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Method for preparing 2R-(2, 5-difluorophenyl) pyrrolidine hydrochloride

A technology of pyrrolidine hydrochloride and dimethylhydroxylamine hydrochloride, which is applied in the field of chemical drug synthesis, can solve the problems of harsh reaction conditions, high cost of raw materials, and high cost of reagents, so as to reduce reagent costs, increase yields, and add materials convenient effect

Active Publication Date: 2015-06-03
PHARORGSYN LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The fourth step requires the use of lithium triethylborohydride, which is not easy to operate in production, is more dangerous (flammable in case of air), has higher reagent costs, and lower yield
[0014] The first step of this route is the one-pot synthesis of compound 8. The operation is cumbersome, the reaction conditions are harsh (no water and no oxygen is required), the e.e value of the product can only reach 93%, and the cost of raw materials is relatively high.

Method used

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  • Method for preparing 2R-(2, 5-difluorophenyl) pyrrolidine hydrochloride
  • Method for preparing 2R-(2, 5-difluorophenyl) pyrrolidine hydrochloride
  • Method for preparing 2R-(2, 5-difluorophenyl) pyrrolidine hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0038] Compound 2 was synthesized.

[0039]

[0040] N, O-dimethylhydroxylamine hydrochloride (30.4g, 0.31mol) was dissolved in dichloromethane (500ml), cooled in an ice bath, stirred, added triethylamine (65g, 0.64mol), and then added dropwise compound 1 ( 40g, 0.28mol), the internal temperature is controlled between 0-6 degrees Celsius. After the addition was complete, the reaction was carried out at room temperature for 3 hours and quenched with dilute hydrochloric acid (1M). The organic layer was separated, and the organic layer was successively washed with saturated NaHCO 3 (100ml) and saturated saline (100ml) each washed once, with anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure to obtain compound 2 (45 g, 96%, light brown liquid).

Embodiment 2

[0042] Compound 3 was synthesized.

[0043]

[0044] 1,4-difluorobenzene (12g, 0.105mol) was dissolved in tetrahydrofuran (50ml), cooled to -70°C,

[0045] Slowly add n-butyllithium (46.4ml, 2.5M, 0.116mol) dropwise, control the internal temperature between -70°C and -60°C, and complete the dropwise addition in 2 hours. The reaction solution was stirred at -70°C for 1 hour, and then a solution of compound 2 in tetrahydrofuran (19 g, 0.116 mol, dissolved in 30 ml tetrahydrofuran) was added dropwise, and the addition was completed in half an hour. The reaction continued to stir at -70°C for 1 hour, raised to room temperature, and stirred for another half an hour, then quenched the reaction with saturated ammonium chloride (50ml), extracted with methyl tert-butyl ether (100ml×2), and then washed with saturated Brine (30ml) was backwashed once, dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated by column chromatography (petroleum...

Embodiment 3

[0047] 1,4-Difluorobenzene (12g, 0.105mol) was dissolved in ether (50ml), cooled to -50°C, slowly added n-butyl lithium (46.4ml, 2.5M, 0.116mol) dropwise, and the internal temperature was controlled at -60 Between ℃ and -50℃, the dropwise addition was completed in 2 hours. The reaction solution was stirred at -50°C for 1 hour, then a diethyl ether solution of compound 2 (19 g, 0.116 mol, dissolved in 30 ml diethyl ether) was added dropwise, and the addition was completed in half an hour. The reaction continued to stir at -50°C for 1 hour, warmed to room temperature, and stirred for another half an hour, then quenched with saturated ammonium chloride (50ml), extracted with methyl tert-butyl ether (100ml×2), and then washed with saturated Brine (30ml) was backwashed once, dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate=40 / 1) to obtain compound 3 (15g, 65.2%, brown liquid )...

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Abstract

The invention discloses a method for preparing 2R-(2, 5-difluorophenyl) pyrrolidine hydrochloride. The method comprises the following steps: (a) reacting a compound (1) with the N, O-dimethyl hydroxylamine hydrochloride to obtain a compound (2); (b) reacting the 1, 4-difluorobenzene and n-butyllithium for 1-3h at -70 DEG C to -50 DEG C in an organic solvent, adding the compound (2) and reacting at the temperature of -70 DEG C to -50 DEG C to obtain a compound (3); (c) reacting the compound (3), a compound (7) and the Ti(OEt)4 in the organic solvent under refluxing to obtain a compound (4); (d) reacting the compound (4) with the sodium borohydride to obtain a compound (5); (e) reacting the compound (5) with the alkali to obtain a compound (6); and (f) reacting the compound (6) in an organic solvent of hydrogen chloride to obtain the 2R-(2, 5-difluorophenyl) pyrrolidine hydrochloride. By adopting the method provided by the invention, the cost is greatly reduced, the yield is obviously increased and the method is safe with a good application future. The reaction route of the method is as shown in the specification.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, and more particularly relates to a preparation method of 2R-(2,5-difluorophenyl)pyrrolidine or a salt thereof. Background technique [0002] Inhibitors of tyrosine receptor kinase (Trk) are the focus of current research. Among the novel inhibitors against tyrosine receptor kinase (Trk) discovered in recent years, many inhibitors have pyrazolo[1,5-a]pyridine and pyrazolo[1,5-a]pyrimidine series structure. These novel inhibitors can effectively inhibit Trk and are useful for the treatment of pain and inflammation, cancer, neurodegenerative diseases and certain infectious diseases. [0003] The parent structure of one of the main series of Trk inhibitor pyrazolo[1,5-a]pyridines disclosed in patents WO2013088256 and WO2013088257 is as follows: [0004] [0005] The parent structure of one of the main series of Trk inhibitor pyrazolo[1,5-a]pyrimidines disclosed in patents WO2011006074, WO2...

Claims

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Application Information

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IPC IPC(8): C07D207/08
CPCC07D207/08
Inventor 范朋高饶卫军
Owner PHARORGSYN LAB
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