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

A synthesis method and difluorophenyl technology are applied in the synthesis field of -2-pyrrolidine, which can solve the problems of weak industrial production operability, poor chiral reduction selectivity, poor safety, and the like, and avoid the need for precious metal catalysts. and the use of metal organic compounds, the effect of good chiral purity and short steps

Pending Publication Date: 2021-04-09
北京蓝博特科技有限公司
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  • Abstract
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Problems solved by technology

[0013] This synthetic method has the following problems: the process route is too long, the raw materials are expensive, the selectivity of chiral reduction is poor, the DE value is about 80%, and the diastereoisomers must be separated through column chromatography. Metal compound sodium hydride, the safety is not very good
[0016] This synthesis method has the following problems: precious metals and coordination compounds are used in the chiral reduction process, which are expensive and difficult to recycle; SEC-BuLi is used in the synthesis process, which is a very active / dangerous organometallic compound, so This step requires deep cooling (-78 degrees), so the cost and feasibility of industrial production are weak

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0077] Embodiment 1: the synthesis of formula 2 compound

[0078]

[0079] In a washed and dried three-necked flask, dissolve 60 grams of 2,5-difluorobenzaldehyde, 76.6 grams of R-tert-butylsulfinamide, 1.0 grams of PPTS, and 169 grams of anhydrous copper sulfate in 500 milliliters of dichloromethane , the oil bath was heated to 40 degrees Celsius, stirred, and refluxed for 3-5 hours. TLC / HPLC monitored the completion of the reaction. The product was filtered and concentrated under reduced pressure. After dissolving, wash with water and separate layers; wash with saturated brine, separate layers; dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 100.5 g of the compound Schiff base of formula 2 (light yellow oily substance), with a yield of 97%, which can be directly obtained without further purification. Carry out the next reaction.

Embodiment 2

[0080] Embodiment 2: the synthesis of formula 3 compound

[0081]

[0082] Dissolve 100.5 grams of Schiff base compound of formula 2 in 500 milliliters of tetrahydrofuran, under nitrogen protection, cool down to -30 degrees Celsius, slowly add 1.5 equivalents of 1 mol / L Grignard reagent dropwise, keep the temperature at about -30 degrees, after the addition is completed, keep the temperature constant After 2-3 hours of reaction, TLC / HPLC detected that the reaction was complete. Quench the reaction with saturated ammonium chloride aqueous solution, separate layers, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 141.0 g of crude compound (light yellow oil) (DE>90%), yield>95 %.

Embodiment 3

[0083] Embodiment 3: the synthesis of formula 4 compound

[0084]

[0085] 141.0 grams of formula 3 compounds, stirred, slowly added the mixture of 3L trifluoroacetic acid and water (TFA:H 2 O volume ratio=95:5), stirred for 1-2 hours, and the temperature was controlled at 25 degrees Celsius. Slowly add 363 grams of triethylsilane dropwise, and control the temperature at 30-40 degrees Celsius. After the dropwise addition, control the temperature at 30 degrees Celsius and stir for 12-24 hours. HPLC detects that the reaction is complete. Concentration under reduced pressure afforded 106 g of crude compound (tan liquid). Without further purification, the next reaction can be carried out directly.

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Abstract

The invention belongs to the technical field of chemical pharmacy, and relates to a synthetic method of (R)-2-(2, 5-difluorophenyl)pyrrolidine. The synthesis method comprises the following steps: (1) carrying out dehydration condensation reaction on a compound as shown in a formula 1 and a chiral induction reagent (R) tert-butylsulfinamide to obtain a compound as shown in a formula 2; (2) carrying out addition reaction on the compound in the formula 2 and a Grignard reagent to obtain a compound in a formula 3; (3) carrying out a reduction / cyclization reaction on the compound shown in the formula 3, trifluoroacetic acid and triethylsilane to obtain a compound shown in a formula 4; (4) splitting the compound shown in the formula 4 by (D)-malic acid to obtain the (R)-2-(2, 5-difluorophenyl) pyrrolidine*D malate compound with EE being greater than 98% shown in the formula 5; and (5) dissociating the compound in the formula 5 with a sodium hydroxide solution to obtain (R)-2-(2, 5-difluorophenyl) pyrrolidine. By utilizing the synthetic method of (R)-2-(2,5-difluorophenyl)pyrrolidine, the cost is low, the optical purity is high, the subsequent separation process is simplified, the raw materials are easy to obtain, the process conditions are mild, and the synthetic method is suitable for synthesizing (R)-2-(2, 5-difluorophenyl) pyrrolidine in large-scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a synthesis method of (R)-2-(2,5-difluorophenyl)pyrrolidine. Background technique [0002] On September 23, 2019, Bayer announced that its precision tumor therapy drug larotrectinib has obtained marketing authorization in the European Union. Larotrectinib, as the first oral TRK inhibitor, is specially used to treat tumors with NTRK gene fusion, and is the first anticancer drug approved in the European Union without distinguishing tumor types. [0003] The biggest difference from previous targeted drugs is that Larotrectinib does not target tumors at a certain anatomical location, but is developed as a broad-spectrum tumor drug for all adults or children with solid tumors carrying NTRK fusion genes. [0004] TRK gene fusion refers to the fusion of NTRK gene family members (NTRK1, NTRK2, NTRK3) with another unrelated gene due to chromosomal variation, resulting in a conform...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08
CPCC07D207/08C07B2200/07
Inventor 开永平文兆峰鲁刚柴宝红范银彬
Owner 北京蓝博特科技有限公司
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