Method of asymmetric alpha-difluoromethylation of beta-ketoester through phase-transfer catalysis

A technology of phase transfer catalysis and difluoromethylation, used in organic chemistry methods, chemical instruments and methods, catalytic reactions, etc.

Active Publication Date: 2020-03-10
XINXIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there has been no case of direct asymmetric difluoromethylation of nucleophiles via asymmetric synthesis

Method used

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  • Method of asymmetric alpha-difluoromethylation of beta-ketoester through phase-transfer catalysis
  • Method of asymmetric alpha-difluoromethylation of beta-ketoester through phase-transfer catalysis
  • Method of asymmetric alpha-difluoromethylation of beta-ketoester through phase-transfer catalysis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of Ia-1 (Ia, R 1 for H, R 2 -R 5 for H)

[0026]

[0027] 1.47 g of cinchonine, 50 mL of tetrahydrofuran, and 1.27 g of benzyl bromide were added to a 50 mL three-necked flask, and the mixture was refluxed for 16 hours under the protection of argon. After the reaction was completed, it was cooled to room temperature, the mixture was poured into 50 mL of ether, filtered, and the solid was recrystallized from methanol / ether to obtain Ia-1 with a yield of 88%.

Embodiment 2

[0029] Preparation of Ia-2 (Ia, R 1 is 4-trifluoromethylphenyl, R 2 -R 5 for H)

[0030]

[0031] Weigh 5.88 g (10 mmol) of cinchonine, add it into 75 mL of dry methyl tert-butyl ether solution, and protect it under argon. 15 mL of methyl tert-butyl ether was added dropwise to 4-bromobenzotrifluoride (11.26 g, 50 mmol) in methyl tert-butyl ether solvent at -20 °C to prepare 4-trifluoromethane by lithium-halogen exchange reaction phenyllithium reagent. The prepared organolithium reagent was quickly added to the cinchonine solution and stirred at -20°C for 1 hour. The mixture was then warmed to room temperature and stirring was continued for 2 hours. After the reaction, the system was quenched with 30 mL of acetic acid, and 60 mL of water and 60 mL of ethyl acetate were added. Then add 5 g of solid iodine and stir vigorously to dissolve it. Subsequently, 2 g of sodium thiosulfate dissolved in 20 mL of water was added to quench the iodine. The mixed solution was adjust...

Embodiment 3

[0033] Preparation of Ia-3 (Ia, R 1 is 4-trifluoromethylphenyl, R 2 -R 3 for CF 3 , R 4 -R 6 for H)

[0034]

[0035] Add 0.43 g of Cn', 8 mL of chloroform, 4 mL of methanol, and 0.46 g of 3,5-trifluoromethylbenzyl bromide into a 50 mL three-necked flask. The reaction was heated to 50°C for 16 hours. After the reaction was completed, it was cooled to room temperature, poured into 50 mL of diethyl ether, and filtered. The crude product was separated by column chromatography with dichloromethane / methanol=15:1, and then recrystallized with methanol / diethyl ether to obtain Ia-3 with a yield of 53%. 1 H NMR (400MHz, CD 3 OD)δ8.56(d,J=1.6Hz,2H),8.49–8.33(m,4H),8.22(s,1H),8.16–8.09(m,1H),7.89–7.71(m,4H), 6.63(d,J=2.5Hz,1H),6.09(ddd,J=17.4,10.4,7.2Hz,1H),5.59–5.44(m,1H),5.43–5.22(m,3H),4.56(ddd, J=11.7,8.4,2.7Hz,1H),4.17(dt,J=9.9,5.3Hz,2H),3.69–3.47(m,1H),3.13(dt,J=11.6,9.1Hz,1H),2.76 –2.41 (m, 2H), 2.03 – 1.76 (m, 3H), 1.15 – 1.02 (m, 1H).

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Abstract

The invention discloses a method of asymmetric alpha-difluoromethylation of beta-ketoester through phase-transfer catalysis. The method includes: performing stirring reaction on beta-ketoester compound IIIa, a phase-transfer catalyst, TMSCF2Br and alkaline in a solvent at -78 to 60 DEG C with thin-layer chromatography for tracing the reaction until the reaction is finished, layering a mixed liquid; collecting the organic layer and spin-drying the solvent, and performing column chromatography separation to obtain chiral alpha-difluoromethyl-beta-ketoester compound IIIb. The effectiveness of themethod is embodied in that by using low-cost and feasible cinchona quaternary ammonium salt being the phase-transfer catalyst, and through the phase-transfer catalysis, the asymmetric alpha-difluoromethylation of beta-ketoester compounds is successfully achieved for the first time. The invention provides a novel and effective approach for synthesizing the alpha-difluoromethyl-beta-ketoester compound having optical activities.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a method for phase-transfer catalyzed asymmetric α-difluoromethylation of β-keto esters. Background technique [0002] Fluorinated compounds play a striking and increasingly important role in pharmaceuticals, agrochemicals, and materials science, and are widely found in natural products, chiral pharmaceuticals, and pesticide intermediates. Among them, difluoromethyl (CF 2 The H) group has attracted much attention as a bioisostere of OH / SH and a lipophilic hydrogen bond donor (J. Med. Chem. 2019, 62, 5628-5637). Because of this, organic molecules containing difluoromethyl groups have been used in many marketed drugs, such as the PDE4 inhibitor Roflumilast and the proton pump inhibitor pantoprazole. [0003] In recent years, many methods have been developed to obtain difluoromethyl-containing compounds. Transition metal catalysis is an effective means for difluoromethy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/343B01J31/02C07D453/04C07C69/757
CPCC07C67/343C07D453/04B01J31/0244C07B2200/07C07C2602/08C07C2602/10C07C2603/74B01J2231/4205C07C69/757
Inventor 王亚坤房立真从梅段迎超高飞宇陈依帆崔静雯
Owner XINXIANG MEDICAL UNIV
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