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Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline
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A technology of fluorophenylamine group and morpholine propoxy group, which is applied in the field of preparation of 4--7-methoxy-6-quinazoline, can solve problems such as high price and reduce reaction steps and reaction routes concise effect
Inactive Publication Date: 2007-02-14
江苏吴中苏药医药开发有限责任公司
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Although this method overcomes the shortcomings of using a large amount of methanesulfonic acid and L-methionine demethylation in the original route, the price of the starting material 3-hydroxyl-4-methoxybenzaldehyde is expensive, which is the 3,4 used in the original route. - More than 20 times that of dimethoxybenzaldehyde
[0011] (Chinese Journal of Medicinal Chemistry, 2005, 15 (1): 39-41) although the method reported by Yuan Li of Shenyang Pharmaceutical University is slightly different from that of J.P. Gildai et al., the starting material used is 3-Hydroxy-4-methoxybenzoic acid methyl ester, its deficiency is similar to the method of J.P. Gilday et al.
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Embodiment 1
[0027] Embodiment 1,3, the preparation of 4-dimethoxy-6-nitrobenzoic acid (III):
[0028] Add 182g of 3,4-dimethoxybenzoic acid (II) to 1000mL of concentrated nitric acid (d, 1.42) at 0-5°C in portions within 1 hour. In crushed ice, the yellow solid was filtered, washed with water, and recrystallized from ethanol to obtain 185 g of yellow needle crystals, mp 190-1°C, yield 81.5%.
Embodiment 2
[0029] Embodiment 2, the preparation of 3-hydroxyl-4-methoxy-6-aminobenzoic acid (V):
[0030]Add 185g of 3,4-dimethoxy-6-nitrobenzoic acid (III) to 1250mL of 10% potassium hydroxide aqueous solution, heat and stir at 20-100°C for 2-4 hours, then, within 1 hour Add 460g of sodium hydrochloride in portions, keep the reaction at 40-70°C for 1 hour, acidify with concentrated hydrochloric acid under ice bath cooling, separate the white precipitate, and crystallize with dilute ethanol to obtain 3-hydroxy-4-methoxy-6-aminobenzoic acid (V), colorless needle crystals, 122.5g, mp214~5°C, yield 82%.
Embodiment 3
[0031] Embodiment 3, the preparation of 6-hydroxyl-7-methoxy-3,4-dihydroquinazolin-4-one (VI)
[0032] 122.5g of 3-hydroxy-4-methoxy-6-aminobenzoic acid (V), mixed with 380mL of formamide, heated to 60-210°C, stirred for 12 hours, cooled, poured into ice water, filtered, After washing with water, 116.7 g of needle crystals of 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (VI) were obtained, mp>200°C, yield 90.8%.
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Abstract
The invention relates to a preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline, which comprises using 3,4-dimethoxybenzoic acid (II) as raw material, synthesizing 2-amido-4-methoxy-5-hydroxybenzoic acid (V), cyclizing to obtain 6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (VI), directly chloridizing to obtain 4-chloro-hydroxy-7-methoxy-quinazoline (VII), reacting directly with 3-chloro-4-fluoroaniline, carrying out amination to obtain 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxy-quinazoline (VIII), finally reacting with morpholinyl chloropropane to obtain Geftinat (I).
Description
technical field [0001] The present invention relates to the preparation method of 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline (gefitinib, I) . Background technique [0002] 4-(3-Chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline (gefitinib) (structural formula I, trade name: Yi Ressa, Iressa) is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, and is currently clinically used for the treatment of non-small cell lung cancer. [0003] [0004] The synthetic route (WO9633980, CN96193526) reported by K H Gibson of Zenica Co., Ltd. is as follows: [0005] [0006] This route uses 6,7-dimethoxy-3,4-dihydroquinazolin-4-one as raw material, and selectively demethylates with methanesulfonic acid and L-methionine to obtain 6-hydroxy-7-methionine Oxy-3,4-dihydroquinazolin-4-one, followed by acetylation to protect the 6-hydroxyl group, chlorination, amination of 3-chloro-4-fluoroaniline, ...
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