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Synthesis method of erlotinib hydrochloride

A technology of erlotinib hydrochloride and its synthesis method, which is applied in the field of synthesis of erlotinib hydrochloride, can solve the problems of cumbersome operation, high raw material price and low yield, and achieve easy separation and purification, easy industrial production, and recovery high rate effect

Inactive Publication Date: 2012-09-19
ZHEJIANG SCI-TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw materials used in this method are expensive and rare, the operation is cumbersome, and the yield is low, so it is only suitable for laboratory research

Method used

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  • Synthesis method of erlotinib hydrochloride
  • Synthesis method of erlotinib hydrochloride
  • Synthesis method of erlotinib hydrochloride

Examples

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preparation example Construction

[0030] The steps of the synthetic method of erlotinib hydrochloride are as follows:

[0031] a. React m-nitrobenzaldehyde, weak base and acetic anhydride with a molar ratio of 1:1~2:1.5~3 at 20~180°C for 5~15 hours, cool, pour into strong alkali solution, and control PH≈ 12. Extract with an organic solvent, adjust the pH of the aqueous layer to 2-3 with concentrated hydrochloric acid under ice cooling, filter with suction, wash with ice water, and dry to obtain m-nitrocinnamic acid;

[0032] b. React m-nitrocinnamic acid and bromine with a molar ratio of 1:1 to 3 in an organic solvent at 20 to 100°C for 2 to 10 hours, evaporate the solvent, and recrystallize to obtain 2,3-dibromo- 3-(3'-nitrophenyl)propanoic acid;

[0033] c. Dissolve 2,3-dibromo-3-(3'-nitrophenyl)propionic acid in dimethylformamide, cool in an ice bath to 0°C, slowly add triethylamine dropwise to 2 , The molar ratio of 3-dibromo-3-(3'-nitrophenyl)propionic acid and triethylamine is 1:1~3, then rise to room ...

Embodiment 1

[0045] (1) Preparation of m-nitrocinnamic acid

[0046] Add 30.22g (0.2mol) of m-nitrobenzaldehyde, 16.4g (0.2mol) of anhydrous sodium acetate and 30.6g (0.3mol) of acetic anhydride into a 250ml reaction flask, and heat to 180°C for 15 hours. After the reaction, cool to room temperature, pour the reaction solution into 300ml 10% sodium hydroxide aqueous solution, stir for half an hour, extract with dichloromethane (150ml×3), separate the water layer, adjust the pH value to 2-3 with concentrated hydrochloric acid, A large amount of solid was precipitated, filtered with suction, the filter cake was washed 2-3 times with ice water, and dried to obtain 33.2 g of white solid, with a yield of 86%.

[0047] (2) Preparation of 2,3-dibromo-3-(3'-nitrophenyl)propionic acid

[0048] Add 33g (0.17mol) of m-nitrocinnamic acid and 150ml of chloroform into a 250ml reaction bottle, stir and dissolve, then add 27.16g (0.17mol) of bromine, and gradually raise the temperature and reflux for 6 h...

Embodiment 2

[0058] (1) Preparation of m-nitrocinnamic acid

[0059] Add 30.22g (0.2mol) of m-nitrobenzaldehyde, 32.8g (0.4mol) of anhydrous sodium acetate and 61.25g (0.6mol) of acetic anhydride into a 250ml reaction flask, and heat to 180°C for 12 hours. After the reaction, cool to room temperature, pour the reaction solution into 300ml 10% sodium hydroxide aqueous solution, stir for half an hour, extract with dichloroethane (150ml×3), separate the water layer, and adjust the pH value to 2-3 with concentrated hydrochloric acid , a large amount of solids were precipitated, filtered with suction, the filter cake was washed 2 to 3 times with ice water, and dried to obtain 34.38 g of white solids, with a yield of 89%.

[0060] (2) Preparation of 2,3-dibromo-3-(3'-nitrophenyl)propionic acid

[0061] Add 33g (0.17mol) of m-nitrocinnamic acid and 150ml of chloroform into a 250ml reaction bottle, stir and dissolve, add bromine 81.5g (0.51mol), and gradually raise the temperature and reflux for ...

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Abstract

The invention relates to a synthesis method of erlotinib hydrochloride, which comprises the following technological process of: a, synthesizing m-nitrocinnamic acid by taking m-nitrobenzaldehyde as raw material; b, carrying out bromine addition to obtain 2, 3-dibromo-3-(3'-nitrophenyl) propanoic acid; c, carrying out decarboxylation and dehydrobromination to obtain (Z)-beta-bromo-(3'-nitrophenyl) ethylene; d, enabling the (Z)-beta-bromo-(3'-nitrophenyl) ethylene to have reaction with metal hydride to obtain m-nitrobenzene acetylene; e, reducing to obtain m-aminophenyl acetylene; and f, enabling the m-aminophenyl acetylene to have reaction with 4-chloro-6, 7-bi-(2-methoxy-ethoxy)-quinazoline, to obtain the erlotinib hydrochloride. The raw materials of the synthesis method are easy to obtain and low in cost, and the synthesis method is mild in reaction conditions, simple and convenient in operation, higher in yield and suitable for amplification.

Description

technical field [0001] The invention relates to a synthesis method of erlotinib hydrochloride, which belongs to the technical field of medicine preparation. Background technique [0002] Erlotinib hydrochloride, the trade name is Tarceva, the chemical name is N-(3-ethynylbenzene)-6,7-bis(methoxyhexyloxy)-4-quinazolinamine salt Salt, its structural formula is shown in formula 1: [0003] [0004] Formula 1 Erlotinib hydrochloride molecular formula [0005] Erlotinib hydrochloride is a 4-anilinoquinazoline oral anti-tumor drug jointly developed by Roche, OSI Biopharmaceutical Company and Genentech Pharmaceutical Company. In 2004, the US FDA approved erlotinib hydrochloride for the treatment of locally advanced and metastatic non-small cell lung cancer. In 2005, it was approved for the treatment of pancreatic cancer. [0006] Erlotinib hydrochloride is an antineoplastic drug based on a new mechanism of action - a targeted therapy drug for tumors, targeting reversible and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
Inventor 朱锦桃张俊李星孙丽文
Owner ZHEJIANG SCI-TECH UNIV
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