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Industrial preparation method for bepotastine besilate or racemoid of bepotastine besilate

A compound and racemization technology, applied in the chemical field, can solve the problems of long reflux time, low condensation reaction yield, high cost, etc., and achieve the effect of simple operation, avoiding heterogeneous reaction, and high yield

Active Publication Date: 2014-08-27
JIANGSU LIANHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the reflux time is too long, it is easy to cause chiral inversion of 2-[4-[(S)-(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine (formula (II)). defect
Lead to low condensation reaction yield and high cost
At present, there is no domestic manufacturer capable of large-scale production of the bepotastine API product

Method used

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  • Industrial preparation method for bepotastine besilate or racemoid of bepotastine besilate
  • Industrial preparation method for bepotastine besilate or racemoid of bepotastine besilate
  • Industrial preparation method for bepotastine besilate or racemoid of bepotastine besilate

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preparation example Construction

[0031] The application provides an industrial preparation method of bepotastine or a racemic compound thereof, the method comprising the following steps:

[0032] a. Condensation reaction: Dissolve 2-[4-[(S)-(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine (formula (II)) or its racemate in organic In the solvent; add alkaline acid-binding agent, ethyl 4-bromobutyrate (formula (Ⅲ)) to carry out condensation reaction;

[0033] b. Post-treatment: After the reaction is completed, it is extracted with ethyl acetate, washed with lye, and processed to obtain the intermediate (4-[4-[(S)-(4-chlorophenyl)pyridin-2-ylmethoxy]piperidine -1-yl]butanoic acid ethyl ester or its racemate 4-[4-[(4-chlorophenyl)pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid ethyl ester);

[0034] c. Ester hydrolysis: Add lye to the intermediate for hydrolysis, adjust the solution to acidity, then add dichloromethane, and process to obtain bepotastine (formula (I)) or its racemic compound

[0035] Prefera...

Embodiment 1

[0047] Embodiment 1: Preparation of ethyl 4-[4-[(S)-(4-chlorophenyl)pyridin-2-ylmethoxy]piperidin-1-yl]butanoate:

[0048] Dissolve 2kg of 2-[4-[(S)-(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine in 20L of acetone, add 1.6kg of ethyl 4-bromobutyrate, grind Potassium carbonate 1.2kg, heated to reflux under stirring, reacted for 12 hours, followed by TLC detection, until the raw material point disappeared, the reaction solution was cooled to room temperature, and filtered to remove insoluble matter. The organic layer was concentrated under reduced pressure at 40°C to obtain an oil. Add 20L of purified water to the oil, stir at room temperature for 0.5h, extract with 30L*3 ethyl acetate, separate the layers, wash the organic layer with 11L of 5% sodium hydroxide solution, and dry with 5kg of anhydrous sodium sulfate for 2h. The desiccant was filtered off, concentrated under reduced pressure to obtain 2.0 kg of oily ethyl 4-[4-[(S)-(4-chlorophenyl)pyridin-2-ylmethoxy]piperidin...

Embodiment 2

[0049] Embodiment 2: Preparation of 4-[4-[(4-chlorophenyl)pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid ethyl ester:

[0050] Dissolve 2kg of 2-[4-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine in 20L of ethanol, add 1.6kg of ethyl 4-bromobutyrate, grind 1.0kg of sodium carbonate , heated to reflux under stirring, reacted for 37 hours, followed by TLC detection, until the raw material point disappeared, the reaction solution was cooled to room temperature, and the insoluble matter was removed by filtration. The organic layer was concentrated under reduced pressure at 40°C to obtain an oil. Add 20L of purified water to the oil, stir at room temperature for 0.5h, extract with 30L*3 ethyl acetate, separate the layers, wash the organic layer with 11L of 5% sodium hydroxide solution, and dry with 5kg of anhydrous sodium sulfate for 2h. The desiccant was filtered off and concentrated under reduced pressure to obtain 2.1 kg of oily ethyl 4-[4-[(4-chlorophenyl)pyridin-2-ylmeth...

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Abstract

The invention provides an industrial preparation method for bepotastine besilate or racemoid of the bepotastine besilate. The method includes the following steps of firstly, dissolving 2-4-[(S)-(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine or racemate of the 2-4-[(S)-(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine in an organic solution; secondly, adding an alkaline acid-binding agent and ethyl 4-bromobutyrate, conducting stirring, temperature rising and backflow, and conducting the condensation reaction; thirdly, conducting cooling and filtering after the reaction ends, and conducting organic layer vacuum concentration to obtain grease; fourthly, adding purified water to the grease, conducting stirring, ethyl acetate extraction and skimming to obtain an organic layer, washing the organic layer with alkaline liquid, drying the organic layer, and conducting reduced pressure distillation after filtering out a drying agent to obtain an intermediate; fifthly, adding alkaline liquid in the intermediate for hydrolyzing, adjusting to acid after hydrolyzing, conducting stirring, filtering and concentrating, adding dichloromethane for stirring and drying, and then conducting filtering and reduced pressure concentration again to obtain the bepotastine besilate or the racemoid of the bepotastine besilate. By means of the method, the operation procedure is simplified, reaction time is shortened, no racemization phenomena can occur, and the method has the advantages of being high in yield, easy to operate and the like.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to an industrial preparation method of bepotastine or its racemic compound. Background technique [0002] Bepotastine, also known as bepotastine or bepotastine, its chemical name is: 4-[4-[(S)-(4-chlorophenyl)-2-pyridylmethoxy ]piperidine-1-yl]butanoic acid, the English name is 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid. Molecular formula: C 21 h 25 ClN 2 o 3 , molecular weight: 388.89. CAS: 125602-71-3. The structural formula is as shown in formula I. [0003] Bepotastine is the active ingredient of the clinical drug Bepotastine Besylate, which is histamine H jointly developed by Tanabe Seiyaku and Ube Industries of Japan. 1 Receptor antagonist for the treatment of allergic rhinitis and urticaria. Approved by the US FDA for marketing in September 2009, this product is a powerful and long-acting oral histamine H 1 Receptor antagonist for the treatment of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 扈田进何秋田宗勇俞波华庆松张德伟
Owner JIANGSU LIANHUAN PHARMA
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