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A kind of preparation method of imatinib mesylate

A technology of imatinib mesylate and mesylate, applied in the field of preparation of imatinib mesylate, can solve the problems of inconvenient storage and use, unsuitability for industrialized production, danger of large-scale production, etc. Simple operation, safe reagents and high yield

Active Publication Date: 2019-07-19
NANJING YOKO PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantages of this method are: trimethylaluminum as an amide condensation agent is a chemical that is easily combustible, and it will react explosively and violently when it contacts with water, which brings potential danger to large-scale production. It is not suitable for industrial production, and the synthesis process uses expensive Palladium catalyst and BINAP ligand, produce isomerization impurity in product preparation process, purification is very difficult, and its route is as shown in the following formula:
The thionyl chloride used in this method is a fuming liquid with a strong pungent smell, which decomposes when it meets water, and is inconvenient to store and use

Method used

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  • A kind of preparation method of imatinib mesylate
  • A kind of preparation method of imatinib mesylate
  • A kind of preparation method of imatinib mesylate

Examples

Experimental program
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preparation example Construction

[0033] The preparation of embodiment 1 formula III compound

[0034] The formula II compound 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride (10.0g, 0.033mol) and tetrahydrofuran (100mL) were added in the reaction flask, and sodium carbonate (6.9 g, 0.065mol, 2equiv), stirred at 20-30°C for 30 minutes, then added N,N'-carbonyldiimidazole (5.3g, 0.033mol, 1equiv) in batches, stirred and reacted at 20-30°C for 2 hours to obtain the compound of formula III The mixed solution was directly used in the next reaction without separation.

Embodiment 2

[0035] The investigation of the influencing factors of the preparation of embodiment 2 formula V compound

[0036] a The effect of temperature on the reaction

[0037] In the mixed solution of the compound of formula III obtained in Example 1, add the compound of formula IV N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (9.4g, 0.033mol, 1 equiv), stirring at 45°C-50°C, monitoring the reaction progress with TLC, developing solvent: dichloromethane / methanol=25:1. After the reaction was completed, it was naturally cooled to room temperature, and water (200 mL) was slowly added to the reaction solution to quench the reaction, filtered, washed with water, and the solid was collected to obtain the crude compound of formula V.

[0038] Table 1 examines the influence of temperature on the reaction

[0039]

[0040] As can be seen from Table 1, temperature is a key factor for the synthesis of compound imatinib of formula V. When the reaction temperature is greater than...

Embodiment 3

[0049] The preparation of embodiment 3 formula V compound

[0050] In the mixed solution of the compound of formula III obtained in Example 1, add the compound of formula IV N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine (9.4g, 0.033mol, 1equiv) and imidazole hydrochloride (6.9g, 0.066mol, 2equiv), stirred and reacted at 15°C to 20°C for 1 hour, cooled naturally to room temperature, and slowly added water (200mL) to the reaction solution to quench the reaction , filter, wash with water, collect the solid to obtain the crude compound of formula V, add acetone (100mL) to reflux and stir to make a slurry, cool to room temperature and stir and crystallize for 2 hours, filter, wash the filter cake with acetone to obtain the compound I of formula V in the form of off-white solid powder Matinib (13.7 g, 84% yield, HPLC purity: 99.8%).

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Abstract

The invention discloses a preparation method of imatinib mesylate. The method specifically comprises steps as follows: 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride type compounds II are taken as a starting material, sodium carbonate and N, N'-carbonyl diimidazole are added, acyl imidazole with higher activity is obtained, separation is not required, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine type compounds IV and a catalyst imidazole hydrochloride are directly added, the mixture reacts, free alkali imatinib is obtained, methylsulfonic acid is added for salt formation, and imatinib mesylate in an alpha crystal form is obtained after recrystallization. The preparation method has the advantages of being mild in reaction condition, lower in cost, simple and convenient to operate, high in yield, good in reaction reproducibility, economical, environment-friendly and suitable for industrial production and producing fewer side reactions.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of imatinib mesylate. Background technique [0002] Imatinib mesylate was approved by the FDA in May 2001 for the treatment of chronic myeloid leukemia (CML), and in 2003 by the FDA for the treatment of gastrointestinal stromal tumors (GIST). The chemical name is 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino] Phenyl] benzamide mesylate, its molecular structural formula is as follows: [0003] [0004] CN1077713A discloses the synthetic method of imatinib: 3-nitrophenyl urea nitrate and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one ring closure reaction obtains N-(3 -Nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine, followed by hydrogenation reduction with palladium on carbon to give N-(3-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine, Then react with 4-(4-methylpiperazinemethyl)-benzoyl chloride to obtain...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
CPCC07B2200/13C07D401/04
Inventor 张峰车晓明朱素华薛峪泉
Owner NANJING YOKO PHARMA