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Synthesis method and intermediate of (R)-2-(2,5-difluorophenyl)pyrrolidine

A technology of difluorophenyl and synthesis method, which is applied in the field of synthesizing chiral-2-pyrrolidine, can solve the problems of harsh reaction conditions, difficulty in industrialization, high cost, etc., and achieve the goal of improving reaction conditions, increasing content, and increasing content Effect

Active Publication Date: 2017-10-24
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method can obtain the required configuration up to 93% content, but the same method needs too low temperature, and the method also needs air-sensitive sec-butyllithium, and expensive palladium acetate and sparteine ​​base, due to too high Harsh reaction conditions and high cost make this method difficult to industrialize

Method used

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  • Synthesis method and intermediate of (R)-2-(2,5-difluorophenyl)pyrrolidine
  • Synthesis method and intermediate of (R)-2-(2,5-difluorophenyl)pyrrolidine
  • Synthesis method and intermediate of (R)-2-(2,5-difluorophenyl)pyrrolidine

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Experimental program
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Embodiment 1

[0065] Embodiment 1: the synthesis of compound 1

[0066]

[0067] Add 2.8g of magnesium bars, 2g of ethylene glycol acetal 3-bromopropanal, 10mL of THF and a grain of iodine into the reaction flask. After heating at 65°C to initiate the reaction, stop heating, cool to room temperature, and add the remaining ethylene glycol dissolved in 60mL of THF at room temperature. Condensate 18g of 3-bromopropanal, stir at room temperature for 30min after addition, set aside.

Embodiment 2

[0068] Embodiment 2: the synthesis of compound 2

[0069]

[0070] Step 1: Synthesis of Compound I:

[0071] Dissolve 7.1g of 2,5-difluorobenzaldehyde and R-tert-butylsulfinamide in 30mL of THF, add 13g of tetraethyl titanate, heat to reflux for 2h, after cooling, add 20mL of water, extract with ethyl acetate, extract Liquid was dried, and the solvent was removed after filtration, and 12 g of products were obtained by column chromatography with petroleum ether ethyl acetate (10:1), and the yield was 98%. 1 H-NMR (400MHz, CDCl 3 ): δ1.26 (s, 9H), 7.12-7.18 (m, 2H), 7.64-7.68 (m, 1H), 8.83 (s, 1H). MS (ESI) 246.53.

[0072] Step 2: Dissolve 16 g of imine compound I synthesized in step 1 in 200 mL of anhydrous dichloromethane, cool to -40°C, and slowly add the mixture of compound 1 prepared in Example 1, and keep the temperature not exceeding - 35 ° C, the addition is complete, and the reaction is continued at this temperature for 5 h. Add saturated aqueous ammonium chlor...

Embodiment 3

[0073] Embodiment 3: the synthesis of compound 3

[0074]

[0075] Dissolve 17.4g of compound 2 in 50mL of THF, add 20mL of 6M hydrogen chloride dissolved in THF, stir at room temperature for 1h, add NaBH in batches 4 After adding 2.8g, stir at room temperature for 1h. The reaction mixture was desolvated under reduced pressure, the residue was dissolved in 50 mL of water, extracted with ethyl acetate, the organic phase was discarded, and the aqueous phase was washed with K 2 CO 3 Basify, extract again with ethyl acetate 3×30mL, acidify the organic phase to acidity with 5M hydrochloric acid, remove the solvent under reduced pressure, dissolve the residue in 20mL isopropanol, freeze and crystallize the isopropanol solution, and obtain 8.1g of the product after filtration , yield 73%, isomer greater than 98%, MS: 184.37, the above hydrochloride was dissolved in 20mL of water and 20mL of ethyl acetate, with K 2 CO 3 Alkaline to alkaline, separate the organic phase, extract...

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Abstract

The present invention discloses a synthesis method of (R)-2-(2,5-difluorophenyl)pyrrolidine. The synthesis method comprises that the Grignard reagent of halogenated propyl acetal and an imine compound I are subjected to an addition reaction; the obtained addition product is subjected to a cyclization reaction to obtain a chiral imine compound II; the imine compound II is subjected to a reduction reaction and post-treatment to obtain the final product; or an imine compound III is subjected to a reduction reaction in the presence of a reduction agent lithium triisobutylhydroborate; the reduction product is subjected to a cyclization reaction under a alkali condition; and the cyclization product is subjected to tert-butyl sulfoxide removal under an acid condition, and post-treatment is performed to obtain the final product. The invention further discloses an intermediate for preparing the compound. According to the present invention, by using the large steric reduction agent or the Grignard reagent, the reaction temperature can be substantially improved, the reaction conditions can be substantially improved compared to the existing method in the patent, and the content of the desired isomer is substantially increased.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method and an intermediate for synthesizing chiral (R)-2-(2,5-difluorophenyl)pyrrolidine induced by a chiral inducing reagent. Background technique [0002] As a receptor target, tropomyosin receptor kinase (Trk) inhibitors have received extensive attention in recent years. Many inhibitors with biological activity have chiral pyrrolidine structures, and some new compounds can effectively inhibit Trk. , showing satisfactory results for the treatment of pain, tumor or neurological diseases. [0003] The Trk inhibitors disclosed in patent documents CN104114553, WO2013088256, WO2013088257 and WO2016077841 all contain (R)-2-(2,5-difluorophenyl)pyrrolidine structure, and its main structure is as follows: [0004] [0005] In the above structures, all contain (R)-2-(2,5-difluorophenyl)pyrrolidine, it can be seen that the (R)-2-(2,5-difluorophenyl)pyrrolidine is ...

Claims

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Application Information

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IPC IPC(8): C07D207/08C07D317/28C07C311/03
CPCC07B2200/07C07C311/03C07D207/08C07D317/28
Inventor 李新生郭幸雪
Owner ZHEJIANG NORMAL UNIVERSITY
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