Synthesis method of panobinostat

A synthesis method, the technology of panobinostat, which is applied in the field of panobinostat synthesis, can solve the problems of raw material toxicity and the like

Inactive Publication Date: 2017-05-17
NANJING CAVENDISH BIO ENG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Synthesis method of panobinostat

Examples

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Embodiment 1

[0060] Preparation of 2-chloro-1-(2-methyl-1H-indol-3-yl)ethanone

[0061] Add 25g (0.19mol) of 2-methylindole, 250ml of acetonitrile, and 40.9g (0.381mol) of 2,6-lutidine into a 500ml four-necked flask, stir and dissolve at 20-30°C, and control the temperature at 25-35°C. ℃, add 32.3g (0.286mol) of chloroacetyl chloride dropwise, after the dropwise addition is completed, continue to stir for 1 hour, point the plate to detect that the raw materials have basically reacted completely, add 250ml of water dropwise, after fully stirring, suction filter, and use acetonitrile / water=150ml / 150ml The filter cake was rinsed and dried at 50° C. to constant weight to obtain 31.56 g of off-white solid with a yield of 79.7%. Mass: m / z 208.03[M+H] + , mp: 217.3°C.

Embodiment 2

[0063] 2-[2-(2-Methyl-1H-indol-3-yl)-2-oxoethyl]isoindoline-1,3-dione

[0064] Add 2-chloro-1-(2-methyl-1H-indol-3-yl)ethanone solid 10g (0.048mol), DMF40ml, phthalimide potassium 10.6g ( 0.057mol), stir, heat up to 85°C, react for 2 hours, start TLC detection until the basic reaction of raw materials is complete, cool down to 20-30°C, filter with suction, rinse the filter cake with 10ml DMF, merge into the filtrate, add water dropwise to the filtrate 100ml, a solid was precipitated, the temperature was controlled at 20-30°C and fully stirred for 30 minutes, suction filtered, rinsed, and dried at 50°C to constant weight to obtain 13.18g of a light yellow solid with a yield of 86%. Mass: m / z 319.06[M+H] + , mp: 220.1°C-223.5°C.

Embodiment 3

[0066] Preparation of 2-amino-1-(2-methyl-1H-indol-3-yl)ethanone

[0067] Add 2-[2-(2-methyl-1H-indol-3-yl)-2-oxoethyl]isoindoline-1,3-dione solid 6g ( 0.019mol), ethanol 60ml, methylamine aqueous solution (25% by weight-30% by weight) 6g, heat up to 85 degrees, stir for 2 hours, start TLC detection, until the raw materials are basically complete, the reaction solution is prepared to make sand, and column chromatography separates , using pure dichloromethane to pass through the column to obtain 2.8 g of a light yellow solid product with a yield of 79%. Mass: m / z 189.06[M+H] +, mp: greater than 250°C

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Abstract

The invention discloses a synthesis method of panobinostat. The synthesis method comprises a step of synthesizing 2-methyl tryptamine or hydrochloride thereof, namely taking 2-methylindole as a raw material, conducting reaction with chloroacetyl chloride or bromoacetyl bromide, and conducting reaction with potassium phthalimide to obtain the 2-methyl tryptamine. According to the technical scheme adopted by the invention, influence of toxic raw materials on the safety of a panobinostat product is avoided; meanwhile, the invention provides the synthesis method applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and more specifically relates to a synthesis method of panobinostat. Background technique [0002] Panobinostat, the 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 [0003] [0004] Panobinostat is a hydroxamic acid small molecule histone deacetylase (HDAC) inhibitor, used for the treatment of multiple myeloma and early acute myeloid leukemia, and was approved for marketing in the United States in February 2015. [0005] Novartis discloses panobinostat compound and its preparation method in patent international application WO02 / 22577A2, and this preparation method adopts 2-methyl-3-indole-oxamide as raw material, through LiAlH 4 2-methyltryptamine can be obtained by reduction, and panobinostat can be obtained by reacting with 4-formyl-cinnamic acid methyl ester and then hydrazine hydrolysis. T...

Claims

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Application Information

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IPC IPC(8): C07D209/14C07D209/16
CPCC07D209/14C07D209/16
Inventor 许永翔
Owner NANJING CAVENDISH BIO ENG TECH
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