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Method for preparing gefitinib intermediate

A technology of hydroxypropoxyl and methoxyquinazoline, which is applied in the field of gefitinib intermediates and its preparation, can solve the problems of reduced purity and quality of final products, reduced product purity, etc., to reduce the generation of by-products, The effect of improving product quality and reducing production costs

Active Publication Date: 2013-02-06
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The purity of the product is reduced; in the cyclization reaction for preparing compound 4, it is also easier to form by-products due to the presence of chlorinated groups
In short, due to the presence of chlorinated groups in this route, by-products will be generated in multiple steps, which will reduce the purity and quality of the final product. After review of the preparation process in this patent, the product purity is only about 90%.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of methyl 5-(3-hydroxypropoxy)-4-methoxy-2-nitrobenzoate

[0042] Put 50 g of 5-hydroxy-4-methoxy-2-nitrobenzoic acid methyl ester and 500 ml of acetonitrile into a 1000 ml four-necked flask, stir to dissolve, then put in 87.5 g of potassium carbonate, and raise the temperature. A mixture of 61 g of 3-bromo-1-propanol and 200 ml of acetonitrile was added dropwise at 75°C for about 1 hour. After dripping, heat and reflux for three hours until the reaction is complete. After the reaction is complete, filter at high temperature, concentrate the mother liquor under reduced pressure, and stop at 90°C. After steaming, add 400ml ethyl acetate and 250ml salt water to wash three times. Dry and decolorize for half an hour and filter. The mother liquor was concentrated to dryness under reduced pressure, and a light blue solid was precipitated. The concentration was stopped, 50 ml of ethyl acetate was added, and the temperature was raised. Reflux to dissolve...

Embodiment 2

[0043] Example 2: Preparation of methyl 5-(3-hydroxypropoxy)-4-methoxy-2-nitrobenzoate

[0044] Put 50g of 5-hydroxy-4-methoxy-2-nitrobenzoic acid methyl ester and 500ml of acetonitrile into a 1000ml four-necked flask, stir to dissolve, then add 87.5g of potassium carbonate and raise the temperature. A mixture of 61 g of 3-chloro-1-propanol and 200 ml of acetonitrile was added dropwise at 75°C for about 30 minutes. After dripping, heat and reflux for 5 hours until the reaction is complete. After the reaction is complete, filter at high temperature, concentrate the mother liquor under reduced pressure, and stop at 90°C. After steaming, add 400ml ethyl acetate and 250ml salt water to wash three times. Dry and decolorize for half an hour and filter. The mother liquor was concentrated to dryness under reduced pressure, and a solid was precipitated, 50 ml of ethyl acetate was added, and the temperature was raised. Reflux to dissolve, cool down slightly, add 100ml n-hexane dropwise...

Embodiment 3

[0045] Example 3: Preparation of methyl 2-amino-5-(3-hydroxypropoxy)-4-methoxybenzoate

[0046] Put 62g of 5-(3-hydroxypropoxy)-4-methoxy-2-nitrobenzoic acid methyl ester and 1000ml of ethyl acetate into a 2000ml autoclave, stir and dissolve it, then add 5.2g of palladium on carbon, Replace with hydrogen several times, set temperature at 30°C, pressure at 0.8MPa, and stir for 12 hours. After stirring, tap the plate until the reaction is complete, and pump the reaction solution into a 1000ml four-neck flask, where a solid precipitates. Reheat to 65°C for 10 minutes, and filter. The mother liquor was concentrated under reduced pressure. When the volume of about 300ml remained, the concentration was stopped, and the temperature was raised again to reflux, but the solution was still unclear, and the temperature was lowered. Suction filtration at room temperature, 200ml n-heptane leaching to obtain 39g of wet product, drying at 65℃ to obtain 37.3g of dry product of methyl 2-amino-5-...

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PUM

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Abstract

The invention relates to a method for preparing a gefitinib intermediate, in particular to a method for preparing 4-chlorine-6-(3-chlorine propoxy)-7-methoxy quinazoline. A formula II compound 6-(3-hydroxy propoxy)-7-methoxy quinazoline-4 (3H)-ketone and thionyl chloride are reacted to obtain the gefitinib intermediate. The formula II compound uses 5-hydroxy-4-methoxy group-2-nitrobenzene methyl formate as a raw material to be condensed with halohydrin shown in a formula VI, nitro is reduced, and formamidine acetate cyclization and thionyl chloride chlorination are reacted to obtain the gefitinib intermediate. The synthesis scheme provided by the invention reduces the generation of by-products by introduction of hydroxyl, the production cost is reduced, meanwhile, the environment pollution is reduced, the quality of products is increased, and the purity of the prepared 4-chlorine-6-(3-chlorine propoxy)-7-methoxy quinazoline is over 98 percent. Compared with the prior art, the method is greatly increased and improved, wherein, X is halogen.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a gefitinib intermediate and a preparation method thereof. Background technique [0002] 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline, English name 4-chloro-6-(3-chloropropoxy)-7-methoxy-quinazoline, CAS number 692059-41- 9, is an important intermediate for the preparation of gefitinib, the structure is shown in the following formula I, [0003] . [0004] Gefitinib, English name gefitinib, chemical name N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-propoxy)quinazoline- 4-Amine is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It competes for the Mg-ATP binding site on the catalytic region of EGFR-TK, blocks its signal transmission and inhibits mitogen-activated protein The activation of kinases promotes cell apoptosis and inhibits tumor angiogenesis. It is suitable for the treatment of locally advanced or metastat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/86C07D239/88
CPCC07D239/88C07D239/86
Inventor 徐建康赵宗敏吴昊蒋志强李桂民
Owner 浙江瑞博制药有限公司
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