CN101830767A - Method for synthesizing difluoromethyl compound - Google Patents

Method for synthesizing difluoromethyl compound Download PDF

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CN101830767A
CN101830767A CN201010146347A CN201010146347A CN101830767A CN 101830767 A CN101830767 A CN 101830767A CN 201010146347 A CN201010146347 A CN 201010146347A CN 201010146347 A CN201010146347 A CN 201010146347A CN 101830767 A CN101830767 A CN 101830767A
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difluoromethyl
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reactive hydrogen
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CN101830767B (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 difluoromethyl trialkyl ammonium salts (R first aR bR c(CF 2H) N +X -) the next synthetic method that contains difluoromethyl compound.
Background technology
Because the peculiar property of fluorine atom, a host of facts show: introduce the physiologically active that difluoromethyl often can effectively improve organic molecule in the molecule.So contain the difluoromethyl compounds at medicine, more and more come into one's own in the fields such as agricultural chemicals and material.((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.) be a kind of approach preferably that achieves the above object with the difluorocarbene as a kind of difluoromethyl or difluoro methylene building block.
The most cost-effective so far difluorocarbene's precursor is Freon22 gas (HCF 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, and needed amount is bigger.In addition ClF 2CCOONa and ClF 2CCOOMe relatively effectively uses wider method ((a) Christensen, S.B., IV; 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 such as Me 3SnCF 3, PhHgCF 3, BrZnCF 3, BrCdCF 3Also can be as Cabbeen reagent, but its synthetic relative complex, the toxicity height, thus limited its application ((a) Seyferth, D. greatly; 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.).A nearest class difluorocarbene reagent such as a PhCOCF who occurs 2Cl, PhSO 2CF 2Cl, efficient 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. certain application also arranged.
Summary of the invention
The purpose 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.Be a kind of efficient and universality is good make that heteroatoms (oxygen, sulphur, selenium or nitrogen) is gone up or Terminal Acetylenes carbon on the method that replaced by difluoromethyl of hydrogen.
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 and contain in the organic molecule of reactive hydrogen, is a kind of mild condition, productive rate height, reagent that universality is high.Wherein, R a, R b, R cBe alkyl or the phenyl of C1-C16, X -Be halogen or other negative ions.
Above-mentioned among the present invention contains the difluoromethyl ammonium salt and can be used for synthesizing corresponding fluorinated organic compound by following reaction takes place, and its synthetic method is as follows:
Under-78 ℃～50 ℃ of organic solvent neutralizations, contain the R that reactive hydrogen is arranged on hydroxyl, sulfydryl, selenium atom or the nitrogen-atoms 1ZH compounds and terminal alkyne
Figure GSA00000085336300021
The compound that class contains reactive hydrogen is a raw material, under the effect of alkali, reacts and generates corresponding salt in 5～60 minutes, adds difluoromethyl trialkyl ammonium salts (R then aR bR cN +(CF 2H) X -As difluorocarbene's reagent react 0.5～10 hour, make the alkynes that compound that hydrogen on the heteroatoms that contains aerobic, sulphur, selenium, nitrogen heteroatom replaced by difluoromethyl or terminal hydrogen are replaced by difluoromethyl; The recommendation response temperature is-78 a ℃～room temperature, preferentially is chosen to reactant salt temperature-78 ℃～10 ℃, 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 the five-membered ring of one to four N, S, Se or O, contain benzo or the benzene connection five-membered heterocycles of one to four N, S, Se or O at least; R wherein 3, R 4Be 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 that replaces; R wherein 5, R 6Be the alkyl of H, halogen, C1-C4, alkoxyl group, nitro, aryl, allyl group or the cyano group etc. of C1-C4;
Described aryl is a 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 cBe alkyl, the phenyl or naphthyl of C1-C16, X -Be halogen (F, Cl, Br, I) or other negative ions, as nitrate radical or cyanogen sulphur root etc.;
Described heteroatoms (oxygen, sulphur, selenium or nitrogen) is gone up the compound of hydrogen or the mol ratio of end alkyne compound, alkali and difluoromethyl trialkyl ammonium salts is 1: 1～4: 1～4, and recommending mol ratio is 1: 1.2～3: 1.2～2.
Type reaction is as follows:
Figure GSA00000085336300041
More than 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, with appropriate solvent extraction, drying, column chromatographic isolation and purification, obtain the product that reactive hydrogen is replaced by difluoromethyl at last then.
Embodiment
Utilize following embodiment will help to understand the present invention, but do not limit content of the present invention.
Embodiment 1
Under the nitrogen protection, p-phenyl phenol
Figure GSA00000085336300042
(85mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300051
83mg, productive rate 75%.
Embodiment 2
Under the nitrogen protection, phenol
Figure GSA00000085336300052
(49mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether.Get product
Figure GSA00000085336300053
With phenylfluoroform is interior mark, nucleus magnetic resonance fluorine spectrum productive rate 52%.
Embodiment 3
Under the nitrogen protection, p-NP
Figure GSA00000085336300054
(70mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300055
93mg, productive rate 98%.
Embodiment 4
Under the nitrogen protection, para-chlorophenol
Figure GSA00000085336300056
(64mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300061
58mg, productive rate 65%.
Embodiment 5
Under the nitrogen protection,
Figure GSA00000085336300062
(112mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the 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 the nitrogen protection,
Figure GSA00000085336300064
(110mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300065
104mg, productive rate 77%.
Embodiment 7
Under the nitrogen protection,
Figure GSA00000085336300066
(110mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300071
109mg, productive rate 81%.
Embodiment 8
Under the nitrogen protection,
Figure GSA00000085336300072
(75mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300073
60mg, productive rate 60%.
Embodiment 9
Under the nitrogen protection,
Figure GSA00000085336300074
(84mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the 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 the nitrogen protection,
Figure GSA00000085336300076
(104mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the 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 the nitrogen protection, (97mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the 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 the nitrogen protection,
Figure GSA00000085336300084
(55mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300085
59mg, productive rate 74%.
Embodiment 13
Under the nitrogen protection,
Figure GSA00000085336300086
(62mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the 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 the nitrogen protection, (72mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300092
90mg, productive rate 93%.
Embodiment 15
Under the nitrogen protection,
Figure GSA00000085336300093
(90mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the 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 the nitrogen protection,
Figure GSA00000085336300095
(95mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300096
102mg, productive rate 85%.
Embodiment 17
Under the nitrogen protection,
Figure GSA00000085336300101
(89mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the 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 the nitrogen protection,
Figure GSA00000085336300103
(73mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300104
89mg, productive rate 91%.
Embodiment 19
Under the nitrogen protection,
Figure GSA00000085336300105
(60mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300106
54mg, productive rate 63%.
Embodiment 20
Under the nitrogen protection,
Figure GSA00000085336300111
(81mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300112
51mg, productive rate 48%.
Embodiment 21
Under the nitrogen protection,
Figure GSA00000085336300113
(87mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300114
93mg, productive rate 83%.
Embodiment 22
Under the nitrogen protection,
Figure GSA00000085336300115
(73mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300116
52mg, productive rate 53%.
Embodiment 23
Under the nitrogen protection,
Figure GSA00000085336300121
(34mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether gets product With phenylfluoroform is interior mark, nucleus magnetic resonance fluorine spectrum productive rate 73%.
Embodiment 24
Under the nitrogen protection, (79mg, 0.5mmol), DMF joins in the reaction tubes for 3 milliliters, and (26mg, 0.65mmol), behind the stirring 10min, (164mg 0.6mmol), allows it slowly rise to room temperature to 5 ℃ of following adding NaH (60%), stirs 2 hours to add difluoromethyl tributyl ammonium chloride.Add H 2O, extracted with diethyl ether, the saturated common salt water washing once, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300124
73mg, productive rate 70%.
Embodiment 25
Under the nitrogen protection, add phenylacetylene in the reaction flask (102mg, 1.0mmol) and the THF3 milliliter, be cooled to 0 ℃, add butyllithium (2.5M) (0.52ml, 1.3mmol), extremely-78 ℃ of reaction postcooling half an hour, and adding difluoromethyl tributyl ammonium chloride (328mg, 1.2mmol), naturally be raised to room temperature, react after 8 hours and to add shrend and go out, extracted with diethyl ether, product
Figure GSA00000085336300126
Make interior mark by phenylfluoroform, nucleus magnetic resonance fluorine spectrum productive rate 45%.
Embodiment 26
Under the nitrogen protection, add phenylacetylene in the reaction flask
Figure GSA00000085336300127
(82mg, 1.0mmol) and 3 milliliters of THF, be cooled to 0 ℃, and adding butyllithium (2.5M) (0.52ml, 1.3mmol), reaction postcooling half an hour is to-78 ℃, (328mg 1.2mmol), is raised to room temperature naturally to add difluoromethyl tributyl ammonium chloride, react after 8 hours and to add shrend and go out, extracted with diethyl ether gets product
Figure GSA00000085336300128
Make interior mark by phenylfluoroform, nucleus magnetic resonance fluorine spectrum productive rate 20%.
Embodiment 27
Under the nitrogen protection, add phenylacetylene in the reaction flask
Figure GSA00000085336300131
(116mg 1.0mmol) with 3 milliliters of THF, is cooled to 0 ℃, adding butyllithium (2.5M) (0.52ml, 1.3mmol), reaction postcooling half an hour is to-78 ℃, (328mg 1.2mmol), is raised to room temperature naturally to add difluoromethyl tributyl ammonium chloride, react after 8 hours and to add shrend and go out, add ammoniacal liquor (1ml, 25%wt%) and Silver Nitrate (338mg, 2mmol) and ether 4ml stirred one hour, use the extracted with diethyl ether separatory again, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300132
70mg, productive rate 42%.
Embodiment 28
Under the nitrogen protection, add phenylacetylene in the reaction flask
Figure GSA00000085336300133
(182mg 1.0mmol) with 3 milliliters of THF, is cooled to 0 ℃, adding butyllithium (2.5M) (0.52ml, 1.3mmol), reaction postcooling half an hour is to-78 ℃, (328mg 1.2mmol), is raised to room temperature naturally to add difluoromethyl tributyl ammonium chloride, react after 8 hours and to add shrend and go out, add ammoniacal liquor (1ml, 25%wt%) and Silver Nitrate (338mg, 2mmol) and ether 4ml stir half an hour, use the extracted with diethyl ether separatory again, anhydrous MgSO 4Dry organic layer.Column chromatography (silicagel column, sherwood oil and ethyl acetate drip washing) obtains product
Figure GSA00000085336300134
93mg, productive rate 40%.

Claims (6)

1. synthetic method that contains difluoromethyl compound is characterized in that containing the R of reactive hydrogen on hydroxyl, sulfydryl, selenium atom or the nitrogen-atoms under-78 ℃～50 ℃ of the organic solvent neutralizations 1ZH compound or contain the terminal alkyne of reactive hydrogen
Figure FSA00000085336200011
Be raw material, under the effect of alkali, react and generated corresponding salt in 5～60 minutes, add difluoromethyl trialkyl ammonium salts R then aR bR cN +(CF 2H) X -As difluorocarbene's reagent react 0.5～10 hour, make the alkynes that compound that reactive hydrogen on the heteroatoms that contains aerobic, sulphur, selenium or nitrogen heteroatom replaced by difluoromethyl or terminal reactive hydrogen are replaced by difluoromethyl;
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 the five-membered ring of one to four N, S, Se or O, contain benzo or the benzene connection five-membered heterocycles of one to four N, S, Se or O at least; R wherein 3, R 4Be the alkyl of H, halogen, C1-C4, alkoxyl group, nitro, aryl, allyl group or the cyano group of C1-C4;
R 2For for the alkyl of C1-C18 or contain R 5And R 6The aryl that replaces; R wherein 5, R 6Be the alkyl of H, halogen, C1-C4, alkoxyl group, nitro, aryl, allyl group and the cyano group of C1-C4;
Described aryl is a 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;
The mol ratio that contains the compound of reactive hydrogen on described oxygen, sulphur, selenium or the nitrogen or contain terminal alkyne, alkali and the difluoromethyl trialkyl ammonium salts of reactive hydrogen is 1: 1～4: 1～4;
R a, R b, R cBe alkyl or the phenyl of C1-C16, X -Be halogen, nitrate radical or cyanogen sulphur root.
2. the method for claim 1 is characterized in that the described R that reactive hydrogen is arranged on hydroxyl, sulfydryl, selenium atom or the nitrogen-atoms that contains 1ZH compounds and terminal alkyne
Figure FSA00000085336200012
The temperature of compounds and alkali reaction is-78 ℃～10 ℃; Described R 1, R 2According to claim 1.
3. the method for claim 1 is characterized in that the described R that reactive hydrogen is arranged on hydroxyl, sulfydryl, selenium atom or the nitrogen-atoms that has 1ZH compounds or terminal alkyne
Figure FSA00000085336200013
Compounds and alkali reaction generate corresponding salt, with difluorocarbene's reagent salt difluoromethyl trialkyl ammonium salts R aR bR cN +(CF 2H) X -The temperature of reaction is a room temperature; Described R 1, R 2, R a, R bAnd R cAccording to claim 1.
4. the method for claim 1, the mol ratio that it is characterized in that the terminal alkyne, alkali and the difluoromethyl trialkyl ammonium salts that contain the compound of reactive hydrogen on described oxygen, sulphur, selenium or the nitrogen or contain reactive hydrogen is for being 1: 1.2～3: 1.2～2.
5. the method for claim 1, it is characterized in that described reaction after, add 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.
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CN105646122A (en) * 2015-01-30 2016-06-08 中国科学院上海有机化学研究所 Compound containing difluoro methylthio groups and preparation method and application thereof
CN106866480A (en) * 2017-04-06 2017-06-20 盐城工学院 Many cyclophane selenide analog derivatives and preparation method thereof
CN108341759A (en) * 2017-01-22 2018-07-31 北京艾德旺科技发展有限公司 A kind of synthetic method of environmentally protective difluoromethyl phenyl sulfide compound

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Publication number Priority date Publication date Assignee Title
CN105646122A (en) * 2015-01-30 2016-06-08 中国科学院上海有机化学研究所 Compound containing difluoro methylthio groups and preparation method and application thereof
CN105646122B (en) * 2015-01-30 2017-11-07 中国科学院上海有机化学研究所 Compound, its preparation method and the application of a kind of methyl mercapto containing difluoro
CN108341759A (en) * 2017-01-22 2018-07-31 北京艾德旺科技发展有限公司 A kind of synthetic method of environmentally protective difluoromethyl phenyl sulfide compound
CN106866480A (en) * 2017-04-06 2017-06-20 盐城工学院 Many cyclophane selenide analog derivatives and preparation method thereof

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