Lafutidine compound and novel preparation method of lafutidine compound

A technology of lafutidine and compounds, which is applied in the field of lafutidine compounds, can solve the problems of low purity of lafutidine, and achieve the effects of easy industrial production, improved product quality, and easy control

Inactive Publication Date: 2012-10-03
HAINAN MEILAN SMITH KLINE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In order to overcome the low defect of the lafutidine prepared by the prior art, the invention provides a method for refining the lafutidine compound, in order to improve the purity of lafutidine and reduce the residue of toxic solvents, and through the method of the present invention The purification method also helps to improve the quality of preparation products, reduce toxic and side effects, and is suitable for large-scale industrial production

Method used

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  • Lafutidine compound and novel preparation method of lafutidine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Take 10g of lafutidine raw material with a long production date (Sichuan Xinyuan Pharmaceutical Co., Ltd., batch number 100908), and the purity is 95.48% as measured by high performance liquid chromatography. The lafutidine raw material was dissolved in 100ml of ethyl acetate, fully stirred to make it completely dissolved, filtered to remove insoluble impurities, and the filtrate was collected once.

[0049] Add 0.2 g of activated carbon to the primary filtrate, stir and adsorb at 40°C for 15 minutes, filter the deactivated carbon, collect the secondary filtrate, and concentrate under reduced pressure at 60°C.

[0050] The above-mentioned concentrated filtrate was heated to a temperature of 70-75° C., kept for half an hour, and then a mixed solvent comprising 50% of the volume of the solution was added with a volume ratio of 0.3:1 of ethanol and water. First cool down to 55°C at a speed of 2°C / hour, then cool down to 20°C at a speed of 4°C / hour, and then cool down to 2°...

Embodiment 2

[0053] Take 10 g of expired lafutidine raw material (Qingdao Guofeng Pharmaceutical Co., Ltd., batch number 20080501), and the purity measured by high performance liquid chromatography is 92.20%. The lafutidine raw material was dissolved in 70ml of toluene, fully stirred to make it completely dissolved, filtered to remove insoluble impurities, and the filtrate was collected once.

[0054] Add 0.3 g of alumina to the primary filtrate, stir and adsorb at 35°C for 10 minutes, filter the de-alumina, collect the secondary filtrate, and concentrate under reduced pressure at 55°C.

[0055] Heat the above-mentioned concentrated filtrate to a temperature of 72-74°C and keep it for one hour, then add a mixed solvent of methanol and water with a volume ratio of 0.4:1 accounting for 40% of the solution volume, first at a speed of 2.5°C / hour Cool down to 55°C, then cool down to 20°C at a speed of 3°C / hour, and then cool down to 5°C at a speed of 5°C / hour, during which crystals slowly preci...

Embodiment 3

[0058] Take 10 g of the lafutidine crude product prepared according to EP0282077, and the purity is 93.25% as measured by high performance liquid chromatography. Dissolve the lafutidine raw material in 60ml of a 1:1 mixed solvent of hexane and cyclohexane, stir well to completely dissolve it, filter to remove insoluble impurities, and collect the filtrate once.

[0059] Add 0.2 g of A-type molecular sieve to the primary filtrate, stir and adsorb at 35°C for 15 minutes, filter and remove the molecular sieve, collect the secondary filtrate, and concentrate under reduced pressure at 60°C.

[0060] Bring the above-mentioned concentrated filtrate to a temperature of 70-72°C and keep it for half an hour, then add a mixed solvent of ethanol and water with a volume ratio of 0.4:1 accounting for 30% of the solution volume, and first cool down at a rate of 1.8°C / hour to 55°C, then lower the temperature to 20°C at a rate of 3°C / hour, and then lower the temperature to 5°C at a rate of 5.5...

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Abstract

The invention relates to a lafutidine compound and a novel preparation method of the lafutidine compound. The preparation method comprises the following steps: 1) dissolving a lafutidine crude product into an organic solvent, filtering and removing insoluble impurities, obtaining the first filtrate; 2) adding adsorptive inorganic substances to the first filtrate, sharply agitating, filtering and removing the adsorptive inorganic substances after standing, obtaining the second filtrate, and compressing and concentrating the second filtrate; (3) heating the second filtrate to 75 DEG C or less, keeping the temperature for a period of time, concentrating the second filtrate, slowly adding a mixing solvent, of which the volume ratio of alcohol to water is 0.2-1, under agitation, reducing the temperature to 2 DEG C at most in a gradient way, recrystallizing, separating, washing and drying the separated crystal to obtain the refined lafutidine; (4) returning any separated crystallized crystallizing mother solution to the step 3). The preparation method disclosed by the invention helps to solve the problems of low purity in rough preparation of lafutidine and lafutidine crude drug, has the characteristics of simplicity, easiness in control and industrial production, the quality of the preparation product is improved, and toxic and side effects are reduced.

Description

technical field [0001] The invention relates to a lafutidine compound and a new preparation method for purifying it, belonging to the technical field of medicine. Background technique [0002] Lafutidine, its chemical name is: (+ / -)-2-[(2-furylmethyl)sulfinyl]-N-[4-[4-(1-piperidinylmethyl)- 2-pyridyl]oxy-(Z)-2-butenyl]acetamide, molecular formula: C 22 h 29 N 3 o 4 S, molecular weight: 431.55, structural formula: [0003] [0004] Lafutidine is an anti-ulcer drug jointly developed by Fujirebio and Taiho in Japan. This product is a potent and long-acting second-generation histamine H2 receptor antagonist with a unique Gastric protection. It was launched in Japan in April 2000. Lavutidine is a second-generation H2 receptor antagonist, mainly used in the treatment of peptic ulcer, which can reduce the basal secretion of gastric acid and inhibit the secretion of gastric acid stimulated by histamine, gastrin and urethane. Compared with other similar drugs (such as cime...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61P25/24
Inventor 杨明贵
Owner HAINAN MEILAN SMITH KLINE PHARMA
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