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Preparation method of larotrectinib intermediate

A technology for latrextinib and intermediates, which is applied in the field of preparation of latrextinib intermediates, can solve the problems of unfavorable industrial production, numerous steps, and reduced atomic economy of the preparation process, so as to improve the reaction yield and operational reliability. controllability, facilitate development, and reduce the effect of noble metal catalysts and other expensive reagents

Active Publication Date: 2018-01-09
哈尔滨医大药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] It can be seen from the above synthetic route that the method involves chiral ligands, metal lithium / zinc reagents, noble metal palladium reagents, and tri-n-butylphosphine tetrafluoroborate and other raw materials or catalysts, and involves harsh conditions such as low temperature, anaerobic, and anhydrous conditions. The reaction conditions, and the steps are numerous, are unfavorable for industrialized production
[0008] Although patents such as US2016 / 0168156, US2015 / 0368238 and CN104672121 have also reported some synthetic methods of the compound, due to the use of chiral sulfoxide or other resolution reagents, the atom economy of the preparation process is reduced

Method used

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  • Preparation method of larotrectinib intermediate
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  • Preparation method of larotrectinib intermediate

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Experimental program
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Effect test

Embodiment 1

[0025] Under nitrogen atmosphere, add (7aS,12R)-12-phenyl-7a,8,9,10-tetrahydro-12H-naphthol[1,2-e]pyrrolo[2,1- b] [1,3]oxazine (II) (3.0g, 10mmol) and 30mL of dry tetrahydrofuran, cooled to 0 ° C, dropwise added 2,5-difluorophenylmagnesium bromide (III) (3.2g, 15mmol ) in THF solution 30mL. Raise the temperature to 25-35° C., keep the temperature and stir the reaction for 3-5 hours, and TLC detects that the reaction is complete. The reaction was quenched with 25 mL of saturated ammonium chloride, extracted three times with dichloromethane, the organic phases were combined, washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. Concentrate, and recrystallize the residue with ethyl acetate to obtain off-white solid 1-[(R)-[(2R)-2-(2,5-difluorophenyl)-1-tetrahydropyrrolidinyl]phenyl Methyl]-2-naphthol (IV) 3.5g, yield 84.3%, FAB-MS m / z: 416[M+H] + .

Embodiment 2

[0027] Add 1-[(R)-[(2R)-2-(2,5-difluorophenyl)-1-tetrahydropyrrolidinyl]phenylmethyl]-2-naphthol ( IV) (2.1g, 5mmol), 10% palladium on carbon (Pd / C) (0.32g, 0.3mmol) and methanol 25mL, hydrogen gas was passed through at room temperature and normal pressure until hydrogen gas was no longer absorbed, and hydrogen gas flow was stopped. The catalyst was recovered by filtration, and the solvent was recovered under reduced pressure to obtain 0.79 g of reddish oil (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine (I), with a yield of 86.3%; 1H NMR (CDCl 3 )δ7.24(m, 1H), 6.94(m, 1H), 6.85(m, 1H), 4.40(t, J=7.6Hz, 1H), 3.16(m, 1H), 3.04(m, 1H), 2.21-2.30(m, 1H), 1.77-1.95(m, 3H), 1.57-1.67(m, 1H); EI-MS m / z: 184[M+H] + .

Embodiment 3

[0029] Add 1-[(R)-[(2R)-2-(2,5-difluorophenyl)-1-tetrahydropyrrolidinyl]phenylmethyl]-2-naphthol (IV ) (2.1g, 3mmol), ceric ammonium nitrate (4.1g, 7.5mmol) and 60mL of a mixed solvent of acetonitrile and water (volume ratio 2:1), stirred at room temperature for 5-7 hours, and TLC detected that the reaction was complete. Filtrate, add sodium bicarbonate solution to the filtrate, and extract three times with dichloromethane, combine the organic phases, and dry over anhydrous sodium sulfate. Concentration under reduced pressure gave 0.76 g of reddish oil (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine (I), yield 83.0%; 1H NMR (CDCl 3 )δ7.24(m, 1H), 6.94(m, 1H), 6.85(m, 1H), 4.40(t, J=7.6Hz, 1H), 3.16(m, 1H), 3.04(m, 1H), 2.21-2.30(m, 1H), 1.77-1.95(m, 3H), 1.57-1.67(m, 1H); EI-MSm / z: 184[M+H] + .

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Abstract

The invention discloses a preparation method of a larotrectinib intermediate (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine, which comprises the following steps that the larotrectinib intermediate (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine is prepared by enabling a chiral induction reagent (7aS,12R)-12-phenyl-7a,8,9,10-tetrahydro-12H-naphthol[1,2-e]pyrrolo[2,1-b]oxazine serving as a raw material to react with a Grignard reagent 2,5-difluorophenyl magnesium bromide by means of an addition reaction and a debenzylation reaction. Compared with the prior art, the preparation method has the advantages of simple process, mild conditions, low side reaction, low cost, and adaptability to industrialized production, and can promote the economic and technological development of the bulk pharmaceutical chemical.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of a latratinib intermediate. Background technique [0002] Larotrectinib is a potent, oral, selective tropomyosin receptor kinase (TRKs) inhibitor developed by LoxoOncology, a biopharmaceutical company located in Stanford, USA. In May 2017, the US Food and Drug Administration (FDA) granted the experimental drug orphan drug status for the treatment of solid tumors carrying NTRK gene fusions. [0003] The chemical name of latratinib is (S)-N-((R)-2-(2,5-difluorophenyl) tetrahydropyrrolidin-1-yl) pyrazol[1,5-a] Pyrimidin-3-yl)-3-hydroxytetrahydropyrrolidine-1-carboxamide, its chemical structure is: [0004] [0005] The preparation method of latratinib has been reported. International patents WO2010 / 048314 and WO2016 / 077841 report the preparation method of latratinib, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08
Inventor 许学农
Owner 哈尔滨医大药业股份有限公司
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