Purification method of 3-azabicyclo-octane hydrochloride

Abstract

Belonging to the technical field of drug intermediate purification, the invention discloses a purification method of 3-azabicyclo-octane hydrochloride. The process includes: adding potassium borohydride and anhydrous zinc chloride into a mixed solvent of dried toluene and tetrahydrofuran at room temperature, mixing them, conducting nitrogen protection, inputting quantified 1, 2-cyclopentyl dicarboximide in batches, carrying out nitrogen protection and mixing, slow raising the temperature to 70-75DEG C, performing thermal preservation reaction for 4h, slowly raising the temperature to 95-105DEG C and performing thermal preservation reflux reaction for 10h to achieve complete reaction, distilling off some organic solvents, then implementing cooling to 30DEG C, slowly adding liquid alkali to pH of 13-14, conducting steam distillation till fraction pH of 7-8, extracting the fraction with an organic solvent for 3-5 times, acidifying the organic solvent layer with refined hydrochloric acid to pH of 1.5-2, carrying out heating backflow to remove water in the organic layer, and performing cooling suction filtration to obtain an azabicyclo solid crude product. The crude product is refined by a mixed solvent of alcohol and ester, thus obtaining the fine azabicyclo solid. The method provided in the invention has the characteristics that the production process is improved, the purity and yield of the target product are enhanced, and the production cost is reduced at the same time.

Description

technical field

[0001] The invention relates to a method for purifying solid 3-azabicyclo[3.3.0]octane hydrochloride, belonging to the technical field of purification of pharmaceutical intermediates. Background technique

[0002] 3-Azabicyclo[3.3.0]octane hydrochloride (also known as azabicyclo) is shown in Formula I. It is a very valuable pharmaceutical intermediate, especially an important intermediate for the synthesis of gliclazide. The azabicyclic is nitrosated, reduced, and condensed to generate gliclazide. The reaction process is as follows:

[0003]

[0004] Grecht

[0005]

[0006] (I) Azabicyclo

[0007] Gliclazide (Gliclazide, GZ) is a second-generation oral sulfonylurea hypoglycemic drug, suitable for non-insulin-dependent diabetes, obese diabetes, senile diabetes and diabetes with cardiovascular complications. Since Gliclazide was successfully developed by the French company Servier and launched in the market in 1972, due to its obvious hypoglycemic ef...

Examples

Embodiment 1

[0018] Put 60g potassium borohydride, 176g anhydrous zinc chloride, 415g dried toluene, and 138g THF into a 2000mL reaction flask at room temperature, mix and protect with nitrogen, and add 50g 1,2-cyclopentadicarboximide in batches , Mix and stir, slowly increase the temperature to 70°C for 4 hours, then slowly increase the temperature to 95~105°C, keep reflux and react for 10 hours to complete the reaction, change the distillation device to evaporate 35% of the organic solvent, then cool to 40°C and add slowly NaOH solution (30%) 800g to pH 13~14, steam distilled to distillate PH=7~8, fractions were extracted three times with 600ml toluene, combined toluene layer was acidified with refined hydrochloric acid to pH=1.5~2, heating Atmospheric reflux to remove the water in the toluene layer, cooling and suction filtration to obtain the crude azabicyclic solid. The crude product was heated and refluxed with a mixed solvent of 100g of ethanol and 100g of methyl acetate to obtain 51...

Embodiment 2

[0020] Put 60g potassium borohydride, 176g anhydrous zinc chloride, 415g dried toluene, and 104g THF into a 2000mL reaction flask at room temperature, mix and protect with nitrogen, and add 50g 1,2-cyclopentadicarboximide in batches , Mix and stir, slowly heat up to 75°C for 4h, keep warm at 95~105°C and reflux for 10 hours to complete the reaction, change the distillation device to evaporate 35% of the organic solvent, then cool down to 40°C, add slowly NaOH solution (30%) 800g to pH 13~14, steam distilled until the distillate PH=7~8, the fractions were extracted three times with 600ml xylene, the combined xylene layer was acidified with refined hydrochloric acid to pH=1.5~2 , The water in the toluene layer was removed by reflux at normal pressure at elevated temperature, and the crude azabicyclic solid product was obtained by suction filtration at lower temperature. The crude product was heated and refluxed for 30 minutes with a mixed solvent of 10g methanol and 100g ethyl ac...

technical field

[0001] The invention relates to a method for purifying solid 3-azabicyclo[3.3.0]octane hydrochloride, belonging to the technical field of purification of pharmaceutical intermediates. Background technique

[0002] 3-Azabicyclo[3.3.0]octane hydrochloride (also known as azabicyclo) is shown in Formula I. It is a very valuable pharmaceutical intermediate, especially an important intermediate for the synthesis of gliclazide. The azabicyclic is nitrosated, reduced, and condensed to generate gliclazide. The reaction process is as follows:

[0003]

[0004] Grecht

[0005]

[0006] (I) Azabicyclo

[0007] Gliclazide (Gliclazide, GZ) is a second-generation oral sulfonylurea hypoglycemic drug, suitable for non-insulin-dependent diabetes, obese diabetes, senile diabetes and diabetes with cardiovascular complications. Since Gliclazide was successfully developed by the French company Servier and launched in the market in 1972, due to its obvious hypoglycemic ef...

Examples

Embodiment 1

[0018] Put 60g potassium borohydride, 176g anhydrous zinc chloride, 415g dried toluene, and 138g THF into a 2000mL reaction flask at room temperature, mix and protect with nitrogen, and add 50g 1,2-cyclopentadicarboximide in batches , Mix and stir, slowly increase the temperature to 70°C for 4 hours, then slowly increase the temperature to 95~105°C, keep reflux and react for 10 hours to complete the reaction, change the distillation device to evaporate 35% of the organic solvent, then cool to 40°C and add slowly NaOH solution (30%) 800g to pH 13~14, steam distilled to distillate PH=7~8, fractions were extracted three times with 600ml toluene, combined toluene layer was acidified with refined hydrochloric acid to pH=1.5~2, heating Atmospheric reflux to remove the water in the toluene layer, cooling and suction filtration to obtain the crude azabicyclic solid. The crude product was heated and refluxed with a mixed solvent of 100g of ethanol and 100g of methyl acetate to obtain 51...

Embodiment 2

[0020] Put 60g potassium borohydride, 176g anhydrous zinc chloride, 415g dried toluene, and 104g THF into a 2000mL reaction flask at room temperature, mix and protect with nitrogen, and add 50g 1,2-cyclopentadicarboximide in batches , Mix and stir, slowly heat up to 75°C for 4h, keep warm at 95~105°C and reflux for 10 hours to complete the reaction, change the distillation device to evaporate 35% of the organic solvent, then cool down to 40°C, add slowly NaOH solution (30%) 800g to pH 13~14, steam distilled until the distillate PH=7~8, the fractions were extracted three times with 600ml xylene, the combined xylene layer was acidified with refined hydrochloric acid to pH=1.5~2 , The water in the toluene layer was removed by reflux at normal pressure at elevated temperature, and the crude azabicyclic solid product was obtained by suction filtration at lower temperature. The crude product was heated and refluxed for 30 minutes with a mixed solvent of 10g methanol and 100g ethyl ac...

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