Preparation method of 2-(2,5-difluorophenyl) pyrrolidine

A technology of difluorophenyl and pyrrolidine, which is applied in the field of preparation of 2-pyrrolidine, can solve the problems of unfavorable industrialization, violent reaction, and low reaction temperature, and achieve reasonable synthesis process design, mild reaction conditions, and low raw material cost Effect

Active Publication Date: 2018-06-29
GUANGDONG SCI FINDER PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] The synthesis process uses 2-pyrrolidone as a raw material, and the total yield is about 36%. The last step: adding sodium borohydride to methanol aqueous solution at room temperature, the reaction is violent, difficult to control, and dangerous to operate
[0017] It can be seen that there are following disadvantages in the preparation technology of 2-(2,5-difluorophenyl)pyrrolidine: the reagent cost of method 1 is high, the reaction

Method used

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  • Preparation method of 2-(2,5-difluorophenyl) pyrrolidine

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Embodiment 1

[0038] An embodiment of the preparation method of 2-(2,5-difluorophenyl)pyrrolidine described in the present invention, the preparation method of 2-(2,5-difluorophenyl)pyrrolidine described in this embodiment comprises The following steps:

[0039] (1), the preparation of 1-chloropyrrolidine: in the reaction flask equipped with thermometer, under nitrogen protection, add N-chlorosuccinimide (43.37g, 325mmol, 1.1eq), methyl tert-butyl ether 160mL, stirred to lower the temperature below 20°C, slowly added pyrrolidine (21.00g, 295mmol, 1.0eq) dropwise, stirred at room temperature for 24 hours, and stopped the reaction; Wash with 80 mL of 20% brine, dry over anhydrous magnesium sulfate, and distill off the solvent under reduced pressure at a temperature not higher than 25°C to obtain 31.00 g of light yellow oil, namely 1-chloropyrrolidine, with a yield of 99%;

[0040] (2), the preparation of 3,4-dihydro-2H-pyrrole: in the reaction bottle equipped with thermometer, nitrogen prote...

Embodiment 2

[0044]An embodiment of the preparation method of 2-(2,5-difluorophenyl)pyrrolidine described in the present invention, the preparation method of 2-(2,5-difluorophenyl)pyrrolidine described in this embodiment comprises The following steps:

[0045] (1), the preparation of 1-chloropyrrolidine: with embodiment 1;

[0046] (2), preparation of 3,4-dihydro-2H-pyrrole: same as Example 1;

[0047] (3), the preparation of 2-(2,5-difluorophenyl) pyrrolidine: in the reaction flask that reflux tube is housed, constant pressure drop filter funnel and thermometer, nitrogen protection, add magnesium chip (2.54g , 104mmol, 1.2eq), 20mL of anhydrous tetrahydrofuran, 1-bromoethane (0.2mL), dropwise added 2,5-difluorobromobenzene (16.80g, 87mmol, 1.0eq, dissolved in 35mL of anhydrous THF) about 1 / 4, stir to raise the temperature to 45°C, stir for 0.5 hours, start the reaction, continue to add 2,5-difluorobromobenzene solution dropwise slowly, keep the reaction for 2 hours after the addition, c...

Embodiment 3

[0049] An embodiment of the preparation method of 2-(2,5-difluorophenyl)pyrrolidine described in the present invention, the preparation method of 2-(2,5-difluorophenyl)pyrrolidine described in this embodiment comprises The following steps:

[0050] (1), the preparation of 1-chloropyrrolidine: with embodiment 1;

[0051] (2), preparation of 3,4-dihydro-2H-pyrrole: same as Example 1;

[0052] (3), the preparation of 2-(2,5-difluorophenyl) pyrrolidine: in the reaction flask that reflux tube is housed, constant pressure drop filter funnel and thermometer, nitrogen protection, add magnesium chip (3.80g , 156mmol, 1.8eq), anhydrous tetrahydrofuran 20mL, 1-bromoethane (0.2mL), dropwise added 2,5-difluorobromobenzene (25.10g, 130mmol, 1.5eq, dissolved in 50mL anhydrous THF) about Quarter, stir and heat up to 45°C, stir for 0.5 hours, start the reaction, continue to slowly add 2,5-difluorobromobenzene solution dropwise, keep warm for 2 hours after the addition, cool down to 25°C, dro...

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Abstract

The invention provides a preparation method of 2-(2,5-difluorophenyl) pyrrolidine. The preparation method comprises the following steps: (1) tetrahydropyrrole reacts with N-chlorosuccinimide to generate 1-chloropyrrolidine; (2) the 1-chloropyrrolidine generated in the step (1) carries out elimination reaction in sodium methylate solution to generate 3,4-dihydro-2H-pyrrole; (3) the 3,4-dihydro-2H-pyrrole generated in the step (2) reacts with a 2,5-difluorobromobenzene Grignard reagent to obtain the 2-(2,5-difluorophenyl) pyrrolidine. The preparation method of the 2-(2,5-difluorophenyl) pyrrolidine provided by the invention has the beneficial effects that the synthetic process is reasonably designed, the reagent is cheap, the purchase is convenient, no heavy metal pollution is caused, the reaction conditions are mild, the cost of raw materials is low, no special equipment is needed, the operation is simple and convenient, and the energy consumption is low, so that the preparation methodis sutiable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of 2-(2,5-difluorophenyl)pyrrolidine. Background technique [0002] Larotrectinib (LOXO-101) sulfate, chemical name: (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- 3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate, CAS number: 1223405-08-0, the structural formula is as follows, [0003] [0004] Larotrectinib (LOXO-101) sulfate is an orally available, selective, and ATP-competitive potent inhibitor of tropomyosin receptor kinase TRK, which was granted breakthrough drug designation by the FDA on July 13, 2016 , for unresectable or metastatic solid tumors in adults and children who are positive for TRK fusion gene mutations. Larotrectinib has demonstrated durable antitumor activity and good tolerability in Trk fusion cancers across a wide range of ages and tumor types. Larotrectinib will be the first tr...

Claims

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Application Information

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IPC IPC(8): C07D207/08
CPCC07D207/08
Inventor 郑玉春丁效明陈荣民张炎
Owner GUANGDONG SCI FINDER PHARMA TECH CO LTD
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