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Synthesis method of cobimetinib

A technology of cabitinib and a synthesis method, which is applied in the field of synthesis of a new anti-tumor drug cabitinib, can solve problems such as increasing the difficulty of industrialized production operation, unfavorable industrialized production promotion and application, long synthesis route, etc., and achieves less impurities and simplification. Manipulate, simplify the effect of compositing steps

Active Publication Date: 2016-10-26
湖南欧亚药业有限公司
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Problems solved by technology

[0019] The synthetic route is also relatively long, which involves acyl nitrile reaction, and the nitrile reagents used include highly toxic reagents such as sodium cyanide, zinc cyanide, cuprous cyanide or trimethylsilyl cyanide, which are highly dangerous and high pollution, thus increasing the difficulty of industrial production operations, which is not conducive to the promotion and application of industrial production

Method used

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  • Synthesis method of cobimetinib
  • Synthesis method of cobimetinib
  • Synthesis method of cobimetinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] A) Preparation of (R)-N-Boc-2-bromopiperidine:

[0039] (R)-N-Boc-2-piperidine carboxylic acid (10.0g, 0.04mol) was dissolved in carbon tetrachloride (70mL), potassium hydroxide (2.7g, 0.05mol) and silver nitrate (8.2g, 0.05mol) were added ), the reaction mixture was stirred at 25°C for 10 minutes, bromine water (8.4g, 0.05mol) was slowly added, the reaction mixture was stirred and reacted at 70°C for 15 hours, TLC was spotted to confirm that the reaction was complete, the rotary evaporation was concentrated to dryness, and water (20mL) was slowly added , cooled to -10°C and crystallized for 3 hours, filtered, recrystallized from isopropanol to obtain (R)-N-Boc-2-bromopiperidine, off-white solid (9.9g), yield 85.5%, the step The reaction formula is as follows:

[0040]

[0041] B) Preparation of 1-benzyloxycarbonyl-3-hydroxy-3-[(2S)-N-Boc-2-piperidinyl]-azetidine:

[0042] (R)-N-Boc-2-bromopiperidine (9.9g, 0.037mol) was dissolved in tetrahydrofuran (40mL), magnesi...

Embodiment 2

[0054] A) Preparation of (R)-N-Boc-2-bromopiperidine:

[0055] (R)-N-Boc-2-piperidine formic acid (22.927g, 0.08mol) was dissolved in chloroform (120mL), sodium hydroxide (3.8g, 0.094mol) and mercuric oxide (20.4g, 0.094mol) were added, and the reaction The mixture was stirred at 25°C for 10 minutes, bromine water (16.3g, 0.10mol) was slowly added, the reaction mixture was stirred and reacted at 80°C for 12 hours, TLC was spotted to confirm that the reaction was complete, concentrated to dryness by rotary evaporation, slowly added water (30mL), cooled to Crystallize at -10°C for 3 hours, filter, and recrystallize from isopropanol to obtain (R)-N-Boc-2-bromopiperidine, off-white solid (17.2g), yield 82.9%, the reaction formula of this step is the same as Embodiment 1;

[0056] B) Preparation of 1-benzyloxycarbonyl-3-hydroxy-3-[(2S)-N-Boc-2-piperidinyl]-azetidine:

[0057] (R)-N-Boc-2-bromopiperidine (17.0g, 0.064mol) was dissolved in methyl tert-butyl ether (70mL), magnesium ...

Embodiment 3

[0065] A) Preparation of (R)-N-Boc-2-bromopiperidine:

[0066](R)-N-Boc-2-piperidine carboxylic acid (18.5g, 0.08mol) was dissolved in dichloromethane (160mL), lithium hydroxide (2.4g, 0.10mol) and silver nitrate (17.1g, 0.10mol) were added , the reaction mixture was stirred at 25°C for 10min, bromine water (17.4g, 0.11mol) was slowly added, the reaction mixture was stirred at 90°C for 10 hours, TLC was spotted to confirm that the reaction was complete, concentrated to dryness by rotary evaporation, slowly added water (35mL), cooled Crystallize at -10°C for 3 hours, filter, and recrystallize from isopropanol to obtain (R)-N-Boc-2-bromopiperidine, off-white solid (18.4g), yield 86.1%, the reaction formula of this step With embodiment 1;

[0067] B) Preparation of 1-benzyloxycarbonyl-3-hydroxy-3-[(2S)-N-Boc-2-piperidinyl]-azetidine:

[0068] (R)-N-Boc-2-Bromopiperidine (26.416g, 0.07mol) was dissolved in ether (70mL), magnesium sticks (2.2g, 0.09mol) were added, and the reacti...

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Abstract

The invention discloses a synthesis method of cobimetinib. The method comprises the following steps: respectively carrying out salt forming reaction and bromination reaction on (R)-N-Boc-2-piperidinecarboxylic acid, silver nitrate (or mercuric oxide) and bromine water successively; reacting obtained (R)-N-Boc-2-bromopiperidine and a magnesium rod at first to generate a Grignard reagent, and then carrying out Grignard reaction on the (R)-N-Boc-2-bromopiperidine and 1-carbobenzoxy azetidine-3-one; carrying out deamination protection reaction on obtained 1-carbobenzoxy-3-hydroxy-3-[(2S)-N-Boc-2-piperidyl]-azetidine; carrying out amidation on obtained 3-hydroxy-3-[(2S)-N-Boc-2-piperidyl]-azetidine and 2,3,4-trifluorobenzoyl chloride; carrying out substitution reaction on obtained [2,3,4-trifluorophenyl] [3-hydroxy-3-(2S)-N-Boc-2-piperidyl-1-azetidinyl] ketone and 2-chloro-4-iodoaniline, and finally carrying out deamination protection reaction to obtain the cobimetinib. The method is reasonable and simple in process route, simple to operate and relatively low in cost, is an environmentally friendly method, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of a new anti-tumor drug carbitinib for treating melanoma. Background technique [0002] The chemical name of the MEK protein kinase inhibitor Cobimetinib is [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3- [(2S)-2-piperidinyl]-1-azetidinyl]methanone, its chemical structural formula is: [0003] [0004] Capetinib is a new anti-tumor drug jointly developed by Exelixis and Genentech in the United States. Its trade name is Cotellic, and it was later developed by Roche in Switzerland for the treatment of solid tumors. Cabetinib is an oral small-molecule MEK inhibitor designed to selectively block the activity of MEK protein, thereby blocking its downstream signaling pathways. Cabetinib and BRAF inhibitor Vemurafenib (Vemurafenib, Zelboraf (trade name) is used in combination to treat advanced melanoma wit...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 陈健
Owner 湖南欧亚药业有限公司
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