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Preparation method of Pregabalin intermediate impurity

A technology of pregabalin and intermediates is applied in the field of preparing impurities of pregabalin intermediates, and the effect of short reaction period is achieved

Inactive Publication Date: 2015-10-28
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, 4-isobutyl-2,6-piperidinedione is very easy to be produced in the ammonolysis process, and there are not many reports on the synthesis of 4-isobutyl-2,6-piperidinedione at present.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0021] Add 50g of 3-isobutylglutaric acid monoamide (compound II) and 200ml of xylene to a 500ml four-neck flask at room temperature, raise the temperature to reflux and divide water for 3 hours, then cool down to 50°C and start vacuum distillation until no obvious liquid flows out. Then add 150ml of chloroform, add 50ml of saturated sodium bicarbonate prepared, separate the water layer, then add 50ml of saturated sodium bicarbonate to the organic layer to wash once, then add 80ml of water to the above system for washing, then separate the water layer, and reduce After concentrating 100ml of chloroform under pressure, cooling down to 5°C for crystallization, suction filtration and drying to obtain the product 4-isobutyl-2,6-piperidinedione. The obtained product is 40.0g, the yield is 88.4%, and the purity is 99.8%. The H-NMR related chemical shifts of 4-isobutyl-2,6-piperidinedione are as follows 1 H-NMR (400MHz, CD 3 OD): 0.91(t, 6H), 1.24(t, 2H), 1.84~1.89(dd, 1H), 1.84~1....

example 2

[0023] Add 50g of 3-isobutylglutaric acid monoamide (compound II) and 150ml of xylene to a 500ml four-neck flask at room temperature, heat up to reflux and divide water for 4 hours, then cool down to 50°C and start vacuum distillation until no obvious liquid flows out , then add 250ml of chloroform, add 50ml of saturated potassium bicarbonate prepared, separate the water layer, then add 50ml of saturated sodium bicarbonate to the organic layer to wash once, then add 80ml of water to the above system for washing, then separate the water layer, After concentrating 100ml of chloroform under reduced pressure, cooling down to 5°C for crystallization, suction filtration and drying to obtain the product 4-isobutyl-2,6-piperidinedione. The obtained product is 40.8g, the yield is 90.2%, and the purity is 99.9%. The H-NMR related chemical shifts of 4-isobutyl-2,6-piperidinedione are as follows 1 H-NMR (400MHz, CD 3 OD): 0.91(t, 6H), 1.24(t, 2H), 1.84~1.89(dd, 1H), 1.84~1.88(m,1H), 2.2...

example 3

[0025] Add 50g of 3-isobutylglutaric acid monoamide (compound II) and 100ml of xylene to a 500ml four-neck flask at room temperature, heat up to reflux and divide water for 5h, then cool down to 60°C and start vacuum distillation until no obvious liquid flows out , then add 100ml of dichloromethane, add 50ml of prepared saturated ammonium bicarbonate, separate the water layer, then add 50ml of saturated sodium bicarbonate to the organic layer and wash once, then add 80ml of water to the above system for washing and then divide and remove the water After concentrating 50ml of dichloromethane under reduced pressure, cooling down to 10°C for crystallization, suction filtration and drying to obtain the product 4-isobutyl-2,6-piperidinedione. The obtained product is 40.5g, the yield is 89.6%, and the purity is 99.8%. The H-NMR related chemical shifts of 4-isobutyl-2,6-piperidinedione are as follows 1 H-NMR (400MHz, CD 3 OD): 0.91(t, 6H), 1.24(t, 2H), 1.84~1.89(dd, 1H), 1.84~1.88(...

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PUM

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Abstract

The present invention provides a preparation method of a Pregabalin intermediate impurity. The method comprises the steps of: adding 3-isobutyl monoamide glutarate in an xylene solvent, raising the temperature to the reflux temperature of xylene and insulating for reaction; after the insulation, lowering the temperature to 50-70 DEG C, conducting reduced pressure distillation until no solvent flows out, adding an extractant to the system, stirring evenly, adding weak base solution to the system, washing twice and washing once with water; separating the water layer, and condensing part of the solvent; cooling, carrying out pumping filtration and drying to obtain the Pregabalin intermediate impurity 4-isobutyl-2,6-piperidinedione. The method provided by the present invention does not require special reagent or reaction condition to reach high yield of Pregabalin intermediate impurity 4-isobutyl-2,6-piperidinedione, and the advantages of high yield and short reaction period.

Description

Technical field [0001] The present invention provides a preparation method for preparing Proven intermediate impurities, which belongs to the field of pharmaceutical and chemical industry. Invention background [0002] Epilepsy is a sudden, repeated and short -term brain dysfunction caused by abnormal discharge of the brain nerve cells.It is manifested as consciousness and spiritual dysfunction. Whether in developed or developing countries, epilepsy is an important public health issue. The International Health Organization is estimated that there are about 50 million epilepsy patients around the world.About 20%to 25%of patients are still difficult to control even if scientific poison uses antiepileptic drugs (AEDS), which has become difficult to treat epilepsy (IE).Proven was studied and developed by the US Pfizer Company. In July 2014, it was approved by the European Pharmaceutical Evaluation Bureau (EMEA) for the treatment of peripheral nerves and some seizures: In December 20...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/02C07D211/88
CPCC07D211/02C07D211/88
Inventor 乔旭慧刘幕松张文灵
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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