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Method of preparing bismuth citrate ranitidine

A technology of bismuth citrate ranitidine and bismuth citrate is applied in directions such as organic chemistry, can solve problems such as low yield, high residual solvent, low production efficiency, etc., and achieves high yield and good product purity Effect

Active Publication Date: 2007-01-31
LIVZON PHARM GRP INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are following problems in this method: 1, because ranitidine and bismuth citrate ranitidine itself are thermally unstable, easy to oxidize at high temperature, cause product purity to be low; 2, because bismuth citrate itself is insoluble in water , so that the reaction is carried out in two phases, resulting in a lower yield (about 50%); 3, the solvent crystallization method is used during the final purification, because bismuth citrate ranitidine is easy to hydrogen bond with the solvent, resulting in relatively low residual solvent High, about 10 times the national standard
Although this method improves the yield a lot, the biggest problem is that too much ammonia water is added, it is difficult to evaporate ammonia gas, about 100 times of water is needed, and the vacuum distillation is more than 10 times, resulting in low production efficiency, and due to prolonged heating. High content of impurities
[0006] In view of the above problems, the researchers proposed some improvement methods: Chinese patent CN1156143 replaces the solvent with dilute ethanol, reacts at room temperature for 20-30 hours, and obtains the final product through the solvent crystallization method. The biggest advantage of this method is that the content of impurities is greatly improved. , but there are still two-phase reaction yield low (about 50%), long reaction time, low production efficiency and solvent residue problems; Chinese patent CN1236779 on the basis of the above method, through ultrasonic catalysis, the reaction time is shortened to 1 hour, Yield increased to 60-70%; Chinese patent CN1256332 uses phase transfer catalyst to catalyze the reaction, which also improves the yield
But several main problems that above-mentioned two kinds of methods exist still remain unresolved: 1, the total yield of two-phase reaction is lower than 70%; 2, need a large amount of ethanol during solvent crystallization, cause aftertreatment difficulty, production efficiency is low; 3, organic solvent The residue exceeds the national standard

Method used

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  • Method of preparing bismuth citrate ranitidine

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Effect test

Embodiment 1

[0013] Embodiment 1, preparation bismuth citrate ranitidine

[0014] Suspend bismuth citrate (11.2g) in 100ml of water, add 20ml of 1mol / L ammonia water and ranitidine base (8.9g). Ammonia gas emerges, monitor the pH value to neutral, stop the reaction, filter the reaction solution, and spray dry to obtain the product.

[0015] The product purity is 99.4%.

Embodiment 2

[0016] Embodiment 2, preparation bismuth citrate ranitidine

[0017] Suspend bismuth citrate (11.2g) in 100ml of water, add ranitidine base (8.9g) and 14mol / L ammonia water 3ml, at this time the pH of the solution is 12, heat to 64°C for reaction, during the reaction Ammonia gas is constantly coming out, monitor the pH value to neutral, stop the reaction, filter the reaction solution, and spray dry to obtain the product.

[0018] The product purity is 99.2%.

Embodiment 3

[0019] Embodiment 3, preparation bismuth citrate ranitidine

[0020] Suspend bismuth citrate (11.2g) in 100ml of water, add ranitidine base (8.9g) and 5mol / L ammonia water 8ml, at this time the pH of the solution is 11, heat to 60°C for reaction, during the reaction Ammonia gas is constantly coming out, monitor the pH value to neutral, stop the reaction, filter the reaction solution, and spray dry to obtain the product.

[0021] The product purity is 99.1%.

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Abstract

The present invention discloses a method for preparing ranitidine bismuth citrate. Said method includes the following steps: making bismuth citrate be suspended in water, adding ranitidine and ammonia water to make reaction, the mole ratio of bismuth citrate, ammonia and ranitidine is 1:1-10:0.9, controlling reaction system pH value and making it be 6-12, its reaction temperature is 4-64deg.C, monitoring pH value, after the pH value is reached to neutrality, stopping reaction, filtering reaction solution and spray-drying so as to obtain the invented ranitidine bismuth citrate.

Description

Technical field [0001] The invention relates to a method for preparing bismuth ranitidine citrate. Background technique [0002] Ranitidine bismuth citrate (RBC), chemical name is N-[2-[5-[(dimethylamino)methyl]-2-furylmethylthio]ethyl] -N-Methyl-2-nitro-1,1-ethylenediamine 2-hydroxy-1,2,3-propanetricarboxylic acid bismuth salt (complex) is a peptic ulcer treatment developed by Glaxo Company medicine, its structural formula is as follows: [0003] [0004] Ranitidine is an organic base compound, which is alkaline; bismuth citrate is a salt obtained by combining citric acid and trivalent bismuth, which is acidic. Ranitidine can be combined with bismuth citrate to form a double salt, Ranitidine bismuth citrate. Bismuth citrate ranitidine has completely different properties from the mechanical mixture of bismuth citrate and ranitidine. It is easily soluble in water and can significantly inhibit pepsin isoenzyme; it not only has the ability of ranitidine to inhibit gastric...

Claims

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Application Information

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IPC IPC(8): C07D307/52
Inventor 冯军白俊杰周瑾李丽
Owner LIVZON PHARM GRP INC
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