Synthesis method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound

A synthesis method and compound technology, applied in alcohol amination, formylation and dehydration reactions, can solve the problems of poor reduction selectivity, complicated post-processing, etc., achieve high selectivity, improve reduction yield, simple operation and processing. Effect

Active Publication Date: 2020-02-14
JIANGXI NORMAL UNIV
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  • Abstract
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  • Claims
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Problems solved by technology

[0008] When lithium aluminum hydride reduces difluoromethylene amide in this route, because the fluorine atom is also very easily reduced, it is easy to generate by-product diphenylthioethylamine, and the target product 2,2-difluoro-phenylthio-ethylamine is produced The rate is only 45%, and excessive flammable and highly dangerous lithium aluminum hydride is used as the reducing agent, the reduction selectivity is poor, and the post-treatment is cumbersome, which restricts the large-scale production of difluoromethyl isocyanide

Method used

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  • Synthesis method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound
  • Synthesis method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound
  • Synthesis method of 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound

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Experimental program
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Effect test

Embodiment 1

[0056]

[0057] Thiophenol (5.5 mL, 1.0 equiv) was dissolved in dimethyl sulfoxide (50 mL), and sodium hydride (2.4 g, 1.1 equiv) was slowly added in ice-cooling condition, and the reaction was stirred at 40° C. for 1 h. Ethyl difluorobromoacetate (12.0 g, 1.1 equiv) was added to the reaction liquid and stirred for 15 h. TLC showed that the raw materials were completely reacted. Quenched with aqueous ammonium chloride and extracted with ether, the organic layer was washed with water and brine successively, washed with anhydrous MgSO 4 Dry and concentrate under reduced pressure to obtain the crude product, 10.7 g of the product separated by column chromatography, the yield is 86%. 1 H NMR (400MHz, CDCl 3 ): δ7.57–7.51(m,2H),7.41–7.35(m,1H),7.31(dd,J=8.2,6.5Hz,3H),4.16(q,J=7.2Hz,2H),1.16( t,J=7.1Hz,3H). 19 F NMR (376MHz, CDCl 3 ): δ-82.21.

Embodiment 2

[0059]

[0060] Dissolve ethyl 2,2-difluoro-2-(phenylthio)acetate (20g, 1.0equiv) in dry ethanol (200mL), add sodium borohydride (6.5g, 2.0equiv) under ice-cooling conditions, and The reaction was stirred for 3 h, and TLC showed that the raw materials were completely reacted. Quenched with aqueous ammonium chloride and extracted with dichloromethane, washed the organic phase with saturated brine, and distilled under reduced pressure to obtain a crude product, which was separated by column chromatography (PE:EA=30:1) to obtain 14.7 g of the product with a yield of 90 %. 1 H NMR (400MHz, CDCl 3 ): δ7.66–7.61(m,2H),7.48–7.36(m,3H),3.87(t,J=11.8Hz,2H); 19 F NMR (376MHz, CDCl 3 ): δ-84.27; 13 CNMR (100MHz, CDCl 3 ) δ 136.5, 130.2, 129.4, 128.3 (t, J = 280.0 Hz), 126.0 (t, J = 2.8 Hz), 65.0 (t, J = 29.9 Hz).

Embodiment 3

[0062]

[0063] 2,2-Difluoro-2-(phenylthio)ethan-1-ol (10 g, 1.0 eqiv) was dissolved in HOAc: H 2 In the mixed solution of O (10:19mL), add 30% H 2 o 2 (3.9g, 2.2equiv) was added to the reaction system, and the reaction system was 2 Under protection, the reaction was stirred at 120°C for about 4 h, the reaction mixture was cooled to room temperature and extracted with EA, and the organic phase was washed with saturated brine and saturated NaHCO 3 The solution was washed, the organic phase was dried with anhydrous sodium sulfate, and the crude product was obtained by distillation under reduced pressure, which was separated by column chromatography (PE:EA=9:1) to obtain 9.9 g of the product with a yield of 85%. 1 H NMR (400MHz, CDCl 3 )δ8.01(d, 2H, J=7.8Hz), 7.80(t, 1H, J=7.5Hz), 7.65(t, J=7.9Hz, 2H), 4.31(t, J=12.8Hz, 2H) ,2.74(s,1H). 19 F NMR (376MHz, CDCl 3 )δ-111.20(t,J=12.9Hz).

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Abstract

The invention discloses a synthesis method of a 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound. The synthesis method is characterized in that the 1, 1-difluoro-2-isonitrile-ethyl phenyl sulfone compound is synthesized from a 2, 2-difluoro-2-(thiophenyl) ethyl acetate compound through the steps of reduction, oxidation, alcohol amination, formylation, dehydration reaction and the like. According to the method, reducing agent lithium aluminum hydride which is dangerous and poor in selectivity is prevented from being used for reducing a difluoromethyl amide intermediate low in reaction activity; the mild reducing agent sodium borohydride is adopted to reduce the 2, 2-difluoro-2-( thiophenyl) ethyl acetate compound high in activity, so that the reduction yield and selectivity are greatly improved, and the method is simple to operate, stable in product property and beneficial to large-scale production.

Description

technical field [0001] The present invention relates to a kind of synthetic method of 1,1-difluoro-2-isonitrile-ethylphenyl sulfone compound, especially to a method using 2,2-difluoro-2-(phenylthio) ethyl acetate The method for efficiently synthesizing difluoroisonitrile aryl sulfone compounds through reduction, oxidation, alcohol amination, formylation and dehydration reactions in sequence, belongs to the technical field of synthesis of pharmaceutical intermediates isonitrile compounds. Background technique [0002] As a class of highly active and important synthetic intermediates, isonitrile compounds have played an irreplaceable role in the field of organic synthesis. Represented by the Ugi reaction, isonitriles are often used to synthesize some amides and polypeptides (Ugi. Angew. Chem. Int. Ed. 2000, 39, 3168.). In 1985, Lieke discovered the first isocyanide for the first time. Isonitrile compounds are widely used in the synthesis of heterocyclic derivatives and are im...

Claims

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Application Information

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IPC IPC(8): C07C315/04C07C317/44
CPCC07C315/04C07C319/14C07C319/20C07C315/02C07C317/44C07C323/52C07C323/12C07C317/18C07C317/28
Inventor 严楠刘瑶张向梅余潇兵胡祥国郭晓红
Owner JIANGXI NORMAL UNIV
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