Synthesis method of panobinostat key intermediate

A synthetic method, panobinostat technology, applied in the field of drug synthesis, can solve the problems of low purity and yield of intermediates, difficulty in quality control of panobinostat raw materials, etc.

Inactive Publication Date: 2018-06-01
南京众慧网络科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] However, the purity and yield of this intermediate are not always high, which becomes an obstacle to the preparat

Method used

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  • Synthesis method of panobinostat key intermediate
  • Synthesis method of panobinostat key intermediate
  • Synthesis method of panobinostat key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 (E)-3-[4-[[[2-(2-Methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]methyl acrylate hydrochloride preparation

[0023] Weigh 5.0g 2-methyltryptamine and 5.75g (E)-3-(4-formylphenyl)methyl acrylate into the reaction flask, add 50ml methanol to dissolve, stir at room temperature for 1h, add 0.05g palladium carbon , Continue to stir for 4h under hydrogen atmosphere at room temperature, the reaction is over, celite is filtered, the solvent is evaporated under reduced pressure to obtain (E)-3-[4-[[[2-(2-methyl-1H-indole-3) -Yl)ethyl]amino]methyl]phenyl]methyl acrylate crude.

[0024] Weigh 4.5 g of the obtained crude (E)-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]methacrylate. In 10ml methanol, add 2.4g hydrogen chloride methanol solution dropwise, stir for 0.5h at room temperature, add 5ml acetone, 1ml water, and stand for 8h at 0-4℃ to obtain 5.53g of the title compound, yield 90%, purity 99.8% by HPLC .

Embodiment 2

[0025] Example 2 (E)-3-[4-[[[2-(2-Methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]methyl acrylate hydrochloride preparation

[0026] Weigh 5.0g 2-methyltryptamine and 5.75g (E)-3-(4-formylphenyl)methyl acrylate into the reaction flask, add 50ml methanol to dissolve, stir at room temperature for 1h, add 0.25g palladium carbon , Continue to stir for 4h under hydrogen atmosphere at room temperature, the reaction is over, celite is filtered, the solvent is evaporated under reduced pressure to obtain (E)-3-[4-[[[2-(2-methyl-1H-indole-3) -Yl)ethyl]amino]methyl]phenyl]methyl acrylate crude.

[0027] Weigh 3.0 g of the obtained crude (E)-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]methacrylate. In 12ml of ethanol, add 1.6g of hydrogen chloride methanol solution dropwise, stir at room temperature for 0.5h, add 5ml of acetone, 1ml of water, and place for 8h at 0-4℃ to obtain 3.1g of the title compound, with a yield of 88% and a purity of 99.8% by HPLC .

Embodiment 3

[0028] Example 3 (E)-3-[4-[[[2-(2-Methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]methyl acrylate hydrochloride preparation

[0029] Weigh 5.0g 2-methyltryptamine and 5.75g (E)-3-(4-formylphenyl)methyl acrylate into the reaction flask, add 50ml methanol to dissolve, stir at room temperature for 1h, add 0.25g palladium carbon , Continue to stir for 4h under hydrogen atmosphere at room temperature, the reaction is over, celite is filtered, the solvent is evaporated under reduced pressure to obtain (E)-3-[4-[[[2-(2-methyl-1H-indole-3) -Yl)ethyl]amino]methyl]phenyl]methyl acrylate crude.

[0030] Weigh 3.0 g of the obtained crude (E)-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]methacrylate. In 10ml methanol, add 1.6g hydrogen chloride methanol solution dropwise, stir at room temperature for 0.5h, add 5ml methyl ethyl ketone, 1ml water, and stand for 8h at 0-4℃ to obtain 3.55g of the title compound, yield 93%, purity 99.5% by HPLC .

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Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a synthesis method of a panobinostat key intermediate. The key intermediate is (E)-3-[4-[[[2-(2-methyl-1H-indole-3-yl)ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride. The method has the advantages that the yield is as high as 85 percent or higher; the impurities are few; the purity is 99.5 percent orhigher; meanwhile, the operation is simple and convenient.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for synthesizing a key intermediate of pabirestat. Background technique [0002] Pabirestat, a drug developed by Novartis for the treatment of multiple myeloma (MM), was approved by the U.S. Food and Drug Administration (FDA) on February 23, 2015, and its chemical name is N-hydroxy-3- [4-[[[2-(2-Methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-acrylamide, the chemical structure is shown in formula I Show: [0003] [0004] Novartis Company discloses in the patent application WO02 / 22577A2 the Pabirestat compound and its preparation method, using 2-methyl-3-indole-oxamide as the raw material, the 2-methyl color is obtained by the reduction of tetrahydroaluminum lithium. After amine, it is reacted with 4-formyl-cinnamate methyl ester, and then hydrazine hydrolysis to obtain pabirestat. The reaction route is as follows: [0005] [0006] Novartis Company discloses an...

Claims

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Application Information

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IPC IPC(8): C07D209/14
CPCC07D209/14
Inventor 王小丽
Owner 南京众慧网络科技有限公司
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