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Preparation method of high-yield afatinib maleate

A technology of afatinib maleate and afatinib, which is applied in the field of preparation of afatinib maleate with high yield, can solve the problems of unavailable and expensive starting materials, etc., and achieve the reduction of degradation impurities The production of safe reagents and the effect of lowering the reaction temperature

Pending Publication Date: 2022-04-12
XIAN XINTONG PHARM RES CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] This route has short steps and high yield, but the starting materials are expensive and not easy to obtain

Method used

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  • Preparation method of high-yield afatinib maleate
  • Preparation method of high-yield afatinib maleate
  • Preparation method of high-yield afatinib maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: preparation P-[2-[[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxygen Diethyl-6-quinazolinyl]amino]-2-oxoethyl]phosphonic acid diethyl ester

[0029] Add 64ml of tetrahydrofuran and 18g of N,N-carbonyl-diimidazole into the reaction flask, stir evenly, control the temperature at 10-40°C, add 22g of diethylphosphonoacetic acid in tetrahydrofuran (32ml) dropwise, and control the temperature at 35-45°C for 0.5 ~2h, an orange-red clear solution was obtained.

[0030] 128ml tetrahydrofuran and 32g N-4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine Add to the reaction bottle, heat up to 30-40°C, stir to dissolve completely, add to the above solution, control the temperature at 30-40°C and react for 1.5-2.5h.

[0031] After the reaction is completed, cool down to a system temperature of 10-20° C., filter, and wash the filter cake with 128 ml of methyl tert-butyl ether, 160 ml of pure water, and 32 ml of met...

Embodiment 2

[0032] Embodiment 2: Preparation of Afatinib

[0033] Preparation of dimethylamino acetal solution: Add 19ml of pure water and 24ml of concentrated hydrochloric acid to the reaction bottle, stir, control the temperature at 0-30°C, add 24g of dimethylamino acetal dropwise, after the dropwise addition, control the temperature for 25 React at ~35°C for 15-20 hours to obtain an orange-red solution, cool in an ice-water bath to 0-20°C, and set aside.

[0034] Preparation of KOH aqueous solution: Add 130ml of pure water and 26g of KOH to a beaker, stir at a temperature of 0-30°C, dissolve completely, freeze to obtain a transparent aqueous solution of 0-20°C, and set aside.

[0035] Into the reaction bottle, add 130ml tetrahydrofuran, 32g intermediate I, 32g anhydrous lithium chloride, stir evenly, the system becomes a white turbid liquid, control the temperature at -20~5°C, add KOH aqueous solution dropwise, and the dropwise addition is completed. Control the temperature at -20~-5°...

Embodiment 3

[0038] Embodiment 3: Refining of Afatinib

[0039] The first refinement of the crude product: add 220ml of ethyl acetate and 25g of crude afatinib to the reaction bottle, stir, heat up to 55-60°C, after dissolving, add 1.5g of activated carbon, control the temperature at 55-60°C and stir for 0.5- 1h, filter with suction, rinse the filter cake with 26ml of ethyl acetate at 40-60°C, transfer the filtrate to a reaction flask, add 220ml of n-heptane dropwise at a temperature of 55-60°C, drop the temperature to 0-20 ℃, a solid precipitated, stirred for 1-2 hours, filtered, the filter cake was rinsed with n-heptane (22 mL), and the off-white color was filtered and dried to obtain 19.8 g of a refined product with a yield of 90% and a purity of 99%.

[0040] The second refinement of the crude product: add 190ml of ethyl acetate and 19g of afatinib primary refined product to the reaction bottle, stir, raise the temperature to 55-60°C to dissolve it, and add 190mL of n-heptyl dropwise a...

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Abstract

The invention discloses a preparation method of afatinib maleate with high yield, which is realized by the following steps: N-4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl] oxy]-4, 6-quinazoline diamine is used as a starting material, and the afatinib maleate is synthesized by two steps. The afatinib maleate bulk drug meeting the drug quality requirement is finally synthesized through two-step refining and salifying. The route reaction is simple, dangerous articles are not involved, conditions are mild and easy to control, the yield of each step is high, the purification method does not involve column chromatography and other methods which are difficult to operate industrially, the process is stable, raw materials are easy to obtain, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular, the invention relates to a preparation method of afatinib maleate with high yield. Background technique [0002] Afatinib maleate, chemical name: N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxy] -6-quinazolinyl]-4-(dimethylamino)-(2E)-butenamide, bis-Z-butenedioate, molecular formula: C 24 h 25 ClFN 5 o 3 2C 4 h 4 o 4 , molecular weight: 718.08 (wherein free base: 485.94), its chemical structural formula is as follows: [0003] [0004] Afatinib is an irreversible EGFR-HER2 dual tyrosine kinase receptor inhibitor. It is used for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC). For metastatic non-small cell lung cancer (NSCLC) patients with tumor epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation. [0005] On July 12, 2013, the U.S. Food and Drug Adm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07C51/41C07C57/145
Inventor 吴小翠郭维博侯晓辉温秀红郭芳
Owner XIAN XINTONG PHARM RES CO LTD
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