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Synthesis method of -2-(2, 5-difluorophenyl) pyrrolidine hydrochloride

A technology of pyrrolidine hydrochloride and difluorophenyl, which is applied in the field of drug synthesis, can solve the problems of difficult acquisition and harsh reaction conditions, and achieve the effects of high safety, mild reaction conditions, and increased safety and operability

Active Publication Date: 2021-01-22
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The raw material L-10 used in this route is not easy to obtain, and isopropy

Method used

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  • Synthesis method of -2-(2, 5-difluorophenyl) pyrrolidine hydrochloride
  • Synthesis method of -2-(2, 5-difluorophenyl) pyrrolidine hydrochloride
  • Synthesis method of -2-(2, 5-difluorophenyl) pyrrolidine hydrochloride

Examples

Experimental program
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Embodiment 1

[0023] Synthesis of Intermediate I

[0024] Add dichloromethane (300 mL) into a 2 L three-necked flask, add aluminum trichloride (283.4 g, 2.5 mol) and succinic anhydride (120.1 g, 1.2 mol) sequentially under stirring, raise the temperature to 35 °C, and dilute Fluorobenzene (114.1 g, 1 mol) was added dropwise to the reaction system, and the dropwise addition was completed within 0.5 h. The reaction was maintained at 35-38°C for 4 h, and the reaction was complete by TLC monitoring. Then the reaction solution was slowly poured into ice water (500 g), then concentrated hydrochloric acid (0.9 L, 6 M) solution was added, stirred for 0.5 h, the organic phase was separated, and the aqueous phase was extracted once with dichloromethane (100 mL). Combine the organic phases, wash the organic phase once with water (300 mL), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is recrystallized from toluene to obtain...

Embodiment 2

[0032] Synthesis of Intermediate I

[0033] Add dichloromethane (600 mL) into a 5 L three-necked flask, add aluminum trichloride (566.8 g, 5.0 mol) and succinic anhydride (240.2 g, 2.4 mol) in sequence under stirring, raise the temperature to 35°C, and dilute Fluorobenzene (228.2 g, 2 mol) was added dropwise to the reaction system, and the dropwise addition was completed within 0.5 h. The reaction was maintained at 35-38°C for 4 h, and the reaction was completed by TLC monitoring. Then the reaction solution was slowly poured into ice water (1000 g), then concentrated hydrochloric acid (1.8 L, 6 M) solution was added, stirred for 0.5 h, the organic phase was separated, and the aqueous phase was extracted once with dichloromethane (200 mL). Combine the organic phases, wash the organic phase once with water (600 mL), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is recrystallized from toluene to obtain...

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Abstract

The invention discloses a synthetic method of 2-(2, 5-difluorophenyl) pyrrolidine hydrochloride, which belongs to the field of drug synthesis. P-difluorobenzene and succinic anhydride are used as rawmaterials and subjected to a Friedel-Crafts reaction to obtain an intermediate I, the intermediate I is reduced to obtain an intermediate II, the intermediate II is subjected to an esterification reaction to obtain an intermediate III, and finally, the intermediate III is subjected to cyclization and salification under the action of liquid ammonia to obtain the 2-(2, 5-difluorophenyl) pyrrolidinehydrochloride. The method has the advantages of mild reaction conditions, cheap and easily available raw materials, high yield and good product purity.

Description

technical field [0001] The invention belongs to the field of medicine synthesis and relates to a synthesis method of 2-(2,5-difluorophenyl)pyrrolidine hydrochloride. Background technique [0002] 2-(2,5-difluorophenyl)pyrrolidine is a pharmaceutical intermediate, after chiral resolution, (2R)-2-(2,5-difluorophenyl)pyrrolidine can be obtained. The active compound is an important intermediate in the synthesis of the antineoplastic drug larotrectinib. [0003] [0004] Chinese patent CN201810066842.5 reports a synthetic route using tetrahydropyrrole as raw material, tetrahydropyrrole and N -Chlorosuccinimide reacts to generate 1-chloropyrrolidine, which is eliminated under the action of sodium methoxide to give 3,4-dihydro-2H-pyrrole, which is then added to the Grignard reagent of 2,5-difluorobromobenzene To obtain 2-(2,5-difluorophenyl)pyrrolidine, the synthesis process is as follows: [0005] . [0006] The reaction condition of this route format is harsh, requires a...

Claims

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Application Information

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IPC IPC(8): C07D207/08C07C51/083C07C59/88C07C303/28C07C309/66C07C29/147C07C33/46
CPCC07D207/08C07C51/083C07C303/28C07C29/147C07C59/88C07C309/66C07C33/46
Inventor 高禄丰张启龙高令峰郑庚修
Owner UNIV OF JINAN
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