Crizotinib intermediate, preparation method and crizotinib preparation method

A technology of crizotinib and intermediates, applied in the field of chemical preparation, can solve the problems of long reaction cycle, unfavorable industrial production, complex reaction, etc., and achieve the effect of reduced production cost, favorable for large-scale industrial production, and simple purification

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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The expensive porcine liver lipase is used in the route, the reaction is complex and needs to be purified by column chromatography, the reaction cycle is long, and it is also unfavorable for industrial production

Method used

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  • Crizotinib intermediate, preparation method and crizotinib preparation method
  • Crizotinib intermediate, preparation method and crizotinib preparation method
  • Crizotinib intermediate, preparation method and crizotinib preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1, the preparation of compound (CZT-2);

[0049] Dissolve 2.07 kg of compound (CZT-1) and 120 g of L-proline in 20 liters of dry absolute ethanol, cool down to 0°C, add 900 g of sodium borohydride slowly in batches, and keep at 0°C after the addition is complete React for 5 hours. After filtration and concentration, 2.1 kg of crude product was obtained, and 1.82 kg of oil (CZT-2) was obtained by distillation under reduced pressure, with a yield of 87% and an e.e value greater than 99%.

Embodiment 2

[0050] Embodiment 2, the preparation of compound (CZT-3);

[0051] 1.82 kg of compound (CZT-2), 1.23 kg of 3-hydroxy-2-nitropyridine and 2.60 kg of triphenylphosphine were dissolved in 15.0 liters of dry toluene, nitrogen protection, and cooled to -20 degrees. Slowly add 2.04 kg of DIAD in 2.62 liters of toluene solution within 3 hours, keep the system temperature between -20°C and -10°C, and slowly raise the temperature to 25°C for 2 hours after the addition is complete. Add 0.16 L of water to quench the reaction, cool to -5°C, filter, and concentrate the filtrate under reduced pressure. Recrystallized with 7.5 liters of absolute ethanol to obtain 2.50 kg of compound (CZT-3), with a yield of 85%.

Embodiment 3

[0052] Embodiment 3, the preparation of compound (CZT-4);

[0053]Dissolve 2.45 kg of compound (CZT-3) in 24.5 liters of absolute ethanol and 24.5 liters of glacial acetic acid, add 2.04 kg of iron powder, react at room temperature for 5 hours, filter with diatomaceous earth, and wash the filter residue with 10 liters of ethyl acetate. Add 75 liters of ethyl acetate in the filtrate, successively with the water of 50 liters * 3, the sodium bicarbonate solution of 50 liters * 2 and the saturated sodium chloride solution washing of 50 liters, filter after drying, concentrate under reduced pressure to obtain 2.35 kilograms of compounds ( CZT-4), yield 99%.

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Abstract

The invention relates to a crizotinib intermediate, a preparation method and a crizotinib preparation method, in particular to an intermediate of crizotinib which has the structure of a formula (CZT-5) as shown in the description and the structure of a formula (CZT-9) as shown in the description, a preparation method of the intermediate and a preparation method of a crizotinib with the structure of a formula (CZT-11). The method provided by the invention has the characteristics of short route, high yield, easiness in acquisition of raw materials, high reaction selectivity and the like, chiral resolution is not required in a synthetic process, the utilization rate of the raw materials is increased, the path costs are low, and therefore, the method can meet requirements of large-scale industrial production.

Description

technical field [0001] The invention relates to a crizotinib intermediate, a preparation method and a preparation method of crizotinib, and belongs to the technical field of chemical preparation. Background technique [0002] Crizotinib is currently the latest and most effective drug for the treatment of progressive lymphoma kinase-positive locally advanced and metastatic non-small cell lung cancer, developed by Pfizer of the United States. Its chemical name is: 3-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyridine Azol-4-yl]pyridin-2-amine. Has the formula (CZT-11) structure: [0003] [0004] The synthesis method disclosed in the patent application US20060128724 of Pfizer of the United States: [0005] [0006] The method route is long, and the amino group in the intermediate compound 5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine needs to be protected during the reaction , two BOCs are needed, which wastes raw materia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D213/73C07F5/02
CPCC07D401/14C07D213/73C07F5/025
Inventor 樊林峰朱杨伟徐忠辉张常宣时鹏仇爱云
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