methanol was added, and crystallized at room temperature to obtain 29.2g of N-amino-3-azabicyclo[3,3,0]octane hydrochloride crystals, which were crystallized twice in the mother liquor to obtain N-amino- 8.6 g of 3-azabicyclo[3,3,0]octane hydrochloride crys...

Embodiment 2

[0036] Add 68.5g (1.0mol) hydrazine monohydrochloride, 33.8g (0.33mol) concentrated hydrochloric acid, 95.4g (0.33mol) cis-cyclopentane-1,2-dimethylsulfonate, and 100.0g water to a 500L reaction flask In, reflux reaction for 4 hours. The reaction solution (containing hydrazine monohydrochloride and hydrazine dihydrochloride) was concentrated under reduced pressure, washed with methanol, and 53.0 g of crystals were precipitated. The mixture was titrated with 1N sodium hydroxide to detect 41.0 g of hydrazine monohydrochloride, and the recovery rate was 90.3%.

[0037] Concentrate the filtrate again, then add 6.1g methanol, and crystallize at room temperature to obtain crystals of 29.4g N-amino-3-azabicyclo[3,3,0]octane hydrochloride, which is crystallized twice in the mother liquor to obtain N-amino-3-azabicyclo[3,3,0]octane hydrochloride crystal 8.8g, total yield 78.0%, content titration 100.1%, GC purity 99.5%.

[0038] 1 H NMR (400MHz, CDCl3): d = 7.0 (s, 2H), 3.16-3.41 (m...

Embodiment 3

[0040] Add 68.5g (1.0mol) hydrazine monohydrochloride, 33.8g (0.33mol) concentrated hydrochloric acid, 66.4.0g (0.33mol) cis-1,2-dichloromethyl-cyclopentane, and 100.0g water to a 500L reaction flask In, reflux reaction for 10 hours. The reaction solution (containing hydrazine monohydrochloride and hydrazine dihydrochloride) was concentrated under reduced pressure, washed with methanol, and 54.0 g of crystals were precipitated. The mixture was titrated with 1N sodium hydroxide to detect 42.1 g of hydrazine monohydrochloride, and the recovery rate was 92.2%.

[0041] Concentrate the filtrate again, then add 6.1g of methanol, and crystallize at room temperature to obtain 28.8g of N-amino-3-azabicyclo[3,3,0]octane hydrochloride crystals (101.87% by titration, 99.66% by GC) , secondary crystallization in the mother liquor to obtain 8.2 g of N-amino-3-azabicyclo[3,3,0]octane hydrochloride crystals (96.88% by titration, 94.53% by GC). The total yield is 75.4%, the content titratio...

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Abstract

The invention relates to a novel method for preparing N- amino-3-DBU [3, 3, 0] octane bromide. The technical problem to be solved is to simplify the preparation process, reduce the pollution and avoid using a carcinogenic substance. The preparing method comprises the following steps that: 1) a substance shown as formula (II) is taken as a raw material and is added with water, the mixture reacts sufficiently with HXO hydrazine at a temperature of between 80 and 200 DEG C to produce the reaction fluid; 2) after the reaction finishes, the reaction fluid is concentrated, water-solubility ethanol is added to dissolve the reaction fluid and to separate out superfluous HXO hydrazine; 3) sediment is filtered; and the mother fluid is processed to produce the N- amino-3-DBU[3, 3, 0] octane bromide.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a novel preparation method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride. Background technique [0002] N-Amino-3-azabicyclo[3,3,0]octane hydrochloride is the key intermediate of the new hypoglycemic drug Gliclazide, and its structure is as follows: [0003] [0004] The known preparation method is to use cis-cyclopentane-1,2-dicarboxylic acid as raw material, through imidization, reduction, nitrosylation, reduction and other steps. The disadvantages of this method are: [0005] 1) The preparation steps are long and the total yield is low; [0006] 2) The operation is complex and requires multiple extractions of organic substances from water; [0007] 3) The environment is highly polluted, especially the intermediate N-nitroso-3-azabicyclo[3,3,0]octane is carcinogenic. [0008] Route 1 as follows: [0009] [0010] Another method uses azabicyclo[3,3,0]...

Claims

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Application Information

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IPC IPC(8): C07D209/94
Inventor 楼科侠李昌龙张少伟张达
Owner NINGBO CHEMGOO PHAMA TECH
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