Technique for preparing olanzapine

A technology of methyl and nitroaniline, which is applied in the field of synthetic routes for the preparation of olanzapine, can solve the problems of low yield and low quality of the final product, achieve high yield, avoid highly toxic heavy metals, and easily control the reaction Effect

Active Publication Date: 2010-06-09
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This synthetic method has low yields...

Method used

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  • Technique for preparing olanzapine
  • Technique for preparing olanzapine
  • Technique for preparing olanzapine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Synthesis of 5-methyl-2-(2-nitroanilino)-3-carboxymethylthiophene V:

[0039] Add 60mL of dimethyl sulfoxide, 5.5g of anhydrous potassium carbonate, 7.1g of o-fluoronitrobenzene, 6g of 2-amino-5-methyl-3-formic acid methyl thiophene into a 100mL three-necked flask, and heat under nitrogen protection React at 60-75°C for 20-30 hours until the reaction of the raw materials is complete, cool to room temperature, pour into 200mL ice water, precipitate solid, filter, wash with water, and recrystallize with ethanol to obtain 6 grams of 5-methyl-2-(2-nitro Anilino)-3-carboxymethylthiophene V (yield: 56%). 1 H NMR (400MHz, CDCl 3 )δ11.88(s, 1H), 8.26(d, J=8.4Hz, 1H), 7.90(d, J=8.4Hz, 1H), 7.60(t, J=7.4Hz, 1H), 7.00(t, J=7.4Hz, 1H), 6.92(s, 1H), 3.92(s, 3H), 2.40(s, 3H); UV: 329.6, 224.8, 193.8nm.

Embodiment 2

[0041] Synthesis of 5-methyl-2-(2-nitroanilino)-3-carboxythiophene IV:

[0042] Add 5.4 g of 5-methyl-2-(2-nitroanilino)-3-methylthiophene V and 100 mL of ethanol into a 250 mL three-necked flask, add 20 mL of 1.75 N aqueous sodium hydroxide solution dropwise under stirring, and the addition is complete Raise the temperature to 40-55°C and react for 3-5 hours until the reaction of 5-methyl-2-(2-nitroanilino)-3-methylthiophene V is complete. Cool to room temperature, add 50 mL of ice water, adjust pH=1-2 with 6N hydrochloric acid, filter, wash with water, and dry to obtain 4 g of red solid 5-methyl-2-(2-nitrophenylamino)-3-carboxythiophene IV ( Yield: 82%). 1 HNMR (400MHz, CDCl 3 )δ12.89(s, 1H), 11.73(s, 1H), 8.22(d, J=8.4Hz, 1H), 7.89(d, J=8.4Hz, 1H), 7.77(t, J=7.4Hz, 1H), 7.14(t, J=7.6Hz, 1H), 6.91(s, 1H), 2.37(s, 3H); 13 CNMR (100MHz, CDCl 3 ): 165.8, 150.3, 137.7, 136.8, 135.7, 127.1, 125.5, 124.0, 121.4, 117.3, 114.7, 14.9; MS: 278 (M + ), 277 (M + -1); IR(film, cm ...

Embodiment 3

[0044] Synthesis of 5-methyl-2-(2-nitroanilino)-3-(4-methylpiperazinyl)carbonylthiophene III:

[0045] Add 4g of 5-methyl-2-(2-nitroanilino)-3-carboxythiophene IV into a 100mL three-necked flask, dissolve 20mL of thionyl chloride in 20mL of toluene, heat to 42°C for reaction, and maintain the reaction temperature to The raw materials were completely reacted, concentrated under reduced pressure to remove thionyl chloride, added 28 mL of acetonitrile to dissolve, added dropwise 8 mL of N-methylpiperazine, poured into ice water after the reaction was completed, extracted with ethyl acetate, combined the organic phases, and concentrated to obtain 4.52 g of III (Yield: 90%). 1 H NMR (400MHz, CDCl 3 )δ10.17(s, 1H), 8.17(d, J=8.7Hz, 1H), 7.39-7.49(m, 2H), 6.86(t, J=8.4Hz, 1H), 6.62(s, 1H), 3.61(s, 4H), 2.44(s, 3H), 2.35(t, J=4.8Hz, 4H), 2.03(s, 3H); 13 C NMR (100MHz, CDCl 3 ): 164.6, 141.6, 139.6, 135.8, 133.6, 133.3, 126.7, 126.3, 123.1, 118.7, 116.1, 54.8, 45.9, 15.3; MS: 361 (...

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Abstract

The invention relates to a synthetic route which takes o-fluoro-nitrolbenzene as starting raw material to prepare olanzapine, which comprises five steps: coupling, saponification, esterification, sulfur substitution and deoxidation.

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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IPC IPC(8): C07D495/04A61P25/18
Inventor 王亚平唐方辉杨晓霞蔡刚华徐雨航李毅
Owner ZHEJIANG HISUN PHARMA CO LTD
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