Erlotinib preparation method suitable for industrial production

A technology of erlotinib and erlotinib hydrochloride, applied in the field of synthesis of N--6,7-di-4-aminoquinazoline and its hydrochloride, can solve hydroxyl protection and deprotection reactions The problems such as cumbersome process and long synthetic route steps can achieve the effect of avoiding the increase of reaction impurities, saving the use of solvents and improving product quality.

Inactive Publication Date: 2015-12-09
海南卓泰制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The synthetic literature of erlotinib has reported a variety of synthetic routes of different routes, such as patents US5747498, CN1860105A, WO2011076813A1, WO2007006091, CN101735157A, etc. reported that erlotinib was obtained by nucleophilic substitution of 4-substituted quinazoline and aromatic amine , but the steps of the synthetic route are long, and highly polluting chlorinated reagents are used for the halogenation reaction, and the protection and deprotection reaction process of the hydroxyl group in some synthetic routes is cumbersome

Method used

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  • Erlotinib preparation method suitable for industrial production
  • Erlotinib preparation method suitable for industrial production
  • Erlotinib preparation method suitable for industrial production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of 4,5-bis(2-methoxyethoxy)-2-aminophenylacetonitrile

[0034] Add 4.00 kg of 4,5-bis(2-methoxyethoxy)-2-nitrophenylacetonitrile and 80.0 kg of drinking water into the reactor, and stir for 20 minutes. Control the reaction temperature at 45-55°C, and add 7.05 kg of sodium dithionite in 10 batches within 5 hours. After the addition was complete, the reaction was continued at 45-55°C, and the reaction was monitored by TLC. After the reaction was complete, the temperature was raised to 65-75°C, and concentrated hydrochloric acid was added dropwise. After the addition, keep the reaction for 2 hours, then cool to 19-25 °C, adjust the pH to 8-9 with ammonia water, stir and crystallize for 2 hours, filter, and wash with drinking water 3.0kg×2. The wet product was air-dried at 65-75°C to obtain 3.45 kg of 4,5-bis(2-methoxyethoxy)-2-aminophenylacetonitrile. (Yield: 96%, HPLC: 95%).

Embodiment 2

[0035] Embodiment 2: ( E Preparation of )-N'-(2-cyano-4,5-bis(2-methoxyethoxy)phenyl)-N,N-dimethylformamidine

[0036]2.34kg of 4,5-bis(2-methoxyethoxy)-2-aminophenylacetonitrile, 2.09kg of N,N-dimethylformamide dimethyl acetal and 4.68kg of N,N-dimethyl Formamide was added into a 20L reaction flask, heated to reflux, and the reaction was stopped after 3 hours. Distillation under reduced pressure gave 2.82 kg of oil, which was directly used in the next reaction without further treatment.

Embodiment 3

[0037] Embodiment 3: the synthesis of erlotinib

[0038] 2.82kg ( E )-N'-(2-cyano-4,5-bis(2-methoxyethoxy)phenyl)-N,N-dimethylformamidine, 1.03kg m-aminophenylacetylene and 8.61kg ice Acetic acid was added in the 20L reaction flask, heated to reflux, and stopped heating after the reaction was complete (monitored by TLC). Cool to 15-25°C, pour the reaction solution into 50.0kg of ice water with stirring, and then add 20.0kg of ethyl acetate. Under stirring at 15-25°C, adjust the pH to 8-9 with ammonia water, a large amount of solids precipitated, stirred for 2 hours, filtered, and the filter cake was air-dried at 60°C to obtain 2.80kg of crude product.

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Abstract

The invention relates to a preparation method of erlotinib and hydrochloride thereof. The preparation method comprises the following steps: 1, reacting 4,5-di(2-methoxyethoxy)-2-nitrophenylacetonitrile with sodium hydrosulfite to obtain 4,5-di(2-methoxyethoxy)-2-aminophenylacetonitrile: controlling the reaction temperature to 45-55DEG C, adding sodium hydrosulfite in batches, adjusting the pH value to 8-9 by using ammonia water after the reaction ends, and directly filtering to obtain 4,5-di(2-methoxyethoxy)-2-aminophenylacetonitrile; and 2, reacting 4,5-di(2-methoxyethoxy)-2-aminophenylacetonitrile with N,N-dimethylformamide dimethyl acetal to obtain a product, and directly reacting the product with m-aminophenylacetylene without purification to obtain erlotinib; and also comprises: carrying out re-crystallization purification treatment on crude erlotinib obtained in step 2 in order to obtain finished erlotinib with the single impurity content being smaller than 0.1%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a kind of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-aminoquinazoline ( Lotinib) and the synthetic method of its hydrochloride. Background technique [0002] Erlotinib was developed by Roche Pharmaceuticals, Switzerland, and is the first tyrosine kinase inhibitor that selectively acts on the epidermal growth factor receptor (EGFR). The drug was approved in the United States, Europe and my country in November 2004, September 2005 and April 2006 respectively. It is suitable for the second-line and third-line treatment of locally advanced or metastatic non-small-cell lung cancer (nonsmall-celllungcancer, NSCLC) that failed two or more chemotherapy regimens. A number of clinical studies have shown that it has definite curative effect, less toxic and side effects, can significantly improve the quality of life of patients, prolong the survival period, and has sh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 魏雪纹李强
Owner 海南卓泰制药有限公司
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