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Synthesis process of N-amino-3-azabicyclo [3, 3, 0] octane hydrochloride

A technology of octane hydrochloride and azabicycle, which is applied in the field of gliclazide intermediate synthesis, can solve problems such as environmental pollution and serious problems, and achieve the effects of easy availability of raw materials, cheap raw materials, and high yield and purity.

Pending Publication Date: 2021-05-28
ANHUI JINDING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This route requires the use of the highly toxic substance hydrazine hydrate, which causes serious environmental pollution.

Method used

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  • Synthesis process of N-amino-3-azabicyclo [3, 3, 0] octane hydrochloride
  • Synthesis process of N-amino-3-azabicyclo [3, 3, 0] octane hydrochloride
  • Synthesis process of N-amino-3-azabicyclo [3, 3, 0] octane hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The synthesis process of N-amino-3-azabicyclo[3,3,0]octane hydrochloride in this embodiment comprises the following steps: 174.2 kg of 2-carbamoyl cyclopentacarboxylic acid ammonium is weighed and added to the reaction kettle, Stir mechanically, raise the temperature of the heating mantle to 240°C, add 206.64kg of p-toluenesulfonic acid and 220kg of water, stir and react for 1.5 hours, distill off the water under normal pressure, filter under reduced pressure, add 278.72kg of toluene to the filtrate, heat up and reflux, so that the toluene and water Azeotrope until the water is completely removed, the filtrate is allowed to stand at room temperature, filtered under reduced pressure, and dried to obtain 106.45 g of 1,2-cyclopentanedicarboximide with a yield of 76.5% and a purity of 98.7% by HPLC.

[0029] Weigh 139.15 kg of 1,2-cyclopentanedicarboximide and add it to the reactor, weigh 77.22 kg of chloramine and dissolve it in 500 kg of ethanol, add it dropwise to the rea...

Embodiment 2

[0033] The synthesis process of N-amino-3-azabicyclo[3,3,0]octane hydrochloride in this embodiment comprises the following steps: 174.2 kg of 2-carbamoyl cyclopentacarboxylic acid ammonium is weighed and added to the reaction kettle, Stir mechanically, heat up the heating mantle to 246°C, add 348.33kg of 30wt% phosphoric acid solution and 300kg of water, stir and react for 2 hours, distill off water under normal pressure, filter under reduced pressure, add 296.14kg of toluene to the filtrate, heat up and reflux, so that toluene and Water was azeotroped until the water was completely removed, and the filtrate was allowed to stand at room temperature, filtered under reduced pressure, and dried to obtain 105.48 g of 1,2-cyclopentanedicarboximide with a yield of 75.8% and a purity of 98.3% by HPLC.

[0034] Weigh 139.15kg of 1,2-cyclopentanedicarboximide into the reactor, weigh 72.07kg of chloramine and dissolve it in 500kg of methanol, add it dropwise to the reactor at room temper...

Embodiment 3

[0038] The synthesis process of N-amino-3-azabicyclo[3,3,0]octane hydrochloride in this embodiment comprises the following steps: 174.2 kg of 2-carbamoyl cyclopentacarboxylic acid ammonium is weighed and added to the reaction kettle, Stir mechanically, heat up the heating mantle to 240°C, add 189.8kg of 25wt% hydrochloric acid solution, and 260kg of water, stir and react for 2.5 hours, distill off water under normal pressure, filter under reduced pressure, add 226.46kg of toluene to the filtrate, heat up and reflux, so that toluene and Water was azeotroped until the water was completely removed, and the filtrate was allowed to stand at room temperature, filtered under reduced pressure, and dried to obtain 105.89 g of 1,2-cyclopentanedicarboximide with a yield of 76.1% and a purity of 98.5% by HPLC.

[0039] Weigh 139.15kg of 1,2-cyclopentanedicarboximide into the reactor, weigh 82.37kg of chloramine and dissolve it in 550kg of ethanol, add it dropwise to the reactor at room tem...

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Abstract

The invention provides a synthesis process of N-amino-3-azabicyclo [3, 3, 0] octane hydrochloride, and relates to the technical field of gliclazide intermediate synthesis. The synthesis process comprises the following steps: heating, dehydrating and cyclizing 2-carbamoyl amine cyclopentanecarboxylate serving as a raw material under the catalysis of an acid catalyst until no water is generated, adding toluene, refluxing and dissolving, and carrying out post-treatment to obtain 1, 2-cyclopentane dicarboximide; reacting the 1, 2-cyclopentane dicarboximide with chloramine under an alkaline condition, and carrying out post-treatment to obtain N-amino-1, 2-cyclopentane dicarboximide; and reducing the amino-1, 2-cyclopentane dicarboximide in the presence of sodium borohydride / aluminum trichloride and an organic solvent, and performing post-treatment to obtain the product. According to the present invention, the three-step synthesis is performed through the catalytic cyclization reaction, the nucleophilic substitution reaction and the reduction reaction, the raw materials are cheap and easily available, the high toxicity product is not generated, the harsh reaction condition is not required, the yield and the purity of each step are high, and the method is suitable for the large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of synthesis of gliclazide intermediates, in particular to a synthesis process of N-amino-3-azabicyclo[3,3,0]octane hydrochloride. Background technique [0002] Gliclazide belongs to the second generation of sulfonylurea oral hypoglycemic drugs, which has the dual functions of lowering blood sugar and improving blood coagulation function. It can not only improve the metabolism of diabetic patients, but also improve or delay the occurrence of diabetic vascular complications. Gliclazide has become one of the most commonly used drugs for the treatment of type 2 diabetes, and it is also the first-line oral hypoglycemic drug in my country. Its chemical structural formula is as follows: [0003] [0004] At present, the following two routes are mainly used for the production of industrialized gliclazide: Japanese patents (publication numbers: JP05065270, JP06041073) use cyclopentane phthalimide as raw material...

Claims

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Application Information

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IPC IPC(8): C07D209/44
CPCC07D209/44
Inventor 蒋爱萍
Owner ANHUI JINDING PHARMA
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