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Synthesis intermediate of erlotinib and preparation method thereof

A form and compound technology, applied in the field of pharmaceuticals, can solve problems such as high cost of raw materials, large pollution, troublesome product purification and post-processing

Active Publication Date: 2012-07-11
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When 3,4-dihydroxybenzaldehyde reacts with hydroxylamine hydrochloride, two cis-trans isomers will be produced. It is difficult to convert both cis-trans isomers into cyano groups, and the reaction yield is low
[0016] It can be seen that the existing synthetic technology of erlotinib hydrochloride has the disadvantages of high raw material cost, complex reaction operation, difficult control of by-products, troublesome product purification and post-treatment, and large pollution.

Method used

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  • Synthesis intermediate of erlotinib and preparation method thereof
  • Synthesis intermediate of erlotinib and preparation method thereof
  • Synthesis intermediate of erlotinib and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 Synthesis of 4-bis-(2-methoxyethoxy)-benzaldehyde (II)

[0051]

[0052] Put 25g of 3,4-dihydroxybenzaldehyde, 60ml of 2-bromoethyl methyl ether, 120ml of dimethylformamide (DMF) and 60g of potassium carbonate into a 500ml reaction flask, and react at 100°C 3-4 hours. After the completion of the reaction as detected by TLC, the DMF was evaporated under reduced pressure, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and dichloromethane was evaporated to obtain 45 g of brown oil with a yield of 97.8%.

[0053] 1 H NMR (400MHz, CDCl 3 )δ: 9.84(s, 1H), 7.43~7.46(m, 2H), 7.00(d, J=8.1Hz, 1H), 4.21~4.25(m, 4H), 3.79~3.83(m, 4H), 3.47 (s, 6H)

Embodiment 2

[0054] Example 2 Synthesis of 2-nitro-4,5-bis-(2-methoxyethoxy)-benzaldehyde (Ⅲ)

[0055]

[0056] 45g of compound II was dissolved in 250ml of glacial acetic acid, the temperature was controlled at 0-10°C, and 94ml of nitric acid was slowly added dropwise at this temperature. After the dropwise addition was completed, it was raised to room temperature and stirred for 12 hours. The next day, the reaction solution was poured into ice water, and ammonia water was slowly added dropwise to adjust the pH of the system to 7-8, filtered, and dried to obtain 38 g of a light yellow solid. The yield was 71.8%.

[0057] 1 HNMR (CDCl 3 , 400MHz) δ: 10.43(s, 1H), 7.67(s, 1H), 7.43(s, 1H), 4.29~4.32(m, 4H), 3.82~3.85(m, 4H), 3.46(s, 6H)

Embodiment 3

[0058] Example 3 Synthesis of 2-nitro-4,5-bis(2-methoxyethoxy)-benzoic acid (Ⅳ)

[0059]

[0060] Dissolve 30g of compound III in 180ml of methanol, add 0.5ml of 30% methanolic sodium hydroxide solution, heat to 45°C, slowly add 60ml of 35% hydrogen peroxide dropwise, and complete the dropwise addition in 3-4 hours, keeping the pH of the solution at 10.5- 11.5, TLC detected that the reaction was complete, poured the reaction solution into ice water, extracted three times with dichloromethane, combined the dichloromethane layers, dried, and concentrated to obtain 24 g of a brownish-red oil with a yield of 75.9%.

[0061] 1 HNMR (MDSO-d, 400MHz) δ: 13.60(brs, 1H), 7.59(s, 1H), 7.31(s, 1H), 4.24~4.27(m, 4H), 3.67-3~69(m, 4H) , 3.31(s, 6H)

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Abstract

The invention relates to a process of a chemical synthesis medicament, in particular to a novel synthesis process of erlotinib hydrochloride serving as an antitumor medicament, and a novel intermediate. The process has the advantages of low-price and readily-available raw materials, mild conditions in a reacting process, no device with special requirements and suitability for industrial production.

Description

technical field [0001] The present invention relates to the pharmaceutical field, more specifically, the present invention relates to a kind of N-(3-ethynylphenyl)-[6,7-bis(2-methoxyethoxy)]quinazolin-4-amine Preparation method of hydrochloride (erlotinib hydrochloride) and related intermediates. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride) is a tyrosinase inhibitor developed by OSI Pharmaceuticals in the United States. It is currently clinically used for the treatment of non-small cell lung cancer. Its chemical name is: N-(3-ethynylphenyl)-[6,7-bis(2-methoxyethoxy)]quinazolin-4-amine hydrochloride. Chemical structure is as shown in formula I: [0003] [0004] The synthetic route of erlotinib hydrochloride is mainly the U.S. Patent US5747498A reported by Pfizer, and its synthetic route is as follows: [0005] [0006] ①Bromoethyl methyl ether ②Potassium nitrate ③Pd / C ④Formamide ⑤Phosphorus oxychloride ⑥M-aminophenylacetylene ⑦HCl ...

Claims

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Application Information

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IPC IPC(8): C07C229/64C07C227/04C07C205/59C07C205/44C07C201/12C07C201/08C07D239/94A61K31/517A61P35/00
Inventor 颜军朱国荣叶德柳志炜
Owner ZHEJIANG HISUN PHARMA CO LTD
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