Preparation method of high-purity crystal

A technology of crystallization and concentration, applied in the field of preparation of high-purity crystallization, can solve problems such as unfavorable commercial production, cumbersome operation, generation of genotoxic impurities, etc., to avoid genotoxic impurities, simple operation, and reduce impurity A and impurity B. produced effect

Pending Publication Date: 2022-02-01
2Y CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] Due to the shortcomings of the above three methods, which are too cumbersome to operate, potentiall

Method used

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  • Preparation method of high-purity crystal
  • Preparation method of high-purity crystal
  • Preparation method of high-purity crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: the preparation of lenvatinib mesylate crude product

[0053]

[0054] Add lenvatinib free base (1 g, 2.34 mmol) to N,N-dimethylformamide (10 mL), and heat to 90° C. to dissolve. After cooling to -20°C, a solution of methanesulfonic acid (0.23 g, 2.34 mmol) in methyl tert-butyl ether (10 mL) was added dropwise. After the addition, keep stirring for 2 hours. Filtration, the filter cake was washed with methyl tert-butyl ether, dried to obtain lenvatinib mesylate crude product (1.16g), the yield was 94.6%, the purity was 99.8%, impurity A: 0.08%, impurity B: 0.05 %.

[0055] H-NMR (600MHz, DMSO-d6): δMSO-(d, 1H), 8.73(s, 1H), 8.38(d, 1H), 8.09(s, 1H), 7.96(d, 2H), 7.66(s ,1H), 7.65(d,1H), 7.37(dd,1H), 7.27(m,1H), 6.96(d,1H), 4.09(s,3H), 2.69(m,1H), 2.36(s, 3H), 0.68 (m, 2H), 0.44 (s, 2H).

Embodiment 2

[0056] Embodiment 2: the preparation of lenvatinib mesylate crude product

[0057] Add lenvatinib (1 g, 2.34 mmol) into dimethyl sulfoxide (10 mL), and heat to 70° C. to dissolve. After cooling to 20°C, a solution of methanesulfonic acid (0.21 g, 2.22 mmol) in ethyl acetate (10 mL) was added dropwise. After the addition, keep stirring for 2 hours. After filtering, the filter cake was washed with ethyl acetate and dried to obtain lenvatinib mesylate crude product (1.10 g), with a yield of 90.1%, a purity of 99.9%, impurity A: 0.05%, and impurity B: 0.05%.

Embodiment 3

[0058] Embodiment 3: the preparation of lenvatinib mesylate crude product

[0059] Add lenvatinib (1 g, 2.34 mmol) into N-methylpyrrolidone (10 mL), and heat to 80° C. to dissolve. After cooling to 0°C, a solution of methanesulfonic acid (0.21 g, 2.22 mmol) in n-butyl acetate (10 mL) was added dropwise. After the addition, keep stirring for 2 hours. After filtering, the filter cake was washed with ethyl acetate and dried to obtain the crude product of lenvatinib mesylate (1.14 g), with a yield of 93.0%, a purity of 99.8%, impurity A: 0.05%, and impurity B: 0.04%.

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Abstract

The invention provides a preparation method of a high-purity crystal, and particularly relates to a preparation method of a mesylate lenvatinib crystal C. The preparation method comprises the following steps: 1) dissolving a lenvatinib free alkali in a good solvent to obtain a solution of the lenvatinib free alkali; 2) clarifying and filtering the solution obtained in the step 1), adding methanesulfonic acid and a poor solvent I or a solution of methanesulfonic acid in the poor solvent I, and carrying out a salt forming reaction to obtain a crude product of the mesylate lenvatinib; 3) putting the obtained crude product of the mesylate into a poor solvent II, and pulping to obtain a mesylate crystal C. The purity of the obtained mesylate crystal C is not lower than 99.5%, the purity of any single impurity is not higher than 0.10%, and the total impurity is not higher than 0.5%. The purity of the lenvatinib mesylate crystal C prepared by the preparation method of the lenvatinib mesylate crystal C is higher, wherein, the contents of an impurity A and an impurity B in the lenvatinib mesylate crystal C are greatly reduced.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of high-purity crystals. Background technique [0002] Lenvatinib mesylate, the Chinese chemical name is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline carboxamide methanesulfonate , the English chemical name is: 4-(3-Chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamid e Mesylate, the trade name is Lenvanix, and its structure is as follows: [0003] [0004] Lenvatinib mesylate is a receptor tyrosine kinase (RTK) inhibitor that inhibits VEGFR1, VEGFR2, and VEGFR3. Lenvatinib mesylate (Lenvatinib) can also inhibit other RTKs associated with pathological neovascularization, tumor growth and cancer progression, including fibroblast growth factor (FGF) receptors FGFR1,2,3,4; platelet derivation Growth factor receptor alpha (PDGFRα), KIT and RET. Lenvatinib combined with everolimus (everolimus) can inc...

Claims

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Application Information

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IPC IPC(8): C07D215/48C07C309/04C07C303/32C07C303/44
CPCC07D215/48C07C309/04C07C303/32C07C303/44C07B2200/13
Inventor 何训贵袁明勇张恒彬周岩锋王元
Owner 2Y CHEM
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