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Method for preparing lapatinib intermediate

A technology of latratinib and intermediates, which is applied in the field of preparation of latratinib intermediates, can solve problems such as unfavorable industrial production, reduced atom economy of preparation process, numerous steps, etc., and achieves improved reaction yield and operational feasibility. controllability, reduction of precious metal catalysts and other expensive reagents, and the effect of promoting development

Active Publication Date: 2017-12-08
SUZHOU LIXIN PHARMA
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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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  • Method for preparing lapatinib intermediate
  • Method for preparing lapatinib intermediate
  • Method for preparing lapatinib intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Under nitrogen atmosphere, add (7aR,10R,12S)-10-(1-benzotriazolyl)-12-phenyl-7a,8,9,10-tetrahydro-12H-naphthalene to a dry reaction flask Phenol[1,2-e]pyrrolo[2,1-b][1,3]oxazine(II) (4.2g, 10mmol) and 50mL of dry tetrahydrofuran were cooled to -30°C, and 2,5 - Difluorophenylmagnesium(III) bromide (3.2 g, 15 mmol) in THF 30 mL. Keep the temperature at -25~-10°C, stir and react for 2-3 hours, and TLC detects that the reaction is complete. Quench the reaction with 25 mL of saturated ammonium chloride, extract three times with dichloromethane, combine the organic phases, wash with 5% sodium hydroxide solution and saturated brine successively, and dry over anhydrous magnesium sulfate. Concentrate, and recrystallize the residue with ethanol to obtain off-white solid (7aR,10R,12S)-10-(2,5-difluorophenyl)-12-phenyl-7a,8,9,10-tetrahydro- 12H-naphthol[1,2-e]pyrrolo[2,1-b][1,3]oxazine (IV) 3.7g, yield 89.6%, FAB-MS m / z: 414[M+H ] + .

Embodiment 2

[0030] Under nitrogen atmosphere, add (7aR,10R,12S)-10-(2,5-difluorophenyl)-12-phenyl-7a,8,9,10-tetrahydro-12H-naphthalene to a dry reaction flask Phenol[1,2-e]pyrrolo[2,1-b][1,3]oxazine(IV) (3.0g, 7.26mmol) and 40mL of dry diethyl ether, cooled to 0°C, added lithium aluminum hydride (0.41g, 10.9mmol), keep the temperature and stir the reaction for 1 hour, and TLC detects that the reaction is complete. Add 20 mL of pure water to quench the reaction, extract three times with ethyl acetate, combine the organic phases, wash with saturated ammonium chloride aqueous solution and 10% sodium chloride aqueous solution successively, and dry over anhydrous sodium sulfate. Concentrate, and recrystallize the residue with ethyl acetate to obtain off-white solid 1-[(S)-[(2R)-2-(2,5-difluorophenyl)-1-tetrahydropyrrolidinyl]phenyl Methyl]-2-naphthol (V) 2.6g, yield 86.3%, FAB-MS m / z: 416[M+H] + .

Embodiment 3

[0032] Add 1-[(S)-[(2R)-2-(2,5-difluorophenyl)-1-tetrahydropyrrolidinyl]phenylmethyl]-2-naphthol ( V) (2.1g, 5mmol), 10% palladium on carbon (Pd / C) (0.32g, 0.3mmol) and 25mL of methanol, hydrogen gas was passed through at room temperature and normal pressure until the hydrogen gas was no longer absorbed, and the hydrogen gas flow was stopped. The catalyst was recovered by filtration, and the solvent was recovered under reduced pressure to obtain 0.8 g of reddish oil (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine (I), with a yield of 87.4%; 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); FAB-MS m / z: 184[M+H] + .

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Abstract

The invention discloses a method for preparing a lapatinib intermediate (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine. The method comprises the following steps: by taking taking chiral induced reagent (7aR,10R,12S)-10-(1-benzotriazole)-12-phenyl-7a,8,9,10-tetrahydro-12H-naphthol[1,2-e]pyrrolo[2,1-b][1,3]oxazine and a Grignard reagent 2,5-difluorophenyl magnesium bromide as raw materials, performing a substitution reaction, a reduction reaction and a debenzylation reaction to prepare the lapatinib intermediate (R)-2-(2,5-difluorophenyl)tetrahydropyrrolidine. Compared with the prior art, the method is simple in process, mild in condition, less in side reaction, low in cost and suitable for industrial production and can promote development of the bulk drug economic technology.

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
CPCC07B2200/07C07D207/08
Inventor 许学农包志坚陈伟谢玲玲黄栋梁薛佳王喆苏健
Owner SUZHOU LIXIN PHARMA
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