CN118108572A - Synthesis method of alkyl trifluoromethyl compounds - Google Patents
Synthesis method of alkyl trifluoromethyl compounds Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- -1 alkyl amine compounds Chemical class 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000003446 ligand Substances 0.000 claims abstract description 11
- 230000009615 deamination Effects 0.000 claims abstract description 10
- 238000006481 deamination reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 12
- 229910052802 copper Inorganic materials 0.000 claims description 12
- 239000010949 copper Substances 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 150000003973 alkyl amines Chemical class 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 5
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 238000006692 trifluoromethylation reaction Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JFJNVIPVOCESGZ-UHFFFAOYSA-N 2,3-dipyridin-2-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=CN=C1C1=CC=CC=N1 JFJNVIPVOCESGZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- PDZKZMQQDCHTNF-UHFFFAOYSA-M copper(1+);thiocyanate Chemical compound [Cu+].[S-]C#N PDZKZMQQDCHTNF-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
- RMSPOVPGDBDYKH-UHFFFAOYSA-N (4-phenylphenyl)methanamine Chemical compound C1=CC(CN)=CC=C1C1=CC=CC=C1 RMSPOVPGDBDYKH-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000004293 19F NMR spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- XHEOXSQMBWJOKP-UHFFFAOYSA-N 1-(trifluoromethyl)-1$l^{3},2-benziodoxol-3-one Chemical compound C1=CC=C2I(C(F)(F)F)OC(=O)C2=C1 XHEOXSQMBWJOKP-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- HVAPLSNCVYXFDQ-UHFFFAOYSA-N 3,3-dimethyl-1-(trifluoromethyl)-1$l^{3},2-benziodoxole Chemical compound C1=CC=C2C(C)(C)OI(C(F)(F)F)C2=C1 HVAPLSNCVYXFDQ-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- IOXOZOPLBFXYLM-UHFFFAOYSA-N 2-(4-nitrophenyl)ethanamine Chemical compound NCCC1=CC=C([N+]([O-])=O)C=C1 IOXOZOPLBFXYLM-UHFFFAOYSA-N 0.000 description 2
- WHPLBPSDTIZFSX-UHFFFAOYSA-N 2-(4-phenylphenyl)ethanamine Chemical compound C1=CC(CCN)=CC=C1C1=CC=CC=C1 WHPLBPSDTIZFSX-UHFFFAOYSA-N 0.000 description 2
- FXNSVEQMUYPYJS-UHFFFAOYSA-N 4-(2-aminoethyl)benzenesulfonamide Chemical compound NCCC1=CC=C(S(N)(=O)=O)C=C1 FXNSVEQMUYPYJS-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 2
- JHSPPBBJOLKJDH-UHFFFAOYSA-N [4-[(4-fluorophenyl)methyl]morpholin-2-yl]methanamine Chemical compound C1COC(CN)CN1CC1=CC=C(F)C=C1 JHSPPBBJOLKJDH-UHFFFAOYSA-N 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- FWIVDMJALNEADT-SFTDATJTSA-N (2s)-n-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-[[(1s)-2,2,2-trifluoro-1-[4-(4-methylsulfonylphenyl)phenyl]ethyl]amino]pentanamide Chemical compound C1=CC([C@H](N[C@@H](CC(C)(F)C)C(=O)NC2(CC2)C#N)C(F)(F)F)=CC=C1C1=CC=C(S(C)(=O)=O)C=C1 FWIVDMJALNEADT-SFTDATJTSA-N 0.000 description 1
- NYGFSJAJCXVXML-UHFFFAOYSA-N 3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide Chemical compound C1C(C(F)(F)F)NCC2=CC(S(=O)(=O)N)=CC=C21 NYGFSJAJCXVXML-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229950009755 odanacatib Drugs 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Abstract
The invention discloses a synthesis method of alkyl trifluoromethyl compounds, which takes alkyl amine compounds as raw materials, and selectively deaminates and trifluoromethylates the alkyl amine compounds in the presence of deamination reagents, trifluoromethylates, catalysts and ligands to obtain the alkyl trifluoromethyl compounds with high selectivity. The method has the advantages of high efficiency, mild reaction condition, convenient operation, shorter reaction time, fewer byproducts and the like, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a synthesis method of an alkyl trifluoromethyl compound, which synthesizes the alkyl trifluoromethyl compound by carrying out selective trifluoromethyl of C-N bond on an alkylamine compound, and belongs to the field of organic synthesis.
Background
Trifluoromethyl compounds are important compounds in organic chemistry and biochemistry due to their wide application [1] in the fields of organic synthesis, detergents, lubricants, pharmaceuticals, pesticides, etc. Extensive analysis of the comprehensive pharmaceutical chemistry database has shown that in 2020, nearly 10% of the mass-market small molecule drugs contain at least one trifluoromethyl group. Of these most popular drugs, 3% contain aliphatic trifluoromethyl [ C (sp 3) -CF3] [2].
At present, various strategies have been developed to selectively introduce trifluoromethyl groups into organic molecules. Such compounds [4] are typically synthesized by dehalogenation of alkyl halides, trifluoromethylation [3], or using primary or secondary alkyl carboxylic acids. There is also a process [5-7] for alkyl trifluoromethyl using an olefin.
In recent years, the use of novel deamination reagents in organic synthesis has attracted considerable attention. The denitrification conditions of such isocephalinamide deamination reagents are generally very mild, the bond formation has a high chemoselectivity and a remarkable functional group tolerance. Work [8-11] by mark.d. levin et al discloses that such isohead amide reagents have good reactivity with alkylamine species, revealing the possibility of alkylamine species and Togni reagents generating alkyltrifluoromethyl compounds. The synergistic catalysis of monovalent copper and Togni reagent and deamination reagent in the present invention has not been reported.
Reference is made to:
[1]Aichholz,R.;Hamon,J.;Fabbro,D.;Caravatti,G.Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3kinase alpha inhibitor selected for clinical evaluation.[J].Med.Chem.Lett.2013,23(13),3741-3748.
[2]McGrath,N.A.;Brichacek,M.;Njardarson,J.A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives.[J].J.Chem.Educ.,2010,87(12),1348-1349.
[3]H.Shen,Z.Liu,P.Zhang,X.Tan,Z.Zhang and C.Li.Trifluoromethylation ofAlkyl Radicals inAqueous Solution.[J].J.Am.Chem.Soc.,2017,139,9843.
[4]X.Tan,Z.Liu,H.Shen,P.Zhang,Z.Zhen and C.Li.Silver-Catalyzed DecarboxylativeTrifluoromethylation of Aliphatic Carboxylic Acids.[J].J.Am.Chem.Soc.,2017,139,12430.
[5]A.Studer.A“Renaissance”in Radical Trifluoromethylation.[J].Angew.Chem.,Int.Ed.,2012,51,8950.
[6]Z.Zhang,L.Zhu and C.Li.Copper-Catalyzed Carbotrifluoromethylation of Unactivated Alkenes Driven by Trifluoromethylation ofAlkyl Radicals.[J].Chin.J.Chem.,2019,37,452.
[7]H.Xiao,H.Shen,L.Zhu and C.Li.Copper-Catalyzed Radical Aminotrifluoromethylation of Alkenes.[J].J.Am.Chem.Soc.,2019,141,11440.
[8]Kennedy,S.H.,Dherange,B.D.,Berger,K.J.et al.Skeletalediting through direct nitrogen deletion ofsecondary amines.[J].Nature.2021,593,223-227.
[9]Ethan E.Hyland,Patrick Q.Kelly,Alexander M.McKillop,BaluD.Dherange,and Mark D.Levin.Unified Access to Pyrimidines and Quinazolines Enabled by N-N Cleaving Carbon Atom Insertion[J].J.Am.Chem.Soc.,2022,144,19258-19264.
[10]Cristina Grosanu,Kathleen J.Berger,Osvaldo Gutierrez,and Mark D.Levin.Direct Deaminative Functionalization[J].J.Am.Chem.Soc.,2023,145,17-24.
[11]Jiang-HaoXue,Yin Li,Dong-Hang Tan,Fang-HaiTu,Yuan Liu,Qingjiang Li,HonggenWang.PhotochemicalDeaminativebromination,chlorination,and iodination of primary amines[J].iScience.,2023.26,106255.
Disclosure of Invention
Aiming at the defects of the existing synthetic route, the invention provides a synthetic method of alkyl trifluoromethyl compounds, which uses copper and Togni reagent to cooperatively catalyze the trifluoromethyl reaction of alkylamine, and has the advantages of easily available raw materials, simple process, mild condition, higher yield, wide substrate range, fewer byproducts and the like.
The synthesis method of the alkyl trifluoromethyl compound takes alkylamine as a raw material, and carries out normal-temperature reaction in the presence of a copper catalyst, a deamination reagent, a Togni reagent and a ligand, and the alkyl trifluoromethyl compound is obtained after separation and purification.
Specifically, alkylamine is dissolved in a solvent under the nitrogen atmosphere, and the reaction is carried out in the presence of a catalyst, a ligand, a deamination reagent and a TogniII reagent at normal temperature, and the target product is obtained after the reaction is finished and separated and purified.
The structural formula of the alkylamine is as follows:
Wherein the substituent R is selected from the following groups:
The structural formula of the deamination reagent is as follows:
the catalyst is copper catalyst, which is selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous thiocyanate or thiophene-2-copper formate, and the dosage of the catalyst is 5mol percent to 50mol percent, calculated by alkyl amine compound.
The ligand is at least one of 1, 10-phenanthroline, dipyridine, 2-methylpyridine, terpyridine, 4-di-tert-butyl-2, 2-dipyridine, 2-phenylpyridine and pyridine, and the addition amount is 5-50 mol% calculated by alkylamine.
The reaction temperature is 15-35 ℃, preferably 23 ℃ and the reaction time is 10-48h.
The solvent is dimethyl sulfoxide, acetonitrile, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, toluene, nitromethane or tetrahydrofuran.
The separation and purification are to add water into the reaction liquid, extract with ethyl acetate, dry with anhydrous sodium sulfate, finally remove the solvent by rotary evaporation, and separate and purify by column chromatography, wherein the eluent in the separation and purification by column chromatography is petroleum ether: ethyl acetate=100:1-5:1, v/v, the target product can be obtained.
The reaction process of the invention is as follows:
The target product of the invention can be used as raw materials of various trifluoromethyl-containing medicaments or some commercial products, for example: 3a can be used as the raw material of the osteoporosis medicine Odanacatib, and 3a is also a commercially available product (CAS number 1204295-81-7); 3b is the starting material for the commercial product 3- (4-BIPHENYL) -1, 1-TRIFLUORO-2-PROPANONE (CAS number 898787-43-4); 3c can be used as a raw material of a commercial product 4- (3, 3-trifluoropropyl) aniline; 3d can be used as a starting material for 3- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (CAS number 870994-42-6).
The beneficial effects of the invention are as follows:
1. the synthesis method of the invention has the advantages of copper catalyzed trifluoromethylation reaction of alkylamine, low price, low toxicity, environmental protection and the like.
2. The synthesis method has the advantages of wide substrate applicability, higher yield, fewer byproducts, compatibility with various functional groups and suitability for alkylamines with various substituents.
Detailed Description
To further illustrate the features and advantages of the present invention, the following describes the technical aspects of the present invention in connection with specific embodiments. The following examples are provided to further illustrate the invention and are not intended to limit the invention.
Example 1:
To a 25mL clear Schlenk tube equipped with a magnetic stirrer was added raw isocephalinamide (2 a) (0.24 mmol) copper catalyst CuCl (0.02 mmol,10 mol%) and ligand 1, 10-phenanthroline (0.02 mmol,20 mol%), togni II reagent (0.24 mmol,1.2 equiv.) and 1.0mL anhydrous acetonitrile under nitrogen; the starting material 4-phenylbenzylamine (1 a) (0.2 mmol) was then dissolved in 1.0mL of anhydrous acetonitrile, slowly added dropwise to Schlenk tube, after reaction at room temperature for 10h, extracted with water and ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and then concentrated in vacuo, and the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1) to give white solid (3 a) (37 mg, 80%). The nuclear magnetic data of the compound are ：1H NMR(600MHz,CDCl3)δ7.60(d,J＝8.1Hz,4H),7.51-7.43(m,2H),7.38(t,J＝8.8Hz,3H),3.42(q,J＝10.8Hz,2H).19F NMR(564MHz,CDCl3)δ-63.14.13C NMR(151MHz,CDCl3)δ141.23,140.64,130.71,129.39-129.16(m),128.97,127.65,127.55,127.25,125.02(q,J＝277.8Hz).,40.04(q,J＝29.9Hz).
Example 2:
To a 25mL clear Schlenk tube equipped with a magnetic stirrer, raw isocephalinamide (2 a) (0.24 mmol) copper catalyst CuBr (0.02 mmol,10 mol%) and ligand 1, 10-phenanthroline (0.02 mmol,20 mol%), togni II reagent (0.24 mmol,1.2 equiv.) were added, and 1.0mL anhydrous acetonitrile was added under nitrogen; the starting material 4-phenylbenzylamine (1 a) (0.2 mmol) was then dissolved in 1.0mL of anhydrous acetonitrile, slowly added dropwise to a Schlenk tube, after reaction at room temperature for 10h, extracted with water and ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate and then concentrated in vacuo, and the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1) to give white solid (3 a) (30 mg, 60%). The nuclear magnetic data of the compound are ：1H NMR(600MHz,CDCl3)δ7.60(d,J＝8.1Hz,4H),7.51-7.43(m,2H),7.38(t,J＝8.8Hz,3H),3.42(q,J＝10.8Hz,2H).19F NMR(564MHz,CDCl3)δ-63.14.13C NMR(151MHz,CDCl3)δ141.23,140.64,130.71,129.39-129.16(m),128.97,127.65,127.55,127.25,125.02(q,J＝277.8Hz).,40.04(q,J＝29.9Hz).
Example 3:
To a 25mL clear Schlenk tube equipped with a magnetic stirrer was added raw isohead amide (2 a) (0.24 mmol) copper catalyst CuCl (0.02 mmol,10 mol%) and its ligand bipyridine (0.02 mmol,20 mol%), togni II reagent (0.24 mmol,1.2 equiv.) and 1.0mL anhydrous acetonitrile under nitrogen atmosphere; the starting material 4-phenylbenzylamine (1 a) (0.2 mmol) was then dissolved in 1.0mL of anhydrous acetonitrile, slowly added dropwise to Schlenk tube, after reaction at room temperature for 10h, extracted with water and ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, then concentrated in vacuo, and the product purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1) to give white solid (3 a) (34 mg, 70%). The nuclear magnetic data of the compound are ：1H NMR(600MHz,CDCl3)δ7.60(d,J＝8.1Hz,4H),7.51-7.43(m,2H),7.38(t,J＝8.8Hz,3H),3.42(q,J＝10.8Hz,2H).19F NMR(564MHz,CDCl3)δ-63.14.13C NMR(151MHz,CDCl3)δ141.23,140.64,130.71,129.39-129.16(m),128.97,127.65,127.55,127.25,125.02(q,J＝277.8Hz).,40.04(q,J＝29.9Hz).
Example 4:
To a 25mL clear Schlenk tube equipped with a magnetic stirrer was added raw isocephalinamide (2 a) (0.24 mmol) copper catalyst CuCl (0.02 mmol,10 mol%) and ligand 1, 10-phenanthroline (0.02 mmol,20 mol%), togni II reagent (0.24 mmol,1.2 equiv.) and 1.0mL dimethyl sulfoxide under nitrogen; the starting material 4-phenylbenzylamine (1 a) (0.2 mmol) was then dissolved in 1.0mL dimethyl sulfoxide, slowly added dropwise to a Schlenk tube, after reaction at room temperature for 10h, extracted with water and ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, and then concentrated in vacuo, and the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1) to give white solid (3 a) (30 mg, 60%). The nuclear magnetic data of the compound are ：1H NMR(600MHz,CDCl3)δ7.60(d,J＝8.1Hz,4H),7.51-7.43(m,2H),7.38(t,J＝8.8Hz,3H),3.42(q,J＝10.8Hz,2H).19F NMR(564MHz,CDCl3)δ-63.14.13C NMR(151MHz,CDCl3)δ141.23,140.64,130.71,129.39-129.16(m),128.97,127.65,127.55,127.25,125.02(q,J＝277.8Hz).,40.04(q,J＝29.9Hz).
Example 5:
4-Phenylphenethylamine (1 b) was used in place of 4-phenylbenzylamine (1 a), otherwise as in example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1) to give white solid (3 b) (37.5 mg, 75%). The nuclear magnetic data of the compound are ：1H NMR(600MHz,CDCl3)δ7.58(dd,J＝12.2,7.8Hz,4H),7.46(t,J＝7.6Hz,2H),7.36(t,J＝7.3Hz,1H),7.29(d,J＝8.1Hz,2H),2.98-2.89(m,2H),2.55-2.36(m,2H).19F NMR(376MHz,CDCl3)δ-66.59.13C NMR(101MHz,CDCl3)δ140.75,139.68,138.06,128.82,128.69,127.47,127.31,127.05,125.35(q,J＝277.8Hz).,35.64(q,J＝28.4Hz),29.02.
Example 6:
4-Nitrophenylethylamine (1 c) was used in place of 4-phenylbenzylamine (1 a) as in example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=50:1) to give pale yellow oily liquid (3 c) (32 mg, 75%) whose nuclear magnetic data were that of the compound ：1H NMR(400MHz,CDCl3)δ8.19(d,J＝8.8Hz,2H),7.38(d,J＝8.7Hz,2H),3.14-2.92(m,2H),2.67-2.26(m,2H).19F NMR(376MHz,CDCl3)δ-66.44.13C NMR(151MHz,CDCl3)δ146.92,146.46,129.20,126.32(q,J＝277.8Hz),124.02,34.96(q,J＝29.0Hz),28.15(q,J＝3.3Hz).
Example 7:
4- (2-aminoethyl) benzenesulfonamide (1 d) was used in place of 4-phenylbenzylamine (1 a), otherwise the same as in example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give a clear oily liquid (3 d) (32 mg, 75%) whose nuclear magnetic data were ：1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝8.3Hz,2H),7.50(d,J＝8.2Hz,2H),7.34(s,2H),2.97-2.85(m,2H),2.72-2.56(m,2H).19F NMR(376MHz,DMSO-d6)δ-64.63.13CNMR(151MHz,DMSO-d6)δ143.57,142.80,129.33,127.67(q,J＝277.8Hz),126.20,33.88(q,J＝27.3Hz),27.64(q,J＝3.3Hz).
Example 8:
Example 1 was repeated except that 2-aminomethyl-4- (4-fluorobenzyl) morpholine (1 e) was used instead of 4-phenylbenzylamine (1 a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give a clear oily liquid (3 e) (42 mg, 77%) whose nuclear magnetic data were ：1H NMR(600MHz,CDCl3)δ7.27(m,2H),7.07-6.94(m,2H),3.93-3.81(m,1H),3.67(m,2H),3.55-3.37(m,2H),2.75(d,J＝11.2Hz,1H),2.63(dd,J＝11.5,1H),2.45-2.28(m,1H),2.29-2.08(m,2H),2.03-1.85(m,1H).19F NMR(564MHz,CDCl3)δ-63.52,-115.41.13C NMR(151MHz,CDCl3)δ162.12(d,J＝245.5Hz),132.98,130.58(d,J＝8.0Hz),125.83(q,J＝276.6Hz),115.16(d,J＝21.1Hz),69.84(q,J＝3.1Hz),66.56,62.18,57.79,52.37,37.97(q,J＝28.4Hz),.
Example 9:
The procedure of example 1 was repeated except that dehydroabietylamine (1 f) was used instead of 4-phenylbenzylamine (1 a). The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1) to give a clear oily liquid (3 f) (43 mg, 65%) whose nuclear magnetic data were ：1H NMR(400MHz,CDCl3)δ7.17(d,J＝8.2Hz,1H),7.01(dd,J＝8.0,1.8Hz,1H),6.90(s,1H),3.06-2.76(m,3H),2.39-2.14(m,2H),2.12-1.95(m,1H),1.85-1.65(m,5H),1.56(m,2H),1.48-1.38(m,1H),1.24(s,6H),1.22(s,3H),1.09(s,3H).19F NMR(376MHz,CDCl3)δ-58.02.13C NMR(151MHz,CDCl3)δ147.15,145.70,134.45,127.25(q,J＝280.9Hz),126.81,124.09,123.95,48.10,46.11(q,J＝25.0Hz),38.16,37.75,37.31,35.91,33.43,30.06,25.49,23.96,20.15,19.45,18.72.
Example 10:
N- (2-aminopropyl) -2- (4-nitrophenyl) acetamide (1 g) was used in place of 4-phenylbenzylamine (1 a), the same as in example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give a white solid (3 g) (37 mg, 65%) of the compound as a nuclear magnetic data ：1H NMR(600MHz,CDCl3)δ8.18(d,J＝8.6Hz,2H),7.45(d,J＝8.6Hz,2H),5.81(s,1H),3.64(s,2H),3.31(q,J＝6.8Hz,2H),2.33-1.97(m,2H),1.76(p,J＝7.3Hz,2H).19F NMR(564MHz,CDCl3)δ-66.19.13C NMR(151MHz,CDCl3)δ169.45,147.17,142.24,130.19,126.82(q,J＝277.8Hz),123.96,43.13,38.62,31.19(q,J＝29.4Hz),22.32(q,J＝2.8Hz).
Claims (8)
1. A synthesis method of alkyl trifluoromethyl compounds is characterized in that:
alkyl amine is used as a raw material, and is reacted in the presence of deamination reagent, trifluoromethylation reagent, catalyst and ligand, and then alkyl trifluoromethyl compounds are obtained after separation and purification;
The structural formula of the alkylamine is as follows:
Wherein the substituent R is selected from the following groups:
The structural formula of the deamination reagent is as follows:
2. The synthesis method according to claim 1, wherein:
specifically, an alkylamine compound is dissolved in a solvent under the atmosphere of nitrogen, and the target product is obtained by separation and purification after the reaction is finished in the presence of a deamination reagent, a Togni II reagent, a copper catalyst and a ligand.
3. The synthesis method according to claim 2, characterized in that:
The copper catalyst is selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous thiocyanate or thiophene-2-copper formate, and the addition amount of the copper catalyst is 5-50 mol%.
4. The synthesis method according to claim 2, characterized in that:
The ligand is at least one selected from 1, 10-phenanthroline, dipyridine, 2-methylpyridine, terpyridine, 4-di-tert-butyl-2, 2-dipyridine, 2-phenylpyridine and pyridine, and the addition amount is 5mol% to 50mol%.
5. The synthesis method according to claim 2, characterized in that:
the solvent is dimethyl sulfoxide, acetonitrile, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, toluene, nitromethane or tetrahydrofuran.
6. The synthesis method according to claim 2, characterized in that:
The reaction temperature is 15-35 ℃ and the reaction time is 10-48h.
7. The synthesis method according to claim 2, characterized in that:
the separation and purification are to add water into the reaction liquid, extract with ethyl acetate, dry with anhydrous sodium sulfate, finally remove the solvent by rotary evaporation, and separate and purify by column chromatography, thus obtaining the target product.
8. The method of synthesis according to claim 7, wherein:
The eluent is petroleum ether during column chromatography separation and purification: ethyl acetate=100:1 to 5:1, v/v.
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