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Preparation method of alkyl nitrile compound

A technology of alkyl halide and alkyl nitrile, applied in the field of preparation of alkyl nitrile compounds, can solve the problems of high price, high toxicity of cyanating reagent, unstable catalyst and the like

Inactive Publication Date: 2020-05-05
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the toxicity of the cyanation reagent used in the preparation method of the existing primary alkyl nitrile compound, the catalyst is unstable in the air, expensive, requires special reaction equipment and The long-term irradiation of ultraviolet light which is harmful to human body, and the defects of poor functional group compatibility and poor substrate universality provide a preparation method of alkyl nitrile compounds

Method used

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  • Preparation method of alkyl nitrile compound
  • Preparation method of alkyl nitrile compound
  • Preparation method of alkyl nitrile compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example 2(6

[0102]

[0103] Under air, add 6-bromo-n-hexanol (1.81g, 10mmol), dichloromethane (20mL), and imidazole (1.36g, 20mmol) successively into the reaction flask equipped with a stirring bar. Slowly added tert-butyldimethylsilyl chloride (2.26g, 15mmol), a large amount of white solid precipitated out, and reacted at room temperature for 7h. The reaction was complete as detected by TLC, the reaction was quenched by saturated ammonium chloride solution, the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, silica gel column chromatography, the eluent was petroleum ether:ethyl acetate=100:1, the product It is 2.33g of yellow liquid, the yield is 79%, 1 H NMR purity greater than 98%. 1 H NMR (400MHz, CDCl 3 )δ3.60(t, J=6.4Hz, 2H), 3.40(t, J=6.8Hz, 2H), 1.86(quint, J=6.8Hz, 2H), 1.55-1.31(m, 6H), 0.89( s,9H),0.04(s,6H); 13 C NMR (100MHz, CDCl 3 )δ62.99, 33.88, 32.78, 32.58, 27.95, 25.94, 24.99, 18.33, -5.31.

preparation example 3(6

[0105]

[0106] Under argon, phthalimide (1.47g, 10mmol), potassium carbonate (4.15g, 30mmol), tetrabutylammonium bromide (322.4mg, 1mmol) were sequentially added to the reaction flask equipped with a stirring bar, The gas was exchanged three times under argon, 1,3-dibromopropane (3.0 mL, 30 mmol) was added, and the mixture was reacted at room temperature for 4 h. TLC detects that the reaction is complete, the reaction is quenched with water, the organic phase is extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and silica gel column chromatography, the eluent is petroleum ether to petroleum ether: ethyl acetate=5: 1, the product is White solid 1.21g, yield 45%, 1 H NMR purity greater than 98%. 1 H NMR (400MHz, CDCl 3 )δ7.87-7.84(m,2H),7.76-7.73(m,2H),3.86-3.83(m,2H),3.44-3.41(m,2H),2.30-2.23(m,2H); 13 C NMR (100MHz, CDCl 3 )δ168.18, 134.01, 131.90, 123.25, 36.64, 31.56, 29.79.

Embodiment 1

[0107] Example 1 (5a)

[0108]

[0109] In a glove box filled with nitrogen, add Zn(CN) to the 4mL sample bottle in sequence 2 (47.0mg, 0.4mmol), n-Bu 4 NCl (277.9mg, 1.0mmol), cap the bottle, remove from the glove box, add N-methylpyrrolidone (0.5mL) and 4a (77.3mg, 0.5mmol) successively under air, cap the bottle, and place at 140°C Reaction 6h. The reaction was complete as detected by TLC, the reaction was quenched with water, the organic phase was extracted with ether, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography, the eluent was petroleum ether: dichloromethane = 3:1, and the product was 57.3 mg of a colorless liquid , yield 79%, 1 H NMR purity greater than 98%. 1 H NMR (400MHz, CDCl 3 )δ7.32-7.17 (m, 5H), 2.76 (t, J = 7.6Hz, 2H), 2.29 (t, J = 7.2Hz, 2H), 1.99-1.92 (m, 2H); 13 C NMR (100MHz, CDCl 3 )δ139.61, 128.53, 128.33, 126.36, 119.42, 34.22, 26.77, 16.22.

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Abstract

The invention discloses a preparation method of an alkyl nitrile compound shown as formula I. The preparation method comprises the following step: in a solvent, in the presence of an additive, carrying out substitution reaction as shown in the specification on a cyanation reagent and an alkyl halide shown as formula II to obtain the alkyl nitrile compound shown as formula I, wherein the cyanationreagent is Zn (CN) 2 and / or Cu (CN) 2; the additive is one or more of an inorganic base, an organic base and a quaternary ammonium salt.

Description

technical field [0001] The invention relates to a preparation method of alkyl nitrile compounds. Background technique [0002] Alkyl nitrile compounds are important intermediates in organic synthesis, which can be converted into many corresponding alkyl amides, alkyl amines, nitrogen-containing heterocycles, alkyl carboxylic acids and their derivatives, etc., and are also used in medicines, pesticides and some Important structural units of organic materials (Fleming, F.F.; Yao, L.; Ravikumar, P.C.; Funk, L.; Shook, B.C.J. Med. Chem. 2010, 53, 7902.). For example, in April 2018, baricitinib, jointly brought by Eli Lilly and Incyte, is a once-daily oral JAK inhibitor, mainly used for the treatment of inflammation and autoimmune diseases; currently, the U.S. FDA Arthritis Advisory Committee has recommended Approved 2 mg baricitinib as a once-daily oral agent for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate resp...

Claims

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Application Information

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IPC IPC(8): C07B43/08C07D209/48C07D209/08C07F7/18C07C253/14C07C255/33C07C255/40C07C255/13C07C255/37C07C255/14B01J27/138B01J27/232B01J31/02
CPCB01J27/138B01J27/232B01J31/0237B01J31/0239B01J31/0244C07B43/08C07C253/14C07D209/08C07D209/48C07F7/188C07F7/1892C07C255/33C07C255/40C07C255/13C07C255/37C07C255/14Y02P20/55
Inventor 刘元红夏爱游解鑫
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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