Preparation method of ALK inhibitor crizotinib and analogue or salt thereof

The technology of a dose of crizotinib and an analog is applied in the synthesis field of anticancer drugs, which can solve the problems of long synthesis route, increase the production cost of crizotinib, low reaction yield, etc. Beneficial effect

Inactive Publication Date: 2016-01-27
NANJING LEIKEXING BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route is longer, and reaction yield is on the low side, has improved the production cost of crizotinib

Method used

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  • Preparation method of ALK inhibitor crizotinib and analogue or salt thereof
  • Preparation method of ALK inhibitor crizotinib and analogue or salt thereof
  • Preparation method of ALK inhibitor crizotinib and analogue or salt thereof

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Embodiment 1

[0027] Step 1: Preparation of 1-(4'-N-Boc)-1'--piperidine-3-(3"-fluoro-2"-nitro)-5"-pyridinepyrazole

[0028]

[0029] Add 5-bromo-3-fluoro-2-nitropyridine (6.60 g, 30 mmol), 1-(N-Boc-4-piperidinyl)-4-pyrazole boronic acid in a 500 ml two-neck round bottom flask (9.00g, 31.5mmol), DMSO (100mL), 2.0M sodium carbonate solution (30ml). The reaction compound was degassed under stirring and protected with nitrogen, then tetrakistriphenylphosphine palladium (0.3mmol) was added, the reaction system was heated to 80°C, and kept stirring at this temperature for 8 hours until 5-bromo-3-fluoro-2 - Nitropyridine disappears. After cooling down to room temperature, add 100ml of water and 200ml of ethyl acetate to the reaction system, separate the aqueous phase and the organic phase, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash once with saturated brine, and dry with anhydrous sodium sulfate , concentrated to remove the solvent to obtain 9.85 g of...

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Abstract

The invention discloses a preparation method of an ALK inhibitor crizotinib and analogue or salt thereof. The method comprise the following steps: 1, 1-(4'-N-Boc)-1'-piperidine-3(3''-fluoro-2''-nitro)-5''-pyridylpyrazole is prepared; 2, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-N-Boc-piperidinyl)-1H-pyrazol-4-yl]-2-nitropyridine is prepared; 3, N-Boc crizotinib is prepared; and 4, crizotinib and analogue or salt thereof is prepared. The method has the following advantages: the synthesis steps are reduced to 4 chemical reaction steps; a total yield is improved to approximately 35%, while the yield of an existing method is only approximately 10%; phenethyl alcohol with (R)- configuration, such as (R)-2,6-dichloro-3-fluorophenylethanol, is directly used as a raw material, such that the raw material can be fully utilized. The method provided by the invention is suitable for industrialized productions.

Description

technical field [0001] The invention relates to a synthesis method of anticancer drugs, in particular to a preparation method of ALK inhibitor crizotinib and analogs or salts thereof. Background technique [0002] Crizotinib, chemical name 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidine Base)-1H-pyrazol-4-yl]-2-aminopyridine, is a highly active ALK / c-Met inhibitor, currently clinically used for the treatment of ALK-positive locally advanced or metastatic non-small cell lung cancer . [0003] The existing production process of crizotinib is firstly obtained from (1S)-1-(2,6- Reaction of dichloro-3-fluorophenyl)ethanol with 3-hydroxy-2-nitropyridine via Mitsunobu to give (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy ]-2-nitropyridine, and then through catalytic reduction, bromination reaction, Boc protection, Suzuki coupling, deprotection group, and other eight-step reactions to complete. The synthetic route is relatively long and the reaction yield is low...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCY02P20/55
Inventor 龙霞
Owner NANJING LEIKEXING BIOTECH CO LTD
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