CN115490628A - 一种二氟乙醇类化合物的制备方法 - Google Patents
一种二氟乙醇类化合物的制备方法 Download PDFInfo
- Publication number
- CN115490628A CN115490628A CN202211084910.3A CN202211084910A CN115490628A CN 115490628 A CN115490628 A CN 115490628A CN 202211084910 A CN202211084910 A CN 202211084910A CN 115490628 A CN115490628 A CN 115490628A
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- CN
- China
- Prior art keywords
- nmr
- difluoroethanol
- mmol
- ethyl acetate
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 difluoroethanol compound Chemical class 0.000 title claims abstract description 145
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 110
- 239000002904 solvent Substances 0.000 claims abstract description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001491 aromatic compounds Chemical class 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 94
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 47
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 38
- VUYQBMXVCZBVHP-UHFFFAOYSA-N 1,1-difluoroethanol Chemical class CC(O)(F)F VUYQBMXVCZBVHP-UHFFFAOYSA-N 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 2
- NNZZMYIWZFZLHU-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanol Chemical compound OC(F)(F)C(F)(F)F NNZZMYIWZFZLHU-UHFFFAOYSA-N 0.000 claims description 2
- CSUFEOXMCRPQBB-UHFFFAOYSA-N 1,1,2,2-tetrafluoropropan-1-ol Chemical compound CC(F)(F)C(O)(F)F CSUFEOXMCRPQBB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- 235000001258 Cinchona calisaya Nutrition 0.000 claims 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229960000948 quinine Drugs 0.000 claims 1
- DKNMRIXYSHIIGC-UHFFFAOYSA-N 2,2-difluoroacetaldehyde Chemical compound FC(F)C=O DKNMRIXYSHIIGC-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003513 alkali Substances 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 4
- 239000002184 metal Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 239000002585 base Substances 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 390
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 101
- 239000012074 organic phase Substances 0.000 description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- 238000012512 characterization method Methods 0.000 description 46
- 238000004440 column chromatography Methods 0.000 description 44
- 238000010791 quenching Methods 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- 239000012071 phase Substances 0.000 description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 19
- 238000004821 distillation Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- VOGSDFLJZPNWHY-UHFFFAOYSA-N 2,2-difluoroethanol Chemical compound OCC(F)F VOGSDFLJZPNWHY-UHFFFAOYSA-N 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- ADZUEEUKBYCSEY-UHFFFAOYSA-N 1h-indole-5-carbaldehyde Chemical compound O=CC1=CC=C2NC=CC2=C1 ADZUEEUKBYCSEY-UHFFFAOYSA-N 0.000 description 2
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 description 2
- RDOAUPPSCNSYPM-UHFFFAOYSA-N 3,4-dihydropyridine Chemical compound C1CC=NC=C1 RDOAUPPSCNSYPM-UHFFFAOYSA-N 0.000 description 2
- TVQLYTUWUQMGMP-UHFFFAOYSA-N 5-iodo-1h-indole Chemical compound IC1=CC=C2NC=CC2=C1 TVQLYTUWUQMGMP-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000005815 base catalysis Methods 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- GOFIUEUUROFVMA-UHFFFAOYSA-N 1-(1h-indol-5-yl)ethanone Chemical compound CC(=O)C1=CC=C2NC=CC2=C1 GOFIUEUUROFVMA-UHFFFAOYSA-N 0.000 description 1
- QMPUSLOHKKZYFV-UHFFFAOYSA-N 1-[4-(dimethylamino)phenyl]-2,2-difluoroethanol Chemical compound CN(C)C1=CC=C(C(O)C(F)F)C=C1 QMPUSLOHKKZYFV-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- YBFCBQMICVOSRW-UHFFFAOYSA-N 1-phenylindole Chemical compound C1=CC2=CC=CC=C2N1C1=CC=CC=C1 YBFCBQMICVOSRW-UHFFFAOYSA-N 0.000 description 1
- JWISBZGCYONAIT-UHFFFAOYSA-N 1-phenylmethoxyindole Chemical compound C1=CC2=CC=CC=C2N1OCC1=CC=CC=C1 JWISBZGCYONAIT-UHFFFAOYSA-N 0.000 description 1
- GEZGAZKEOUKLBR-UHFFFAOYSA-N 1-phenylpyrrole Chemical compound C1=CC=CN1C1=CC=CC=C1 GEZGAZKEOUKLBR-UHFFFAOYSA-N 0.000 description 1
- ZCBIFHNDZBSCEP-UHFFFAOYSA-N 1H-indol-5-amine Chemical compound NC1=CC=C2NC=CC2=C1 ZCBIFHNDZBSCEP-UHFFFAOYSA-N 0.000 description 1
- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 description 1
- SZSZDBFJCQKTRG-UHFFFAOYSA-N 1h-indole-6-carbonitrile Chemical compound N#CC1=CC=C2C=CNC2=C1 SZSZDBFJCQKTRG-UHFFFAOYSA-N 0.000 description 1
- KUFFULVDNCHOFZ-UHFFFAOYSA-N 2,4-xylenol Chemical compound CC1=CC=C(O)C(C)=C1 KUFFULVDNCHOFZ-UHFFFAOYSA-N 0.000 description 1
- ZFLFWZRPMDXJCW-UHFFFAOYSA-N 2,5-dimethyl-1h-indole Chemical compound CC1=CC=C2NC(C)=CC2=C1 ZFLFWZRPMDXJCW-UHFFFAOYSA-N 0.000 description 1
- HYVGFUIWHXLVNV-UHFFFAOYSA-N 2-(n-ethylanilino)ethanol Chemical compound OCCN(CC)C1=CC=CC=C1 HYVGFUIWHXLVNV-UHFFFAOYSA-N 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- KLLLJCACIRKBDT-UHFFFAOYSA-N 2-phenyl-1H-indole Chemical compound N1C2=CC=CC=C2C=C1C1=CC=CC=C1 KLLLJCACIRKBDT-UHFFFAOYSA-N 0.000 description 1
- 229940061334 2-phenylphenol Drugs 0.000 description 1
- SVLZRCRXNHITBY-UHFFFAOYSA-N 4-chloro-1h-indole Chemical compound ClC1=CC=CC2=C1C=CN2 SVLZRCRXNHITBY-UHFFFAOYSA-N 0.000 description 1
- MNVMYTVDDOXZLS-UHFFFAOYSA-N 4-methoxyguaiacol Natural products COC1=CC=C(O)C(OC)=C1 MNVMYTVDDOXZLS-UHFFFAOYSA-N 0.000 description 1
- LAVZKLJDKGRZJG-UHFFFAOYSA-N 4-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=CC2=C1C=CN2 LAVZKLJDKGRZJG-UHFFFAOYSA-N 0.000 description 1
- QHPQWRBYOIRBIT-UHFFFAOYSA-N 4-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C=C1 QHPQWRBYOIRBIT-UHFFFAOYSA-N 0.000 description 1
- ILINOHVVKWYAFM-UHFFFAOYSA-N 5,6-dichloro-1h-indole Chemical compound C1=C(Cl)C(Cl)=CC2=C1NC=C2 ILINOHVVKWYAFM-UHFFFAOYSA-N 0.000 description 1
- SBOITLSQLQGSLO-UHFFFAOYSA-N 5-bromo-1-methylindole Chemical compound BrC1=CC=C2N(C)C=CC2=C1 SBOITLSQLQGSLO-UHFFFAOYSA-N 0.000 description 1
- ODFFPRGJZRXNHZ-UHFFFAOYSA-N 5-fluoroindole Chemical compound FC1=CC=C2NC=CC2=C1 ODFFPRGJZRXNHZ-UHFFFAOYSA-N 0.000 description 1
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 1
- BPYBYPREOVLFED-UHFFFAOYSA-N 6-(trifluoromethyl)-1h-indole Chemical compound FC(F)(F)C1=CC=C2C=CNC2=C1 BPYBYPREOVLFED-UHFFFAOYSA-N 0.000 description 1
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 1
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 description 1
- SHVCSCWHWMSGTE-UHFFFAOYSA-N 6-methyluracil Chemical compound CC1=CC(=O)NC(=O)N1 SHVCSCWHWMSGTE-UHFFFAOYSA-N 0.000 description 1
- FPMICYBCFBLGOZ-UHFFFAOYSA-N 6-phenylmethoxy-1h-indole Chemical compound C=1C=C2C=CNC2=CC=1OCC1=CC=CC=C1 FPMICYBCFBLGOZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- JRKLRIAIMIKGHT-UHFFFAOYSA-N 8-bromoquinoline-4-carbaldehyde Chemical compound C1=CN=C2C(Br)=CC=CC2=C1C=O JRKLRIAIMIKGHT-UHFFFAOYSA-N 0.000 description 1
- WBONGMFKXUSKAI-UHFFFAOYSA-N 8-hydroxynaphthalene-2-carbonitrile Chemical compound C1=C(C#N)C=C2C(O)=CC=CC2=C1 WBONGMFKXUSKAI-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BGGDEYLNSNKIGJ-UHFFFAOYSA-N CC1=C(C(C(F)F)O)C2=CC(C)=CC=C2N1 Chemical compound CC1=C(C(C(F)F)O)C2=CC(C)=CC=C2N1 BGGDEYLNSNKIGJ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- MYYLTWLDIMKDRI-UHFFFAOYSA-N OC(C(F)F)C(C1=CC=CC=C1C=C1)=C1O Chemical compound OC(C(F)F)C(C1=CC=CC=C1C=C1)=C1O MYYLTWLDIMKDRI-UHFFFAOYSA-N 0.000 description 1
- JBYBJRNVSDFUMS-UHFFFAOYSA-N OC(C(F)F)C1=CNC2=C1C(C=O)=CC=C2 Chemical compound OC(C(F)F)C1=CNC2=C1C(C=O)=CC=C2 JBYBJRNVSDFUMS-UHFFFAOYSA-N 0.000 description 1
- MNKVOYBLGXDDAC-UHFFFAOYSA-N OC(C(F)F)c1c[nH]c2ccccc12 Chemical compound OC(C(F)F)c1c[nH]c2ccccc12 MNKVOYBLGXDDAC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- JMXMXKRNIYCNRV-UHFFFAOYSA-N bis(hydroxymethyl)phosphanylmethanol Chemical compound OCP(CO)CO JMXMXKRNIYCNRV-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
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Abstract
本发明公开了一种二氟乙醇类化合物的制备方法,该方法包括如下步骤:在醇溶剂和碱催化剂存在下,加入芳香类化合物和式(I)所示的化合物进行反应,得到式(II)所示的化合物。本发明选择的式(I)所示的化合物首先在碱的醇溶剂中进行水解,原位生成二氟乙醛;再和芳香类化合物通过反应得到二氟乙醇类化物,该反应条件简单、产率高。避免了使用金属催化剂,同时也避免了二氟乙醛对酸碱不稳定,在室温下不易保存的缺陷。
Description
技术领域
本发明涉及有机合成技术领域,尤其是涉及一种二氟乙醇类化合物的制备方法。
背景技术
二氟甲基(CF2H)被认为是氧原子或羰基的生物等位体,将这部分引入分子中可以改变化合物的亲脂性,产生构象偏好,诱导与蛋白质残基的相互作用,并提高代谢稳定性,因此在化学的许多方面有潜在的应用。特别是,二氟乙醇部分存在于许多治疗药物、候选药物和医学研究类似物中,它具有广泛的药理活性,例如抗癌、抗高血压、抗炎、抗抑郁等。此外,含有这种亚结构的化合物显示出优异的材料性能,也可用作有机转化的有机催化剂或配体。
在过去十年中,虽然已经有科研人员合成了二氟乙醇类的化合物,但是其制备方法存在很多缺陷,例如相关技术中采用二氟乙醛作为原料,以LiAlH4或过渡金属钌催化氢化反应。但是一方面二氟乙醛对酸碱都不稳定,室温下不易保存,另一方面,LiAlH4是及其危险的化学品,不安全;并且使用了过渡金属催化剂。
因此,有必要提供一种新的二氟乙醇类化合物的制备方法。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此,本发明提出一种二氟乙醇类化合物的制备方法,能够有效避免使用金属催化剂,反应条件温和,收率高,适用于工业化生产。
本发明的第一方面实施例提供一种二氟乙醇类化合物的制备方法,包括如下步骤:
在醇溶剂和碱存在下,加入芳香类化合物和式(I)所示的化合物进行反应,得到式(II)所示的化合物;
所述芳香类化合物选自如下结构式中的一种:
式(I)所示的化合物和式(II)所示的化合物的结构式如下:
其中,R选自取代或未取代的苯磺酰基、苯基或萘基;
R1选自H、取代或未取代的苯基;
R2为一个或多个基团,R1分别独立地选自H、C1~10的烷基、取代或未取代的苯基、取代或未取代的C1~10的烷氧基、C1~10的卤代烷基、卤素、C1~10的羧基、硝基、氰基、醛基、乙酰基;
R3选自H、C1~10的烷基、取代或未取代的苯基;
R4为一个或多个基团,R4独立地选自H、C1~10的烷基、C1~10的烷氧基、取代或未取代的苯基;
R5选自羟基、-NR8R9;
R6为一个或多个基团,R6选自H、氰基;
R7选自H、C1~10的烷基;
R8和R9独立地选自H、取代或未取代的C1~10的烷基、取代或未取代的苯基;
或者R8和R9通过C1~10的烷基成环。
根据本发明实施例的,至少具有如下有益效果:
本发明选择的式(I)所示的化合物首先在碱的醇溶剂中进行水解,原位生成二氟乙醛;再和芳香类化合物通过碱催化反应得到二氟乙醇类化物,该反应条件简单、产率高。避免了使用金属催化剂,同时也避免了二氟乙醛对酸碱不稳定,在室温下不易保存的缺陷。
根据本发明的一些实施例,所述芳香类化合物和所述式(I)所示的化合物的摩尔比为1:2~4。
根据本发明的一些实施例,所述醇溶剂与芳香类化合物的体积摩尔比为1mL:(0.1~0.3)mmol。
根据本发明的一些实施例,所述醇溶剂选自甲醇、乙醇、异丙醇、二氟乙醇、三氟乙醇、六氟异丙醇、五氟乙醇或四氟丙醇中的至少一种。
根据本发明的一些实施例,所述醇溶剂选自三氟乙醇。
根据本发明的一些实施例,所述碱选自无机碱或无机碱。
根据本发明的一些实施例,所述无机碱选自碳酸钠、碳酸钾、碳酸铯、碳酸锂、磷酸钠、碳酸钾、磷酸氢钾、磷酸氢钠、氢氧化钠或氢氧化钾中的至少一种。
根据本发明的一些实施例,所述有机碱选自三乙胺、N,N-二异丙基乙胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯。
根据本发明的一些实施例,所述反应的温度为50℃~120℃。
根据本发明的一些实施例,所述反应的温度为60~100℃。
根据本发明的一些实施例,所述反应的时间为6h~24h。
根据本发明的一些实施例,所述反应的时间为8h~20h。
根据本发明的一些实施例,所述反应完成后还包括提纯的步骤。
根据本发明的一些实施例,所述提纯的步骤包括淬灭、洗涤、萃取、浓缩、柱层析。
定义和术语
“取代或未取代的苯磺酰基”表示苯环上至少有一个氢原子被本文所定义的取代基所取代,例如,取代基可以是C1~5的烷基、卤素、卤素取代的C1~5的烷基;优选地,可以是对甲基苯磺酰基、邻甲基苯磺酰基、对氟苯磺酰基、邻氟苯磺酰基,对三氟甲基苯磺酰基、邻三氟苯磺酰基。
“取代或未取代的C1~10的烷基”表示碳原子总数为10的烷基,包括C1~10的直链烷基、C1~10的支链烷基和C3~10的环烷基,其中烷基中至少有一个H被本文所定义的基团所取代。
“取代或未取代的苯基”表示苯基中至少有一个H被本文所定义的基团所取代。
“取代或未取代的C1~10的烷氧基”表示烷氧基中任选有至少一个H被本文所定义的相应基团所取代。
“C1~10的卤代烷基”表示C1~10的烷基,优选如上所定义的烷基,它被一个或多个相同或不同的卤原子取代,例如-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3等。
“卤素”包括氟、氯、溴、碘中的任意一个或两个以上。
本文使用的“取代或未取代的”是指基团可以被或可以不被一个或更多个选自以下的基团进一步取代:烷基、烯基、炔基、芳基、卤素、卤代烷基、卤代烯基、卤代炔基、卤代芳基、羟基、烷氧基、烯氧基、芳氧基、苄氧基、卤代烷氧基、卤代烯氧基、卤代芳氧基、硝基、硝基烷基、硝基烯基、硝基炔基、硝基芳基、硝基杂环基、氨基、烷基氨基、二烷基氨基、烯基氨基、炔基氨基、芳基氨基、二芳基氨基、苯基氨基、二苯基氨基、苄基氨基、二苄基氨基、肼基、酰基、酰氨基、二酰氨基、酰氧基、杂环基、杂环氧基、杂环基氨基、卤代杂环基、羧基酯。
本发明的其它特征和优点将在随后的说明书中阐述,并且,部分地从说明书中变得显而易见,或者通过实施本发明而了解。
具体实施方式
以下是本发明的具体实施例,并结合实施例对本发明的技术方案作进一步的描述,但本发明并不限于这些实施例。
本发明所采用的试剂、方法和设备,如无特殊说明,均为本技术领域常规试剂、方法和设备。
实施例1
实施例1提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入吲哚23.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为91%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.30(s,1H),7.72(d,J=7.9Hz,1H),7.38(d,J=8.2Hz,1H),7.25(s,1H),7.24(t,J=7.5Hz,1H),7.17(t,J=7.5Hz,1H),6.00(td,J=56.0,4.3Hz,1H),5.17-5.11(m,1H),2.45(d,J=4.2Hz,1H).13C NMR(126MHz,Chloroform-d)δ137.2,128.0,126.5,122.5,120.1,119.5,115.8(t,J=245.0Hz),109.8,68.3(t,J=25.4Hz),33.0.19F NMR(471MHz,Chloroform-d)δ-126.10(ddd,J=282.3,55.8,10.0Hz),-127.32(ddd,J=281.6,56.4,11.6Hz).HRMS(ESI):calcdfor C10H8F2NO[M+H]-:196.0568,found:196.0559.
实施例2
实施例2提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(1-甲基-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入1-甲基吲哚26mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为87%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.71(d,J=8.0Hz,1H),7.34(d,J=8.2Hz,1H),7.27(td,J=7.5,1.0Hz,1H),7.16(td,J=7.4,1.0Hz,1H),7.16(s,1H),5.98(td,J=56.1,4.5Hz,1H),5.15-5.10(m,1H),3.78(s,3H),2.34(s,1H).13C NMR(126MHz,Chloroform-d)δ137.0,127.9,126.4,122.3,119.9,119.4,115.7(t,J=244.7Hz),109.6,109.6(t,J=3.4Hz),68.1(t,J=25.2Hz),32.9.19F NMR(471MHz,Chloroform-d)δ-126.17(ddd,J=282.5,56.7,10.0Hz),-127.21(ddd,J=282.5,57.4,12.1Hz).HRMS(ESI):calcd for C11H12F2NO[M+H]+:212.0881,found:212.0878.
实施例3
实施例3提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(1-苯基-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入1-苯基吲哚38.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为89%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.78(d,J=7.9Hz,1H),7.56-7.48(m,5H),7.45(s,1H),7.39(t,J=7.1Hz,1H),7.28-7.21(m,2H),6.05(td,J=56.12,4.4Hz,1H),5.21(t,J=10.1Hz,1H),2.41(s,1H).13C NMR(126MHz,Chloroform-d)δ139.1,136.3,129.7,127.1,127.0,124.5,123.1,120.9,119.7,115.6(t,J=245.4Hz),112.1(t,J=3.7Hz),110.9,68.2(t,J=25.5Hz),29.7.19F NMR(471MHz,Chloroform-d)δ-126.10(ddd,J=282.4,55.7,9.4Hz),-127.09(ddd,J=282.5,56.5,11.5Hz).HRMS(ESI):calcd for C16H12F2NO[M+H]-:272.0881,found:272.0883.
实施例4
实施例4提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(1-(4-甲氧基苄基)-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入1-苄氧基吲哚47.2mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为45%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.74(d,J=7.9Hz,1H),7.33(d,J=8.2Hz,1H),7.26-7.21(m,2H),7.17(td,J=8.0,0.96Hz,1H),7.09(d,J=8.7Hz,2H),6.84(d,J=8.7Hz,2H),5.99(td,J=56.0,4.5Hz,1H),5.24(s,2H),5.17-5.11(m,1H),3.78(s,3H).13C NMR(126MHz,Chloroform-d)δ159.4,136.8,128.9,128.5,127.2,126.7,122.6,120.2,119.7,115.8(t,J=244.7Hz),114.3,110.4(t,J=3.7Hz),110.3,68.4(t,J=25.4Hz),55.4,49.8.19F NMR(471MHz,Chloroform-d)δ-126.00(ddd,J=281.4,55.8,9.1Hz),-127.18(ddd,J=281.4,57.1,12.1Hz).HRMS(ESI):calcd for C18H18F2NO2[M+H]+:318.1300,found:318.1297.
实施例5
实施例5提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(2-苯基-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入2-苯基吲哚38.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为50%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.24(s,1H),7.82(d,J=7.9Hz,1H),7.51(d,J=6.7Hz,2H),7.47-7.40(m,3H),7.34(d,J=8.1Hz,1H),7.22(t,J=7.6Hz,1H),7.15(t,J=7.5Hz,1H),6.21(td,J=56.5,5.7Hz,1H),5.13-5.08(m,1H),2.35(s,1H).13C NMR(126MHz,Chloroform-d)δ138.4,136.0,131.7,129.1,129.1,128.9,126.6,123.0,120.8,120.5,115.6(t,J=244.5Hz),111.4,107.7(d,J=6.6Hz),68.7(t,J=26.6Hz).19F NMR(471MHz,Chloroform-d)δ-123.67(ddd,J=283.1,55.8,8.7Hz),-124.95(ddd,J=283.1,57.1,10.5Hz).HRMS(ESI):calcd for C16H12F2NO[M+H]-:272.0881,found:272.0883.
实施例6
实施例6提供一种二氟乙醇类化合物的制备方法,其化合物为1-(4-氯-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入4-氯吲哚30mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为88%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.34(d,J=2.6Hz,1H),7.27(dd,J=7.4,1.6Hz,1H),7.14-7.09(m,2H),6.12(td,J=55.5,3.0Hz,1H),5.82-5.75(m,1H),2.61(d,J=5.2Hz,1H).13C NMR(126MHz,Chloroform-d)δ137.6,125.3,124.8,123.3,121.5,115.8(t,J=245.6Hz),111.7(t,J=3.9Hz),110.5,67.2(t,J=23.9Hz).19F NMR(471MHz,Chloroform-d)δ-125.63(ddd,J=279.2,55.2,9.1Hz),-131.17(ddd,J=279.2,55.7,14.9Hz).HRMS(ESI):calcd for C10H7ClF2NO[M+H]-:230.0178,found:230.0178.
实施例7
实施例7提供一种二氟乙醇类化合物的制备方法,其化合物为3-(2,2-二氟-1-羟乙基)-1H-吲哚-4-碳醛,步骤如下:
取15mL耐压管,加入4-甲醛吲哚29mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为77%。
产品的表征数据为:1H NMR(500MHz,DMSO-d6)δ11.76(s,1H),10.27(s,1H),7.78(d,J=8.0Hz,1H),7.70(d,J=7.3Hz,1H),7.67(d,J=2.6Hz,1H),7.32(t,J=7.7Hz,1H),6.05(td,J=46.5,4.9Hz,1H),5.98(d,J=5.7Hz,1H),5.75–5.69(m,1H).13C NMR(126MHz,DMSO-d6)δ194.0,137.7,129.1,128.3,127.0,123.0,120.6,118.7,117.0(t,J=242.6Hz),113.0(t,J=4.3Hz),67.0(t,J=22.8Hz).19F NMR(471MHz,DMSO-d6)δ-125.11(ddd,J=273.8,55.5,8.8Hz),-129.28(ddd,J=273.8,56.3,14.8Hz).HRMS(ESI):calcd forC11H8F2NO2[M+H]-:224.0517,found:224.0521.
实施例8
实施例8提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(4-硝基-1H-吲哚-3-基)乙烷-1-醇,制备方法如下:
取15mL耐压管,加入4-硝基吲哚32.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为76%。产品的表征数据为:1H NMR(500MHz,Methanol-d4)δ7.82(d,J=7.8Hz,1H),7.77(d,J=8.9Hz,1H),7.70(s,1H),7.26(t,J=8.0Hz,1H),5.85(td,J=56.2,4.0Hz,1H),5.54-5.49(m,1H).13C NMR(126MHz,Methanol-d4)δ144.1,140.8,129.7,121.4,119.1,119.0,118.6,118.1(t,J=244.0Hz),112.5(t,J=4.0Hz),68.2(t,J=24.7Hz).19F NMR(471MHz,Methanol-d4)δ-128.25(ddd,J=281.2,56.2,8.6Hz),-130.25(ddd,J=281.2,56.5,12.9Hz).HRMS(ESI):calcd for C10H7F2N2O3[M+H]-:241.0419,found:241.0419.
实施例9
实施例9提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(5-甲氧基-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入5-甲氧基吲哚29.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为60%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.28(d,J=11.2Hz,1H),7.28(s,1H),7.18(d,J=2.3Hz,1H),6.91(dd,J=8.8,2.4Hz,1H),6.01(td,J=56.2,4.2Hz,1H),5.15-5.09(m,1H),3.86(s,3H),2.28(d,J=4.4Hz,1H).13C NMR(126MHz,Chloroform-d)δ154.7,131.4,126.5,124.0,115.8(t,J=245.1Hz),113.4,112.3,111.3(t,J=3.5Hz),101.1,68.5(t,J=25.2Hz),56.0.19F NMR(471MHz,Chloroform-d)δ-126.12(ddd,J=282.5,55.7,10.3Hz),-127.29(ddd,J=281.9,56.7,11.7Hz).HRMS(ESI):calcd for C11H10F2NO2[M+H]-:226.0674,found:226.0673.
实施例10
实施例10提供一种二氟乙醇类化合物的制备方法,其化合物为1-(5-氨基-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇的合成:
取15mL耐压管,加入5-氨基吲哚26.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为53%。产品的表征数据为:1H NMR(500MHz,DMSO-d6)δ10.64(s,1H),7.16(d,J=2.6Hz,1H),7.07(d,J=8.5Hz,1H),6.78(d,J=1.8Hz,1H),6.50(dd,J=8.5,2.1Hz,1H),6.04(td,J=56.4,4.7Hz,1H),5.73(d,J=4.6Hz,1H),5.08(s,2H),4.84-4.79(m,1H).13C NMR(126MHz,DMSO-d6)δ141.1,130.0,127.1,123.8,116.6(t,J=243.2Hz),112.1,111.6,110.1(t,J=3.9Hz),102.4,66.8(t,J=24.6Hz).19F NMR(471MHz,DMSO-d6)δ-124.77(dd,J=21.2,11.3Hz),-124.89(dd,J=20.3,11.3Hz).HRMS(ESI):calcd for C10H11F2N2O[M+H]+:213.0833,found:213.0831.
实施例11:
实施例11提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(5-氟-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入5-氟吲哚27mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为88%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.26(s,1H),7.36(dd,J=9.6,2.5Hz,1H),7.30–7.27(m,2H),(td,J=9.0,2.5Hz,1H),5.94(td,J=56.2,4.2Hz,1H),5.10–5.04(m,1H),2.43(d,J=4.2Hz,1H).13C NMR(126MHz,Chloroform-d)δ158.1(d,J=235.7Hz),132.7,126.2(d,J=9.9Hz),125.0,115.5(t,J=245.2Hz),112.2(d,J=9.7Hz),111.4(d,J=26.0Hz),110.8(t,J=3.2Hz),104.5(d,J=23.9Hz),68.2(t,J=25.3Hz).19F NMR(471MHz,Chloroform-d)δ-123.27–-123.32(m),-126.35(ddd,J=282.7,55.6,10.2Hz),-127.25(ddd,J=282.8,56.8,11.8Hz).HRMS(ESI):calcd for C10H7F3NO[M+H]-:214.0474,found:214.0473.
实施例12
实施例12提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(5-碘-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入5-碘吲哚48.6mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为87%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.33(s,1H),8.02(s,1H),7.44(d,J=10.0Hz,1H),7.13(d,J=2.4Hz,1H),7.08(d,J=8.6Hz,1H),5.92(td,J=56.0,4.2Hz,1H),5.02(t,J=10.4Hz,1H),2.64(s,1H).13C NMR(126MHz,Chloroform-d)δ135.2,131.1,128.3,128.2,124.2,115.4(t,J=245.0Hz),113.4,110.4(t,J=3.6Hz),83.9,68.0(t,J=25.4Hz).19FNMR(471MHz,Chloroform-d)δ-126.17(ddd,J=282.6,55.6,10.2Hz),-127.20(ddd,J=282.4,56.3,11.6Hz).HRMS(ESI):calcd for C10H7F2INO[M+H]-:321.9534,found:321.9530.
实施例13:
实施例13提供一种二氟乙醇类化合物的制备方法,其化合物为1-(3-(2,2-二氟-1-羟乙基)-1H-吲哚-5-基)乙烷-1-酮,步骤如下:
取15mL耐压管,加入5-乙酰基吲哚31.8mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为81%。
产品的表征数据为:1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),8.40(s,1H),7.76(dd,J=8.6,1.6Hz,1H),7.50(d,J=2.4Hz,1H),7.47(d,J=8.6Hz,1H),6.18(td,J=55.9,4.3Hz,1H),6.04(d,J=5.2Hz,1H),5.13-5.07(m,1H),2.61(s,3H).13C NMR(126MHz,DMSO-d6)δ197.6,138.9,128.8,126.1,125.7,122.0,121.4,116.4(t,J=243.7Hz),113.6(t,J=3.5Hz),111.5,66.5(t,J=24.6Hz),26.7.19F NMR(471MHz,DMSO-d6)δ-125.20(ddd,J=276.7,56.6,12.8Hz),-126.32(ddd,J=275.1,55.6,11.3Hz).HRMS(ESI):calcd forC12H12F2NO2[M+H]+:240.0830,found:240.0829.
实施例14
实施例14提供一种二氟乙醇类化合物的制备方法,其化合物为3-(2,2-二氟-1-羟乙基)-1H-吲哚-5-羧酸,步骤如下:
取15mL耐压管,加入5-羧基吲哚32.2mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为66%。产品的表征数据为:1H NMR(500MHz,Methanol-d4)δ8.49(d,J=1.0Hz,1H),7.85(dd,J=8.6,1.6Hz,1H),7.43(d,J=7.2Hz,2H),6.02(td,J=56.0,4.4Hz,1H),5.12(td,J=10.9,4.5Hz,1H),1.99(s,2H).13C NMR(126MHz,Methanol-d4)δ171.4z,140.8,127.3,126.5,124.3,123.8,122.7,117.5(t,J=244.0Hz),114.1(t,J=3.5Hz),112.2,68.7(t,J=24.8Hz).19F NMR(471MHz,Methanol-d4)δ-127.50(ddd,J=281.2,56.1,10.8Hz),-128.18(ddd,J=281.1,55.6,12.0Hz).HRMS(ESI):calcd for C11H8F2NO3[M+H]-:240.0466,found:240.0465.
实施例15
实施例15提供一种二氟乙醇类化合物的制备方法,其化合物为3-(2,2-二氟-1-羟乙基)-1H-吲哚-5-碳腈的合成:
取15mL耐压管,加入5-氰基吲哚28.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为84%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.66(s,1H),8.12(s,1H),7.45-7.43(m,3H),6.95(td,J=56.0,4.4Hz,1H),5.19–5.13(m,1H),2.59(d,J=4.0Hz,1H).13C NMR(126MHz,Chloroform-d)δ138.1,126.0,125.8,125.8,125.5,120.5,115.6(t,J=245.5Hz),112.5,112.4(t,J=3.7Hz),103.7,68.3(t,J=25.9Hz).19F NMR(471MHz,Chloroform-d)δ-126.42(ddd,J=285.2,56.7,10.8Hz),-127.18(ddd,J=284.0,55.6,9.9Hz).HRMS(ESI):calcdfor C11H7F2N2O[M+H]-:221.0520,found:221.0520.
实施例16
实施例16提供一种二氟乙醇类化合物的制备方法,其化合物为3-(2,2-二氟-1-羟乙基)-1H-吲哚-5-碳醛,步骤如下:
取15mL耐压管,加入5-醛基吲哚28.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在.80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为89%。产品的表征数据为:1H NMR(500MHz,DMSO-d6)δ11.65(s,1H),9.99(s,1H),8.32(s,1H),7.66(dd,J=8.5,1.4Hz,1H),7.55(dd,J=5.4,3.0Hz,2H),6.18(td,J=56.5,4.5Hz,1H),6.09(s,1H),5.10(t,J=9.9Hz,1H).13C NMR(126MHz,DMSO-d6)δ192.7,139.8,128.8,126.5,126.0,125.5,121.2,116.4(t,J=243.6Hz),113.8(t,J=7.1Hz),112.4,66.6(t,J=24.7Hz).19F NMR(471MHz,DMSO-d6)δ-125.13(ddd,J=276.5,56.3,12.2Hz),-126.10(ddd,J=276.2,55.7,11.4Hz).HRMS(ESI):calcd for C11H8F2NO2[M+H]-:224.0517,found:224.0521.
实施例17
实施例17提供一种二氟乙醇类化合物的制备方法,其化合物为1-(6-(苄氧基)-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入6-苄氧基吲哚44.6mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为86%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.11(s,1H),7.57(d,J=8.7Hz,1H),7.43(d,J=7.2Hz,2H),7.37(t,J=7.4Hz,2H),7.32(t,J=7.2Hz,1H),7.07(d,J=2.4Hz,1H),6.90(dd,J=8.7,2.2Hz,1H),6.85(d,J=2.1Hz,1H),5.94(td,J=56.1,4.3Hz,1H),5.05(s,3H),2.51(s,1H).13C NMR(126MHz,Chloroform-d)δ155.9,137.2,136.9,128.6,127.9,127.5,122.3,120.3,120.0,115.6(t,J=245.1Hz),111.2(t,J=3.6Hz),111.1,96.2,70.6,68.3(t,J=25.3Hz).19F NMR(471MHz,Methanol-d4)δ-126.98(d,J=280.6Hz),-128.27(d,J=280.6Hz).HRMS(ESI):calcd for C17H14F2NO2[M+H]-:302.0987,found:302.0988.
实施例18
实施例18提供一种二氟乙醇类化合物的制备方法,其化合物为1-(6-氯-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入6-氯基吲哚30.3mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为87%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.25(s,1H),7.64(d,J=8.5Hz,1H),7.37(d,J=1.7Hz,1H),7.28(d,J=2.5Hz,1H),7.14(dd,J=8.5,1.7Hz,1H),5.96(td,J=56.1,4.3Hz,1H),5.15-5.09(m,1H),2.38(d,J=4.3Hz,1H).13C NMR(126MHz,Chloroform-d)δ136.6,128.8,124.5,123.9,121.2,120.4,115.6(t,J=245.0Hz),111.6(t,J=3.6Hz),111.4,68.2(t,J=25.0Hz).19F NMR(471MHz,Chloroform-d)δ-126.41(ddd,J=282.2,56.9,10.1Hz),-127.18(ddd,J=283.5,56.4,11.1Hz).HRMS(ESI):calcd for C10H7ClF2NO[M+H]-:230.0178,found:230.0179.
实施例19
实施例19提供一种二氟乙醇类化合物的制备方法,其化合物为1-(6-溴-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入6-溴基吲哚39.2mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为87%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.27(s,1H),7.56(d,J=8.5Hz,1H),7.50(d,J=1.5Hz,1H),7.25(dd,J=8.5,1.5Hz,1H),7.21(d,J=2.5Hz,1H),5.94(td,J=56.0,4.3Hz,1H),5.12–5.06(m,1H),2.49(d,J=4.2Hz,1H).13C NMR(126MHz,Chloroform-d)δ137.0,124.7,123.9,123.7,120.7,116.3,115.5(t,J=245.0Hz),114.4,111.5(t,J=3.5Hz),68.1(t,J=25.5Hz).19F NMR(471MHz,Chloroform-d)δ-126.34(d,J=282.7Hz),-127.22(d,J=282.7Hz).HRMS(ESI):calcd for C10H7BrF2NO[M+H]-:273.9673,found:273.9676.
实施例20
实施例20提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(6-(三氟甲基)-1H-吲哚-3-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入6-三氟甲基吲哚37.0mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为76%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.54(s,1H),7.83(d,J=8.4Hz,1H),7.68(s,1H),7.44(s,1H),7.41(d,J=8.4Hz,1H),5.98(td,J=56.1,4.4Hz,1H),5.21-5.15(m,1H),2.48(d,J=3.7Hz,1H).13C NMR(126MHz,Chloroform-d)δ135.1,128.2,125.9,124.9(q,J=271.8Hz),125.0(q,J=32.1Hz),120.0,117.1(q,J=3.6Hz),115.6(t,J=245.5Hz),111.7(t,J=3.6Hz),109.1(q,J=4.5Hz),68.2(t,J=25.6Hz).19FNMR(471MHz,Chloroform-d)δ-60.81,-126.77(t,J=10.3Hz),-126.89(t,J=9.9Hz).HRMS(ESI):calcd for C11H7F5NO[M+H]-:264.0442,found:264.0443.
实施例21
实施例21提供一种二氟乙醇类化合物的制备方法,其化合物为3-(2,2-二氟-1-羟乙基)-1H-吲哚-6-碳腈,步骤如下:
取15mL耐压管,加入6-氰基吲哚28.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为88%。产品的表征数据为:1H NMR(500MHz,Methanol-d4)δ7.03(d,J=8.3Hz,1H),6.98(s,1H),6.78(s,1H),6.51(d,J=9.5Hz,1H),5.18(td,J=56.1,4.2Hz,1H),4.30(td,J=11.3,4.1Hz,1H).13C NMR(126MHz,Methanol-d4)δ136.9,130.9,129.3,122.9,121.6,121.5,117.5,117.5(t,J=243.6Hz),113.7(t,J=3.5Hz),104.8,68.5(t,J=25.2Hz).19F NMR(471MHz,Methanol-d4)δ-127.78(ddd,J=280.8,56.3,10.7Hz),-128.43(ddd,J=281.5,55.9,11.4Hz).HRMS(ESI):calcd for C11H7F2N2O[M+H]-:221.0520,found:221.0520.
实施例22
实施例22提供一种二氟乙醇类化合物的制备方法,其化合物为1-(5,6-二氯-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入5,6-二氯吲哚37.2mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为80%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.42(s,1H),7.78(s,1H),7.43(s,1H),7.26(s,1H),5.93(td,J=56.1,4.3Hz,1H),5.06(td,J=10.7,4.2Hz,1H),2.76(s,1H).13C NMR(126MHz,Chloroform-d)δ134.9,126.6,125.5,125.2,124.4,120.6,115.4(t,J=245.3Hz),112.9,110.9(t,J=3.6Hz),68.0(t,J=25.5Hz).19F NMR(471MHz,Chloroform-d)δ-126.39(ddd,J=282.8,55.6,10.3Hz),-127.27(ddd,J=282.2,55.3,10.2Hz).HRMS(ESI):calcd forC10H6Cl2F2NO[M+H]-:263.9789,found:263.9789.
实施例23
实施例23提供一种二氟乙醇类化合物的制备方法,其化合物为1-(5-溴-1-甲基-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入5-溴-1-甲基吲哚42.0mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为74%。
产品的表征数据为:1H NMR(500MHz,Methanol-d4)δ7.72(s,1H),7.19–7.15(m,3H),5.85(td,J=56.2,4.2Hz,1H),4.90(td,J=11.4,4.3Hz,1H),3.66(s,3H).13C NMR(126MHz,Methanol-d4)δ137.3,130.6,129.8,125.6,123.2,117.5(t,J=243.7Hz),113.7,112.2,111.5(t,J=3.6Hz),68.5(t,J=25.1Hz),33.0.19F NMR(471MHz,Methanol-d4)δ-127.61(ddd,J=281.2,56.4,11.1Hz),-128.27(ddd,J=281.4,57.0,11.7Hz).HRMS(ESI):calcd for C11H9BrF2NO[M+H]-:287.9830,found:287.9840.
实施例24
实施例24提供一种二氟乙醇类化合物的制备方法,其化合物为1-(2,5-二甲基-1H-吲哚-3-基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入2,5-二甲基吲哚29.0mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在80℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为35%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.89(s,1H),7.48(s,1H),7.17(d,J=8.2Hz,1H),6.98(d,J=8.2Hz,1H),6.06(td,J=56.6,5.6Hz,1H),5.05–5.0(m,1H),2.42(d,J=9.8Hz,6H),2.35(s,1H).13C NMR(126MHz,Chloroform-d)δ134.3,133.5,129.5,126.8,123.2,118.7,115.5(t,J=244.4Hz),110.2,106.0(t,J=4.0Hz),68.8(t,J=26.5Hz),21.5,12.1.19F NMR(471MHz,Chloroform-d)δ-125.63(d,J=10.2Hz),-125.75(d,J=10.2Hz).HRMS(ESI):calcd for C12H12F2NO[M+H]-:224.0881,found:224.0881.
实施例25
实施例25提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(1H-吡咯-2-基)乙烷-1-醇和1,1'-(1H-吡咯-3,4-二酰基)双(2,2-二氟乙烷-1-醇),步骤如下:
取15mL耐压管,加入吡咯13.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,2,2-二氟-1-(1H-吡咯-2-基)乙烷-1-醇收率为45%;1,1'-(1H-吡咯-3,4-二酰基)双(2,2-二氟乙烷-1-醇)收率为23%。
2,2-二氟-1-(1H-吡咯-2-基)乙烷-1-醇的表征数据为:1H NMR(500MHz,Chloroform-d)δ8.55(s,1H),6.87–6.81(m,1H),6.24(s,1H),6.21(q,J=2.8Hz,1H),5.84(td,J=55.8,3.6Hz,1H),4.91(t,J=9.9Hz,1H),2.54(s,1H).13C NMR(126MHz,Chloroform-d)δ127.6,118.1,114.0(t,J=245.3Hz),107.8,107.0,67.0(t,J=24.8Hz).19F NMR(471MHz,Chloroform-d)δ-127.26(ddd,J=284.3,55.5,10.4Hz),-129.17(ddd,J=283.5,56.0,12.8Hz).HRMS(ESI):calcd for C6H6F2NO[M+H]-:146.0411,found:146.0411.
1,1'-(1H-吡咯-3,4-二酰基)双(2,2-二氟乙烷-1-醇)的表征数据为:1H NMR(500MHz,Chloroform-d)δ9.01(s,1H),6.19(s,2H),5.82(td,J=55.6,3.2Hz,2H),4.84(t,J=11.2Hz,2H),3.08(s,2H).13C NMR(126MHz,Chloroform-d)δ126.8(q,J=3.2Hz),114.8(t,J=245.2Hz),108.4,108.3,67.9(td,J=25.0,2.7Hz).19F NMR(471MHz,Chloroform-d)δ-127.26(ddd,J=285.2,55.5,10.0Hz),-129.06(ddd,J=284.9,55.9,12.0,8.5Hz).HRMS(ESI):calcd for C8H8F4NO2[M+H]-:226.0485,found:226.0483.
实施例26
实施例26提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(1-苯基-1H-吡咯-2-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入1-苯基吡咯28.6mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为64%。产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.47(t,J=7.6Hz,2H),7.42–7.40(m,3H),6.89(dd,J=2.7,1.7Hz,1H),6.48(d,J=3.5Hz,1H),6.31(t,J=3.2Hz,1H),5.92(td,J=55.7,4.2Hz,1H),4.68-4.62(m,1H),2.23(d,J=6.3Hz,1H).13C NMR(126MHz,Chloroform-d)δ139.1,129.4,128.2(t,J=4.0Hz),127.9,126.3,124.2,115.2(t,J=245.0Hz),109.4,109.0,65.7(t,J=25.5Hz).19F NMR(471MHz,Chloroform-d)δ-125.17(ddd,J=282.8,55.4,9.3Hz),-127.70(ddd,J=283.4,56.3,12.5Hz).HRMS(ESI):calcd for C12H10F2NO[M+H]-:222.0724,found:222.0733.
实施例27
实施例27提供一种二氟乙醇类化合物的制备方法,其化合物为1-(4-(二甲氨基)苯基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入N,N-二甲基苯胺24.2mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为75%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.27(d,J=8.7Hz,2H),6.73(d,J=8.7Hz,2H),5.75(td,J=56.2,4.8Hz,1H),4.70(td,J=10.2,4.8Hz,1H),2.96(s,6H),2.36(s,1H).13C NMR(126MHz,Chloroform-d)δ151.1,128.2,123.7,116.2(t,J=245.0Hz),112.6,73.6(t,J=24.6Hz),40.6.19F NMR(471MHz,Chloroform-d)δ-127.01(ddd,J=282.4,56.1,10.1Hz),-127.69(ddd,J=282.7,57.0,10.6Hz).HRMS(ESI):calcdfor C10H14F2NO[M+H]+:202.1037,found:202.1034.
实施例28
实施例28提供一种二氟乙醇类化合物的制备方法,其化合物为1-(4-(二乙氨基)苯基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入N,N-二乙基苯胺29.8mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为71%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.24(d,J=8.7Hz,2H),6.68(d,J=8.8Hz,2H),5.76(td,J=56.2,4.8Hz,1H),4.68(td,J=10.3,4.8Hz,1H),3.36(q,J=7.1Hz,4H),2.33(s,1H),1.17(t,J=7.1Hz,6H).13C NMR(126MHz,Chloroform-d)δ148.4,128.5,122.3(t,J=3.2Hz),116.2(t,J=244.5Hz),111.6,73.9–73.5(m),44.5,12.6.19FNMR(471MHz,Chloroform-d)δ-126.88(ddd,J=281.8,56.4,9.6Hz),-127.65(ddd,J=281.8,55.9,10.6Hz).HRMS(ESI):calcd for C12H18F2NO[M+H]+:230.1350,found:230.1347.
实施例29
实施例29提供一种二氟乙醇类化合物的制备方法,其化合物为1-(4-(乙基(2-羟乙基)氨基)苯基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入N-乙基-N-羟乙基苯胺33.0mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为63%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.16(d,J=8.6Hz,2H),6.66(d,J=8.7Hz,2H),5.66(td,J=56.2,4.8Hz,1H),4.61-4.56(m,1H),3.68(t,J=5.8Hz,2H),3.38-3.31(m,4H),2.72(s,1H),1.95(s,1H),1.07(t,J=7.0Hz,3H).13C NMR(126MHz,Chloroform-d)δ148.8,128.5,123.6(t,J=3.3Hz),116.1(t,J=245.0Hz),112.4,73.4(t,J=25.0Hz),60.2,52.4,45.6,11.9.19F NMR(471MHz,Chloroform-d)δ-126.94(ddd,J=282.3,56.2,9.8Hz),-127.60(ddd,J=281.8,56.7,10.0Hz).HRMS(ESI):calcd forC12H16F2NO2[M+H]-:244.1143,found:244.1142.
实施例30
实施例30提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(2,3,6,7-四氢-1H,5H-吡啶[3,2,1-ij]喹啉-9-基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入2,3,6,7-四氢-1H,5H-吡啶[3,2,1-ij]喹啉34.6mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为66%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ6.79(s,2H),5.74(td,J=56.3,4.9Hz,1H),4.59–4.54(m,1H),3.14(t,J=3.6Hz,4H),2.74(t,J=6.5Hz,4H),2.36(s,1H),1.98-1.93(m,4H).13C NMR(126MHz,Chloroform-d)δ143.6,125.9,122.7(t,J=3.2Hz),121.6,116.2(t,J=244.8Hz),73.8(t,J=25.0Hz),50.0,27.8,21.9.19F NMR(471MHz,Chloroform-d)δ-126.59(ddd,J=282.2,55.7,9.0Hz),-127.46(ddd,J=281.4,56.7,11.2Hz).HRMS(ESI):calcd for C14H18F2NO[M+H]+:254.1350,found:254.1345.
实施例31
实施例31提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(4-(甲氨基)苯基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入N-甲基苯胺21.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为70%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.21(d,J=8.5Hz,2H),6.61(d,J=8.6Hz,2H),5.73(td,J=56.2,4.8Hz,1H),4.68(td,J=10.2,4.8Hz,1H),2.83(s,3H).13C NMR(126MHz,Chloroform-d)δ150.0,128.4,124.4(t,J=3.3Hz),116.2(t,J=244.3Hz),112.5,73.7(t,J=24.6Hz),30.7.19F NMR(471MHz,Chloroform-d)δ-127.00(ddd,J=282.1,56.3,9.6Hz),-127.67(ddd,J=281.2,55.3,10.4Hz).HRMS(ESI):calcdfor C9H12F2NO[M+H]+:188.0881,found:188.0878.
实施例32
实施例32提供一种二氟乙醇类化合物的制备方法,其化合物为2,2-二氟-1-(3-甲基-5-(甲氨基)苯基)乙烷-1-醇,步骤如下:
取15mL耐压管,加入N-甲基-5-甲基苯胺24.2mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为55%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.28(d,J=8.5Hz,1H),6.50(dd,J=8.4,2.5Hz,1H),6.43(d,J=2.3Hz,1H),5.80(td,J=56.2,5.2Hz,1H),5.02-4.97(m,1H),2.83(s,3H),2.32(s,3H),1.59(s,1H),1.25(s,1H).13C NMR(126MHz,Chloroform-d)δ149.5,137.6,127.7,123.0(t,J=6.0Hz),116.5(t,J=245.0Hz),114.2,110.3,69.8(t,J=24.9Hz),30.5,19.6.19F NMR(471MHz,Chloroform-d)δ-126.12(ddd,J=282.4,57.0,11.7Hz),-127.24(ddd,J=282.5,55.4,8.2Hz).HRMS(ESI):calcd for C10H14F2NO[M+H]+:202.1037,found:202.1035.
实施例33
实施例33提供一种二氟乙醇类化合物的制备方法,其化合物为1-(4-(二甲氨基)苯基)-22-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入异丙基苯胺27.0mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为62%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.18(d,J=8.5Hz,2H),6.57(d,J=8.6Hz,2H),5.73(td,J=56.2,4.8Hz,1H),4.66(td,J=10.2,4.8Hz,1H),3.62(p,J=6.3Hz,1H),1.20(d,J=6.3Hz,6H).13C NMR(126MHz,Chloroform-d)δ148.2,128.5,124.1(t,J=3.4Hz),116.2(t,J=245.0Hz),113.2,73.6(t,J=24.6Hz),44.3,23.0.19F NMR(471MHz,Chloroform-d)δ-126.93(ddd,J=281.7,56.3,9.5Hz),-127.66(ddd,J=281.7,56.3,10.8Hz).HRMS(ESI):calcd for C11H16F2NO[M+H]+:216.1194,found:216.1192.
实施例34
实施例34提供一种二氟乙醇类化合物的制备方法,其化合物为1-(4-(苄基氨基)苯基)-2,2-二氟乙烷-1-醇,步骤如下:
取15mL耐压管,加入苄基苯胺36.6mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在90℃,N2保护条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为56%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.35(s,2H),7.34(d,J=2.3Hz,2H),7.30-7.26(m,1H),7.19(d,J=8.4Hz,2H),6.63(d,J=8.4Hz,2H),5.73(td,J=56.0,4.9Hz,1H),4.67(td,J=10.1,4.8Hz,1H),4.33(s,2H),4.17(s,1H),2.37(s,1H).13CNMR(126MHz,Chloroform-d)δ148.7,139.0,128.7,128.3,127.4,127.3,124.5(t,J=3.5Hz),116.0(t,J=245.1Hz),112.7,73.5(t,J=24.5Hz),48.1.19F NMR(471MHz,Chloroform-d)δ-126.98(ddd,J=282.9,55.9,9.9Hz),-127.68(ddd,J=282.7,57.3,11.5Hz).HRMS(ESI):calcd for C15H15F2NO[M+H]+:264.1194,found:264.1190.
实施例35
实施例35提供一种二氟乙醇类化合物的制备方法,其化合物为4-(2,2-二氟-1-羟乙基)-2,6-二甲基苯酚,步骤如下:
取15mL耐压管,加入2,6-二甲基苯酚24.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为60%。
产品的表征数据为:1H NMR(500MHz,Methanol-d4)δ6.97(s,2H),5.75(td,J=56.2,4.7Hz,1H),4.58-4.52(m,1H),2.21(s,6H).13C NMR(126MHz,Methanol-d4)δ154.6,129.5(t,J=3.2Hz),128.5,125.5,117.8(t,J=243.8Hz),74.2(t,J=24.3Hz),16.7.19FNMR(471MHz,Methanol-d4)δ-128.26(ddd,J=281.0,55.6,9.6Hz),-129.11(ddd,J=281.2,55.5,12.0Hz).HRMS(ESI):calcd for C10H11F2O2[M+H]-:201.0721,found:201.0721.
实施例36
实施例36提供一种二氟乙醇类化合物的制备方法,其化合物为2-(2,2-二氟-1-羟乙基)-4,6-二甲基苯酚,步骤如下:
取15mL耐压管,加入2,4-二甲基苯酚24.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为45%。
产品的表征数据为:1H NMR(500MHz,DMSO-d6)δ8.36(s,1H),6.97(s,1H),6.85(s,1H),6.13(d,J=5.4Hz,1H),5.98(td,J=55.8,3.6Hz,1H),5.11-5.04(m,1H),2.17(s,3H),2.13(s,3H).13C NMR(126MHz,DMSO-d6)δ150.3,130.8,127.8,126.1,124.5,124.3(t,J=3.3Hz),116.1(t,J=243.3Hz),67.4(t,J=22.9Hz),20.3,16.5.19F NMR(471MHz,DMSO-d6)δ-125.43(ddd,J=275.4,55.4,8.2Hz),-129.51(ddd,J=275.6,56.3,16.9Hz).HRMS(ESI):calcd for C10H11F2O2[M+H]-:201.0721,found:201.0721.
实施例37
实施例37提供一种二氟乙醇类化合物的制备方法,其化合物为4-(叔丁基)-2-(2,2-二氟-1-羟乙基)苯酚和1,1'-(5-(叔丁基)-2-羟基-1,3-苯撑)双(2,2-二氟乙烷-1-醇),步骤如下:
取15mL耐压管,加入对叔丁基苯酚30.0mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,4-(叔丁基)-2-(2,2-二氟-1-羟乙基)苯酚的收率为44%;1,1'-(5-(叔丁基)-2-羟基-1,3-苯撑)双(2,2-二氟乙烷-1-醇)的收率为11%。
4-(叔丁基)-2-(2,2-二氟-1-羟乙基)苯酚的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.28(dd,J=8.5,2.5Hz,1H),7.11(d,J=2.3Hz,1H),6.98(s,1H),6.82(d,J=8.5Hz,1H),5.94(td,J=55.2,4.7Hz,1H),4.96-4.91(m,1H),1.81(s,1H),1.28(s,9H).13C NMR(126MHz,Chloroform-d)δ153.0,143.6,127.5,126.0,119.1-119.1(m),116.8,114.9(t,J=245.6Hz),75.1-74.7(m),34.2,31.6.19F NMR(471MHz,Chloroform-d)δ-125.83(ddd,J=284.2,55.2,7.9Hz),-128.91(ddd,J=284.3,57.1,13.1Hz).HRMS(ESI):calcd for C12H15F2O2[M+H]-:229.1034,found:229.1041.
1,1'-(5-(叔丁基)-2-羟基-1,3-苯撑)双(2,2-二氟乙烷-1-醇)的表征数据为:1HNMR(500MHz,Chloroform-d)δ8.19(d,J=21.7Hz,1H),7.19(s,2H),6.96(td,2H),4.97-4.96(m,2H),1.72(s,2H),1.28(s,9H).13C NMR(126MHz,Chloroform-d)δ151.7(d,J=4.6Hz),143.5,126.8(d,J=6.0Hz),120.8-120.8(m),120.7-120.7(m),114.7(t,J=245.7Hz),74.2-73.8(m),74.1-73.7(m),34.2,31.3.19F NMR(471MHz,Chloroform-d)δ-125.56(ddd,J=283.3,54.3,7.7Hz),-125.81(ddd,J=284.1,55.5,8.8Hz),-129.33(ddd,J=284.4,57.2,14.2Hz),-129.33(ddd,J=284.4,56.8,13.8Hz).HRMS(ESI):calcd forC14H17F4O3[M+H]-:309.1108,found:309.1118.
实施例38
实施例38提供一种二氟乙醇类化合物的制备方法,其化合物为3-(2,2-二氟-1-羟乙基)-[1,1'-联苯]-2-醇、5-(2,2-二氟-1-羟乙基)-[1,1'-联苯]-2-醇和1,1'-(2-羟基-[1,1'-联苯]-3,5-二酰基)双(22-二氟乙烷-1-醇),步骤如下:
取15mL耐压管,加入2-苯基苯酚56.0mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,3-(2,2-二氟-1-羟乙基)-[1,1'-联苯]-2-醇的收率为14%;5-(2,2-二氟-1-羟乙基)-[1,1'-联苯]-2-醇的收率为25%;1,1'-(2-羟基-[1,1'-联苯]-3,5-二酰基)双(2,2-二氟乙烷-1-醇)的收率为45%。
3-(2,2-二氟-1-羟乙基)-[1,1'-联苯]-2-醇的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.51–7.46(m,5H),7.43–7.40(m,1H),7.28(d,J=7.7Hz,2H),7.03(t,J=7.6Hz,1H),6.04(td,J=55.4,4.5Hz,1H),5.09–5.04(m,1H).13C NMR(126MHz,Chloroform-d)δ150.9,136.5,131.0,129.3,129.2,129.2,128.5,128.1,121.4(t,J=3.3Hz),120.8,114.8(t,J=245.1Hz),72.9-72.5(m).19F NMR(471MHz,Chloroform-d)δ-125.68(ddd,J=282.8,55.2,7.5Hz),-129.56(ddd,J=282.9,56.5,14.0Hz).HRMS(ESI):calcd forC14H11F2O2[M+H]-:249.0721,found:249.0730.
5-(2,2-二氟-1-羟乙基)-[1,1'-联苯]-2-醇的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.51–7.45(m,4H),7.41(t,J=7.1Hz,1H),7.31(d,J=7.0Hz,2H),7.00(d,J=9.0Hz,1H),5.76(td,J=56.0,5.0Hz,1H),5.40(s,1H),4.79(td,J=10.0,4.8Hz,1H),2.50(s,1H).13C NMR(126MHz,Chloroform-d)δ153.1,136.5,129.4,129.2,129.0,128.4,128.2,128.0,116.2,115.8(t,J=245.2Hz),73.3(t,J=24.6Hz).19F NMR(471MHz,Chloroform-d)δ-127.36(dd,J=9.7,5.3Hz),-127.48(dd,J=9.7,5.8Hz).HRMS(ESI):calcd for C14H11F2O2[M+H]-:249.0721,found:249.0730.
1,1'-(2-羟基-[1,1'-联苯]-3,5-二酰基)双(2,2-二氟乙烷-1-醇)的表征数据为:1H NMR(500MHz,Chloroform-d)δ7.53–7.47(m,4H),7.44(t,J=7.4Hz,1H),7.35(dd,J=5.7,4.1Hz,2H),6.67(d,J=19.7Hz,1H),6.13–5.66(m,2H),5.13–5.03(m,1H),4.79(tt,J=10.0,4.1Hz,1H),2.67(s,2H).13C NMR(126MHz,Chloroform-d)δ151.7(d,J=10.9Hz),136.1(d,J=3.7Hz),129.9,129.6(d,J=8.5Hz),129.2(d,J=5.3Hz),128.3(d,J=2.7Hz),128.1(d,J=5.3Hz),127.1(d,J=5.0Hz),121.7,121.6,115.7(t,J=245.4Hz),114.6(t,J=245.4Hz),73.0(t,J=25.0Hz),72.3(t,J=24.4Hz).19F NMR(471MHz,Chloroform-d)δ-125.45–-126.45(m),-127.19–-127.80(m),-129.49(ddd,J=149.2,56.0,14.1Hz),-130.10(ddd,J=149.2,55.8,14.1Hz).HRMS(ESI):calcd for C16H13F4O3[M+H]-:329.0795,found:329.0806.
实施例39
实施例39提供一种二氟乙醇类化合物的制备方法,其化合物为1-(2,2-二氟-1-羟乙基)萘-2-醇,步骤如下:
取15mL耐压管,加入萘酚28.8mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为44%。产品的表征数据为:1HNMR(500MHz,Chloroform-d)δ8.47(s,1H),7.77(t,J=8.7Hz,2H),7.73(d,J=8.6Hz,1H),7.49(t,J=7.7Hz,1H),7.35(t,J=7.5Hz,1H),7.12(d,J=8.9Hz,1H),6.06(td,J=55.7,4.4Hz,1H),5.86(dt,J=13.8,5.5Hz,1H),3.88(s,1H).13C NMR(126MHz,Chloroform-d)δ155.4,131.9,131.4,129.0,128.9,127.3,123.5,121.0,119.5,114.7(t,J=246.2Hz),109.6(t,J=3.2Hz),71.2-70.8(m).19F NMR(471MHz,Chloroform-d)δ-125.47(ddd,J=282.8,55.1,6.7Hz),-128.50(ddd,J=282.8,56.6,14.0Hz).HRMS(ESI):calcd forC12H9F2O2[M+H]-:223.0565,found:223.0570.
实施例40
实施例40提供一种二氟乙醇类化合物的制备方法,其化合物为8-(2,2-二氟-1-羟乙基)-7-羟基-2-萘腈,步骤如下:
取15mL耐压管,加入7-氰基萘酚33.8mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为57%。产品的表征数据为:1H NMR(500MHz,DMSO-d6)δ10.67(s,1H),8.52(d,J=9.0Hz,1H),8.42(d,J=1.7Hz,1H),7.92(d,J=8.9Hz,1H),7.66(dd,J=9.0,1.8Hz,1H),7.32(d,J=8.9Hz,1H),6.50(s,1H),6.34(td,J=56.0,5.0Hz,1H),5.69(td,J=13.0,12.5,5.0Hz,1H).13C NMR(126MHz,DMSO-d6)δ156.4,134.9,134.6,131.1,127.3,126.4,126.3,119.6,119.6,116.2(t,J=243.8Hz),115.1(t,J=3.1Hz),104.6,66.5(t,J=25.2Hz).19F NMR(471MHz,DMSO-d6)δ-124.01(t,J=10.8Hz),-124.13(t,J=10.8Hz).HRMS(ESI):calcd for C13H8F2NO2[M+H]-:248.0517,found:248.0526.
实施例41
实施例41提供一种二氟乙醇类化合物的制备方法,其化合物为(8R,9S,13S,14S,17R)-2-(2,2-二氟-1-羟乙基)-17-乙炔基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊烷[a]菲-3,17-二醇和(8R,9S,13S,14S,17R)-2,4-双(2,2-二氟-1-羟乙基)-17-乙炔基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊烷[a]菲-3,17-二醇,步骤如下:
取15mL耐压管,加入(8R,9S,13S,14S,17R)-17-乙炔基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊烷[a]菲-3,17-二醇59.3mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸115.2mg(0.40mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在60℃条件下反应16小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,(8R,9S,13S,14S,17R)-2-(2,2-二氟-1-羟乙基)-17-乙炔基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊烷[a]菲-3,17-二醇的收率为40%;(8R,9S,13S,14S,17R)-2,4-双(2,2-二氟-1-羟乙基)-17-乙炔基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊烷[a]菲-3,17-二醇的收率24%。
(8R,9S,13S,14S,17R)-2-(2,2-二氟-1-羟乙基)-17-乙炔基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊烷[a]菲-3,17-二醇的表征数据为:1H NMR(500MHz,DMSO-d6)δ9.31(s,1H),7.25(s,1H),6.49(s,1H),5.97(t,J=55.7Hz,1H),5.83(d,J=5.3Hz,1H),5.34(s,1H),4.98–4.95(m,1H),2.69(s,2H),2.30(s,1H),2.10–2.06(m,2H),1.86(t,J=12.7Hz,1H),1.78–1.76(m,2H),1.69–1.57(m,3H),1.32-1.24(m,4H),0.76(s,3H).13C NMR(126MHz,DMSO-d6)δ152.1,136.8,130.4(d,J=7.9Hz),124.9(d,J=7.6Hz),121.4(d,J=3.4Hz),116.1(t,J=243.2Hz),114.7,89.0(d,J=2.7Hz),78.1,75.1,66.5(t,J=23.8Hz),49.0,46.7(d,J=2.5Hz),43.4(d,J=13.2Hz),40.4,38.8,32.6(d,J=5.1Hz),28.9(d,J=12.7Hz),27.0(d,J=8.8Hz),26.3(d,J=13.3Hz),22.5,12.7.19F NMR(471MHz,DMSO-d6)δ-125.41(dd,J=274.0,56.2Hz),-128.85–-130.04(m).HRMS(ESI):calcd for C22H25F2O3[M+H]-:375.1766,found:375.1762.
(8R,9S,13S,14S,17R)-2,4-双(2,2-二氟-1-羟乙基)-17-乙炔基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊烷[a]菲-3,17-二醇的表征数据为:1H NMR(500MHz,DMSO-d6)δ7.40(d,J=5.0Hz,1H),6.22(t,J=55.3Hz,1H),6.05(t,J=56.4Hz,1H),5.41(s,1H),5.27(s,1H),5.08(s,1H),2.89(d,J=16.2Hz,1H),2.75–2.52(m,2H),2.39(s,1H),2.17(d,J=2.2Hz,2H),1.96-1.84(m,3H),1.76–1.65(m,3H),1.40-1.30(m,4H),0.82(s,3H).13C NMR(126MHz,DMSO-d6)δ153.4,135.7,131.6,125.9(d,J=10.4Hz),122.8,119.3,116.4(t,J=245.6Hz),116.0(t,J=245.6Hz),89.4,78.6,75.6,69.5,69.4,49.5,47.0(d,J=1.8Hz),44.2(d,J=8.9Hz),39.3,38.7(d,J=4.6Hz),33.0(d,J=5.3Hz),27.5,26.9(d,J=13.5Hz),26.7,22.9,13.1.19F NMR(471MHz,DMSO-d6)δ-124.14–-127.60(m),-127.93–-130.59(m).HRMS(ESI):calcd for C24H27F4O4[M+H]-:455.1839,found:455.1843.
实施例42
实施例42提供一种二氟乙醇类化合物的制备方法,其化合物为5-(2,2-二氟-1-羟乙基)嘧啶-2,4(1H,3H)-二酮,步骤如下:
取15mL耐压管,加入尿嘧啶22.4mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸230.4mg(0.80mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在100℃条件下反应24小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为85%。产品的表征数据为:1H NMR(500MHz,Methanol-d4)δ7.48(s,1H),5.97(td,J=56.0,3.3Hz,1H),4.76-4.70(m,1H).13C NMR(126MHz,Methanol-d4)δ165.5,153.1,142.1,116.2(t,J=243.4Hz),110.0(t,J=3.6Hz),67.6(t,J=24.3Hz).19F NMR(471MHz,Methanol-d4)δ-129.88(ddd,J=281.2,55.6,7.7Hz),-133.04(ddd,J=281.3,56.2,15.5Hz).HRMS(ESI):calcd for C6H5F2N2O3[M+H]-:191.0262,found:191.0260.
实施例43
实施例43提供一种二氟乙醇类化合物的制备方法,其化合物为5-(2,2-二氟-1-羟乙基)-6-甲基嘧啶-2,4(1H,3H)-二酮,步骤如下:
取15mL耐压管,加入6-甲基尿嘧啶25.2mg(0.20mmol)、2,2-二氟乙烯基4-(三氟甲基)苯磺酸230.4mg(0.80mmol)、无水碳酸钾13.8mg(0.1mmol)、三氟乙醇1mL,在100℃条件下反应24小时。反应结束后加入10mL水淬灭反应,再加入10mL乙酸乙酯和5mL饱和食盐水洗涤,分层收集有机相,水相再用乙酸乙酯萃取2次,每次乙酸乙酯用量为5mL,合并有机相,加入无水硫酸钠干燥,减压蒸馏除去溶剂,再经柱层析得到产品,收率为74%。
产品的表征数据为:1H NMR(500MHz,Chloroform-d)δ6.11(td,J=56.8,5.4Hz,1H),4.84–4.79(m,1H),2.27(s,3H).13C NMR(126MHz,Chloroform-d)δ166.2,154.8,152.7,116.9(t,J=242.2Hz),107.1(t,J=3.7Hz),68.5(t,J=27.3Hz),16.7.19F NMR(471MHz,Chloroform-d)δ-123.49(ddd,J=284.2,57.0,11.7Hz),-123.61(ddd,J=285.7,56.6,10.0Hz).HRMS(ESI):calcd for C7H7F2N2O3[M+H]-:205.0419,found:205.0424.
由上述实施例1至43可以看出:该反应适用底物广(主要为吲哚类化合物、苯酚类化合物、吡咯类化合物、苯胺类化合物和嘧啶类化合物),该反应通过碱催化,使二氟乙烯基化合物形成二氟乙醛中间体与底物发生Friedel-Crafts反应生成二氟乙醇类化合物。因此相比于其他金属催化二氟乙醇类化合物的合成,本发明只需用到少量的碱催化。该反应适用的底物类型丰富,说明其反应官能团耐受性好,因此适用范围广;反应产率高,部分的反应产率高达90%以上;反应中使用的原料和溶剂等廉价易得,反应过程快且操作简单安全,因此,具有大规模生产的潜力。
上面结合本发明实施例作了详细说明,但本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。
Claims (10)
1.一种二氟乙醇类化合物的制备方法,其特征在于,包括如下步骤:
在醇溶剂和碱催化剂存在下,加入芳香类化合物和式(I)所示的化合物进行反应,得到式(II)所示的化合物;
所述芳香类化合物选自如下结构式中的一种:
式(I)所示的化合物和式(II)所示的化合物的结构式如下:
其中,R选自取代或未取代的苯磺酰基、苯基或萘基;
R1选自H、取代或未取代的苯基;
R2为一个或多个基团,R1分别独立地选自H、C1~10的烷基、取代或未取代的苯基、取代或未取代的C1~10的烷氧基、C1~10的卤代烷基、卤素、C1~10的羧基、硝基、氰基、醛基、乙酰基;
R3选自H、C1~10的烷基、取代或未取代的苯基;
R4为一个或多个基团,R4独立地选自H、C1~10的烷基、C1~10的烷氧基、取代或未取代的苯基;
R5选自羟基、-NR8R9;
R6为一个或多个基团,R6选自H、氰基;
R7选自H、C1~10的烷基;
R8和R9独立地选自H、取代或未取代的C1~10的烷基、取代或未取代的苯基;
或者R8和R9通过C1~10的烷基成环。
2.根据权利要求1所述的二氟乙醇类化合物的制备方法,其特征在于,所述芳香类化合物和所述式(I)所示的化合物的摩尔比为1:2~4。
3.根据权利要求1所述的二氟乙醇类化合物的制备方法,其特征在于,所述醇溶剂与所述芳香类化合物的体积摩尔比为1mL:(0.1~0.3)mmol。
4.根据权利要求1所述的二氟乙醇类化合物的制备方法,其特征在于,所述醇溶剂选自甲醇、乙醇、异丙醇、二氟乙醇、三氟乙醇、六氟异丙醇、五氟乙醇或四氟丙醇中的至少一种。
5.根据权利要求1所述的二氟乙醇类化合物的制备方法,其特征在于,所述碱催化剂选自无机碱或无机碱。
6.根据权利要求5所述的二氟乙醇类化合物的制备方法,其特征在于,所述无机碱选自碳酸钠、碳酸钾、碳酸铯、碳酸锂、磷酸钠、碳酸钾、磷酸氢钾、磷酸氢钠、氢氧化钠或氢氧化钾中的至少一种。
7.根据权利要求5所述的二氟乙醇类化合物的制备方法,其特征在于,所述有机碱选自三乙胺、DIPEA、吡啶、DMAP、DBU、奎宁类催化剂。
8.根据权利要求1所述的二氟乙醇类化合物的制备方法,其特征在于,所述反应的温度为50℃~120℃。
9.根据权利要求1所述的二氟乙醇类化合物的制备方法,其特征在于,所述反应的时间为6h~24h。
10.根据权利要求1所述的二氟乙醇类化合物的制备方法,其特征在于,所述反应完成后还包括提纯的步骤。
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