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Preparation method of alkyl nitrile compound

A technology of alkyl halides and compounds, which is applied in the field of preparation of alkyl nitrile compounds, and can solve problems such as poor functional group compatibility, high price, and poor substrate universality

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

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Problems solved by technology

[0016] 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 alkyl nitrile compound, the catalyst is unstable in the air, expensive, requires a special reaction device and is harmful to the human body. The long-term irradiation of harmful ultraviolet light, poor compatibility of functional groups, poor substrate universality and other defects provide a method for the preparation 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
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Effect test

preparation example 6(1

[0132]

[0133] Under the protection of argon, N-benzyl-3-pyrrolidinol (1.06g, 6mmol), toluene (11mL), phosphorus oxychloride (2.3mL, 24.6mmol) were successively added to the reaction flask, heated to reflux for 4h, and detected by TLC The response is complete. The reaction solution was slowly poured into ice water to quench the reaction, the solid potassium carbonate adjusted the pH of the system to alkaline, the organic phase was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated, silica gel column chromatography, the eluent was n-pentane to ethyl acetate, the product is a yellow liquid 807.4mg, yield 69%, 1 H NMR purity greater than 98%. 1 H NMR (400MHz, CDCl 3 )δ7.31-7.22 (m, 5H), 4.39-4.33 (m, 1H), 3.66 (dd, J = 24.8Hz, 12.8Hz, 2H), 3.07 (dd, J = 10.4Hz, 6.4Hz, 1H) ,2.78-2.61(m,3H),2.45-2.35(m,1H),2.10-2.02(m,1H); 13 C NMR (100MHz, CDCl 3 )δ138.47,128.62,128.24,127.02,63.21,59.93,56.24,52.45,35.80.IR(neat):2794,1495,1453,1377,1350,1...

preparation example 7(1

[0135]

[0136] Under argon protection, add phenylpropanal (1.34g, 10.7mmol) and tetrahydrofuran (20mL) successively in the reaction flask equipped with a stirring bar, ice-water bath, methylmagnesium bromide (2mL, 1M in THF, 12mmol) slowly Add it into the system, return to room temperature and react for 20h, and TLC detects that the reaction is complete. Quench the reaction with saturated ammonium chloride solution, extract the organic phase with dichloromethane, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate, perform silica gel column chromatography, and the eluent is petroleum ether: ethyl acetate = 10:1 , the product was a colorless liquid, which was directly used in the next reaction.

[0137] Under the protection of argon, the above crude product, triphenylphosphine (5.25g, 20mmol), and dichloromethane (20mL) were added to the reaction flask equipped with a stirrer in sequence, and trichloroacetamide (3.25g , 20mmol), rea...

preparation example 8(1

[0139]

[0140] Silica gel column chromatography, eluent is sherwood oil, product is colorless liquid 851.4mg, two-step total yield 47%, 1 H NMR purity greater than 98%. 1 H NMR (400MHz, CDCl 3 )δ7.30-7.26(m,2H),7.21-7.17(m,3H),3.83-3.77(m,1H),2.91-2.84(m,1H),2.77-2.65(m,1H),2.03- 1.95(m,2H),1.84-1.64(m,2H),1.01(t,J=7.6Hz,3H); 13 C NMR (100MHz, CDCl 3 )δ141.20,128.49,128.42,125.98,64.75,39.72,32.71,31.55,10.85.IR(neat):3060,3027,2967,2939,2874,1603,1496,1454,1381,1301,1237,1030,966,903,836,807,746,698,660. HRMS(EI)C 11 h 15 Cl[M] + : Calculated value: 182.0862, Measured value: 182.0857.

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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 and a catalyst, Zn (CN) 2 and an alkyl halide shown as formula II are subjected to a coupling reaction as shown in the specification to obtain the alkyl nitrile compound as shown in the formula I, wherein theadditive comprises an alkali, the catalyst comprises a nickel compound and a phosphine ligand; the nickel compound is one or more of zero-valent nickel, monovalent nickel salt and divalent nickel salt; when the nickel compound contains zero-valent nickel or divalent nickel salt, the catalyst further comprises a reducing agent. According to the preparation method disclosed by the invention, cyanation of an alkyl halide can be simply, conveniently and efficiently realized by using a cheap catalytic system, and the preparation method also has good functional group compatibility and substrate universality.

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, Saxagliptin and Vildagliptin, which are used for the treatment of type II diabetes, form a covalent bond between the cyano group on the pyrrole ring and the hydroxyl group on the key amino acid to cut off its hydrolysis channel, thereby achieving the therapeutic effect on type II diabetes. Cilomilast, a drug for treating inflammation and asthma, and Verapamil and Gallopamil, drugs for treating arrhythmia and angina...

Claims

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Application Information

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IPC IPC(8): C07B43/08C07D211/96C07C253/14C07C255/46C07C255/47C07C255/13C07C255/40C07C255/33C07C255/37C07J41/00C07D207/16C07D211/34C07C43/174C07C255/54C07C43/225
CPCC07B43/08C07D211/96C07C253/14C07J41/0094C07D207/16C07D211/34C07C43/174C07C255/54C07C43/225C07C2601/14C07C2602/10C07C2602/08C07C2601/18C07C2603/74C07C255/46C07C255/47C07C255/13C07C255/40C07C255/33C07C255/37Y02P20/55Y02E60/10
Inventor 刘元红夏爱游解鑫
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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