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Chiral alpha-deuterium (hydrogen) alpha-fluoroketone compound and asymmetric catalytic synthesis method thereof

A synthetic method and technology of fluoroketones, applied in the field of asymmetric catalysis, can solve problems such as synthetic methods that have not been reported yet, and achieve the effect of enriching the library of chiral α-fluoroketones and promoting the application

Inactive Publication Date: 2019-08-30
EAST CHINA NORMAL UNIV
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Problems solved by technology

[0007] So far, chemists have developed many asymmetric catalytic reactions to efficiently synthesize chiral α-fluorocarbonyl compounds, and systematically study chiral α-tertiary carbon α-fluoroketones, especially α-deuterated The synthesis method of α-fluoroketones has not been reported yet

Method used

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  • Chiral alpha-deuterium (hydrogen) alpha-fluoroketone compound and asymmetric catalytic synthesis method thereof
  • Chiral alpha-deuterium (hydrogen) alpha-fluoroketone compound and asymmetric catalytic synthesis method thereof
  • Chiral alpha-deuterium (hydrogen) alpha-fluoroketone compound and asymmetric catalytic synthesis method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Synthesis of chiral α-deuterated α-fluoroketones II-1:

[0088]

[0089] Add chiral tetragonal acid catalyst A (9.0mg, 0.015mmol), deuterated methanol (3.0mL), and monofluoroenol silyl ether I-1 (65.4mg, 0.3mmol) to a 5.0mL reaction bottle in the glove box , deuterium water (5.5uL, 0.3mmol), and the reaction solution was stirred at 25°C for 2 days. TLC detects that the raw materials have basically reacted, and the reaction is stopped. Direct loading column chromatography obtained white solid product II-1 with 98% yield and 95% deuteration rate. HPLC analysis (Chiralpak AS-H, i PrOH / hexane=10 / 90, 1.0mL / min, 230nm; t r (minor) = 11.04min,t r (major)=13.41min) gave the isomeric composition of the product: 90%ee, [α] 20 D =-8.6 (c=0.5, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 ): δ7.79(d, J=7.6Hz, 1H), 7.68-7.64(m, 1H), 7.47-7.41(m, 2H), 5.26(ddd, J=50.8Hz, J=7.6Hz, J= 4.4Hz, 0.06H), 3.62(dd, J=17.2Hz, J=7.2Hz, 1H), 3.22(dd, J=23.2Hz, J=17.2Hz, 1H); 13 C NMR (100MHz, ...

Embodiment 2

[0091] Synthesis of chiral α-deuterated α-fluoroketones II-2:

[0092]

[0093] Add chiral tetragonal acid catalyst B (9.0mg, 0.015mmol), deuterated methanol (3.0mL), and monofluoroenol silyl ether I-1 (65.4mg, 0.3mmol) to a 5.0mL reaction bottle in the glove box , deuterium water (5.5uL, 0.3mmol), and the reaction solution was stirred at 25°C for 2 days. TLC detects that the raw materials have basically reacted, and the reaction is stopped. Direct loading column chromatography obtained white solid product II-2 with 99% yield and 96% deuteration rate. HPLC analysis (Chiralpak AS-H, i PrOH / hexane=10 / 90, 1.0mL / min, 230nm; t r (minor) = 13.41min,t r(major)=11.04min) gave the isomeric composition of the product: 89%ee, [α] 20 D =+8.5 (c=0.5, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 ): δ7.79(d, J=7.6Hz, 1H), 7.68-7.64(m, 1H), 7.47-7.41(m, 2H), 5.26(ddd, J=50.8Hz, J=7.6Hz, J= 4.4Hz, 0.04H), 3.62(dd, J=17.2Hz, J=7.2Hz, 1H), 3.22(dd, J=23.2Hz, J=17.2Hz, 1H); 13 C NMR (100MHz, C...

Embodiment 3

[0095] Synthesis of chiral α-deuterated α-fluoroketones II-3:

[0096]

[0097] Add chiral tetragonal acid catalyst A (9.0mg, 0.015mmol), deuterated methanol (3.0mL), and monofluoroenol silyl ether I-2 (67.2mg, 0.3mmol) to a 5.0mL reaction bottle in the glove box , deuterium water (5.5uL, 0.3mmol), and the reaction solution was stirred at 25°C for 2 days. TLC detects that the raw materials have basically reacted, and the reaction is stopped. The product II-3 was obtained as a yellow liquid with 86% yield and 96% deuteration rate by direct column chromatography. HPLC analysis (Chiralpak OJ-H, i PrOH / hexane=3 / 97, 1.0mL / min, 205nm; t r (minor) = 14.03min,t r (major)=16.71min) gave the isomeric composition of the product: 84%ee, [α] 27 D =-4.6 (c=0.5, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 ): δ7.71-7.66(m, 2H), 7.20-7.15(m, 2H), 5.78(d, J=58.8Hz, 0.04H); 13 C NMR (100MHz, CDCl 3 ): δ192.97(d, J=14.0Hz, 1C), 171.40(d, J=3.0Hz, 1C), 139.48, 124.58(d, J=157.0Hz, 1C), 118.30,...

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Abstract

The invention discloses a chiral alpha-deuterium (hydrogen) alpha-fluoroketone compound and an asymmetric catalytic synthesis method thereof. The compound has the structure represented by the following formula (I), has potential biological activity and pharmacodynamic activity, provides a strong technical support for the development of new drugs, and has high practical value. The synthesis methodstarts from using distilled water or deuterium water and a nucleophilic reagent monofluoroenol silicon ether as raw materials, the chiral alpha-deuterium (hydrogen) alpha-fluoroketone compound is efficiently synthesized in one step by an asymmetric deuterium (proton) lysis reaction catalyzed by a chiral amine-hydrogen bond donor bifunctional catalyst, and the specific reaction process is shown inthe reaction formula (A). The method has the characteristics that the raw materials are cheap and easy to obtain; the reaction conditions are mild, and the operation is simple and convenient; and thesubstrate structure is rich and diverse, the good-to-excellent yield and enantioselectivity can be obtained, and the like.

Description

technical field [0001] The invention belongs to the technical field of organic compounds, and relates to a class of chiral α-tertiary carbon α-deuterium (hydrogen) α-fluoroketone compounds and a process for synthesizing such compounds from monofluoroenol silyl ether and distilled water or deuterium water Asymmetric catalytic approach. Background technique [0002] Fluorine is located in the main group VII of the second period of the periodic table, and is the most electronegative element with a small atomic radius. Many research results have shown that the introduction of fluorine atoms or fluorine-containing groups into organic compounds can improve the physical and chemical properties of the corresponding compounds, as well as increase the bioavailability, lipophilicity, binding affinity, and metabolic stability of bioactive molecules. properties and membrane permeability. Therefore, the selective introduction of fluorine atoms or fluorine-containing groups into known dr...

Claims

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Application Information

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IPC IPC(8): C07C45/51C07D307/83C07C49/697C07C49/755C07C49/687C07C49/80C07B41/06C07B59/00
CPCC07B41/06C07B59/001C07B59/002C07B2200/05C07B2200/07C07C45/513C07D307/83C07C2601/16C07C2602/08C07C2602/10C07C2602/12C07C49/697C07C49/755C07C49/687C07C49/80
Inventor 周剑廖奎余金生
Owner EAST CHINA NORMAL UNIV
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