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Method for synthesizing gefitinib and intermediate thereof

A synthesis method and technology of gefitinib are applied in the field of synthesis of quinazoline derivatives, can solve problems such as amplification and influence on reaction scale, and achieve the effects of shortening reaction route, improving reaction yield and overcoming dangerous raw materials

Inactive Publication Date: 2014-01-22
TIANJIN PHARMACN MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] According to the reference document 1, when using 3-hydroxy-4 methoxybenzaldehyde or 3-hydroxy-4 methoxybenzoic acid ester and other low-cost raw material starting reactants to synthesize gefitinib, Both need to undergo nitrification reduction reaction, and this step has a greater risk in large-scale production, which affects the enlargement of the reaction scale

Method used

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  • Method for synthesizing gefitinib and intermediate thereof
  • Method for synthesizing gefitinib and intermediate thereof
  • Method for synthesizing gefitinib and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 (divided into Examples 1-1 to 1-12 according to different reaction conditions)

[0032] experimental method

[0033] Put compound 5 and formamidine acetate as reactants into a polar aprotic solvent, add L-proline and Cu(I) salt, and heat to the reaction temperature under the protection of nitrogen until the reaction is complete. Ethyl acetate was added and the layers were washed with water. The organic phase was collected, filtered, concentrated under reduced pressure, and the crude product was refined to obtain compound 5.

[0034] Compound 5 was prepared from compound 4. The dosage of compound 4 in each group was uniformly 10 mmol. Formamidine acetate was used for formamidine salt, and CuI was used for Cu(I) salt.

[0035] Example number

1-1

1-2

1-3

1-4

1-5

1-6

Dosage of formamidine acetate / mmol

15

15

15

15

15

15

L-proline dosage / mmol

2

2

2

2

2

2

CuI / mmol ...

Embodiment 2

[0038] Embodiment 2: the preparation of compound 2

[0039] The formula is as follows (compound 1 is 3-hydroxy-4-methoxybenzoic acid):

[0040] Material name

Feeding amount

Compound 1

10gram

Methanol

100mL

[0041] concentrated sulfuric acid

20mL

[0042] operation process

[0043] Add compound 1 and methanol into the reaction flask, stir at room temperature, add concentrated sulfuric acid dropwise, and heat to reflux. After the reaction is complete, cool the solution to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, concentrate to remove methanol, filter and wash with water to obtain Compound 2 (methyl 3-hydroxy-4-methoxybenzoate).

Embodiment 3

[0044] Embodiment 3: the preparation of compound 3,

[0045] The ratio is as follows:

[0046] Material name

[0047] Add the compound 2 and acetone obtained according to the method of Example 2 into the reaction flask, stir at room temperature, NBS in batches, and heat to reflux. After the reaction is completed for about 1 hour, cool the solution to room temperature, add saturated aqueous sodium bicarbonate solution, and concentrate Acetone was removed, and compound 3 was obtained by filtering and washing with water.

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PUM

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Abstract

The invention provides a method for synthesizing gefitinib and an intermediate thereof. The method comprises the following steps: a compound 4 serving as a raw material is subjected to quinazoline annulations (iv) with carboxamidine or salt thereof in a polar aprotic solvent under catalysis of Cu(I) salt, L-proline and alkali to synthesize a compound 5; the compound 5 and 3-hydroxy-4-methoxybenzoic acid serving as initial raw materials are subjected to esterification, bromination, condensation, quinazoline annulation, substitution and other steps to prepare gefitinib.

Description

field of invention [0001] The invention relates to a synthesis method of quinazoline derivatives. Background technique [0002] Gefitinib, the English name is Gefitinib. The chemical name is N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-propoxy)quinazolin-4-amine, and the English chemical name is N -(3-Chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine; CAS No. 184475-35-2; Molecular formula C 22 h 24 ClFN 4 o 3 , with a molecular weight of 446.90. The chemical structural formula is as follows: [0003] [0004] Gefitinib is suitable for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) who have previously received chemotherapy or are not suitable for chemotherapy. The existing synthetic methods of gefitinib are mainly as described in reference document 1 - Chinese literature "Research progress on the synthesis of gefitinib" (Sun Weimin et al., Fine and Specialty Chemicals, May 2011; 40-41). I...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCC07D239/90C07D239/94
Inventor 何磊田东奎李国伟袁素霞尚虹
Owner TIANJIN PHARMACN MEDICAL TECH
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