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Olanzapine intermediate and method for preparing olanzapine using same

An intermediate, the technology of olanzapine, which is applied in the field of preparation of olanzapine, can solve problems such as difficult removal, difficult handling, and low yield, and achieve the effects of avoiding waste, reducing costs, and improving quality

Active Publication Date: 2012-12-26
四川省百草生物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] (1) It is difficult to directly react piperazine or N-methylpiperazine with 2-methyl-4-amino-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride , which needs to be prepared under high temperature and long-term reflux reaction, and there are many impurities in the product, which requires repeated refining to obtain olanzapine that meets the pharmaceutical requirements, the yield is low, and the process is complicated
[0007] (2) Reaction of the above-mentioned piperazine or N-methylpiperazine with 2-methyl-4-amino-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride Among them, the exchange reaction of the amine group is a reversible reaction, and 2-methyl-4-amino-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride cannot be combined with piperazine or The reaction of N-methylpiperazine is complete, in order to make the remaining 2-methyl-4-amino-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride in olanzapine The salt meets the requirements, and the amount of piperazine or N-methylpiperazine must be greatly excessive to promote the reaction (2-methyl-4-amino-10H-thieno[2,3-b][1,5] The molar ratio of benzodiazepine hydrochloride to piperazine or N-methylpiperazine is 1:10-20), but the large excess of piperazine or N-methylpiperazine makes workup difficult , and caused a large amount of waste of piperazine or N-methylpiperazine; in addition, the 2-methyl-4-amino-10H-thieno[2,3-b][1 , 5] Benzodiazepines are similar in nature to olanzapine, and are difficult to remove during refining, thereby affecting the quality of olanzapine for medicine

Method used

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  • Olanzapine intermediate and method for preparing olanzapine using same
  • Olanzapine intermediate and method for preparing olanzapine using same
  • Olanzapine intermediate and method for preparing olanzapine using same

Examples

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Embodiment 1

[0024] The intermediate of olanzapine: 2-methyl-4-chloro-10H-thieno[2,3-b][1,5]benzodiazepine Synthesis:

[0025] Fully dissolve 100g of 2-methyl-4-amino-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride in 500ml of chloroform, and then add 40ml of Thionyl chloride was heated to 60°C and reacted for 6 hours. After all the raw materials were reacted, chloroform and excess thionyl chloride were distilled off under reduced pressure to obtain 108g of olanzapine intermediate: 2-methyl -4-Chloro-10H-thieno[2,3-b][1,5]benzodiazepine.

Embodiment 2

[0027] The synthesis of olanzapine: 2-methyl-4-chloro-10H-thieno[2,3-b][1,5]benzodiazepine 100g was dissolved in 400ml dimethyl sulfoxide and 400ml toluene In the mixed solution, add 54 g of N-methylpiperazine under stirring condition, raise the temperature to 120° C. and react for 8 hours. After all the raw materials have been reacted, toluene and dimethyl sulfoxide are removed by distillation under reduced pressure, and the resulting residual solution is cooled to room temperature. Then pour into 2000ml of ice water to precipitate the solid, filter and wash the resulting solid with ice water, and dry to obtain olanzapine: 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thieno [2,3-b][1,5]benzodiazepines.

Embodiment 3

[0029] Synthesis of olanzapine: 2-methyl-4-chloro-10H-thieno[2,3-b][1,5]benzodiazepine 65g was dissolved in 390ml dimethyl sulfoxide and 270ml toluene Add 14.3 g of N-methylpiperazine to the mixture under stirring condition, raise the temperature to 60°C and react for 16 hours, after all the raw materials have been reacted, distill off toluene and dimethyl sulfoxide under reduced pressure, and cool the obtained residue to room temperature , and then poured into 1000ml of ice water to precipitate the solid, filtered and washed with ice water, and dried to obtain olanzapine: 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thiophene And[2,3-b][1,5]benzodiazepines.

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Abstract

The invention discloses an olanzapine intermediate and a method for preparing olanzapine using the intermediate. The method comprises the following steps of: making 2-methyl-4-amino-10H-thieno [2,3-b][1,5] benzodiazepine hydrochloride to react with thionyl chloride to prepare the olanzapine intermediate, namely,2-methyl-4-chloro-10H-thieno [2,3-b][1,5] benzodiazepine; and making 2-methyl-4-chloro-10H-thieno [2,3-b][1,5] benzodiazepine to react with N-methyl piperazine to prepare olanzapine. The method provided by the invention has the advantages of simple process, high yield and good purity of the obtained olanzapine, and being able to avoid the generation of impurities difficult to be removed, and improve the medicinal quality of olanzapine greatly.

Description

technical field [0001] The present invention relates to an intermediate of olanzapine: 2-methyl-4-chloro-10H-thieno[2,3-b][1,5]benzodiazepine, its preparation method and utilization The method for preparing olanzapine from the olanzapine intermediate. Background technique [0002] Olanzapine is a new type of atypical antipsychotic, acting on the central nervous system, and is a thiophenobenzodiazepine serotonin / dopamine antagonist. The chemical name of olanzapine is: 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thieno[2,3-b][1,5]benzodiazepine , the structural formula is as follows: [0003] [0004] Chinese patent CN201110149626.5 discloses a preparation method of the antipsychotic olanzapine, the method comprising: preparing 2-amino-3-cyano-5 with malononitrile, propionaldehyde and sulfur in the presence of triethylamine -Methylthiophene, 2-amino-3-cyano-5-methylthiophene, under the action of NaH, uses tetrahydrofuran as a solvent, and undergoes nucleophilic substitution ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 蒋红斌杨文罗睿
Owner 四川省百草生物药业有限公司
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