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Mefatinib composition, related compound, and preparation method and application of Mefatinib composition

A composition and compound technology, applied in the directions of organic chemistry methods, drug combinations, carboxylate preparation, etc., can solve the problems of compound 1 that cannot be completely converted, difficult to cure, and has many impurities

Active Publication Date: 2018-11-23
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, compound 1 cannot be completely converted, the purity of the crude product is less than 70%, and there are many impurities, and the product-related substances are complicated. The crude product of free base of meiwatinib is oily and difficult to solidify. It must be purified by column chromatography, and the batch yield is low. , only suitable for scales of 10g level
Overall, the method has low yield, difficult purification, high cost and low batch yield
Therefore, this synthesis process and the resulting product are not suitable for industrial applications

Method used

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  • Mefatinib composition, related compound, and preparation method and application of Mefatinib composition
  • Mefatinib composition, related compound, and preparation method and application of Mefatinib composition
  • Mefatinib composition, related compound, and preparation method and application of Mefatinib composition

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The preparation of embodiment 1 meihuatinib composition

[0063] 1. Salt forming step

[0064] Add 479.7g of ethyl acetate and 812.6g of purified water into the reaction kettle, raise the temperature to about 50°C, then add 406.3g of A10 into the reaction kettle, stir to dissolve them all; add 203.1g of maleic acid to 1145.5g of acetic acid Add the ethyl acetate solution of maleic acid to the reaction kettle dropwise at 50°C, continue to stir for 1 hour after the dropwise addition, cool down naturally, stir and crystallize through liquid crystallization, filter, filter The cake was washed with 3.44Kg of ethyl acetate and dried under vacuum at 35°C to obtain the crude product of mevatinib.

[0065] 2. Recrystallization step

[0066] Add 10.51Kg of ethyl acetate and 1.05Kg of water into a 10L reaction kettle, raise the temperature to 50°C, add 525.7g of the above-prepared crude mevatinib, stir until fully dissolved and then lower to room temperature. Add 3.0 g meivatin...

Embodiment 2

[0069] Embodiment 2 Salt formation, crystallization condition

[0070] Referring to the salt-forming method in Example 1, the mass ratio of fixed ethyl acetate to water is about 10:1, and the amount of materials input and the results are shown in the table below.

[0071]

[0072] The results show that the amount of water added has a greater impact on the purity of the product and the content of the residual formula (II) compound in the product. Adding a lot of water is conducive to the promotion of product purity and the reduction of the content of the compound of formula (II), but if the amount of water added is too large, the compound of formula (II) will increase instead. In addition, the amount of water added also has an impact on the yield of the product, but the test found that stirring overnight can ensure that the yield is above 90%.

[0073] Referring to the recrystallization method of Example 1, the ratio of the crude product of meiwatinib, ethyl acetate and wat...

Embodiment 3

[0079] Synthesis of embodiment 3 formula (II) compound (cis isomer)

[0080]

[0081] The first step: the synthesis of 4-(dimethylamino)-2-yne butanoic acid

[0082] (At -78°C, n-butyllithium hexane solution (2.5M, 33.4mmol, 13.4ml) was slowly added dropwise to 1-dimethylamine-2-propyne (33.4mmol, 3.6ml, 2.78g) in dry tetrahydrofuran (15ml) solution. The resulting mixture was stirred at -78°C for 1 hour, crushed dry ice (335mmol, 11.72g) was added in one go, and stirred for 15 minutes. The reaction solution was poured into 300ml of water and washed with 100ml of ethyl acetate After washing three times, the aqueous phase was concentrated under reduced pressure. The resulting residue was dissolved in methanol, filtered to remove insoluble salts, and the filtrate was concentrated under reduced pressure to obtain 6.05 g of crude 4-(dimethylamino)-2-ynebutyric acid containing a large amount of inorganic salts.

[0083] MS (ESI) m / z = 128.2 [M+1].

[0084] The second step: the sy...

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Abstract

The invention discloses a Mefatinib composition, a related compound, and a preparation method and application of the Mefatinib composition. The Mefatinib composition comprises Mefatinib disclosed in aformula (I) and compound, wherein the normalized percentage content of the compound is 1.0% or lower, and the compound is disclosed by a formula (II) which is not zero. The Mefatinib composition canbe used for treating or preventing various adaptation diseases related to EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor-2) kinase functions, and a toxic reaction occurrence rate is low. The compound disclosed by the formula (II) can be used as the standard substance of relevant substances in the Mefatinib, and is used for the quality control of Mefatinibraw material drugs or preparations. The formula (I) and the formula (II) are shown in the description.

Description

technical field [0001] The present invention relates to mivatinib composition, related compounds, preparation method and application thereof. Background technique [0002] Mefatinib, its chemical name is: 2-butenalamino, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-difluoromethyloxy]- 6-Quinazolinyl]-4-(dimethylamino)-(2E)-dimaleate; molecular formula: C 21 h 19 CIF 3 N 5 o 2 .2C 4 h 4 o 4 ; Molecular weight: 698.0, the structural formula is as follows: [0003] [0004] Patent document CN102838550A discloses the quinazoline crotyl compound (maiwatinib free base) represented by the following formula, [0005] [0006] The compound is proved to be an ideal high-efficiency dual irreversible tyrosine kinase inhibitor, which can inhibit the activity and phosphorylation of the kinase by acting on the intracellular part of EGFR to compete with ATP, and block the EGFR tyrosine kinase ATP Binding site to achieve the purpose of specific inhibition of EGFR. The compound ca...

Claims

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Application Information

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IPC IPC(8): A61K31/517C07D239/94C07C57/145C07C51/41A61P35/00
CPCA61K31/517A61P35/00C07B2200/13C07D239/94
Inventor 吕裕斌黄雪惠金燕芬殷建明李邦良
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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