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Reducing preparation method for lafutidine

A technology of lafutidine and a reducing agent, which is applied in the field of preparation of lafutidine, can solve the problems of reducing the total yield of synthetic lafutidine, high synthetic cost of lafutidine, etc., and simplify the post-processing process , avoid loss, improve the effect of 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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  • Reducing preparation method for lafutidine
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  • Reducing preparation method for lafutidine

Examples

Experimental program
Comparison scheme
Effect test

experiment example

[0056] Experimental example: the effect of hydrazine on the production of dihydrolafutidine

[0057] In order to verify the effect of hydrazine on the production of dihydrolafutidine, the inventors designed and carried out the following experiments.

[0058] 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.

[0059]

[0060] In the above test, the compound of formula 3 and the compound of formula 4 were condensed to obtain lafut...

Embodiment 1

[0061] Example 1: N-(4-(4-piperidinylmethyl)pyridinyl-2-oxo)-2- Enyl) phthalimide (formula 2 compound) preparation

[0062] 1 kg of N-(4-(4-piperidinylmethyl)pyridyl-2-oxo)-2-enbutyl)phthalimide maleate was added into the 5L reactor, Add 2.7 liters of ethyl acetate and stir well. 1.3 liters of aqueous solution of 250 g of sodium hydroxide was added dropwise, and the temperature during the dropwise addition did not exceed 20°C. After dropping, continue to stir until the feed liquid is clear. The ethyl acetate phase was separated. Return the water phase to the reactor, add 0.5 liter of ethyl acetate, stir and extract, combine the ethyl acetate phase, add anhydrous magnesium sulfate, filter out the desiccant, distill under reduced pressure and recover ethyl acetate to obtain an oily substance.

Embodiment 2

[0071] Embodiment 2: the present invention prepares lafutidine with reducing agent reduction method

[0072] 1. Preparation of 2-hydroxymethyl-N-(4-(4-piperidinylmethyl)pyridyl-2-oxo)-2-enbutyl)benzamide (compound of formula 5)

[0073]

[0074] 1600 milliliters of isopropanol and 263 milliliters of water were put into the reaction flask, and 73 grams (0.187 mol) of 2 oil was added, and the reaction liquid was clear after mechanical stirring for 5 minutes. At 25°C, 35.3 g (0.934 mol) of sodium borohydride was added in batches, and the stirring reaction was continued for 15 hours. TLC showed that the reaction of the raw materials was complete, and a large amount of white solid was generated. Take a small amount of filtration, H NMR spectrum and mass spectrum prove to be 2-hydroxymethyl-N-(4-(4-piperidinylmethyl)pyridyl-2-oxo)-2-enylbutyl)benzamide (compound of formula 5). 1 H NMR (CDCl 3 ): δ1.41-1.42(m, 2H); 1.52-1.57(m, 4H); 2.33(s, 4H); 3.36(s, 2H); 4.17-4.19(t, 2H);...

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Abstract

The invention relates to a reducing preparation method for lafutidine, which comprises the following steps: reducing a compound shown in formula 2 or a pharmaceutically acceptable salt thereof with a reducing agent to obtain a compound shown in formula 5; heating to decompose the compound shown in formula 5 to obtain a compound shown in formula 3; carrying out condensation reaction on the compound shown in formula 3 and a compound shown in formula 4 to obtain lafutidine; and optionally converting the obtained lafutidine into a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The new chemical synthesis method that the present invention relates to, more specifically relate to a kind of method that prepares lafutidine by reduction. 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 an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D213/64
Inventor 周宜遂苏新海李梦琳宋亚云李如兴
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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