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Method for preparing lafutidine by virtue of aminolysis

A technology of lafutidine and methylamine, applied in the new field of chemical synthesis, can solve the problems of high synthetic cost of lafutidine, reduce the total yield of synthetic lafutidine, etc., and achieve simplified post-treatment process, The effect of avoiding loss and improving synthesis yield

Inactive Publication Date: 2011-10-12
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Obviously, the method of repeated recrystallization and refining of crude product lafutidine taken in the synthetic preparation process of existing lafutidine cannot meet the above-mentioned requirements
Simultaneously, the repeated recrystallization steps have greatly reduced the total yield of synthetic lafutidine, causing the synthetic cost of lafutidine to remain high

Method used

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  • Method for preparing lafutidine by virtue of aminolysis
  • Method for preparing lafutidine by virtue of aminolysis
  • Method for preparing lafutidine by virtue of aminolysis

Examples

Experimental program
Comparison scheme
Effect test

experiment example

[0058] Experimental example: the effect of hydrazine on the production of dihydrolafutidine

[0059] In order to verify the effect of hydrazine on the production of dihydrolafutidine, the inventors designed and carried out the following experiments.

[0060] Dissolve 1 equivalent of the compound of formula 3 obtained by hydrazinolysis in a solvent, add 10 equivalents of hydrazine hydrate, heat and reflux for a certain period of time, evaporate the solvent to dryness, dissolve with ethyl acetate, wash with saturated sodium chloride solution, and dry over anhydrous magnesium sulfate. The compound of formula 3 obtained by evaporating ethyl acetate, further condenses with 2-furan methylsulfinyl acetate p-nitrophenol ester (compound of formula 4) to obtain lafutidine, check wherein dihydrolafutidine with liquid chromatography Ding impurity content.

[0061]

[0062] In the above test, the compound of formula 3 and the compound of formula 4 were condensed to obtain lafut...

Embodiment 2

[0071] Example 2: cis-N-methyl-N-(4-(4-piperidinylmethyl)pyridinyl-2-oxo)-2- Enyl) phthalamide (formula 5 compound) preparation

[0072] 200 grams (0.394 moles) of N-(4-(4-piperidinylmethyl) pyridyl-2-oxo)-2-ene butyl) phthalimide (formula 2 compound) Forate was suspended in 2L of absolute ethanol, and 540 ml (3.94 mol) of 25% methylamine aqueous solution was added under stirring at room temperature. The reaction solution was quickly clarified, then cloudy, and gradually produced a large amount of white solid. Filtration obtains this solid, proves that this solid is cis-N-methyl-N-(4-(4-piperidylmethyl)pyridyl-2-oxo)-2- Butyl) phthalamide (compound of formula 5). 1 H NMR (CDCl 3 ): δ1.41-1.42 (2H, m, 3-CH 2 ); 1.52-1.57 (4H, m, 2-CH 2 ); 2.33 (4H, s, 1-CH 2 ); 2.89-2.90 (3H, d, 4-CH 3 ); 3.36 (2H, m, 5-CH 2 ); 4.12-4.14 (2H, t, 7-CH 2 ); 4.93-4.94 (2H, d, 6-CH 2 ); 5.67-5.87 (2H, m, 8-H, 9-H); 6.89-7.75 (7H, m, Ar); MS: 423 (M+1).

[0073]

Embodiment 3

[0074] Embodiment 3: Lafutidine is prepared by aminolysis method of the present invention

[0075] 1. The preparation of cis-4-(4-piperidinylmethyl)pyridyl-2-oxo)-2-butenamine (formula 3 compound)

[0076] 200 grams (0.394 moles) of N-(4-(4-piperidinylmethyl) pyridyl-2-oxo)-2-ene butyl) phthalimide (formula 2 compound) Forate was suspended in 2L of absolute ethanol, and 540 ml (3.94 moles) of 25% methylamine aqueous solution was added under stirring at room temperature. The reaction solution was quickly clarified, then cloudy, and gradually produced a large amount of white solid (compound of formula 5). After continuing to stir at room temperature for 8 hours, the reaction solution became clear, and 500 milliliters of 20% NaOH solution (95 grams were dissolved in 500 milliliters of water) was added for reaction for 2 hours. TLC showed that N-(4-(4-piperidinylmethyl)pyridine Base-2-oxo)-2-enbutyl)phthalimide (compound of formula 2) has been completely converted to cis-4-(4-p...

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Abstract

The invention relates to a method for preparing lafutidine by virtue of aminolysis. The method comprises the following steps: reacting a compound shown in a formula 2 or a pharmaceutically acceptable salt thereof with amine RNH2 so as to generate a compound shown in a formula 5, wherein R represents hydrogen, linear-chain or branched C1-4 alkyl, phenyl or C1-4 alkyl substituted phenyl; reacting the compound shown in the formula 5 with the amine RNH2 so as to obtain a compound shown in a formula 3, wherein R represents hydrogen, linear-chain or branched C1-4 alkyl, phenyl or C1-4 alkyl substituted phenyl; condensing the compound shown in the formula 3 and a compound shown in a formula 4 so as to obtain the lafutidine; and optionally, converting the obtained lafutidine into a pharmaceutically acceptable salt of the lafutidine.

Description

technical field [0001] The present invention relates to a new chemical synthesis method, in particular to a method for preparing lafutidine through aminolysis. Background technique [0002] Peptic ulcer disease is a common and frequently-occurring disease. Currently, the main therapeutic drugs for peptic ulcer include proton pump inhibitors, H 2 Receptor antagonists, gastric mucosal protective agents, antacids, etc. Lafutidine is a potent, long-acting second-generation histamine H developed jointly by Fujirebio and Taiho. 2 Receptor antagonists, listed in Japan in April 2000, the trade names are Storga and Protecadin. Lafutidine 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 (cimetidine and famotidine), it has a higher 2 The receptor blocking effect is more effective and durable; compared with other similar drugs, lafutidine has another pharmacologica...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D213/64
Inventor 周宜遂李梦琳苏新海李如兴江超戎娜
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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