CN101830767B - Method for synthesizing difluoromethyl compound - Google Patents

Method for synthesizing difluoromethyl compound Download PDF

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CN101830767B
CN101830767B CN201010146347.9A CN201010146347A CN101830767B CN 101830767 B CN101830767 B CN 101830767B CN 201010146347 A CN201010146347 A CN 201010146347A CN 101830767 B CN101830767 B CN 101830767B
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difluoromethyl
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CN101830767A (en
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胡金波
王飞
黄维洲
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention relates to a method for synthesizing compound containing difluoromethyl group, in particular to a method for synthesizing difluoromethyl ether, thioether, selenide, difluoromethyl amine and difluoromethyl alkyne compounds. Difluoromethyl trialkyl ammonium salt (RaRbRc(CF2H)N+X-) applied as a difluorocarbene reagent and a compound containing active hydrogen are used as raw materials, and a compound in which the active hydrogen is substituted by difluoromethyl is obtained in the presence of alkali at proper temperature. The active hydrogen compound is a compound having active hydrogen on the hetero atom of oxygen, sulfur, selenium or ammonia or on the end of terminal alkyne. The difluoromethyl trialkyl ammonium salt used in the invention is a highly effective difluorocarbene reagent with a good universal adaptation.

Description

A kind of method of synthesizing difluoromethyl compound
Technical field
The present invention relates to the synthetic method of fluorine-containing medicines, pesticide intermediate, is to utilize first difluoromethyl trialkyl ammonium salts (R ar br c(CF 2h) N +x -) the next synthetic method containing difluoromethyl compound.
Background technology
Due to the peculiar property of fluorine atom, a host of facts show: the physiologically active of introducing difluoromethyl in molecule and often can effectively improve organic molecule.So, more and more come into one's own in the fields such as agricultural chemicals and material at medicine containing difluoromethyl compounds.((a) Kirsch, P.Modern Fluoroorganic Chemistry:Synthesis, Reactivity, Applications; Wiley-VCH:Weinheim, 2004. (b) OrganofluorineCompounds:chemistry and Applications; Hiyama, T., Ed.; Springer:New York, 2000.) using difluorocarbene as a kind of difluoromethyl or difluoro methylene building block be the good approach of one achieving the above object.
The most cost-effective difluorocarbene's precursor is Freon22 gas (HCF so far 2cl) ((a) Miller, T.G.; Thanassi, J.W.J.Org.Chem.1960,25,2009. (b) Shen, T.Y.; Lucas, S.; Sarett, L.H.Tetrahedron Lett.1961,2,43. (c) Langlois, B.J.Fluorine Chem.1988,41,247. (d) Morimota, K.; Makino, K.; Sakata, G.J.Fluorine Chem.1992,59,417.), but Freon gas has destruction to atmospheric ozone layer.And its reactive behavior is general, needed amount is larger.In addition ClF 2cCOONa and ClF 2cCOOMe is also wider method ((a) Christensen, S.B., the IV of relative efficiency application; Dabbs, H.E.; Karpinski, J.M.PCT International Application, WO 96/23754,1996. (b) Ho, J.Z.; Elmore, C.S.; Wallace, M.A.; Yao, D.; Braun, M.P.; Dean, D.C.; Melillo, D.G.; Chen, C.-Y.Helvetica Chim.Acta 2005,88,1040. (c) O ' shea, P.D.; Chen, C.-Y.; Chen, W.; Dagneau, P.; Frey, L.F.; Grabowski, E.J.J.; Marcantonio, K.M.; Reamer, R.A.; Tan, L.; Tillyer, R.D.; Roy, A.; Wang, X.; Zhao, D.J.Org.Chem.2005,70,3021.).The metallic compound of trifluoromethyl is as Me 3snCF 3, PhHgCF 3, BrZnCF 3, BrCdCF 3also can serve as Cabbeen reagent, but its synthetic relative complex, and toxicity is high, thereby has greatly limited its application ((a) Seyferth, D.; Hoppe, S.P., J.Organomet.Chem., 1971,26,64. (b) Seyferth, D.; Hoppe, S.P; Darragh.K.V., J.Am.Chem.Soc.1969,91,6536.).The class difluorocarbene reagent occurring is recently as PhCOCF 2cl, PhSO 2cF 2cl, efficiency is higher, has fewer environmental impacts, but universality general (Zhang, L.; Zheng, J.; Hu, J., J.Org.Chem., 2006,71,9845; Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G.J.; Federsel, H ,-J., Chen.Comm., 2007,5149).Other is as CF 2br 2((a) Dolbier, W.R.; Burkholder, Jr.C R, J.Org.Chem., 1990,55; 589; (b) Dolbier, W.R.; Wojtowicz, J.H.; Burkholder, C.R., J.Org.Chem., 1990; 55,5420; (c) Crabbe, P.; Cervantes, A.; Cruz A.; Galeazzi, E.; Iriarte, J.; Velarde, E., J.Am.Chem.Soc, 1973,95,6655), FSO 2cF 2cOOH (Chen, Q.-Y.; Wu, S.-W.J.Fluorine Chem.1989,44,433.), FSO 2cF 2cOOSiMe 3(Tian, F.; Virginie, B.; Duan, J.X., Dolbier, W.R.Jr.; Chen, Q.Y., Org Lett., 2000,2,563.) etc. also have certain application.
Summary of the invention
The object of this invention is to provide the synthetic method that contains difluoromethyl compound, is exactly the method for synthesizing difluoromethyl ether, thioether, selenide compounds and difluoromethyl amine, difluoromethyl acetylene compound specifically.A kind of efficient and universality is good makes the method that the hydrogen on the upper or Terminal Acetylenes carbon of heteroatoms (oxygen, sulphur, selenium or nitrogen) is replaced by difluoromethyl.
Method of the present invention adopts difluoromethyl trialkyl ammonium salts R ar br cn +(CF 2h) X -as difluorocarbene's reagent, it can be introduced difluoromethyl in the organic molecule that contains reactive hydrogen, is a kind of mild condition, productive rate is high, universality is high reagent.Wherein, R a, R b, R cfor alkyl or the phenyl of C1-C16, X -for halogen or other negative ions.
Above-mentioned in the present invention can be for synthesizing corresponding fluorinated organic compound by there is following reaction containing difluoromethyl ammonium salt, and its synthetic method is as follows:
At-78 DEG C～50 DEG C of organic solvent neutralizations, contain the R that has reactive hydrogen on hydroxyl, sulfydryl, selenium atom or nitrogen-atoms 1zH compounds and terminal alkyne the compound that class contains reactive hydrogen is raw material, under the effect of alkali, reacts and within 5～60 minutes, generates corresponding salt, then adds difluoromethyl trialkyl ammonium salts (R ar br cn +(CF 2h) X -as difluorocarbene's reagent react 0.5～10 hour, make the alkynes being replaced by difluoromethyl containing compound that on the heteroatoms of aerobic, sulphur, selenium, nitrogen heteroatom, hydrogen is replaced by difluoromethyl or end hydrogen; Recommendation response temperature is-78 DEG C～room temperature, is preferentially chosen to reactant salt temperature-78 DEG C～10 DEG C, and salt and difluorocarbene's reagent react temperature are room temperature.
Described Z is S, O, Se or N;
R 1for alkyl, the vinyl of C1-C18, contain R 3and R 4the aryl that replaces, at least contain one to four N, S, Se or O five-membered ring, at least contain one to four N, S, Se or O benzo or benzene connection five-membered heterocycles; Wherein R 3, R 4for the alkyl of H, halogen, C1-C4, alkoxyl group, nitro, aryl, allyl group or the cyano group etc. of C1-C4;
R 2for for the alkyl of C1-C18, contain R 5and R 6the aryl replacing; Wherein R 5, R 6for the alkyl of H, halogen, C1-C4, alkoxyl group, nitro, aryl, allyl group or the cyano group etc. of C1-C4;
Described aryl is phenyl or naphthyl;
Described organic solvent is acetonitrile, toluene, tetrahydrofuran (THF), ether, glycol dimethyl ether, hexanaphthene, Skellysolve A or normal hexane etc.;
Described alkali can be lithium diisopropylamine, n-Butyl Lithium, potassium tert.-butoxide, sodium hydride, potassium hydride KH, hydrolith, cesium hydroxide or potassium hydroxide etc.;
R a, R b, R cfor alkyl, the phenyl or naphthyl of C1-C16, X -for halogen (F, Cl, Br, I) or other negative ions, as nitrate radical or cyanogen sulphur root etc.;
The upper compound of hydrogen of described heteroatoms (oxygen, sulphur, selenium or nitrogen) or the mol ratio of end alkyne compound, alkali and difluoromethyl trialkyl ammonium salts are 1: 1～4: 1～4, and recommending mol ratio is 1: 1.2～3: 1.2～2.
Type reaction is as follows:
Above a few class reaction substrates without exception be the compound that contains reactive hydrogen, after reaction finishes, can add the suitable shrend reaction of going out, then with appropriate solvent extraction, be dried, column chromatographic isolation and purification, finally obtain the product that reactive hydrogen is replaced by difluoromethyl.
Embodiment
Utilize following embodiment will contribute to understand the present invention, but do not limit content of the present invention.
Embodiment 1
Under nitrogen protection, p-phenyl phenol (85mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 83mg, productive rate 75%.
Embodiment 2
Under nitrogen protection, phenol (49mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether.Obtain product taking phenylfluoroform as interior mark, Enantiomeric excess productive rate 52%.
Embodiment 3
Under nitrogen protection, p-NP (70mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 93mg, productive rate 98%.
Embodiment 4
Under nitrogen protection, para-chlorophenol (64mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 58mg, productive rate 65%.
Embodiment 5
Under nitrogen protection, (112mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 123mg, productive rate 90%.
Embodiment 6
Under nitrogen protection, (110mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 104mg, productive rate 77%.
Embodiment 7
Under nitrogen protection, (110mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 109mg, productive rate 81%.
Embodiment 8
Under nitrogen protection, (75mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 60mg, productive rate 60%.
Embodiment 9
Under nitrogen protection, (84mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 90mg, productive rate 83%.
Embodiment 10
Under nitrogen protection, (104mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 112mg, productive rate 87%.
Embodiment 11
Under nitrogen protection, (97mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 85mg, productive rate 70%.
Embodiment 12
Under nitrogen protection, (55mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 59mg, productive rate 74%.
Embodiment 13
Under nitrogen protection, (62mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 78mg, productive rate 90%.
Embodiment 14
Under nitrogen protection, (72mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 90mg, productive rate 93%.
Embodiment 15
Under nitrogen protection, (90mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 111mg, productive rate 97%.
Embodiment 16
Under nitrogen protection, (95mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 102mg, productive rate 85%.
Embodiment 17
Under nitrogen protection, (89mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 62mg, productive rate 54%.
Embodiment 18
Under nitrogen protection, (73mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 89mg, productive rate 91%.
Embodiment 19
Under nitrogen protection, (60mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 54mg, productive rate 63%.
Embodiment 20
Under nitrogen protection, (81mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 51mg, productive rate 48%.
Embodiment 21
Under nitrogen protection, (87mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 93mg, productive rate 83%.
Embodiment 22
Under nitrogen protection, (73mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 52mg, productive rate 53%.
Embodiment 23
Under nitrogen protection, (34mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, obtains product taking phenylfluoroform as interior mark, Enantiomeric excess productive rate 73%.
Embodiment 24
Under nitrogen protection, (79mg, 0.5mmol), 3 milliliters of DMF join in reaction tubes, at 5 DEG C, add NaH (60%) (26mg, 0.65mmol), stir after 10min, add difluoromethyl tributyl ammonium chloride (164mg, 0.6mmol), allow it slowly rise to room temperature, stir 2 hours.Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 73mg, productive rate 70%.
Embodiment 25
Under nitrogen protection, in reaction flask, add phenylacetylene (102mg, 1.0mmol), with THF3 milliliter, be cooled to 0 DEG C, add butyllithium (2.5M) (0.52ml, 1.3mmol), reaction is cooled to-78 DEG C after half an hour, adds difluoromethyl tributyl ammonium chloride (328mg, 1.2mmol), naturally be raised to room temperature, react and add shrend to go out after 8 hours, extracted with diethyl ether, obtains product mark in being done by phenylfluoroform, Enantiomeric excess productive rate 45%.
Embodiment 26
Under nitrogen protection, in reaction flask, add phenylacetylene (82mg, 1.0mmol) with 3 milliliters of THF, be cooled to 0 DEG C, add butyllithium (2.5M) (0.52ml, 1.3mmol), reaction is cooled to-78 DEG C after half an hour, add difluoromethyl tributyl ammonium chloride (328mg, 1.2mmol), be naturally raised to room temperature, react and add shrend to go out after 8 hours, extracted with diethyl ether obtains product mark in being done by phenylfluoroform, Enantiomeric excess productive rate 20%.
Embodiment 27
Under nitrogen protection, in reaction flask, add phenylacetylene (116mg, 1.0mmol) with 3 milliliters of THF, be cooled to 0 DEG C, add butyllithium (2.5M) (0.52ml, 1.3mmol), reaction is cooled to-78 DEG C after half an hour, add difluoromethyl tributyl ammonium chloride (328mg, 1.2mmol), be naturally raised to room temperature, reacting added shrend to go out after 8 hours, adding ammoniacal liquor (1ml, 25%wt%) and Silver Nitrate (338mg, 2mmol) and ether 4ml stirs one hour, use again extracted with diethyl ether separatory, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 70mg, productive rate 42%.
Embodiment 28
Under nitrogen protection, in reaction flask, add phenylacetylene (182mg, 1.0mmol) with 3 milliliters of THF, be cooled to 0 DEG C, add butyllithium (2.5M) (0.52ml, 1.3mmol), reaction is cooled to-78 DEG C after half an hour, add difluoromethyl tributyl ammonium chloride (328mg, 1.2mmol), be naturally raised to room temperature, reacting added shrend to go out after 8 hours, add ammoniacal liquor (1ml, 25%wt%) and Silver Nitrate (338mg, 2mmol) and ether 4ml and stir half an hour, use again extracted with diethyl ether separatory, anhydrous MgSO 4dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product 93mg, productive rate 40%.

Claims (7)

1. contain a synthetic method for difluoromethyl compound, it is characterized in that, at-78 DEG C～50 DEG C of organic solvent neutralizations, on sulphur, oxygen or selenium atom, connecting the R of reactive hydrogen 1zH compound or the terminal alkyne that contains reactive hydrogen for raw material, under the effect of alkali, react and within 5～60 minutes, generate corresponding salt, then add difluoromethyl R ar br cbase ammonium salt R ar br cn +(CF 2h) X -as difluorocarbene's reagent react 0.5～10 hour, make the alkynes that compound that on oxygen, sulphur or selenium heteroatoms, reactive hydrogen is replaced by difluoromethyl or end reactive hydrogen are replaced by difluoromethyl;
Described Z is S, O or Se;
R 1for alkyl, the vinyl of C1-C18, contain R 3and R 4the aryl replacing, the quinary heterocyclic radical that contains to four N, S, Se or O, the benzo that contains to four N, S, Se or O or benzene connection quinary heterocyclic radical; Wherein R 3, R 4for the alkyl of H, halogen, C1-C4, alkoxyl group, nitro, aryl, allyl group or the cyano group of C1-C4;
R 2for the alkyl of C1-C18 or contain R 5and R 6the aryl replacing; Wherein R 5, R 6for the alkyl of H, halogen, C1-C4, alkoxyl group, nitro, aryl, allyl group and the cyano group of C1-C4;
Described aryl is phenyl or naphthyl;
Described organic solvent is acetonitrile, toluene, tetrahydrofuran (THF), ether, glycol dimethyl ether, hexanaphthene, Skellysolve A or normal hexane;
Described alkali is lithium diisopropylamine, n-Butyl Lithium, potassium tert.-butoxide, sodium hydride, potassium hydride KH, hydrolith, cesium hydroxide or potassium hydroxide;
On described oxygen, sulphur or selenium, connect the compound of reactive hydrogen or the terminal alkyne that contains reactive hydrogen, alkali and difluoromethyl R ar br cthe mol ratio of base ammonium salt is 1: 1～4: 1～4;
R a, R b, R cfor alkyl or the phenyl of C1-C16, X -for halogen or nitrate radical.
2. the method for claim 1, is characterized in that connecting on described sulphur, oxygen or selenium atom the R of reactive hydrogen 1zH compounds and terminal alkyne the temperature of compounds and alkali reaction is-78 DEG C～10 DEG C; Described R 1, R 2as claimed in claim 1.
3. the method for claim 1, is characterized in that connecting on described sulphur, oxygen or selenium atom the R of reactive hydrogen 1zH compounds or terminal alkyne compounds and alkali reaction generate corresponding salt, with difluoromethyl R ar br cbase ammonium salt R ar br cn +(CF 2h) X -the temperature of reaction is room temperature; Described R 1, R 2, R a, R band R cas claimed in claim 1.
4. the method for claim 1, is characterized in that connecting the compound of reactive hydrogen or the terminal alkyne that contains reactive hydrogen, alkali and difluoromethyl R on described oxygen, sulphur or selenium ar br cthe mol ratio of base ammonium salt is 1: 1.2～3: 1.2～2.
5. the method for claim 1, is characterized in that after described reaction, adds the shrend reaction of going out.
6. the method for claim 1, is characterized in that described reaction product adopts solvent extraction, column chromatographic isolation and purification.
7. contain a synthetic method for difluoromethyl compound, it is characterized in that adopting following method to obtain respectively:
(1) under nitrogen protection, 60mg, 0.5mmol, DMF3 milliliter joins in reaction tubes, adds 60%NaH26mg at 5 DEG C, and 0.65mmol stirs after 10min, adds difluoromethyl tributyl ammonium chloride 164mg, and 0.6mmol, allows it slowly rise to room temperature, stirs 2 hours; Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer, column chromatography: silicagel column, sherwood oil and ethyl acetate drip washing obtain product 54mg, productive rate 63%;
(2) under nitrogen protection, 81mg, 0.5mmol, DMF3 milliliter joins in reaction tubes, adds 60%NaH26mg at 5 DEG C, and 0.65mmol stirs after 10min, adds difluoromethyl tributyl ammonium chloride 164mg, and 0.6mmol, allows it slowly rise to room temperature, stirs 2 hours, adds H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer; Column chromatography: silicagel column, sherwood oil and ethyl acetate drip washing obtain product 51mg, productive rate 48%;
(3) under nitrogen protection, 87mg, DMF3 milliliter joins in reaction tubes, adds 60%NaH26mg at 5 DEG C, and 0.65mmol stirs after 10min, adds difluoromethyl tributyl ammonium chloride 164mg, and 0.6mmol, allows it slowly rise to room temperature, stirs 2 hours; Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer; Column chromatography: silicagel column, sherwood oil and ethyl acetate drip washing obtain product 93mg, productive rate 83%;
(4) under nitrogen protection, 73mg, 0.5mmol, DMF3 milliliter joins in reaction tubes, adds 60%NaH26mg at 5 DEG C, and 0.65mmol stirs after 10min, adds difluoromethyl tributyl ammonium chloride 164mg, and 0.6mmol, allows it slowly rise to room temperature, stirs 2 hours; Add H 2o, extracted with diethyl ether, saturated common salt water washing once, anhydrous MgSO 4dry organic layer; Column chromatography: silicagel column, sherwood oil and ethyl acetate drip washing obtain product 52mg, productive rate 53%;
(5) under nitrogen protection, 34mg, 0.5mmol, DMF3 milliliter joins in reaction tubes, adds 60%NaH26mg at 5 DEG C, and 0.65mmol stirs after 10min, adds difluoromethyl tributyl ammonium chloride 164mg, and 0.6mmol, allows it slowly rise to room temperature, stirs 2 hours; Add H 2o, extracted with diethyl ether, obtains product taking phenylfluoroform as interior mark, Enantiomeric excess productive rate 73%.
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Ewelina Nawrot,et al.Difluoromethyltrialkylammonium Salts-Their Expeditious Synthesis from Chlorodifluoromethane and Tertiary Amines in the Presence of Concentrated Aqueous Sodium Hydroxide. The Catalytic Process.《J.Org.Chem.》.2007,第72卷(第26期),10258-10260.

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