Method for preparing olanzapine

A technology of cyano and methylthiophene, which is applied in the field of synthetic routes for the preparation of olanzapine, and can solve the problems of low quality and low yield of final products

Active Publication Date: 2012-05-30
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This synthetic method has low yields and the quality of the final product is not high

Method used

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  • Method for preparing olanzapine
  • Method for preparing olanzapine
  • Method for preparing olanzapine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of 2-(2-nitroanilino)-3-cyano-5-methylthiophene III:

[0031] Add 65mL of o-fluoronitrobenzene, 375mL of dimethyl sulfoxide, 75g of 2-amino-3-cyano-5-methylthiophene and 225g of potassium carbonate into a 1L three-necked flask, and heat to 60-70°C to react 4-7 Hours until the reaction of 2-amino-3-cyano-5-methylthiophene is complete. Cooled to room temperature, poured into 3L of ice water, extracted three times with dichloromethane, combined the organic phases, dried the organic phases with anhydrous magnesium sulfate, filtered, concentrated, and recrystallized from ethanol to obtain 104 g of yellow solid III (yield: 74.3%). 1 H NMR (400MHz, CDCl 3 )δ9.62(s, 1H), 8.24(d, J=8.6Hz, 1H), 7.52(dd, J=8.4Hz, 1H), 7.20(d, J=8.4Hz, 1H), 6.97(dd, J=7.3Hz, 1H), 6.78(s, 1H), 2.47(s, 3H); 13 C NMR (100MHz, CDCl 3 ): 148.9, 141.2, 136.2, 136.1, 134.1, 126.6, 123.9, 119.9, 116.1, 113.7, 104.6, 15.6; MS: 258 (M + ); IR(film, cm -1 ): 3304, 2921, 2361, 2225, 1611, 1502;...

Embodiment 2

[0033] Synthesis of 2-(2-aminoanilino)-3-cyano-5-methylthiophene II:

[0034] 104g2-(2-nitroanilino)-3-cyano-5-methylthiophene III is dissolved in 450mLN, in the mixed solvent of N-dimethylformamide and 100mL water, add 30g ammonium chloride and 66g iron powder, heat up to 60-80°C and react for 6-9 hours, cool to ambient temperature after all the raw materials have reacted, filter, pour the filtrate into 2.5L cold water, precipitate a light gray precipitate, filter, wash, dry the solid, and anhydrous Ethanol was recrystallized to obtain 64.8 g of Crystal II (yield: 68.9%). 1 H NMR (400MHz, CDCl 3 )δ7.21(d, J=7.8Hz, 1H), 7.09(dd, J=7.6Hz, 1H), 6.77-6.84(m, 2H), 6.46(s, 1H), 6.16(s, 1H), 3.81(s, 2H), 2.27(s, 3H); 13 C NMR (100MHz, CDCl 3 ): 161.9, 141.4, 127.9, 127.7, 124.9, 122.3, 119.5, 116.9, 116.2, 86.8, 15.0; MS: 229 (M + -1); IR(film, cm -1 ): 3383, 3300, 3206, 3041, 2361, 2205, 1540; UV: 308, 217.8nm.

Embodiment 3

[0036] Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (I):

[0037] Dissolve 24.5g 2-(2-aminoaniline)-3-cyano-5-methylthiophene II and 40mL N-methylpiperazine in a mixed solvent of 60mL dimethyl sulfoxide and 60mL toluene, add 1.6g Anhydrous zinc chloride, heated to reflux for 14-16 hours until the raw material II has completely reacted. Cool to ambient temperature, pour into 400mL water, precipitate a light gray precipitate, filter, wash, dry, and recrystallize the solid with acetonitrile to obtain 26.5g of light yellow crystal I (yield: 79%), with a purity greater than 99%. 1 H NMR (400MHz, CDCl 3 )δ7.02(d, J=7.8Hz, 1H), 6.97(dd, J=7.5Hz, 1H), 6.88(dd, J=1.6, 7.6Hz, 1H), 6.60(d, J=7.7Hz, 1H), 6.30(s, 1H), 4.97(s, `H), 3.54(t, J=4Hz, 4H), 2.50(t, J=4.9Hz, 4H), 2.35(s, 3H), 2.31( s, 3H); 13 C NMR (100MHz, CDCl 3 ): 157.6, 151.7, 142.5, 141.0, 129.1, 128.2, 124.7, 123.7, 123.0, 119.7, 118.9, 55.1, 46.8, 46, 2, 15.5; MS: 313(M + +1); ...

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Abstract

The invention relates to a synthetic route for preparing olanzapine by using o-fluoro-nitrobenzene as a raw material. In the method, the o-fluoro-nitrobenzene is used as a starting material to prepare the olanzapine by steps of coupling, reduction and ring closing.

Description

Technical field: [0001] The invention relates to a synthetic route for preparing olanzapine by using o-fluoronitrobenzene as a raw material. Background technique: [0002] Olanzapine (olanzapine), also known as Zaipura, is developed by the Lilly Company of the United States and was launched in the United States in October 1996. It is an atypical antipsychotic drug for the treatment of schizophrenia. Clinical trials have shown that it is more antipsychotic than haloperidol. Psychotropic drugs have better efficacy and fewer extrapyramidal side effects. The chemical name is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, and its molecular formula is: [0003] [0004] The common synthetic routes of olanzapine are as follows: [0005] (1) EP04544436A1 discloses two different one-step methods for preparing olanzapine. [0006] The first method is to combine 4-amino-10H-thiophene[2,3-b][1,5]benzodiazepine hydrochloride with N-methylpiperazine in an ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61P25/18
Inventor 王亚平杨晓霞唐方辉蔡刚华徐雨航李毅
Owner ZHEJIANG HISUN PHARMA CO LTD
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