Preparation method of alpha-crystal form imatinib mesylate

A technology of imatinib mesylate and crystal form, which is applied in the field of chemical drug synthesis, and can solve the problems of incomplete reaction, unsuitability for industrial production, and high production cost

Inactive Publication Date: 2013-04-24
NANJING CORE TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantage of this method is that the yield of the cyclization reaction to generate the pyrimidine ring is very low, the reaction time is long and the reaction is not complete
[0009] Chinese patent CN1630648A discloses a method for preparing imatinib. The amide condensing agent trimethylaluminum used in the preparation process is a spontaneously combustible chemical, which is potentially dangerous in large-scale production and is not suitable for

Method used

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  • Preparation method of alpha-crystal form imatinib mesylate
  • Preparation method of alpha-crystal form imatinib mesylate
  • Preparation method of alpha-crystal form imatinib mesylate

Examples

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Embodiment

[0031] Example Preparation of α crystal form imatinib mesylate

[0032] (1) Synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoyl chloride (formula (Ⅲ))

[0033] In a 1000mL four-necked round-bottomed flask, install a mechanical stirrer, a reflux condenser, and a thermometer, add 200mL of toluene to the round-bottomed flask, start stirring, add 50g of imatic acid (4-[(4-methylpiperazine-1 -yl)methyl]benzoic acid dihydrochloride), slowly add 25 mL of thionyl chloride under stirring, heat up to 80-90°C, keep stirring for 4 hours, turn off the heating and naturally cool down to room temperature, concentrate in vacuo to obtain oily thing. used directly in the next step.

[0034] (2) 4-(4-methyl-1-piperazine)methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimidineaminophenyl-aniline (formula (IV)) Synthesis

[0035] In a 1000mL three-necked flask, add 37g of imaamine (N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine), add 150mL of pyridine and 35ml of triethylamine, Add drop...

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Abstract

The invention discloses a preparation method of alpha-crystal form imatinib mesylate. The preparation method comprises the following steps that 1, 4-[(4-methyl piperazine-1-yl)methyl]benzoic acid dihydrochloride shown in the formula II is converted into an acyl chloride shown in the formula III by an acylating chlorination reagent; 2, the acyl chloride shown in the formula III and N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidin undergo a condensation reaction in the presence of an alkali to produce a compound shown in the formula IV; and 3, the compound shown in the formula IV and methylsulfonic acid undergo a salt forming reaction in the presence of an organic solvent to produce a compound shown in the formula I. The preparation method can realize preparation of stable alpha-crystal form imatinib mesylate and allows mild process conditions. The stable alpha-crystal form imatinib mesylate can be after-treated simply and has high purity. The preparation method has a low reaction cost and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis and relates to α crystal form 4-(4-methyl-1-piperazine)methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimidineamino Process for the preparation of phenyl-aniline mesylate (imatinib mesylate). Background technique [0002] Imatinib Mesylate, the chemical name is 4-(4-methyl-1-piperazine)methyl-N-4-methyl-3-4-(3-pyridine)-2- Pyrimidine aminophenyl-aniline mesylate compound, the structural formula is as follows: [0003] [0004] Imatinib mesylate, developed by Novartis, Switzerland, is a derivative of aniline and is a specific tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib mesylate can inhibit Bcr-Abl tyrosine kinase at the cellular level in vivo and in vitro, and can selectively inhibit Bcr-Abl positive cell line cells, chronic myelogenous leukemia and acute lymphoblastic leukemia with PH chromosome positive Pr...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 王雪根何凌云郭莉芹周磊吴邵嘉卢向阳赵国新
Owner NANJING CORE TECH CO LTD
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