CN112266345B - Preparation method of alpha, alpha-difluoro-beta-ketone sulfone compound - Google Patents
Preparation method of alpha, alpha-difluoro-beta-ketone sulfone compound Download PDFInfo
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- CN112266345B CN112266345B CN202011192540.6A CN202011192540A CN112266345B CN 112266345 B CN112266345 B CN 112266345B CN 202011192540 A CN202011192540 A CN 202011192540A CN 112266345 B CN112266345 B CN 112266345B
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- alkyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 77
- 238000006243 chemical reaction Methods 0.000 claims abstract description 143
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 125000003118 aryl group Chemical group 0.000 claims abstract description 47
- 229940125904 compound 1 Drugs 0.000 claims abstract description 33
- 239000003999 initiator Substances 0.000 claims abstract description 32
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims abstract description 29
- 239000003960 organic solvent Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 180
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims description 64
- 229940096017 silver fluoride Drugs 0.000 claims description 62
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical group [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 62
- 238000010898 silica gel chromatography Methods 0.000 claims description 58
- 125000005842 heteroatom Chemical group 0.000 claims description 28
- -1 cyano, hydroxy Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 229910052786 argon Inorganic materials 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 125000000524 functional group Chemical group 0.000 abstract description 17
- 229910001512 metal fluoride Inorganic materials 0.000 abstract description 6
- 230000004048 modification Effects 0.000 abstract description 5
- 238000012986 modification Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229930014626 natural product Natural products 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000013341 scale-up Methods 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 164
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 108
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 53
- 238000004293 19F NMR spectroscopy Methods 0.000 description 53
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 239000003208 petroleum Substances 0.000 description 53
- 239000007787 solid Substances 0.000 description 53
- 239000012300 argon atmosphere Substances 0.000 description 49
- 239000012299 nitrogen atmosphere Substances 0.000 description 49
- 239000011734 sodium Substances 0.000 description 46
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 4
- 150000001719 carbohydrate derivatives Chemical class 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 235000003270 potassium fluoride Nutrition 0.000 description 3
- 239000011698 potassium fluoride Substances 0.000 description 3
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 2
- UTOIEVWJKDLJGE-AQRBRUGDSA-N (4r,6s)-6-[(e)-2-[4-(4-fluorophenyl)-2,6-di(propan-2-yl)pyrimidin-5-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C=1C=C(F)C=CC=1C1=NC(C(C)C)=NC(C(C)C)=C1\C=C\[C@@H]1C[C@@H](O)CC(=O)O1 UTOIEVWJKDLJGE-AQRBRUGDSA-N 0.000 description 2
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical class CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- WOADNNTWYZOWNV-UHFFFAOYSA-N 3-cycloheptyl-9-(dimethylamino)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CC=NC=2SC(C2=O)=C1N=CN2C1CCCCCC1 WOADNNTWYZOWNV-UHFFFAOYSA-N 0.000 description 1
- HZYLVYNCWLAIGF-UHFFFAOYSA-N 4-[[[2-(cyclohexylamino)-2-oxoethyl]-(4-propan-2-ylbenzoyl)amino]methyl]-N-hydroxybenzamide Chemical compound CC(C)c1ccc(cc1)C(=O)N(CC(=O)NC1CCCCC1)Cc1ccc(cc1)C(=O)NO HZYLVYNCWLAIGF-UHFFFAOYSA-N 0.000 description 1
- MWVKLRSIDOXBSE-UHFFFAOYSA-N 5-(1-piperidin-4-ylpyrazol-4-yl)-3-(6-pyrrolidin-1-yl-1,3-benzoxazol-2-yl)pyridin-2-amine Chemical compound NC1=NC=C(C2=CN(N=C2)C2CCNCC2)C=C1C(OC1=C2)=NC1=CC=C2N1CCCC1 MWVKLRSIDOXBSE-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VCUKKMIXURRDKL-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-ethylphenyl)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(CC)=CC=C1N1C(=O)C(SC=2C3=C(N(C)C)C=CN=2)=C3N=C1 VCUKKMIXURRDKL-UHFFFAOYSA-N 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 1
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- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- YBFBENHWPRGUMU-UHFFFAOYSA-N chembl398496 Chemical compound OC(=O)C1=CC=CC=C1NC(=O)N1CCN(C=2N=C3C=CC(O)=CC3=NC=2)CC1 YBFBENHWPRGUMU-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
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- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- QWLICVXJMVMDDQ-UHFFFAOYSA-N fluoro acetate Chemical compound CC(=O)OF QWLICVXJMVMDDQ-UHFFFAOYSA-N 0.000 description 1
- 239000004811 fluoropolymer Substances 0.000 description 1
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 238000004377 microelectronic Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 239000011941 photocatalyst Substances 0.000 description 1
- 229960000249 pregnenolone Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
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- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
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Abstract
The invention provides a preparation method of an alpha, alpha-difluoro-beta-ketosulfone compound, belonging to the technical field of chemistry. Firstly, a composition for preparing the compound shown in the formula I is provided, which comprises the following components: compound 1, a fluoride initiator and an organic solvent; wherein Ar is1And Ar2Each independently selected from substituted or unsubstituted aromatic group, substituted or unsubstituted hetero atom aromatic group. Also provides a method for preparing the alpha, alpha-difluoro-beta-ketosulfone compound by using the composition. The invention uses metal fluoride as initiator, and can prepare a series of compounds under mild condition. The preparation method has simple synthetic route, good yield and high purity; has the advantages of excellent functional group adaptability and the like, can be used for preparing alpha, alpha-difluoro-beta-ketosulfone compounds with various functional groups, and can be successfully applied to the later modification of natural products and drug molecules. In addition, the reaction scale of the invention can be enlarged to gram level, can be used for industrial scale-up production, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of chemistry, and particularly relates to a preparation method of an alpha, alpha-difluoro-beta-ketosulfone compound.
Background
Fluorine atoms have large electronegativity and small atomic radius, so that introduction of a single fluorine atom or a plurality of fluorine atoms into a compound can significantly change certain characteristics and properties of the original compound, so that the compound has a plurality of special physicochemical properties. Many fluorine-containing compounds have wide application in the fields of medicine, agriculture, materials and the like. For example, in the field of materials, fluoropolymers have excellent properties such as good chemical stability and low surface energy, and thus have been widely used in the fields of rubber, resins, microelectronics industry, surfactants, and the like. Among fluorine-containing compounds, alpha-difluoro-beta-ketosulfone compounds are important compounds and have wide application.
At present, the preparation of alpha, alpha-difluoro-beta-ketosulfone compounds mainly comprises the following methods:
the method comprises the following steps:
the method uses beta-ketone sulfone compounds as raw materials, and the beta-ketone sulfone compounds and fluorine reagents such as acetoxy fluorine and the like undergo nucleophilic reaction under the action of alkali to obtain monofluorine beta-ketone sulfone compounds and alpha, alpha-difluoro-beta-ketone sulfone compounds. The reaction generates a large amount of byproducts such as monofluoro beta-ketosulfone compounds, which are not easy to separate and have poor chemical selectivity.
The method 2 comprises the following steps:
the method uses ester as a raw material, and performs nucleophilic fluoralkylation under the action of strong alkali to obtain the alpha, alpha-difluoro-beta-ketone sulfone compound. According to the method, ultralow-temperature reaction conditions are required, strong alkali lithium bis (trimethylsilyl) amide is required to be used as a reaction reagent, and the adaptability of functional groups is poor.
The method 3 comprises the following steps:
the method uses aryl azo tetrafluoroborate, sodium pyrosulfite and 2, 2-difluoroenol silicon-based ether as raw materials to complete three-component reaction under photocatalysis to obtain the alpha, alpha-difluoro-beta-ketone sulfone compound. The reaction requires the use of expensive reaction equipment and a photocatalyst, and the functional group adaptability is poor due to the limitation of the preparation of 2, 2-difluoroenol silyl ether.
In summary, the existing methods for preparing α, α -difluoro- β -ketosulfone compounds suffer from the problems of low chemical selectivity, harsh reaction conditions, poor functional group adaptability and the like. The research on a method for preparing the alpha, alpha-difluoro-beta-ketosulfone compound, which has the advantages of easy separation, mild condition, good functional group adaptability and excellent chemical selectivity, is needed.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of an alpha, alpha-difluoro-beta-ketosulfone compound.
The invention provides a composition for preparing an alpha, alpha-difluoro-beta-ketosulfone compound shown in formula I, which comprises the following components: compound 1, a fluoride initiator and an organic solvent;
wherein Ar is1And Ar2Each independently selected from substituted or unsubstituted aromatic group, substituted or unsubstituted hetero atom aromatic group.
Further, the air conditioner is provided with a fan,
Ar1and Ar2Are respectively and independently selected from 0 to 5R1Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R1A substituted 5-to 10-membered heteroatomic aromatic group;
R1are respectively and independently selected from 0 to 5R4Substituted C1～C8Alkyl, cyano, hydroxy, trifluoromethyl, 4-to 6-membered aryl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R3And a 3-to 8-membered heterocyclic group; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are independently selected from hydrogen and 0-5R4Substituted C1～C8Alkyl, 4-6 membered aryl, p-toluenesulfonyl, trifluoromethyl, substituted with 0-5R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 5R4A substituted 3-to 8-membered heterocyclic group, substituted with 0 to 5R4A substituted 5-to 17-membered heteroatomic aromatic group;
R4are respectively and independently selected from 0 to 5R5Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R5A substituted 5-to 10-membered heteroatomic aromatic group, substituted with 0 to 5R5Substituted 5-to 17-membered heterocyclic group, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C8Alkyl, -OR60 to 5R6Substituted 6-to 10-membered aromatic group, 3-to 8-membered heterocyclic group, -C (O) OR6；
R6Are each independently selected from C1～C8Alkyl, halogen;
the heteroatom is O, S or N; the number of the heteroatoms is 1-6.
Further, the air conditioner is provided with a fan,
Ar1and Ar2Are respectively and independently selected from 0 to 3R1Substituted phenyl, substituted by 0-1R1Substituted naphthyl, substituted by 0-1R1Substituted thienyl, substituted with 0-1R1Substituted by
Is coated with 0 to 5R1Substituted by
Is coated with 0 to 1R1Substituted by
Or by 0 to 1R1Substituted by
R1Are respectively and independently selected from 0 to 1R4Substituted C1～C4Alkyl, cyano, hydroxy, trifluoromethyl, phenyl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R3Morpholinyl; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are independently selected from hydrogen and 0-1R4Substituted C1～C2Alkyl, phenyl, p-toluenesulfonyl, trifluoromethyl, substituted with 0 to 3R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 1R4Substituted tetrahydropyrrolyl, substituted with 0-3R4Substituted by
R4Are respectively and independently selected from 0 to 1R5Substituted phenyl, substituted by 0-3R5Substituted C7～C17Aryl group, substituted by 0 to 1R5Substituted thienyl, substituted with 0-4R5Substituted 5-to 9-membered heterocyclyl, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group; the hetero atom of the heterocyclic group is O, and the number of the hetero atoms is 1-5;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C4Alkyl, -OR60 to 1R6Substituted phenyl, piperidinyl, -C (O) OR6；
R6Are each independently selected from C1～C2Alkyl, halogen.
Further, the fluoride initiator is selected from metal fluorides;
and/or the organic solvent is selected from one or more of acetonitrile, acetone, N-methyl pyrrolidone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide;
and/or the equivalent ratio of the compound 1 to the fluoride initiator is 1: (0.1 to 1);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-1) mmol: (0.1-1) mL;
preferably, the first and second electrodes are formed of a metal,
the fluoride initiator is selected from silver fluoride, potassium fluoride and cesium fluoride;
and/or, the organic solvent is selected from acetonitrile;
and/or the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 0.5);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-0.5) mmol: (0.1-0.5) ml;
more preferably, the amount of the organic solvent is,
the fluoride initiator is selected from silver fluoride;
and/or the equivalent ratio of the compound 1 to the fluoride initiator is 1: (0.1 to 0.2);
and/or the molar volume ratio of the compound 1 to the organic solvent is 0.2 mmol: 0.5 mL.
The invention also provides application of the composition in preparation of the alpha, alpha-difluoro-beta-ketosulfone compound;
preferably, the alpha, alpha-difluoro-beta-ketosulfone compound is prepared by the following preparation method: reacting the compound 1 with a fluoride initiator in an organic solvent to obtain the compound;
more preferably, the reaction is carried out under the protection of inert gas;
and/or the reaction temperature is 50-100 ℃;
and/or, after the reaction, further purifying, wherein the purification comprises the following steps: concentrating the reaction solution, and performing silica gel column chromatography;
further preferably, the inert gas is nitrogen or argon;
and/or the reaction temperature is 60-80 ℃;
more preferably, the reaction time is 10-30 h.
The invention also provides a preparation method of the alpha, alpha-difluoro-beta-ketone sulfone compound, which comprises the following steps:
reacting the compound 1 with a fluoride initiator in an organic solvent to obtain a compound 2;
wherein Ar is1And Ar2Each independently selected from substituted or unsubstituted aromatic group, substituted or unsubstituted hetero atom aromatic group;
preferably, the first and second electrodes are formed of a metal,
Ar1and Ar2Are respectively and independently selected from 0 to 5R1Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R1A substituted 5-to 10-membered heteroatomic aromatic group;
R1are respectively and independently selected from 0 to 5R4Substituted C1～C8Alkyl, cyano, hydroxy, trifluoromethyl, 4-to 6-membered aryl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R3And a 3-to 8-membered heterocyclic group; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are independently selected from hydrogen and 0-5R4Substituted C1～C8Alkyl, 4-6 membered aryl, p-toluenesulfonyl, trifluoromethyl, substituted with 0-5R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 5R4A substituted 3-to 8-membered heterocyclic group, substituted with 0 to 5R4A substituted 5-to 17-membered heteroatomic aromatic group;
R4are respectively and independently selected from 0 to 5R5Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R5A substituted 5-to 10-membered heteroatomic aromatic group, substituted with 0 to 5R5Substituted 5-to 17-membered heterocyclic group, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C8Alkyl, -OR60 to 5R6Substituted 6-to 10-membered aromatic group, 3-to 8-membered heterocyclic group, -C (O) OR6；
R6Are each independently selected from C1～C8Alkyl, halogen;
the heteroatom is O, S or N; the number of the heteroatoms is 1-6.
Further, the air conditioner is provided with a fan,
Ar1and Ar2Are respectively and independently selected from 0 to 3R1Substituted phenyl, substituted by 0-1R1Substituted naphthyl, substituted by 0-1R1Substituted thienyl, substituted with 0-1R1Substituted by
Is coated with 0 to 5R1Substituted by
Is coated with 0 to 1R1Substituted by
Or by 0 to 1R1Substituted by
R1Are respectively and independently selected from 0 to 1R4Substituted C1～C4Alkyl, cyano, hydroxy, trifluoromethyl, phenyl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R3Morpholinyl; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are independently selected from hydrogen and 0-1R4Substituted C1～C2Alkyl, phenyl, p-toluenesulfonyl, trifluoromethyl, substituted with 0 to 3R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 1R4Substituted tetrahydropyrrolyl, substituted with 0-3R4Substituted by
R4Are respectively and independently selected from 0 to 1R5Substituted phenyl, substituted by 0-3R5Substituted C7～C17Aryl group, substituted by 0 to 1R5Substituted thienyl, substituted with 0-4R5Substituted 5-to 9-membered heterocyclyl, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group; the hetero atom of the heterocyclic group is O, and the number of the hetero atoms is 1-5;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C4Alkyl, -OR60 to 1R6Substituted phenyl, piperidinyl, -C (O) OR6；
R6Are each independently selected from C1～C2Alkyl, halogen.
Further, the fluoride initiator is selected from metal fluorides;
and/or the organic solvent is selected from one or more of acetonitrile, acetone, N-methyl pyrrolidone, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide;
and/or the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 1);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-1) mmol: (0.1-1) mL
Preferably, the first and second electrodes are formed of a metal,
the fluoride initiator is selected from silver fluoride, potassium fluoride and cesium fluoride;
and/or, the organic solvent is selected from acetonitrile;
and/or the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 0.5);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-0.5) mmol: (0.1-0.5) ml;
more preferably, the fluoride initiator is selected from silver fluoride;
and/or the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 0.2);
and/or the molar volume ratio of the compound 1 to the organic solvent is 0.2 mmol: 0.5 mL.
Further, the reaction is carried out under the protection of inert gas;
and/or the reaction temperature is 50-100 ℃;
and/or, the reaction is further followed by purification, the purification comprising the steps of: concentrating the reaction solution, and performing silica gel column chromatography;
preferably, the inert gas is nitrogen or argon;
and/or the reaction temperature is 60-80 ℃;
more preferably, the reaction time is 10-30 h.
The invention also provides a compound prepared by the preparation method.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The structures of the compounds in the invention are all structures capable of stably existing.
The aryl in the invention refers to a carbocycle containing at least one double bond and no heteroatom, and the aryl can be monocyclic, condensed ring, bridged ring or spiro ring, such as phenyl, naphthyl, anthryl, benzo heterocyclic radical and the like; the 6-to 10-membered aromatic group means that the carbon ring contains 6 to 10 carbon atoms.
The heteroatom aromatic group in the invention refers to a carbon ring containing at least one double bond and containing heteroatoms, the heteroatom aromatic group can be monocyclic, condensed ring, bridged ring or spiro ring, the heteroatoms are selected from O, S or N, and the number of the heteroatoms is 1, 2, 3, 4, 5 or 6; the 5-to 10-membered hetero-atom aromatic group means that the sum of the number of hetero atoms and carbon atoms in the carbon ring is 5 to 10.
The heterocyclic group in the present invention means a carbocyclic ring containing no double bond but containing a hetero atom, the heterocyclic group may be monocyclic, condensed, bridged or spiro ring, the hetero atom is selected from O, S or N, the number of hetero atoms is 1, 2, 3, 4, 5 or 6, the heterocyclic group may be selected from, for example, morpholinyl; the 3-8 membered heterocyclic group means that the sum of the number of hetero atoms and carbon atoms in the carbocyclic ring is 3-8.
The cycloalkyl refers to a carbon ring which does not contain double bonds and heteroatoms, the cycloalkyl can be monocyclic, condensed rings, bridged rings or spiro rings, and the 3-8-membered cycloalkyl refers to the carbon ring containing 3-8 carbon atoms.
The minimum and maximum carbon atom contents of the hydrocarbon groups in the present invention are indicated by prefixes, e.g. prefix (C)a～Cb) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1～C8The alkyl refers to a straight chain or branched chain alkyl containing 1-8 carbon atoms; c1～C8The alkoxy group means an alkoxy group having 1 to 8 carbon atoms.
In the present invention, halogen is fluorine, chlorine, bromine or iodine.
The existing preparation method of the alpha, alpha-difluoro-beta-ketone sulfone compound has the problems of low chemical selectivity, poor functional group adaptability, harsh reaction conditions, low atom economy and the like, and is only limited to the preparation of the alpha, alpha-difluoro-beta-ketone sulfone compound with a simple structure. The invention uses metal fluoride, such as silver fluoride, as an initiator, and can prepare a series of alpha, alpha-difluoro-beta-ketosulfone compounds under mild conditions. The preparation method has simple synthetic route, good yield and high purity; the functional group-containing alpha, alpha-difluoro-beta-ketosulfone derivative has the advantages of excellent functional group adaptability, 100% atom economy and the like, can be used for preparing alpha, alpha-difluoro-beta-ketosulfone compounds with various functional groups, and can be successfully applied to the later modification of natural products and drug molecules. In addition, the reaction scale of the invention can be enlarged to gram level, can be used for industrial scale-up production, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
The general synthetic route of the alpha, alpha-difluoro-beta-ketone sulfone compound comprises the following steps:
wherein Ar is1And Ar2Selected from aromatic groups with or without various substituents and aromatic groups containing hetero atoms.
The preparation method mainly comprises the following steps:
compound 1(0.2mmol,1equiv), fluoride initiator (0.1-0.2equiv) and organic solvent (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-top vial with a magnetic stirrer. And stirring the small bottle at 60-80 ℃ for 20h, cooling to room temperature after the reaction is finished, concentrating the reaction solution, and directly performing silica gel column chromatography to obtain the alpha, alpha-difluoro-beta-ketosulfone compound (compound 2).
Wherein, the fluoride initiator comprises metal fluorides such as silver fluoride, potassium fluoride, cesium fluoride and the like; the organic solvent includes acetonitrile, acetone, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide and the like.
Example 1, Ar1Universality of functional groups
1. Preparation of Compound 2a of the present invention
Compound 1a (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-top vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2a as a white solid in 97% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.19-8.17(m,2H),7.90(d,J＝8.0Hz,2H),7.72-7.68(m,1H),7.56-7.52(m,2H),7.44(d,J＝8.4Hz,2H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.75.13C NMR(101MHz,Chloroform-d)δ184.0(t,J＝23.2Hz),147.8,135.4,132.1,131.0,130.8(t,J＝3.1Hz),130.3,129.4,128.9,116.6(t,J＝301.9Hz),21.9.HRMS m/z calculated for C15H12F2O3S[M+Na]+:333.0367,found:333.0371.
2. Preparation of Compound 2b of the present invention
Compound 1b (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-top vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2b as a white solid in a yield of 93% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝7.2Hz,2H),8.03(d,J＝7.6Hz,2H),7.83-7.79(m,1H),7.75-7.61(m,3H),7.54(t,J＝7.6Hz,2H).19F NMR(376MHz,Chloroform-d)δ-101.48.13C NMR(101MHz,Chloroform-d)δ183.9(t,J＝23.2Hz),136.2,135.6,132.7,132.1,131.1,130.9(t,J＝4.0Hz),129.7,129.0,116.6(t,J＝303.0Hz).HRMS m/z calculated for C14H10F2O3S[M+Na]+:319.0211,found:319.0215
3. Preparation of Compound 2c of the present invention
Compound 1c (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-top vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2c as a white solid in a yield of 96% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝6.8Hz,2H),7.83-7.79(m,2H),7.72-7.67(m,1H),7.58-7.51(m,1H),7.53(m,3H),2.48(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.51.13C NMR(101MHz,Chloroform-d)δ183.9(t,J＝23.2Hz),140.1,137.0,135.5,132.5,132.2,131.2,130.9(t,J＝3.0Hz),129.5,129.0,128.2,116.7(t,J＝302.0Hz),21.4.HRMS m/z calculated for C15H12F2O3S[M+Na]+:333.0367,found:333.0374
4. Preparation of Compound 2d of the present invention
Compound 1d (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2d as a white solid in a yield of 93% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.21(d,J＝7.2Hz,2H),7.96(d,J＝8.4Hz,2H),7.72(t,J＝7.6Hz,1H),7.57(t,J＝7.6Hz,2H),7.51(d,J＝8.4Hz,2H),3.11-3.04(m,1H),1.34(s,3H),1.33(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.67.13C NMR(101MHz,Chloroform-d)δ184.0(t,J＝23.2Hz),158.2,135.3,132.1,131.2,130.8(t,J＝3.2Hz),129.7,128.9,127.8,116.6(t,J＝302.0),34.5,23.5.HRMS m/z calculated for C17H16F2O3S[M+Na]+361.0680,found:361.0686.
5. Preparation of Compound 2e of the present invention
Compound 1e (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2e as a white solid in 85% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝7.2Hz,2H),7.94(d,J＝8.8Hz,2H),7.71-7.63(m,3H),7.54(t,J＝8.0Hz,2H),1.37(s,9H).19F NMR(376MHz,Chloroform-d)δ-101.65.13C NMR(101MHz,Chloroform-d)δ184.1(t,J＝23.2Hz),160.7,135.4,132.2,131.0,130.9(t,J＝4.0Hz),129.5,129.0,126.8,116.7(t,J＝302.0Hz),35.7,31.1.HRMS m/z calculated for C22H18F2O6S[M+Na]+:375.0837,found:375.0836.
6. Preparation of Compound 2f of the present invention
Under a nitrogen or argon atmosphere, compound 1f (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2f as a white solid in 66% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.20(d,J＝7.2Hz,2H),8.02(dd,J＝8.0,1.2Hz,1H),7.74-7.68(m,1H),7.66-7.62(m,1H),7.55(t,J＝7.6Hz,2H),7.45-7.42(m,2H),2.77(s,3H).19F NMR(376MHz,Chloroform-d)δ-100.98.13C NMR(101MHz,Chloroform-d)δ184.0(t,J＝23.2Hz)142.2,136.0,135.5,133.44,133.36,132.2,131.4,130.9(t,J＝3.0Hz),129.0,127.0,117.4(t,J＝303.0Hz),21.1.HRMS m/z calculated for C15H12F2O3S[M+Na]+:333.0367,found:333.0369.
7. Preparation of Compound 2g of the present invention
Under a nitrogen or argon atmosphere, compound 1g (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) to obtain 2g of the compound as a white solid in a yield of 80% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.90(dd,J＝7.6,1.6Hz,1H),8.38(dd,J＝6.0,1.6Hz,1H),8.25(d,J＝8.0Hz,1H),8.22(d,J＝7.6Hz,2H),7.98(dd,J＝6.8,1.6Hz,1H),7.78-7.62(m,4H),7.55(t,J＝7.6Hz,2H).19F NMR(376MHz,Chloroform-d)δ-100.83.13C NMR(101MHz,Chloroform-d)δ183.8(t,J＝23.2Hz),137.9,135.5,135.0,134.3,132.2,130.9(t,J＝3.0Hz),130.6,129.5,129.2,129.0,128.7,127.6,125.0(t,J＝2.0Hz),124.5,117.5(t,J＝303Hz).HRMS m/z calculated for C18H12F2O3S[M+Na]+:369.0367,found:369.0375.
8. Preparation of Compound 2h of the invention
Under a nitrogen or argon atmosphere, compound 1h (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2h as a white solid with a yield of 96% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.63(d,J＝1.6Hz,1H),8.21(d,J＝7.2Hz,2H),8.07-8.02(m,2H),8.00-7.95(m,2H),7.77-7.70(m,1H),7.70-7.65(m,2H),7.54(t,J＝8.0Hz,2H).19F NMR(376MHz,Chloroform-d)δ-101.22.13C NMR(101MHz,Chloroform-d)δ184.0(t,J＝23.2Hz),136.5,135.5,134.1,132.2,132.1,130.9(t,J＝3.0Hz),130.6,130.0,129.9,129.5,129.0,128.22,128.20,124.4,116.8(t,J＝302.0Hz).HRMS m/z calculated for C18H12F2O3S[M+Na]+:369.0367,found:369.0361.
9. Preparation of Compound 2i of the present invention
Compound 1i (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2i as a white solid in 82% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.20(d,J＝7.2Hz,2H),8.08(d,J＝8.4Hz,2H),7.85(d,J＝8.8Hz,2H),7.71(t,J＝7.2Hz,1H),7.66-7.64(m,2H),7.60-7.42(m,5H).19F NMR(376MHz,CDCl3)δ-101.47.13C NMR(101MHz,Chloroform-d)δ184.0(t,J＝23.2Hz),149.1,138.7,135.5,132.2,131.6,131.0,130.9(d,J＝3.0Hz),129.33,129.29,129.0,128.2,127.6,116.7(t,J＝302.0Hz).HRMS m/z calculated for C20H14F2O3S[M+H]+:373.0704,found:373.0708.
10. Preparation of Compound 2j of the present invention
Compound 1j (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2j as a white solid in 88% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝7.2Hz,2H),8.08-8.03(m,2H),7.74-7.69(m,1H),7.58-7.54(m,2H),7.36-7.32(m,2H).19F NMR(376MHz,Chloroform-d)δ-98.81,-101.40.13C NMR(101MHz,Chloroform-d)δ183.7(t,J＝23.1Hz),167.5(d,J＝261.5Hz),135.5,134.1(d,J＝10.3Hz),131.9,130.8(t,J＝23.1Hz),128.9,128.5(d,J＝3.2Hz),117.2(d,J＝23.0Hz),116.4(t,J＝302.5Hz).HRMS m/z:calculated for C14H9F3O3S[M+Na]+337.0117,found:337.0112.
11. Preparation of Compound 2k of the present invention
Compound 1k (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography was directly performed (petroleum ether/ethyl acetate: 20/1, v/v) to obtain compound 2k as a white solid in 84% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.18-8.15(m,2H),7.73-7.65(m,3H),7.55(t,J＝8.0Hz,2H),7.48(t,J＝7.6Hz,1H),2.42(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.36,-112.49.13C NMR(101MHz,Chloroform-d)δ183.8(t,J＝23.2Hz),161.0(d,J＝252.5Hz)135.6,135.1(d,J＝17.2Hz),132.8(d,J＝5.0Hz),132.0,131.5(d,J＝7.1Hz),130.9(t,J＝3.0Hz),129.0,126.8(d,J＝4.0Hz),117.5(d,J＝26.3Hz),116.6(t,J＝303.0Hz),15.3.HRMS m/z calculated for C15H11F3O3S[M+Na]+:351.0273,found:350.0283.
12. Preparation of Compound 2l of the invention
Under a nitrogen or argon atmosphere, compound 1l (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain 2l of compound as a white solid in 98% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.18-8.15(m,2H),7.96(d,J＝8.8Hz 2H),7.74-7.69(m,1H),7.65-7.62(m,2H),7.55(t,J＝7.6Hz,2H).19F NMR(376MHz,Chloroform-d)δ-101.32.13C NMR(101MHz,Chloroform-d)δ183.6(t,J＝23.1Hz),143.3,135.6,132.3,131.9,131.0,130.8(t,J＝3.2Hz),130.0,129.0,116.4(t,J＝303.0Hz).HRMS m/z:calculated for C14H9ClF2O3S[M+Na]+352.9821,found:352.9821.
13. Preparation of Compound 2m of the present invention
Compound 1m (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 100/1, v/v) was directly performed to obtain compound 2m as a white solid in a yield of 73% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.19-8.12(m,2H),7.91-7.85(m,2H),7.85-7.76(m,2H),7.75-7.63(m,1H),7.63-7.51(m,2H).19F NMR(376MHz,Chloroform-d)δ-101.28.13C NMR(101MHz,Chloroform-d)δ183.7(t,J＝23.2Hz),135.7,133.1,132.4,132.3,132.0,131.6,130.9(t,J＝3.0Hz),129.1,116.5(t,J＝302.0Hz).HRMS m/z calculated for C14H9BrF2O3S[M+Na]+:396.9316,found:396.9318.
14. Preparation of Compound 2n of the present invention
Compound 1n (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer under nitrogen or argon blanket. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 100/1, v/v) was directly performed to obtain compound 2n as a white solid in 82% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.19-8.12(m,2H),8.05-7.98(m,2H),7.75-7.66(m,3H),7.57-7.53(m,2H).19F NMR(376MHz,Chloroform-d)δ-101.30.13C NMR(101MHz,Chloroform-d)δ183.7(t,J＝23.1Hz),139.1,135.7,132.3,132.04,131.99,130.9(t,J＝3.2Hz),129.0,116.5(t,J＝302.9Hz),105.3.HRMS m/z calculated for C14H9F2IO3S[M+Na]+:444.9177,found:444.9185.
15. Preparation of Compound 2o of the invention
Compound 1o (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2o as a white solid in a yield of 78% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.22-8.10(m,6H),7.72(t,J＝7.2Hz,1H),7.56(t,J＝8.0Hz,2H),2.70(s,3H).19F NMR(376MHz,CDCl3)δ-101.15.13C NMR(101MHz,Chloroform-d)δ196.6,183.6(t,J＝23.2Hz),142.6,136.4,135.8,132.0,131.5,130.9(t,J＝3.0Hz),129.2,129.1,116.6(t,J＝303.0Hz),27.1.HRMS m/z calculated for C16H12F2O4S[M+H]+:339.0497,found:339.0493.
16. Preparation of Compound 2p of the present invention
Compound 1p (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-top vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2p as a white solid in a yield of 75% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.29(d,J＝8.4Hz,2H),8.19-8.13(m,2H),8.10(d,J＝8.4Hz,2H),7.75-7.66(m,1H),7.55(t,J＝7.6Hz,2H),3.99(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.13.13C NMR(101MHz,Chloroform-d)δ183.5(t,J＝23.2Hz),165.2,136.9,136.5,135.7,132.0,131.1,130.9(t,J＝3.0Hz),130.6,129.1,116.6(t,J＝303.0Hz),53.0.HRMS m/z calculated for C16H12F2O5S[M+Na]+:377.0266,found:377.0273.
17. Preparation of Compound 2q of the invention
Compound 1q (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2q as a white solid in 88% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝7.2Hz,2H),7.71-7.63(m,2H),7.54(t,J＝7.6Hz,2H),7.38(d,J＝2.0Hz,1H),7.05(d,J＝8.8Hz,1H),3.99(s,3H),3.93(s,3H).19F NMR(376MHz,CDCl3)δ-101.76.13C NMR(101MHz,Chloroform-d)δ184.1(t,J＝23.2Hz),155.7,149.6,135.5,132.2,130.9(t,J＝3.0Hz),128.9,126.1,123.4,116.7(t,J＝302.0Hz),112.5,111.1,56.6,56.5.HRMS m/z calculated for C16H14F2O5S[M+Na]+:379.0422,found:379.0423.
18. Preparation of Compound 2r of the present invention
Under a nitrogen or argon atmosphere, compound 1r (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2r as a white solid in a yield of 91% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.21-8.14(m,2H),7.97-7.89(m,2H),7.73-7.64(m,1H),7.57-7.49(m,2H),7.12-7.04(m,2H),3.91(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.85.13C NMR(101MHz,Chloroform-d)δ183.7(t,J＝23.9Hz),165.4,134.9,132.9,131.7,130.4(t,J＝3.2Hz),128.4,122.8,116.1(t,J＝301.2Hz),114.5,55.5.HRMS m/z calculated for C15H12F2O4S[M+Na]+:349.0317,found:349.0319.
19. Preparation of Compound 2s of the present invention
Compound 1s (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2s as a white solid in a yield of 58% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.76(d,J＝8.8Hz,1H),8.55(d,J＝8.8Hz,1H),8.36(d,J＝7.6Hz,1H),8.22(d,J＝8.4Hz,2H),7.70-7.60(m,3H),7.57-7.53(m,2H),7.25(d,J＝8.0Hz,1H),2.91(s,6H).19F NMR(376MHz,CDCl3)δ-100.63.13C NMR(101MHz,Chloroform-d)δ183.9(t,J＝23.2Hz),135.4,134.9,134.2,132.2,132.1,130.9(t,J＝3.0Hz),130.1,129.5,130.0,129.0,128.0,123.5,119.6,117.6(t,J＝303.0Hz),116.0,45.6.HRMS m/z calculated for C20H17F2NO3S[M+H]+:390.0970,found:390.0975.
20. Preparation of Compound 2t of the present invention
Under a nitrogen or argon atmosphere, compound 1t (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2t as a white solid in a yield of 90% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝7.2Hz,2H),7.79-7.77(m,2H),7.68(t,J＝7.6Hz,1H),7.52(t,J＝7.6Hz,2H),6.93(d,J＝8.8Hz,1H),4.73(t,J＝8.8Hz,2H),3.30(t,J＝8.8Hz,2H).19F NMR(376MHz,Chloroform-d)δ-101.80.13C NMR(101MHz,Chloroform-d)δ184.3(t,J＝23.2Hz),167.1,135.4,133.4,132.2,130.9(t,J＝3.0Hz),129.4,128.9,128.2,123.1,116.7(t,J＝301.0Hz),110.3,73.0,28.8.HRMS m/z calculated for C16H12F2O4S[M+Na]+:361.0317,found:361.0326.
Example 2, Ar2Universality of functional groups
1. Preparation of Compound 2u of the present invention
Compound 1u (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 100/1, v/v) was directly performed to obtain compound 2u as a white solid in 85% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.08(d,J＝8.0Hz,2H),7.89(d,J＝8.4Hz,2H),7.44(d,J＝8.0Hz,2H),7.33(d,J＝8.4Hz,2H),2.50(s,3H),2.46(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.69.13C NMR(101MHz,CDCl3)δ183.4(t,J＝23.2Hz),147.7,147.0,131.13(t,J＝3.0Hz),131.06,130.3,129.74,129.71,129.6,116.7(t,J＝302.0Hz),22.1.HRMS m/z calculated for C16H14F2O3S[M+Na]+:347.0524,found:347.0532.
2. Preparation of Compound 2v of the present invention
Compound 1v (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was complete, cooled to room temperature, the reaction was concentrated and subjected directly to silica gel column chromatography (petroleum ether/ethyl acetate 100/1, v/v) to give compound 2v as a white solid in 92% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ7.85(d,J＝8.0Hz,1H),7.81(s,1H),7.75(d,J＝8.2Hz,2H),7.38-7.34(m,1H),7.30-7.29(m,3H),2.36(s,3H),2.30(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.60.13C NMR(101MHz,Chloroform-d)δ184.2(t,J＝23.1Hz),147.7,138.9,136.3,132.2,131.1(t,J＝2.7Hz),131.0,130.3,129.6,128.8,128.3(t,J＝3.6Hz),116.6(t,J＝302.0Hz),22.0,21.4.HRMS m/z calculated for C16H14F2O3S[M+Na]+:347.0524,found:347.0531.
3. Preparation of Compound 2w of the present invention
Under a nitrogen or argon atmosphere, compound 1w (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 100/1, v/v) was directly performed to obtain compound 2w as a white solid in 87% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ7.94-7.85(m,4H),7.43(d,J＝8.0Hz,2H),7.28(d,J＝7.6Hz,1H),2.49(s,3H),2.35(s,3H),2.34(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.51.13C NMR(101MHz,Chloroform-d)δ183.5(t,J＝23.2Hz),147.6,145.9,137.5,131.7,131.0,130.3,130.2,130.1,129.7,128.9(t,J＝3.0Hz),116.8(d,J＝302.0Hz),22.0,20.4,19.9.HRMS m/z calculated for C17H16F2O3S[M+Na]+:361.0680,found:361.0688.
4. Preparation of Compound 2x of the invention
Compound 1x (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer under nitrogen or argon blanket. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) to obtain compound 2x as a white solid in 98% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.79(s,1H),8.12(dd,J＝8.8,1.8Hz,1H),8.05(d,J＝8.2Hz,1H),7.96-7.87(m,4H),7.71-7.67(m,1H),7.63-7.59(m,1H),7.44(d,J＝8.1Hz,2H),2.50(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.27.13C NMR(101MHz,Chloroform-d)δ183.7(t,J＝23.0Hz),147.7,136.4,134.5(t,J＝4.4Hz),132.2,131.0,130.6,130.3,130.1,129.5,129.4,128.8,127.8,127.3,124.7(t,J＝2.0),116.8(t,J＝301.8),22.0.HRMS m/z calculated for C19H14F2O3S[M+Na]+383.0524,found:383.0537.
5. Preparation of Compound 2y of the present invention
Compound 1y (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer under nitrogen or argon blanket. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2y as a white solid in 98% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.27(d,J＝8.2Hz,2H),7.92(d,J＝8.1Hz,2H),7.80-7.73(m,2H),7.69-7.62(m,2H),7.53-7.42(m,5H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.75.13C NMR(101MHz,Chloroform-d)δ183.4(t,J＝23.0Hz),148.0,147.7,139.3,131.5(t,J＝3.3Hz),131.0,130.8,130.3,129.4,129.1,128.8,127.42,127.41,116.7(t,J＝301.7Hz),22.0.HRMS m/z calculated for C21H16F2O3S[M+Na]+409.0680,found:409.0680.
6. Preparation of Compound 2z of the present invention
Compound 1z (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2z as a white solid in 97% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.16(d,J＝8.4Hz,2H),7.88(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),6.97(d,J＝8.8Hz,2H),4.14(q,J＝6.8Hz,2H),2.49(s,3H),1.45(t,J＝7.2Hz,3H).19F NMR(376MHz,Chloroform-d)δ-101.48.13C NMR(101MHz,Chloroform-d)δ181.7(t,J＝22.2Hz),165.0,147.6,133.6(t,J＝3.0Hz),131.0,130.3,129.6,125.0,116.9(t,J＝301.0Hz),114.7,64.3,22.0,14.7.HRMS m/z calculated for C17H16F2O4S[M+Na]+:377.0630,found:377.0630.
7. Preparation of Compound 2aa of the invention
Compound 1aa (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2aa, a white solid, with a yield of 90% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.08-8.00(m,1H),7.92-7.83(m,3H),7.43(d,J＝8.4Hz,2H),7.06(t,J＝8.4Hz,1H),3.99(s,3H),2.49(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.73,-133.16.13C NMR(101MHz,Chloroform-d)δ181.3(t,J＝23.0Hz),154.2(d,J＝10.7Hz),151.9(d,J＝250.0Hz),147.9,131.0,130.4,129.5(q,J＝3.6Hz),129.3,125.1(d,J＝5.8Hz),118.3(dt,J＝20.2,3.3Hz),116.7(d,J＝301.1Hz),112.66,56.6,22.0.HRMS m/z calculated for C16H13F3O4S[M+Na]+:381.0379,found:381.0378.
8. Preparation of Compound 2ab of the invention
Compound 1ab (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2ab as a white solid in a yield of 93% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.09(d,J＝8.8Hz,2H),7.80(d,J＝8.0Hz,2H),7.43-7.29(m,4H),7.23-7.10(m,1H),7.05-7.00(m,2H),6.97-6.93(m,2H),2.41(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.61.13C NMR(101MHz,Chloroform-d)δ181.9(t,J＝23.2Hz),164.2,154.5,147.6,133.6(t,J＝3.0Hz),131.0,130.3,130.2,129.4,126.3,125.4,120.8,117.0,116.7(t,J＝301.0Hz)22.0.HRMS m/z calculated for C21H16F2O4S[M+Na]+425.0630,found:425.0627.
9. Preparation of Compound 2ac of the invention
Compound 1ac (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2ac as a white solid in a yield of 81% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.12(d,J＝8.8Hz,2H),7.88(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),6.89(d,J＝8.8Hz,2H),3.86(t,J＝4.8Hz,4H),3.42(t,J＝4.8Hz,4H),2.49(s,3H).19F NMR(376MHz,CDCl3)δ-101.39.13C NMR(101MHz,Chloroform-d)δ180.5(t,J＝22.2Hz),155.3,147.5,133.6(t,J＝3.0Hz),131.0,130.3,129.8,122.2,117.2(t,J＝301.0Hz),112.7,66.5,46.9,22.1.HRMS m/z calculated for C19H19F2NO4S[M+H]+:396.1076,found:396.1078.
10. Preparation of Compound 2ad of the present invention
Compound 1ad (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2ad as a white solid in a yield of 92% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.13(d,J＝8.4Hz,2H),7.86(d,J＝8.0Hz,2H),7.75-7.70(m,2H),7.44(d,J＝8.0Hz,2H),7.34(d,J＝8.4Hz,2H),7.21-7.14(m,2H),2.49(s,3H),2.45(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.97.13C NMR(101MHz,Chloroform-d)δ182.9(t,J＝23.2Hz),154.7,148.0,146.2,132.9(t,J＝3.0Hz),132.0,131.0,130.6,130.4,130.2,129.1,128.5,122.8,116.5(t,J＝301.0Hz),22.0,21.8.HRMS m/z calculated for C22H18F2O6S[M+Na]+:503.0405,found:503.0410.
11. Preparation of Compound 2ae of the present invention
Compound 1ae (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer under nitrogen or argon. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2ae as a white solid in a yield of 75% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.26(d,J＝9.2Hz,2H),7.89(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.36(d,J＝8.0Hz,2H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-57.49,-102.11.13C NMR(101MHz,Chloroform-d)δ182.6(t,J＝23.2Hz),154.2,147.9,133.2(t,J＝4.0Hz),131.0,130.3,130.0,129.1,120.2,120.5(q,J＝260.6Hz),116.5(t,J＝302.0Hz),22.0.HRMS m/z calculated for C16H11F5O4S[M+Na]+417.0190,found:417.0193.
12. Preparation of Compound 2af of the invention
Compound 1af (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 5/1, v/v) to obtain compound 2af as a white solid in a yield of 77% and a purity of > 95%.
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),7.99(d,J＝8.8Hz,2H),7.89(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,2H),6.97(d,J＝8.8Hz,2H),2.47(s,3H).19F NMR(376MHz,DMSO-d6)δ-101.17.13C NMR(101MHz,DMSO-d6)δ180.3(t,J＝22.2Hz),164.9,148.2,133.7(t,J＝3.0Hz),130.7,130.6,128.4,122.9,116.5(t,J＝301.0Hz),116.1,21.4.HRMS m/z calculated for C15H12F2O4S[M+Na]+:349.0317,found:349.0320.
13. Preparation of Compound 2ag of the invention
Under a nitrogen or argon atmosphere, compound 1ag (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate 20/1, v/v) was directly performed to obtain compound 2ag as a white solid in 86% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.24(dd,J＝8.4,5.2Hz,2H),7.89(d,J＝8.1Hz,2H),7.44(d,J＝8.0Hz,2H),7.21(t,J＝8.6Hz,2H),2.50(s,3H).19F NMR(376MHz,Chloroform-d)δ-99.95,-101.88.13C NMR(101MHz,Chloroform-d)δ182.5(t,J＝23.2Hz),167.2(d,J＝262.9Hz),148.0,134.1(dt,J＝10.1,3.3,Hz),131.1,130.4,129.3,128.89-128.40(m),116.6(t,J＝301.5Hz),116.4(d,J＝22.1Hz),22.0.HRMS m/z calculated for C15H11F3O3S[M+Na]+:357.0273,found:357.0275.
14. Preparation of Compound 2ah of the present invention
Compound 1ah (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 20/1, v/v) was directly performed to obtain compound 2ah as a white solid in 82% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.15-8.05(m,2H),7.89(d,J＝8.0Hz,2H),7.69-7.62(m,1H),7.54-7.41(m,3H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.14.13C NMR(101MHz,Chloroform-d)δ183.1(t,J＝23.2Hz),147.9,135.3,135.2,133.5,131.0,130.5(t,J＝3.0Hz),130.3,130.2,129.1,129.0(t,J＝4.0Hz),116.4(t,J＝302.0Hz),22.0.HRMS m/z calculated for C15H11ClF2O3S[M+Na]+366.9978,found:366.9978.
15. Preparation of Compound 2ai of the present invention
Compound 1ai (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2ai as a white solid in a yield of 96% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.00-7.97(m,2H),7.85(d,J＝8.0Hz,2H),7.53(d,J＝8.4Hz,1H),7.43(d,J＝8.0Hz,2H),7.13(d,J＝8.4Hz,2H),6.86(d,J＝8.8Hz,2H),4.10(s,2H),4.02(q,J＝6.8Hz,2H),2.51(s,3H),1.41(t,J＝6.8Hz,3H).19F NMR(376MHz,CDCl3)δ-101.84.13C NMR(101MHz,Chloroform-d)δ183.1(t,J＝23.2Hz),157.9,147.9,142.4,140.5,133.2(t,J＝3.0Hz),131.1,130.7,130.4,130.3,130.2,130.1,130.0(t,J＝3.0Hz),129.3,116.6(t,J＝302.0Hz),114.8,63.6,38.6,22.1,15.0.HRMS m/z calculated for C24H21ClF2O4S[M+Na]+:501.0709,found:501.0713.
16. Preparation of Compound 2aj of the invention
Compound 1aj (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) to obtain compound 2aj as a white solid in a yield of 92% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝8.4Hz,2H),7.88(d,J＝8.0Hz,2H),7.72-7.65(m,2H),7.44(d,J＝8.0Hz,2H),2.50(s,3H),1.23(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.05.13C NMR(101MHz,Chloroform-d)δ183.3(t,J＝23.2Hz),148.0,132.4,132.3(t,J＝3.0Hz),131.4,131.0,130.9,130.4,129.2,116.6(t,J＝302.0Hz),22.1.HRMS m/z calculated for C15H11BrF2O3S[M+Na]+:410.9473,found:410.9480.
17. Preparation of Compound 2ak of the present invention
Compound 1ak (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2ak, a white solid, yield 73%, purity > 95%.
1H NMR(400MHz,Chloroform-d)δ8.20(d,J＝8.8Hz,2H),8.02(d,J＝8.8Hz,2H),7.82(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,3H),2.60(s,3H),2.44(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.18.13C NMR(101MHz,Chloroform-d)δ197.2,183.9(t,J＝23.6Hz),148.0,141.5,135.1 131.1(t,J＝3.0Hz),131.0,130.4,129.1,128.4,116.4(t,J＝302.0Hz),27.0,22.0.HRMS m/z calculated for C17H15F2O4S[M+H]+353.0654,found:353.0659.
18. Preparation of Compound 2al of the invention
Compound 1al (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2al as a white solid in 80% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.24(d,J＝8.8Hz,2H),8.18(d,J＝8.8Hz,2H),7.90(d,J＝8.3Hz,2H),7.45(d,J＝8.1Hz,2H),3.97(s,3H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.17.13C NMR(101MHz,Chloroform-d)δ184.0(t,J＝23.5Hz),165.8,147.9,135.6,135.1,131.0,130.7(t,J＝3.2Hz),130.3,129.8,129.2,116.4(t,J＝301.7Hz),52.7,22.0.HRMS m/z calculated for C17H14F2O5S[M+Na]+391.0422,found:391.0430.
19. Preparation of Compound 2am of the invention
Compound 1am (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) to obtain compound 2am as a white solid in a yield of 56% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.28(d,J＝8.0Hz,2H),7.89(d,J＝8.0Hz,2H),7.84(d,J＝8.4Hz,2H),7.47(d,J＝8.4Hz,2H),2.52(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.39.13C NMR(101MHz,Chloroform-d)δ183.6(t,J＝24.2Hz),148.3,135.0,132.6,131.2(t,J＝3.0Hz),131.1,130.5,128.9,118.5,117.5,116.4(t,J＝302.0Hz),22.1.HRMS m/z calculated for C16H11F2NO3S[M+Na]+:358.0320,found:358.0321.
20. Preparation of Compound 2an of the invention
Compound 1an (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 3/1, v/v) was directly performed to obtain compound 2an as a white solid with a yield of 69% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.20(d,J＝8.0Hz,2H),7.91(d,J＝8.4Hz,2H),7.87(d,J＝8.0Hz,2H),7.44(d,J＝8.0Hz,2H),7.42-7.24(m,4H),7.32-7.29(m,1H),6.74(t,J＝5.6Hz,1H),4.64(d,J＝5.6Hz,2H),2.50(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.10.13C NMR(101MHz,Chloroform-d)δ183.7(t,J＝24.2Hz),166.1,148.1,140.2,137.8,134.2,131.2(t,J＝3.0Hz),131.1,130.4,129.2,129.0,128.0,127.9,127.6,116.5(t,J＝302.0Hz),44.4,22.1.HRMS m/z calculated for C23H19F2NO4S[M+H]+:444.1076,found:444.1075.
21. Preparation of Compound 2ao of the invention
Compound 1ao (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2ao as a white solid in a yield of 75% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.30(d,J＝8.4Hz,2H),7.90(d,J＝8.4Hz,2H),7.81(d,J＝8.4Hz,2H),7.46(d,J＝8.4Hz,2H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-63.54,-102.35.13C NMR(101MHz,Chloroform-d)δ183.7(t,J＝23.9Hz),148.2,136.3(q,J＝33.2Hz),134.8,131.3(t,J＝3.1Hz),131.1,130.5,129.1,126.0(q,J＝3.6Hz),123.4(q,J＝274.1Hz),116.5(t,J＝301.59Hz),22.1.HRMS m/z calculated for C16H11F5O3S[M+Na]+:401.0241,found:401.0245.
22. Preparation of Compound 2ap of the present invention
Compound 1ap (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 2/1, v/v) was directly performed to obtain compound 2ap as a white solid in a yield of 81% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.49(dd,J＝6.8,1.6Hz,1H),8.39(d,J＝2.0Hz,1H),7.88(d,J＝8.0Hz,2H),7.46(d,J＝8.4Hz,2H),7.09(d,J＝8.8Hz,1H),3.34(s,3H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.31.13C NMR(101MHz,Chloroform-d)δ181.7,181.6(t,J＝24.2Hz),158.3,156.1,148.2,141.7,131.1,130.5,129.0,128.1(t,J＝4.0Hz),128.0,117.3,116.6(t,J＝301.0Hz),110.4,26.8,22.1.HRMS m/z calculated for C18H13F2NO5S[M+Na]+:416.0375,found:416.0380.
23. Preparation of Compound 2aq of the invention
Compound 1aq (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) to obtain compound 2aq as a white solid in a yield of 76% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ9.09(dd,J＝2.4,2.0Hz,1H),8.82(d,J＝2.0Hz,1H),8.50-8.30(m,2H),8.24(d,J＝8.8Hz,1H),7.92(d,J＝8.0Hz,2H),7.57(dd,J＝4.0,4.0Hz,1H),7.46(d,J＝8.0Hz,2H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.58.13C NMR(101MHz,Chloroform-d)δ183.4(t,J＝23.2Hz),153.9,150.7,147.9,138.4,134.3(t,J＝4.0Hz),131.0,130.5,130.3,129.8,129.2,128.6(t,J＝1.1Hz),127.3,122.4,116.7(t,J＝302.0Hz),22.0.HRMS m/z calculated for C18H13F2NO3S[M+Na]+384.0476,found:384.0481.
24. Preparation of Compound 2ar of the present invention
Under a nitrogen or argon atmosphere, compound 1ar (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) to obtain compound 2ar as a white solid in 84% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.60-8.51(m,1H),7.88(d,J＝8.0Hz,2H),7.71(dd,J＝4.0,1.2Hz,1H),7.44(d,J＝8.0Hz,2H),7.38(dd,J＝5.2,2.4Hz,1H),2.51(s,3H).19F NMR(376MHz,Chloroform-d)δ-104.34.13C NMR(101MHz,Chloroform-d)δ177.1(t,J＝23.9Hz),147.7,139.0(t,J＝5.4Hz),136.1,131.0,130.3,129.3,128.3(t,J＝1.7Hz),126.5,116.2(t,J＝300.6Hz),22.0.HRMS m/z calculated for C13H10F2O3S2[M+Na]+338.9932,found:338.9938.
25. Preparation of Compound 2as of the invention
Compound 1as (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) to obtain compound 2as, a white solid in 62% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.56(s,1H),8.03(d,J＝8.8Hz,1H),7.91(d,J＝8.0Hz,2H),7.41(d,J＝8.4Hz,2H),7.36(d,J＝8.8Hz,1H),7.14(d,J＝3.2Hz,1H),6.66(d,J＝3.2Hz,1H),3.81(s,3H),2.48(s,3H).19F NMR(376MHz,Chloroform-d)δ-100.37.13C NMR(101MHz,Chloroform-d)δ183.0(t,J＝22.2Hz),147.5,140.2,131.2,131.0,130.2,129.9,128.1,127.0(t,J＝5.0Hz),124.1-124.0(m,2C),117.2(t,J＝302.0Hz),109.7,104.3,33.2,22.0.HRMS m/z calculated for C18H15F2NO3S[M+Na]+:386.0633,found:386.0641.
26. Preparation of Compound 2at of the present invention
Compound 1at (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-top vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2at as a white solid in a yield of 80% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.05-8.01(m,2H),7.90-7.85(m,2H),7.52-7.46(m,2H),7.40(d,J＝8.0Hz,2H),7.35(d,J＝8.1Hz,1H),7.08-7.01(m,3H),6.73-6.68(m,1H),4.20(s,2H),2.48(s,3H),2.43(s,3H).19F NMR(376MHz,Chloroform-d)δ-101.54,-114.94.13C NMR(101MHz,Chloroform-d)δ183.3(t,J＝23.6Hz),162.2(d,J＝246.8Hz),147.6,145.6,142.0,141.7,139.2,131.7(t,J＝3.0Hz),131.1,131.0,130.7(d,J＝4.2Hz),130.4,130.2,129.7(t,J＝3.7Hz),129.5,127.2(d,J＝8.0Hz),126.5,122.9,116.6(t,J＝301.7Hz),115.8(d,J＝21.7Hz),34.0,22.0,20.1.HRMS m/z calculated for C27H21F3O3S2[M+Na]+537.0776,found:537.0775.
The reaction result proves the universality of the preparation method of the alpha, alpha-difluoro-beta-ketone sulfone compound: 1. to Ar1As for the aromatic ring, the aromatic ring (2a, 2c-2e) with alkyl substituent, the (2f) with ortho substituent and the condensed ring (2g-2h) have good effects; some functional groups such as halogen atoms (2j-2n) can also be made reaction compatible. In addition, excellent yields can be obtained with different electrical properties such as the presence of electron withdrawing carbonyl groups (2o-2p) and electron donating groups (2q-2 t). 2. To Ar2For the aromatic ring, the alkyl-substituted (2u-2w), the electron-donating functional group (2z-2ac), the benzene sulfonate (2ad) and the trifluoromethoxy (2ae) have excellent compatibility; higher yields can also be obtained with unprotected hydroxy compound (2 af). The (2ag-2aj) and the electron-withdrawing group (2ak-2ao) each containing a halogen atom such as fluorine, chlorine or bromine can be obtained in a good yield. Meanwhile, the invention has good universality on aromatic rings containing heteroatoms such as quinoline (2aq), thiophene (2ar,2at) and indole (2 as).
Example 3 preparation of a Compound of the invention
1. Preparation of Compound 2au of the invention
Under a nitrogen or argon atmosphere, compound 1au (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially to a screw-cap vial with a magnetic stirrer. The vial was stirred at 80 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography was directly performed (petroleum ether/ethyl acetate: 20/1, v/v) to obtain compound 2au as a white solid in a yield of 80% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.24-8.22(m,2H),8.20-8.17(m,2H),7.88(d,J＝8.4Hz,2H),7.44(d,J＝8.0Hz,2H),4.97(td,J＝11.2,4.4Hz,1H),2.50(s,3H),2.18–2.08(m,1H),1.94(m,1H),1.79-1.70(m,2H),1.63-1.51(m,2H),1.21-1.05(m,2H),0.98-0.89(m,7H),0.80(d,J＝6.8Hz,3H).19F NMR(376MHz,Chloroform-d)δ-102.17.13C NMR(101MHz,Chloroform-d)δ184.0(t,J＝23.2Hz),164.9,148.0,136.5,135.1,131.1,130.8(t,J＝3.0Hz),130.4,129.9,129.3,116.5(t,J＝302.0Hz),76.0,47.3,41.0,34.3,31.6,26.6,23.7,22.1,22.0,16.6.HRMS m/z calculated for C26H30F2O5S[M+Na]+:515.1674,found:515.1672.
2. Preparation of Compound 2av of the present invention
Compound 1av (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon blanket to a screw-top vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 5/1, v/v) was directly performed to obtain compound 2av as a white solid in 87% yield and 95% purity.
1H NMR(400MHz,Chloroform-d，amide rotamers)δ8.04(d,J＝8.0Hz,1H),8.00(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,2H),7.38-7.34(m,3H),7.29(d,J＝8.0Hz,1H),5.24(t,J＝7.6Hz,0.6H),4.92(dd,J＝9.2Hz,J＝5.6Hz,0.4H),3.90-3.83(m,0.4H),3.82-3.77(m,0.6H),3.52-3.47(m,1H),3.21-3.06(m,3H),3.04-2.94(m,1H),2.77(s,1.2H),2.72(s,1.8H),2.43(s,3H),1.66-1.35(m,6H),1.26(s,5.4H),1.13(s,3.6H).19F NMR(376MHz,Chloroform-d)δ-101.70.13C NMR(101MHz,Chloroform-d)δ183.4(t,J＝22.7Hz),167.5,167.2,154.9,153.9,147.7,147.6,147.3,146.9,130.9,130.8(t,J＝2.5Hz),130.23,130.20,130.1,129.5,116.5(t,J＝302.1Hz),80.6,80.4,57.3,55.3,46.4,46.2,43.7,43.6,35.8,29.5,29.0,28.1,28.0,26.5,26.4,26.0,25.9,24.6,24.4,21.9.HRMS m/z calculated for C29H36F2N2O6S[M+Na]+:601.2154,found:601.2155.
3. Preparation of Compound 2aw of the invention
Compound 1aw (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, it was cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate 4/1, v/v) was directly performed to obtain compound 2aw as a white solid in a yield of 96% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.10(d,J＝8.0Hz,2H),7.88(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),5.07(d,J＝8.2Hz,1H),4.64(q,J＝7.2Hz,1H),3.72(s,3H),3.26-3.09(m,2H),2.49(s,3H),1.40(s,9H).19F NMR(376MHz,Chloroform-d)δ-101.80.13C NMR(101MHz,Chloroform-d)δ183.6(t,J＝23.2Hz),171.9,155.1,147.8,144.8,131.2(t,J＝3.0Hz),131.1,130.9,130.4,130.0,129.4,116.6(t,J＝301.0Hz),80.4,54.2,52.6,38.7,28.4,22.0.HRMS m/z calculated for C24H27F2NO7S[M+Na]+:534.1369,found:534.1372.
4. Preparation of Compound 2ax of the invention
Compound 1ax (0.2mmol,1equiv), silver fluoride (2.5mg,0.1equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated and directly subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 1/1, v/v) to obtain compound 2ax as a white solid in a yield of 72% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d,amide rotamers)δ8.21(d,J＝8.4Hz,1.6H),8.17(d,J＝8.4Hz,0.4H),7.88(d,J＝8.0Hz,2H),7.70(d,J＝8.4Hz,1.6H),7.51(d,J＝8.4Hz,0.4H),7.44(d,J＝8.0Hz,2H),4.68(dd,J＝8.8Hz,J＝4.8Hz,0.8H),4.28(dd,J＝8.8Hz,J＝4.8Hz,0.2H),3.78(s,2.4H),3.64-3.58(m,1H),3.56(s,0.6H),3.51-3.45(m,1H),2.50(s,3H),2.38-2.29(m,1H),2.09-2.01(m,2H),1.96-1.88(m,1H).19F NMR(376MHz,Chloroform-d)δ-102.05.13C NMR(101MHz,Chloroform-d)δ183.6(t,J＝23.6Hz),172.4,168.1,148.0,142.4,133.0,130.9(m,2C),130.3,129.2,127.6,127.0,61.1,59.2,52.5,49.8,46.7,29.7,29.4,25.3,22.7,22.0.HRMS m/z calculated for C22H21F2NO6S[M+Na]+:488.0950,found:488.0956.
5. Preparation of Compound 2ay of the present invention
Compound 1ay (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography was directly performed (petroleum ether/ethyl acetate: 20/1, v/v) to obtain compound 2ay as a white solid in a yield of 57% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.31(q,J＝7.6Hz,4H),7.91(d,J＝8.4Hz,2H),7.46(d,J＝8.0Hz,2H),6.87–6.73(m,2H),2.82–2.69(m,2H),2.52(s,3H),2.19(s,3H),1.88-1.73(m,2H),1.64-1.56(m,3H),1.54-1.50(m,1H),1.44-1.35(m,4H),1.29-1.21(m,10H),1.17-1.05(m,6H),0.88-0.85(m,12H),19F NMR(376MHz,Chloroform-d)δ-102.17.13C NMR(101MHz,Chloroform-d)δ184.1(t,J＝24.2Hz),164.6,150.3,148.1,142.5,135.61,135.55,131.2,130.9(t,J＝3.0Hz),130.5,130.4,129.3,127.7,121.3,121.1,119.1,116.5(t,J＝302.0Hz),76.4,40.3,39.5,37.59,37.57,37.4,32.9,32.8,31.1,28.1,24.9,24.6,24.4,22.9,22.8,22.6,22.1,21.1,19.9,19.8,16.3.HRMS m/z calculated for C43H56F2O6S[M+Na]+:761.3658,found:761.3653.
6. Preparation of Compound 2az of the present invention
Compound 1az (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 10/1, v/v) was directly performed to obtain compound 2az as a white solid in a yield of 50% and a purity of > 95%.
1H NMR(400MHz,Chloroform-d)δ8.26-8.19(m,4H),7.89(d,J＝8.0Hz,2H),7.45(d,J＝8.0Hz,2H),4.72(d,J＝12.0Hz,1H),4.65(dd,J＝7.6,2.8Hz,1H),4.44(d,J＝2.8Hz,1H),4.37(d,J＝12.0Hz,1H),4.26(d,J＝7.6Hz,1H),3.96(d,J＝12.8Hz,1H),3.81(d,J＝12.8Hz,1H),2.51(s,3H),1.55(s,3H),1.46(s,3H),1.37(s,3H),1.35(s,3H).19F NMR(376MHz,CDCl3)δ-102.17.13C NMR(101MHz,Chloroform-d)δ184.1(t,J＝24.2Hz),164.8,148.1,135.5,135.4,131.1,130.9(t,J＝3.0Hz),130.5,130.1,129.3,116.5(t,J＝302.0Hz),109.3,109.1,101.6,70.9,70.8,70.2,66.2,61.5,26.6,26.0,25.6,24.1,22.1.HRMS m/z calculated for C28H30F2O10S[M+Na]+:619.1420,found:619.1428.
7. Preparation of Compound 2aaa of the present invention
Compound 1aaa (0.2mmol,1equiv), silver fluoride (5.0mg,0.2equiv) and acetonitrile (0.5mL) were added sequentially under nitrogen or argon atmosphere to a screw-cap vial with a magnetic stirrer. The vial was stirred at 60 ℃ for 20h, after the reaction was completed, cooled to room temperature, the reaction solution was concentrated, and silica gel column chromatography (petroleum ether/ethyl acetate: 7/1, v/v) was directly performed to obtain compound 2aaa as a white solid in 66% yield and 95% purity.
1H NMR(400MHz,Chloroform-d)δ8.19(q,J＝8.8Hz,4H),7.87(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),5.42(d,J＝4.4Hz,1H),4.92-4.84(m,1H),2.55-2.43(m,5H),2.18-2.16(m,1H),2.11(s,3H),2.06-1.90(m,4H),1.77-1.58(m,5H),1.56-1.45(m,4H),1.26-1.15(m,4H),1.06(s,3H),0.63(s,3H).19F NMR(376MHz,Chloroform-d)δ-102.15.13C NMR(101MHz,Chloroform-d)δ209.6,184.0(t,J＝23.5Hz),164.7,148.0,139.4,136.4,135.1,131.0,130.7(t,J＝3.0Hz),130.4,129.9,129.2,122.8,116.4(t,J＝301.0Hz),75.4,63.7,56.9,50.0,44.0,38.8,38.1,37.0,36.7,31.89,31.86,31.6,27.8,24.6,22.9,22.0,21.1,19.4,13.3.
Experiments prove that the preparation method can be used for performing later modification on complex small molecules which are derived from natural products or have biological activity, and the L (-) -menthol derivatives (2au), the amino acids (2av-2ax), the tocopherols (2av-2ay), the carbohydrate derivatives (2az) and the pregnenolone (2 aa) can achieve good effects.
Example 4 expansion of the preparation method of the invention
Compound 2a was prepared using compound 1a as the starting material by the method described in example 1, using 1.085g of compound 1 a. The process of the present invention is illustrated as being scalable to gram-scale and yields up to 90% of compound 2 a.
In summary, the present invention uses metal fluorides, such as silver fluoride, as initiators, and can prepare a series of α, α -difluoro- β -ketosulfones compounds under mild conditions. The preparation method has simple synthetic route, good yield and high purity; the functional group-containing alpha, alpha-difluoro-beta-ketosulfone derivative has the advantages of excellent functional group adaptability, 100% atom economy and the like, can be used for preparing alpha, alpha-difluoro-beta-ketosulfone compounds with various functional groups, and can be successfully applied to the later modification of natural products and drug molecules. In addition, the reaction scale of the invention can be enlarged to gram level, can be used for industrial scale-up production, and has good application prospect.
Claims (20)
1. A composition for preparing alpha, alpha-difluoro-beta-ketosulfone compounds shown in formula I is characterized in that: it consists of the following components: compound 1, a fluoride initiator and an organic solvent;
wherein Ar is1And Ar2Each independently selected from substituted or unsubstituted aromatic group, substituted or unsubstituted hetero atom aromatic group;
the fluoride initiator is selected from silver fluoride;
the organic solvent is selected from acetonitrile.
2. The composition of claim 1, wherein:
Ar1and Ar2Are respectively and independently selected from 0 to 5R1Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R1A substituted 5-to 10-membered heteroatomic aromatic group;
R1are respectively and independently selected from 0 to 5R4Substituted C1～C8Alkyl, cyano, hydroxy, trifluoromethyl, 4-to 6-membered aryl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R3And a 3-to 8-membered heterocyclic group; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are independently selected from hydrogen and 0-5R4Substituted C1～C8Alkyl, 4-6 membered aryl, p-toluenesulfonyl, trifluoromethyl, substituted with 0-5R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 5R4A substituted 3-to 8-membered heterocyclic group, substituted with 0 to 5R4A substituted 5-to 17-membered heteroatomic aromatic group;
R4are respectively and independently selected from 0 to 5R5Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R5A substituted 5-to 10-membered heteroatomic aromatic group, substituted with 0 to 5R5Substituted 5-to 17-membered heterocyclic group, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C8Alkyl, -OR60 to 5R6Substituted 6-to 10-membered aromatic group, 3-to 8-membered heterocyclic group, -C (O) OR6；
R6Are each independently selected from C1～C8Alkyl, halogen;
the heteroatom is O, S or N; the number of the heteroatoms is 1-6.
3. The composition of claim 1, wherein:
Ar1and Ar2Are respectively and independently selected from 0 to 3R1Substituted phenyl, substituted by 0-1R1Substituted naphthyl, substituted by 0-1R1Substituted thienyl, substituted with 0-1R1Substituted by
Is coated with 0 to 5R1Substituted by
Is coated with 0 to 1R1Substituted by
Or by 0 to 1R1Substituted by
R1Are respectively and independently selected from 0 to 1R4Substituted C1～C4Alkyl, cyano, hydroxy, trifluoromethyl, phenyl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R3Morpholinyl; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are independently selected from hydrogen and 0-1R4Substituted C1～C2Alkyl, phenyl, p-toluenesulfonyl, trifluoromethyl, substituted with 0 to 3R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 1R4Substituted tetrahydropyrrolyl, substituted with 0-3R4Substituted by
R4Are respectively and independently selected from 0 to 1R5Substituted phenyl, substituted by 0-3R5Substituted C7～C17Aryl group, substituted by 0 to 1R5Substituted thienyl, substituted with 0-4R5Substituted 5-to 9-membered heterocyclyl, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group; the hetero atom of the heterocyclic group is O, and the number of the hetero atoms is 1-5;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C4Alkyl, -OR60 to 1R6Substituted phenyl, piperidinyl, -C (O) OR6；
R6Are each independently selected from C1～C2Alkyl, halogen.
4. The composition of claim 1, wherein:
the equivalent ratio of the compound 1 to the fluoride initiator is 1: (0.1-1);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-1) mmol: (0.1-1) mL.
5. The composition of claim 4, wherein:
the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 0.5);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-0.5) mmol: (0.1-0.5) ml.
6. The composition of claim 5, wherein:
the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 0.2);
and/or the molar volume ratio of the compound 1 to the organic solvent is 0.2 mmol: 0.5 mL.
7. Use of a composition according to any one of claims 1 to 6 in the preparation of an α, α -difluoro- β -ketosulfone.
8. Use according to claim 7, characterized in that: the alpha, alpha-difluoro-beta-ketone sulfone compound is prepared by the following preparation method: and reacting the compound 1 with a fluoride initiator in an organic solvent to obtain the compound.
9. Use according to claim 8, characterized in that: the reaction is carried out under the protection of inert gas;
and/or the reaction temperature is 50-100 ℃;
and/or, the reaction is further followed by purification, the purification comprising the steps of: concentrating the reaction solution, and performing silica gel column chromatography.
10. Use according to claim 9, characterized in that: the inert gas is nitrogen or argon;
and/or the reaction temperature is 60-80 ℃.
11. Use according to claim 10, characterized in that: the reaction time is 10-30 h.
12. A preparation method of alpha, alpha-difluoro-beta-ketosulfone compounds is characterized by comprising the following steps: it comprises the following steps:
reacting the compound 1 with a fluoride initiator in an organic solvent to obtain a compound shown in a formula I;
wherein Ar is1And Ar2Each independently selected from substituted or unsubstituted aromatic group, substituted or unsubstituted hetero atom aromatic group;
the fluoride initiator is selected from silver fluoride;
the organic solvent is selected from acetonitrile.
13. The method of manufacturing according to claim 12, wherein: ar (Ar)1And Ar2Are respectively independentSelected from 0 to 5R1Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R1A substituted 5-to 10-membered heteroatomic aromatic group;
R1are respectively and independently selected from 0 to 5R4Substituted C1～C8Alkyl, cyano, hydroxy, trifluoromethyl, 4-to 6-membered aryl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R33-to 8-membered heterocyclic group; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are respectively and independently selected from hydrogen and 0-5R4Substituted C1～C8Alkyl, 4-6 membered aryl, p-toluenesulfonyl, trifluoromethyl, substituted with 0-5R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 5R4A substituted 3-to 8-membered heterocyclic group, substituted with 0 to 5R4A substituted 5-to 17-membered heteroatomic aromatic group;
R4are respectively and independently selected from 0 to 5R5Substituted 6-to 10-membered aromatic group, substituted with 0 to 5R5A substituted 5-to 10-membered heteroatomic aromatic group, substituted with 0 to 5R5Substituted 5-to 17-membered heterocyclic group, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C8Alkyl, -OR6And a quilt cover of 0-5R6Substituted 6-to 10-membered aromatic group, 3-to 8-membered heterocyclic group, -C (O) OR6；
R6Are each independently selected from C1～C8Alkyl, halogen;
the heteroatom is O, S or N; the number of the heteroatoms is 1-6.
14. The method of manufacturing according to claim 13, wherein:
Ar1and Ar2Are respectively and independently selected from 0 to 3R1Substituted phenyl, substituted by 0-1R1Substituted naphthyl, substituted by 0-1R1Substituted thienyl, substituted with 0-1R1Substituted by
Is coated with 0 to 5R1Substituted by
Is coated with 0 to 1R1Substituted by
Or by 0 to 1R1Substituted by
R1Are respectively and independently selected from 0 to 1R4Substituted C1～C4Alkyl, cyano, hydroxy, trifluoromethyl, phenyl, halogen, -C (O) R2、-C(O)OR2、-NR2R3、-OR2、-C(O)NR2R3Morpholinyl; or two R on the same carbon atom1The substituents form ═ O, ═ S;
R2、R3are independently selected from hydrogen and 0-1R4Substituted C1～C2Alkyl, phenyl, p-toluenesulfonyl, trifluoromethyl, substituted with 0 to 3R4Substituted 3-to 6-membered cycloalkyl group substituted with 0 to 1R4Substituted tetrahydropyrrolyl, substituted with 0-3R4Substituted by
R4Are respectively and independently selected from 0 to 1R5Substituted phenyl, substituted by 0-3R5Substituted C7～C17Aryl radical, by 0-1R5Substituted thienyl, substituted with 0-4R5Substituted 5-to 9-membered heterocyclyl, -C (O) R5、-C(O)OR5、-NR5R5’、C1～C16An alkyl group; the hetero atom of the heterocyclic group is O, and the number of the hetero atoms is 1-5;
R5、R5' are each independently selected from hydrogen, tert-butyloxycarbonyl, C1～C4Alkyl, -OR60 to 1R6Substituted phenyl, piperidinyl, -C (O) OR6；
R6Are each independently selected from C1～C2Alkyl, halogen.
15. The method for producing as claimed in claim 12, characterized in that:
the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 1);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-1) mmol: (0.1-1) mL.
16. The method of claim 15, wherein:
the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 0.5);
and/or the molar volume ratio of the compound 1 to the organic solvent is (0.1-0.5) mmol: (0.1-0.5) ml.
17. The method of manufacturing according to claim 16, wherein:
the equivalent ratio of compound 1 to fluoride initiator is 1: (0.1 to 0.2);
and/or the molar volume ratio of the compound 1 to the organic solvent is 0.2 mmol: 0.5 mL.
18. The method of manufacturing according to claim 12, wherein: the reaction is carried out under the protection of inert gas;
and/or the reaction temperature is 50-100 ℃;
and/or, the reaction is further followed by purification, the purification comprising the steps of: concentrating the reaction solution, and performing silica gel column chromatography.
19. The method of claim 18, wherein: the inert gas is nitrogen or argon;
and/or the reaction temperature is 60-80 ℃.
20. The method of claim 19, wherein: the reaction time is 10-30 h.
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Non-Patent Citations (5)
| Title |
|---|
| An efficient fluorination of b-ketosulfones promoted by a room-temperature ionic liquid at ambient conditions under ultrasound irradiation using SelectfluorTM F-TEDA-BF4;Mohammad Reza Poor Heravi;《Chinese Chemical Letters》;20101231;第1399-1402页 * |
| Catalytic AgF-Initiated Intramolecular 1,3-Sulfonyl Migration of gem-Difluorovinyl Sulfonates to α,α-Difluoro-β-ketosulfones;Baojian Xiong等;《Org. Lett.》;20201118;第9263-9268页 * |
| Photoredox-catalyzed sulfonylation of difluoroenoxysilanes with the insertion of sulfur dioxide;Fu-Sheng He 等;《Chem. Commun.》;20200710;第9469-9472页 * |
| Preparation of 2,2-difluoro-1-arylethenylstannane as a precursor of 1,1-diaryl-2,2-difluoroethenes;Lee, Hyo Young 等;《Bulletin of the Korean Chemical Society》;20121231;第379-380页 * |
| Synthesis of 2,2-diaryl-1,1-difluoroethenes via Pd-catalyzed dehydrosulfonylative cross-coupling of α-[difluoro(phenylsulfonyl)methyl]benzyl tosylates with arylboronic acids;Zhang, Rui 等;《Tetrahedron》;20181231;第5295-5302页 * |
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