CN105481748B - 5-氟多取代二氢吡咯衍生物及其制备方法 - Google Patents
5-氟多取代二氢吡咯衍生物及其制备方法 Download PDFInfo
- Publication number
- CN105481748B CN105481748B CN201610070648.5A CN201610070648A CN105481748B CN 105481748 B CN105481748 B CN 105481748B CN 201610070648 A CN201610070648 A CN 201610070648A CN 105481748 B CN105481748 B CN 105481748B
- Authority
- CN
- China
- Prior art keywords
- preparation
- fluorine
- cdcl
- nmr
- polysubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 70
- 239000011737 fluorine Substances 0.000 title claims abstract description 69
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical class C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- -1 vinyl compound Chemical class 0.000 claims abstract description 76
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 12
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000004185 ester group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 146
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 238000003756 stirring Methods 0.000 description 24
- 239000003208 petroleum Substances 0.000 description 23
- 239000002994 raw material Substances 0.000 description 23
- 238000004293 19F NMR spectroscopy Methods 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 229910001868 water Inorganic materials 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 150000007980 azole derivatives Chemical class 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229930192474 thiophene Natural products 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WLTCKEHCTUYJGI-UHFFFAOYSA-N Diethyl aminomalonate Chemical compound CCOC(=O)C(N)C(=O)OCC WLTCKEHCTUYJGI-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- MZTCCUSKMMNHNV-UHFFFAOYSA-N N1C=CCC1.[F] Chemical compound N1C=CCC1.[F] MZTCCUSKMMNHNV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002240 furans Chemical class 0.000 description 3
- 150000003951 lactams Chemical class 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- OMUJNTLGTTUMQX-UHFFFAOYSA-N 2-sulfonyl-1,3-dihydropyrrole toluene Chemical class S(=O)(=O)=C1NC=CC1.CC1=CC=CC=C1 OMUJNTLGTTUMQX-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Chemical group 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ZVJLAFKXWRALGA-UHFFFAOYSA-N azane diethyl 2-propylpropanedioate Chemical compound N.CCOC(=O)C(CCC)C(=O)OCC ZVJLAFKXWRALGA-UHFFFAOYSA-N 0.000 description 1
- ITCMXBVIXVDAKR-UHFFFAOYSA-M azanium tetrabutylazanium diacetate Chemical compound C(C)(=O)[O-].[NH4+].C(CCC)[N+](CCCC)(CCCC)CCCC.C(C)(=O)[O-] ITCMXBVIXVDAKR-UHFFFAOYSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical class ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 description 1
- 229960004617 sapropterin Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical class *S(*)(=O)=O 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明涉及一种5‑氟多取代二氢吡咯衍生物,其结构如式(III)所示。其制备方法为,在碱的作用下,含三氟甲基烯类化合物与酰胺丙二酸二乙酯类化合物发生环化反应,经萃取、浓缩、柱层析得到所述5‑氟多取代二氢吡咯衍生物;反应过程如反应式(1)所示。本发明制备方法反应条件温和,操作简单,获得了5‑氟多取代二氢吡咯化合物结构骨架。
Description
技术领域
本发明属于化学合成领域,涉及一类含氟二氢吡咯衍生物的制备方法,具体涉及一类5-氟多取代二氢吡咯衍生物及其制备方法。
背景技术
二氢吡咯结构单元广泛存在于天然产物及药物试剂中,常常被作为合成四氢吡咯,吡咯的前导化合物(参见:(a)H.G.Cheon,H.Lim and D.H.Lee,Eur.J.Pharmacol.,2001,411,181;(b)H.G.Cheon,S.S.Lee,H.Lim and D.H.Lee,Eur J.Pharmacol.,2001,411,187;(c)C.W.Bird and G.W.H.Cheeseman,in Comprehensive HeterocyclicChemistry,ed.A.R.Katritzky and C.W.Rees,Pergamon,Oxford,UK,1984,vol.4,p.8;(d)D.Walker and J.D.Hiebert,Chem.Rev.,1967,67,153;(e)Y.K.Shim,J.I.Youn,J.S.Chun,T.H.Park,M.H.Kim and W.J.Kim,Synthesis,1990,753.)。因此,寻找高效地制备此类物质的方法,具有重要的意义,特别是制备它们的含氟类似物意义卓著((a)I.Coldham andR.Hufton,Chem.Rev.,2005,105,2765.(b)F.Bellina and R.Rossi,Tetrahedron,2006,62,7213;(c)M.Brichacek and J.T.Njardarson,Org.Biomol.Chem.,2009,7,1761;(d)T.Yamazaki,T.Taguchi,I.Ojima,In Fluorine in Medicinal Chemistry and ChemicalBiology;I.Ojima,,Eds.;Wiley-Blackwell:Weinheim,2009;pp 3-46;(e)J.-P.Bégué,D.Bonnet-Delpon,Bioorganic and Medicinal Chemistry of Fluorine;Wiley-VCH:Weinheim,2008.),因为氟原子的引入往往能进一步提高分子的药学活性。在众多含氟化合物中,单氟杂环已经成为有机化合物领域一个重要的分支,它们在药学、工业领域都有良好的应用((a)A.A.Gakh,K.L.Kirk,Fluorinated heterocycles.American ChemicalSociety,Washington DC,2009;(b)V.A.Petrov,Fluorinated heterocyclic compounds:synthesis,chemistry,and applications.Wiley,Hoboken,2009;(c)J.Ichikawa,Chim.Oggi,2007,25,54.)。虽然已经有相当多的文献报道了二氢吡咯的合成策略,但是对于含氟二氢吡咯的合成文献却很少((a)M.S.Novikov,A.F.Khlebnikov,M.V.Shevchenko,J.Fluorine.Chem.,2003,123,177;(b)M.S.Novikov,A.F.Khlebnikov,M.V.Shevchenko,R.R.Kostikov,D.Vidovic,Russ.J.Org.Chem.,2005,41,1496;(c)J.Ichikawa,M.Fujiwara,Y.Wada,T.Okauchi,T.Minami,Chem.Commun.2000,1887;(d)T.Fujita,M.Ikeda,M.Hattori,K.Sakoda,J.Ichikawa,Synthesis.,2014,46,1493.)。
发明内容
本发明进一步丰富了单氟杂环化合物的合成方法学,提供一种原料易得、反应条件温和、化学选择性好的单氟二氢吡咯环衍生物的合成方法,制备得到一类新的5-氟多取代二氢吡咯衍生物。
本发明提供了一种5-氟多取代二氢吡咯衍生物,结构如式(III)所示,
其中,R1为酯基、羰基、炔基;R2为芳基、杂芳基、烷基、氢;PG包括Ac(乙酰基),Ts(对甲苯磺酰基),Cbz(苄氧羰基),Ns(对硝基苯磺酰基),优选地为Ts(对甲苯磺酰基)。
进一步地,所述芳基包括苯基、或邻、对位的取代苯基、萘基;所述杂芳基为呋喃、噻吩。
更进一步地,所述酯基为乙氧羰基,所述羰基为苯甲酰基,所述炔基为苯基乙炔基;所述邻、对位的取代苯基为4-溴苯基、4-甲氧基苯基、4-氯苯基、2-氯苯基、4-硝基苯基、4-氰基苯基、4-三氟甲基苯基,所述萘基为2-萘基;所述呋喃为2-呋喃基、所述噻吩为2-噻吩基,所述烷基为异丁基。
即,式(III)中,所述R1为乙氧羰基、苯甲酰基、苯基乙炔基;所述R2为4-溴苯基、苯基、4-甲氧基苯基、4-氯苯基、2-氯苯基、4-硝基苯基、4-氰基苯基、4-三氟甲基苯基、2-萘基、2-呋喃基、2-噻吩基、异丁基、氢;所述PG为乙酰基、苄氧酰基、对甲苯磺酰基、对硝基苯磺酰基。
本发明中,所述式(III)所示的5-氟多取代2H-吡喃衍生物包括:3-(4-溴苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-溴苯基)-5-氟代-1-乙酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-溴苯基)-5-氟代-1-对硝基苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-溴苯基)-5-氟代-1-苄氧酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-苯基-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-甲氧基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-氯苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-氯苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-硝基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-氰基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-三氟甲基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-萘基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-呋喃基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-噻吩基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-异丁基-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,4-(苯乙炔基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2(3H)-二羧酸二乙酯,3-苯基-4-苯甲酰基-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2(3H)-二羧酸二乙酯。
本发明提出的制备方法以2-三氟甲基-1-烯烃(即含三氟甲基基团的烯类化合物)、酰胺丙二酸二乙酯类化合物为原料,将其溶于有机溶剂,在碱的作用下经加成消除串联反应得到本发明的多取代多官能团化的单氟二氢吡咯衍生物。
本发明提供的如式(III)所示的单氟取代二氢吡咯衍生物的制备方法是,在碱的作用下,式(I)所示含三氟甲基烯类化合物与式(II)所示酰胺丙二酸二乙酯类化合物发生环化反应,经萃取、浓缩、柱层析得到所述5-氟多取代二氢吡咯衍生物;所述制备方法的反应过程如反应式(1)所示,
其中R1为酯基、羰基、炔基;R2为芳基、杂芳基、烷基、氢;PG包括Ac(乙酰基),Ts(对甲苯磺酰基),Cbz(苄氧羰基),Ns(对硝基本磺酰基)。优选地为Ts(对甲苯磺酰基)。
所述酯基为乙氧羰基,所述羰基为苯甲酰基,所述炔基为苯基乙炔基;所述芳基为苯基、4-溴苯基、4-甲氧基苯基、4-氯苯基、2-氯苯基、4-硝基苯基、4-氰基苯基、4-三氟甲基苯基、2-萘基,所述杂芳基为2-呋喃基、2-噻吩基,所述烷基为异丁基。
即,反应式(1)中,所述R1为乙氧羰基、苯甲酰基、苯基乙炔基;所述R2为4-溴苯基、苯基、4-甲氧基苯基、4-氯苯基、2-氯苯基、4-硝基苯基、4-氰基苯基、4-三氟甲基苯基、2-萘基、2-呋喃基、2-噻吩基、异丁基、氢;所述PG为乙酰基、苄氧酰基、对甲苯磺酰基、对硝基苯磺酰基。
其中,根据本发明方法制备得到的式(III)所示的5-氟多取代二氢吡咯衍生物,包括:3-(4-溴苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-溴苯基)-5-氟代-1-乙酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-溴苯基)-5-氟代-1-对硝基苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-溴苯基)-5-氟代-1-苄氧酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-苯基-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-甲氧基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-氯苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-氯苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-硝基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-氰基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(4-三氟甲基苯基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-萘基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-呋喃基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-(2-噻吩基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,3-异丁基-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2,4(3H)-三羧酸三乙酯,4-(苯乙炔基)-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2(3H)-二羧酸二乙酯,3-苯基-4-苯甲酰基-5-氟代-1-对甲苯磺酰基-1H-吡咯-2,2(3H)-二羧酸二乙酯。
在一具体实施方案中,本发明的式(III)所示的5-氟多取代二氢吡咯衍生物的制备过程为,将含三氟甲基烯类化合物溶解在有机溶剂中,在无机碱的作用下,在室温条件下与酰胺丙二酸二乙酯类化合物发生环化反应,反应完成后萃取,浓缩,经柱层析得到如式(III)所示的5-氟多取代二氢吡咯衍生物。
本发明制备方法中,反应在有机溶剂中进行。具体地,在制备式(III)5-氟多取代二氢吡咯衍生物的步骤中,所述有机溶剂是N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)、乙腈。所述的有机溶剂不局限于上述有机溶剂。
本发明制备方法中,所述有机溶剂的用量为8.0~10.0mL/mmol酰胺丙二酸二乙酯类化合物。
本发明制备方法中,所述碱是无机碱,进一步地是碱盐,选自于碳酸钾、碳酸钠。具体地,在制备式(III)5-氟多取代二氢吡咯衍生物的步骤中,所述碱盐包括碳酸钾,碳酸钠等。优选地,所述碱为碳酸钾。
本发明制备方法中,所述含三氟甲基烯类化合物、酰胺丙二酸二乙酯类化合物、碱的摩尔比为三氟甲基烯类化合物:酰胺丙二酸二乙酯类化合物:碱=3.0-1.0:1.0-2.0:1.0-2.0;优选地,所述含三氟甲基烯类化合物、酰胺丙二酸二乙酯类化合物、碱的摩尔比为三氟甲基烯类化合物:酰胺丙二酸二乙酯类化合物:碱=1.5:1.0:1.2。
本发明制备方法中,去除溶剂的方式包括:先用乙醚或乙酸乙酯反应后的反应液进行萃取,干燥并旋蒸去除溶剂,从而得到粗产品。
本发明制备方法中,所述柱层析是采用体积比为石油醚:乙酸乙酯=5:1~3:1的淋洗剂。
本发明制备方法的创新之一在于,本发明制备方法反应温度优良,如,制备式(III)5-氟多取代二氢吡咯衍生物0℃-50℃;优选地,为室温条件下进行的。
本发明制备方法中,反应时间约为4~12小时;优选地,为6小时。
本发明制备方法中的各原料、包括有机溶剂、碱等,均可市场购得并直接使用,例如,有机溶剂采用N,N-二甲基甲酰胺,碱采用无机碱。在一具体实施方案中,本发明制备方法为,先称取一定量的分子筛,式(II)酰胺丙二酸二乙酯类化合物物质的量1.2倍的碳酸钾,置于干燥的反应管中。在氮气氛围下,按一定比例称取式(I)含三氟甲基基团的烯类化合物,式(II)酰胺丙二酸二乙酯类化合物类化合物。例如:式(I)含三氟甲基基团的烯类化合物:式(II)酰胺丙二酸二乙酯类化合物类化合物摩尔比=1.5:1.0,随后向反应管中注入2mLDMF。然后,在室温反应条件下反应,搅拌过程中通过薄层层析硅胶板(TLC)监测反应进行程度,反应时间约为4~12小时,反应结束后先用乙醚或者乙酸乙酯进行萃取后干燥并旋蒸去除溶剂,然后,将粗产品进行柱层析,得到式(I II)5-氟多取代二氢吡咯衍生物纯品。其中,例如,用体积比为石油醚:乙酸乙酯=5:1~3:1的淋洗剂进行柱层析。
本发明5-氟多取代二氢吡咯衍生物的制备方法,以含三氟甲基基团的烯类化合物,酰胺丙二酸二乙酯类化合物为原料,在无机碱作用下反应得到包含烷基,杂芳基,芳基及取代芳基,酯基,羰基、炔基等基团的5-氟多取代二氢吡咯衍生物,产物结构如式(III)所示。本发明有益效果包括,原料易得,反应条件温和,操作简单,能快速且高效地合成5-氟多取代二氢吡咯衍生物。本发明通过其它路径开拓了反应产物一系列的合成应用,实现了脱Ts,氧化脱酯,脱氟亲核取代,金属催化的偶联反应等,本发明制备的5-氟多取代二氢吡咯化合物,可以用于合成多官能团化的内酰胺,单氟芳香吡咯等一系列生物活性分子,在药学、有机合成领域具有重要的意义。
本发明的制备方法的创新之处是利用含三氟甲基基团的烯类化合物,酰胺丙二酸二乙酯类化合物为原料,在无机碱作用下一锅法经连续两步脱氟取代反应高效制备5-氟多取代二氢吡咯衍生物。
本发明还提出了如上所述的5-氟多取代二氢吡咯衍生物在制备无氟多取代二氢吡咯衍生物、吡咯烷酮、吡咯及含氟吡咯衍生物中的应用。
本发明提供多种结构的单氟二氢吡咯化合物骨架,不仅对单氟多取代二氢吡咯类化合物的合成具有重要意义,而且对新药的合成筛选和药物研究都具有非常重要意义。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
本发明提出的5-氟多取代二氢吡咯衍生物的制备方法,将如式(I)所示的含三氟甲基基团的烯类化合物化合物,如式(II)所示的酰胺丙二酸二乙酯类化合物放入装有分子筛和式(II)酰胺丙二酸二乙酯类化合物物质的量1.2倍的碳酸钾的干燥反应管中,,其中,含三氟甲基基团的烯类化合物:酰胺丙二酸二乙酯类化合物=1.5:1.0,在室温条件下反应,除去溶剂,经柱层析得到如式(III)所示的5-氟多取代二氢吡咯衍生物;
其中R1为酯基、羰基、炔基;R2为芳基、杂芳基、烷基、氢;PG包括Ac,Ts,Cbz,Ns。
优选地,所述芳基包括苯基、或邻、对位的取代苯基、萘基;所述杂芳基为呋喃、噻吩。
实施例1
将原料3-(4-溴苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)放入盛有预先活化的分子筛和式(I I)酰胺基丙二酸二乙酯物质的量1.2倍的碳酸钾的干燥反应管中,在室温下充分反应,反应6小时,通过TLC和碘缸显色检测反应,至对甲苯磺酰氨基丙二酸二乙酯完全消失。反应结束后加入5.0ml蒸馏水淬灭反应,用乙醚或者乙酸乙酯(3*5.0ml)进行萃取,合并有机相干燥并旋蒸去除溶剂,然后将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=4:1)得到5-氟多取代二氢吡咯衍生物纯品III-1(156mg,82%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ8.06(d,J=7.5Hz,2H),7.41(d,J=8.7Hz,2H),7.36(d,J=8.2Hz,2H),7.12(brs,2H),4.82(d,J=5.7Hz,1H),4.63–4.32(m,2H),4.18–3.92(m,2H),3.89–3.55(m,2H),2.46(s,3H),1.44(t,J=7.1Hz,3H),1.09(t,J=7.1Hz,3H),1.02(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-96.19.13C NMR(101MHz,CDCl3)δ167.13,163.52,161.81(d,J=5.7Hz),156.16(d,J=295.0Hz),145.41,136.42,135.11,135.10,131.13,129.52,129.09(d,J=1.8Hz),122.33,85.87(d,J=3.9Hz),77.40,63.49,62.75,60.32,50.42(d,J=1.8Hz),21.62,14.00,13.93,13.31.HRMS(ESI)calcd for C26H27BrFNNaO8S[M+Na+]:634.0517,found:634.0520.
实施例2
将3-(4-溴苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),乙酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌6h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-2(18mg,12%)。
无色油状物.1H NMR(500MHz,CDCl3)δ7.41(d,J=7.6Hz,2H),7.12(brs,2H),4.60(d,J=2.9Hz,1H),4.39-4.33(m,2H),4.21–3.96(m,1H),3.74–3.44(m,1H),2.40(d,J=4.9Hz,3H),1.37(t,J=5.9Hz,3H),1.12(t,J=5.9Hz,3H),0.89(t,J=6.0Hz,3H).19F NMR(282MHz,CDCl3)δ-99.39.13C NMR(126MHz,CDCl3)δ166.72(d,J=3.7Hz),166.45,162.74,162.05(d,J=5.8Hz),155.34(d,J=295.4Hz),135.40,135.39,131.17,122.24,88.03(d,J=5.0Hz),73.80,63.12,62.17,60.51,48.93,23.71(d,J=11.2Hz),14.02,13.94,13.33.HRMS(ESI)calcd for C21H23BrFNNaO7[M+Na+]:522.0534,found:522.0541.
实施例3
将3-(4-溴苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对硝基苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌4h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-3(79mg,41%)。
黄色油状物.1H NMR(300MHz,CDCl3)δ8.41(s,4H),7.43(d,J=8.6Hz,2H),7.11(brs,2H),4.83(d,J=5.9Hz,1H),4.65–4.36(m,2H),4.28–3.93(m,2H),3.91–3.60(m,2H),1.46(t,J=7.1Hz,3H),1.11(t,J=7.1Hz,3H),1.05(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-97.31.13C NMR(101MHz,CDCl3)δ166.85,163.36,161.41(d,J=5.7Hz),155.09(d,J=295.0Hz),150.75,144.51,134.44,131.29,130.62,130.60,124.08,122.64,87.07(d,J=3.8Hz),77.73,63.8,63.15,60.69,50.35,13.99,13.96,13.35.HRMS(ESI)calcd forC25H24BrFN2NaO10S[M+Na+]:665.0211,found:665.0219.
实施例4
将3-(4-溴苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),苄氧酰基氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌6h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-4(18mg,10%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ7.41(d,J=8.7Hz,2H),7.33(s,5H),7.13(brs,2H),5.22(q,J=12.1Hz,2H),4.70(d,J=5.5Hz,1H),4.34(q,J=7.1Hz,2H),4.19–3.96(m,2H),3.64–3.14(m,2H),1.30(t,J=7.1Hz,3H),1.13(t,J=7.1Hz,3H),0.77(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-96.64.13C NMR(101MHz,CDCl3)δ166.85,163.02,162.07(d,J=5.7Hz),156.26(d,J=301.8Hz),149.96(d,J=3.6Hz),135.48,135.47,134.55,131.15,128.56,128.49,128.25,122.21,87.32(d,J=3.4Hz),74.34,68.82,63.21,62.26,60.36,49.64,14.02,13.84,13.19.HRMS(ESI)calcd for C27H27BrFNNaO8[M+Na+]:614.0796,found:614.0801.
实施例5
将3-苯基-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌8h,硅胶柱色谱纯化(石油醚:乙酸乙酯=5:1),得到5-氟多取代二氢吡咯衍生物纯品III-5(141mg,88%)。
无色油状物.1H NMR(400MHz,CDCl3)δ8.07(d,J=7.4Hz,2H),7.35(d,J=8.1Hz,2H),7.25(s,5H),4.86(d,J=5.7Hz,1H),4.57–4.37(m,2H),4.16–3.88(m,2H),3.79–3.47(m,2H),2.44(s,3H),1.44(t,J=7.1Hz,3H),1.05(t,J=7.1Hz,3H),0.96(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-97.11.13C NMR(101MHz,CDCl3)δ167.23(s),163.55(s),161.85(d,J=5.7Hz),155.90(d,J=294.8Hz),145.21,136.51,135.93,135.92,129.42,128.99(d,J=1.8Hz),128.09,127.89,86.24(d,J=3.4Hz),77.63,63.31,62.45,60.10,50.98(d,J=1.7Hz),21.52,13.88,13.85,13.18.HRMS(ESI)calcd for C26H28FNNaO8S[M+Na+]:556.1412,found:556.1418.
实施例6
将3-(4-甲氧基苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌10h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-6(79mg,47%)。
黄色固体.Mp93-95℃.1H NMR(400MHz,CDCl3)δ8.07(d,J=7.5Hz,2H),7.36(d,J=8.2Hz,2H),7.15(brs,2H),6.79(d,J=8.9Hz,2H),4.81(d,J=5.7Hz,1H),4.62–4.33(m,2H),4.18–3.88(m,2H),3.76(s,3H),3.81–3.62(m,2H),2.46(s,3H),1.44(t,J=7.1Hz,3H),1.08(t,J=7.1Hz,3H),1.02(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-97.22.13CNMR(101MHz,CDCl3)δ167.38,163.71,162.02(d,J=5.7Hz),159.46,155.85(d,J=294.7Hz),145.23,136.62,129.48,129.09(d,J=1.8Hz),127.89,127.88,113.37,86.45(d,J=3.3Hz),77.75,63.32,62.55,60.19,55.15,50.58(d,J=1.6Hz),21.63,14.02,13.95,13.35.HRMS(ESI)calcd for C27H30FNNaO9S[M+Na+]:586.1518,found:586.1530.
实施例7
将3-(4-氯苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌7h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-7(143mg,84%)。
白色固体.Mp124-126℃.1H NMR(400MHz,CDCl3)δ8.06(d,J=7.4Hz,2H),7.36(d,J=8.2Hz,2H),7.25(d,J=7.3Hz,2H),7.18(brs,2H),4.83(d,J=5.7Hz,1H),4.56–4.33(m,2H),4.16–3.92(m,2H),3.84–3.61(m,2H),2.46(s,3H),1.44(t,J=7.1Hz,3H),1.08(t,J=7.1Hz,3H),1.02(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-96.25.13C NMR(101MHz,CDCl3)δ167.14,163.53,161.82(d,J=5.7Hz),156.14(d,J=294.9Hz),145.41,136.41,134.57,134.56,134.13,129.51,129.09(d,J=1.8Hz),128.17,85.93(d,J=3.8Hz),77.47,63.48,62.73,60.31,50.35(d,J=1.8Hz),21.62,13.99,13.93,13.31.HRMS(ESI)calcd for C26H27ClFNNaO8S[M+Na+]:590.1022,found:590.1028.
实施例8
将3-(2-氯苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌6h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-8(138mg,81%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ8.01(d,J=7.8Hz,2H),7.35(d,J=8.2Hz,2H),7.34(dd,J=7.8,1.4Hz,1H),7.21-7.09(m,2H),7.01(dd,J=7.7,1.6Hz,1H),5.45(d,J=5.0Hz,1H),4.44(q,J=7.0Hz,1H),4.16–3.76(m,3H),3.63-3.53(m,1H),2.45(s,3H),1.41(t,J=7.1Hz,3H),1.01(t,J=7.1Hz,3H),0.99(t,J=7.1Hz,3H).19F NMR(282MHz,CDCl3)δ-97.76.13C NMR(101MHz,CDCl3)δ166.49,163.49,161.49(d,J=5.6Hz),156.28(d,J=295.7Hz),145.32,136.41,135.04,134.53(d,J=2.0Hz),129.52,129.34,129.29,129.26,128.86(d,J=1.4Hz),126.44,87.00(d,J=3.0Hz),77.20,63.41,62.61,60.14,47.28(d,J=2.1Hz),21.58,13.78(2C),13.20.HRMS calcd for C26H27ClFNNaO8S:590.1022,found:590.1021.
实施例9
将3-(4-硝基苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌5h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-9(161mg,93%)。
黄色固体.Mp158-159℃.1H NMR(500MHz,CDCl3)δ8.13(d,J=8.8Hz,2H),8.04(d,J=8.1Hz,2H),7.44(brs,2H),7.36(d,J=8.2Hz,2H),4.96(d,J=5.5Hz,1H),4.54–4.37(m,2H),4.14–3.92(m,2H),3.86–3.64(m,2H),2.45(s,3H),1.44(t,J=7.1Hz,3H),1.07(t,J=7.1Hz,3H),1.00(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-95.17.13C NMR(126MHz,CDCl3)δ166.80,163.30,161.57(d,J=5.6Hz),156.34(d,J=295.4Hz),147.55,145.61,143.39,136.02,129.53(2C),129.00,123.00,85.38(d,J=4.4Hz),77.07,63.67,62.87,60.43,50.17(d,J=0.6Hz),21.54,13.90,13.85,13.25.HRMS(ESI)calcd forC26H27FN2NaO10S[M+Na+]:601.1263,found:601.1270.
实施例10
将3-(4-氰基苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌5h,硅胶柱色谱纯化(石油醚:乙酸乙酯=3:1),得到5-氟多取代二氢吡咯衍生物纯品III-10(157mg,94%)。
白色固体.Mp 109-111℃.1H NMR(500MHz,CDCl3)δ8.05(d,J=7.8Hz,2H),7.58(d,J=8.6Hz,2H),7.37(d,J=8.2Hz,4H),4.90(d,J=5.6Hz,1H),4.57–4.38(m,2H),4.18–3.89(m,2H),3.88–3.53(m,2H),2.47(s,3H),1.45(t,J=7.1Hz,3H),1.08(t,J=7.1Hz,3H),1.01(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-95.20.13C NMR(126MHz,CDCl3)δ166.94,163.42,161.70(d,J=5.7Hz),156.40(d,J=295.4Hz),145.64,141.53,136.13,131.73,129.58,129.14,129.13,118.38,112.06,85.35(d,J=4.4Hz),77.20,63.72,62.92,60.50,50.54(d,J=1.6Hz),21.67,13.99,13.95,13.34.HRMS(ESI)calcd forC27H27FN2NaO8S[M+Na+]:581.1364,found:581.1365.
实施例11
将3-(4-三氟甲基苯基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌6h,硅胶柱色谱纯化(石油醚:乙酸乙酯=5:1),得到5-氟多取代二氢吡咯衍生物纯品III-11(151mg,84%)。
白色固体.Mp 157-158℃.1H NMR(500MHz,CDCl3)δ8.06(d,J=7.9Hz,2H),7.55(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,4H),4.92(d,J=5.6Hz,1H),4.69–4.36(m,2H),4.18–3.93(m,2H),3.85–3.50(m,2H),2.46(s,3H),1.45(t,J=7.1Hz,3H),1.08(t,J=7.1Hz,3H),0.95(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-62.67(s,3F),-95.78(s,1F).13C NMR(126MHz,CDCl3)δ167.05,163.50,161.78(d,J=5.7Hz),156.27(d,J=295.1Hz),145.54,140.16,136.26,130.36(q,J=32.5Hz),129.55,129.11,129.10,124.90(q,J=3.5Hz),123.88(q,J=272.1Hz),85.67(d,J=4.1Hz),77.37,63.61,62.79,60.40,50.49,21.61,13.95,13.92,13.16.HRMS(ESI)calcd for C27H27F4NNaO8S[M+Na+]:624.1286,found:624.1293.
实施例12
将3-(2-萘基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌10h,硅胶柱色谱纯化(石油醚:乙酸乙酯=5:1),得到5-氟多取代二氢吡咯衍生物纯品III-12(128mg,73%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ8.10(d,J=7.4Hz,2H),7.85–7.69(m,4H),7.50–7.42(m,3H),7.38(d,J=8.1Hz,2H),5.05(d,J=5.4Hz,1H),4.64–4.35(m,2H),4.16–3.86(m,2H),3.69–3.38(m,2H),2.48(s,3H),1.49(t,J=7.1Hz,3H),1.03(t,J=7.1Hz,3H),0.79(t,J=7.1Hz,3H).19F NMR(282MHz,CDCl3)δ-96.86.13C NMR(101MHz,CDCl3)δ167.40,163.61,162.02(d,J=5.7Hz),156.13(d,J=295.0Hz),145.33,136.64,133.46,133.11,132.93,129.54,129.16,129.14,127.97,127.61,127.55,126.20,126.10,86.43(d,J=3.2Hz),77.84,63.50,62.54,60.27,51.21,21.67,14.01(2C),13.10.HRMS(ESI)calcd for C30H30FNNaO8S[M+Na+]:606.1568,found:606.1575.
实施例13
将3-(2-呋喃基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌8h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-13(140mg,89%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ8.03(d,J=7.8Hz,2H),7.33(d,J=7.8Hz,2H),7.32(brs,1H),6.30(dd,J=3.2,1.8Hz,1H),6.18(d,J=3.2Hz,1H),4.98(d,J=5.2Hz,1H),4.62–4.34(m,2H),4.17–3.88(m,4H),2.43(s,3H),1.40(t,J=7.1Hz,3H),1.14(t,J=5.3Hz,3H),1.11(t,J=5.3Hz,3H).19F NMR(282MHz,CDCl3)δ-96.94.13C NMR(101MHz,CDCl3)δ166.82,163.55,161.65(d,J=5.7Hz),155.95(d,J=294.9Hz),149.32(d,J=2.6Hz),145.24,142.39,136.43,129.46,128.86(d,J=1.5Hz),110.67,109.29,84.53(d,J=4.5Hz),76.71,63.42,62.97,60.19,45.05(d,J=2.6Hz),21.52,13.96,13.79,13.43.HRMS(ESI)calcd for C24H26FNNaO9S[M+Na+]:546.1205,found:546.1210.
实施例14
将3-(2-噻吩基)-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌8h,硅胶柱色谱纯化(石油醚:乙酸乙酯=5:1),得到5-氟多取代二氢吡咯衍生物纯品III-14(126mg,78%)。
白色固体.Mp 103-105℃.1H NMR(400MHz,CDCl3)δ8.08(d,J=7.6Hz,2H),7.36(d,J=8.1Hz,2H),7.22(dd,J=3.9,2.4Hz,1H),6.93(d,J=4.0Hz,2H),5.15(d,J=5.5Hz,1H),4.61–4.34(m,2H),4.16–3.97(m,2H),3.96–3.76(m,2H),2.45(s,3H),1.44(t,J=7.1Hz,3H),1.11(t,J=7.1Hz,3H),1.09(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-96.85.13C NMR(101MHz,CDCl3)δ166.98,163.35,161.74(d,J=5.6Hz),156.20(d,J=295.5Hz),145.31,139.64,136.48,129.51,129.00(d,J=1.6Hz),127.43,126.67,125.74,86.95(d,J=4.0Hz),77.89,63.48,62.82,60.30,46.23(d,J=2.5Hz),21.61,13.99,13.89,13.38.HRMS(ESI)calcd for C24H26FNNaO8S2[M+Na+]:562.0976,found:562.0984.
实施例15
将3-异丁基-2-(三氟甲基)丙烯酸乙酯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌4h,硅胶柱色谱纯化(石油醚:乙酸乙酯=5:1),得到5-氟多取代二氢吡咯衍生物纯品III-15(146mg,95%)。
无色油状物.1H NMR(400MHz,CDCl3)δ8.03(d,J=7.6Hz,2H),7.34(d,J=8.3Hz,2H),4.55–4.24(m,4H),4.23–3.97(m,2H),3.74-3.66(m,1H),2.44(s,3H),1.77–1.66(m,1H),1.57–1.41(m,2H),1.38(t,J=7.2Hz,3H),1.37(t,J=7.2Hz,3H),1.23(t,J=7.1Hz,3H),0.96(d,J=6.1Hz,3H),0.86(d,J=6.3Hz,3H).19F NMR(282MHz,CDCl3)δ-98.76.13CNMR(101MHz,CDCl3)δ168.19,164.90,162.41(d,J=5.7Hz),154.56(d,J=295.2Hz),145.16,136.54,129.51,128.98(d,J=1.6Hz),87.44(d,J=1.0Hz),76.72,63.20,63.11,60.23,44.00,39.21(d,J=0.8Hz),25.41,23.42,21.66,21.16,14.18,13.87,13.77.HRMS(ESI)calcd for C24H32FNNaO8S[M+Na+]:536.1725,found:536.1737.
实施例16
将(3-(三氟甲基)丁-3-烯-1-炔基)苯(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌4h,硅胶柱色谱纯化(石油醚:乙酸乙酯=5:1),得到5-氟多取代二氢吡咯衍生物纯品III-16(127mg,87%)。
黄色固体.Mp76-78℃.1H NMR(500MHz,CDCl3)δ8.00(d,J=8.1Hz,2H),7.40–7.35(m,2H),7.33(d,J=8.2Hz,2H),7.31–7.26(m,3H),4.55–4.19(m,4H),3.30(d,J=5.4Hz,2H),2.43(s,3H),1.38(t,J=7.1Hz,6H).19F NMR(376MHz,CDCl3)δ-110.86.13C NMR(126MHz,CDCl3)δ167.52(2C),151.67(d,J=285.6Hz),144.80,136.79,131.10,129.37,128.51,128.50,128.22,122.65,94.28(d,J=3.4Hz),78.68(d,J=5.1Hz),73.99(d,J=10.0Hz),72.71,63.19(2C),37.82,21.51,13.78(2C).HRMS(ESI)calcd for C25H24FNNaO6S[M+Na+]:508.1201,found:508.1199.
实施例17
将(Z)or(E)-1,3-二苯基-2-(三氟甲基)丙-2-烯-1-酮(0.45mmol),对甲苯磺酰氨基丙二酸二乙酯(0.3mmol)作为原料,其他操作参考实施例1,反应搅拌12h,硅胶柱色谱纯化(石油醚:乙酸乙酯=4:1),得到5-氟多取代二氢吡咯衍生物纯品III-17(76mg or 48mg,45%or 28%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ8.04(d,J=7.4Hz,2H),7.72(d,J=7.4Hz,2H),7.58–7.49(m,1H),7.43(t,J=7.5Hz,2H),7.39-7.29(m,4H),7.27–7.20(m,3H),5.13(d,J=5.5Hz,1H),4.83–4.12(m,2H),3.94–3.39(m,2H),2.41(s,3H),1.46(t,J=7.1Hz,3H),1.01(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-95.22.13C NMR(101MHz,CDCl3)δ187.59(d,J=4.7Hz),167.29,163.95,154.64(d,J=291.4Hz),145.38,138.48,136.39,135.48,132.38,129.47,129.15,129.13,128.34,128.31,128.21,128.08,95.20(d,J=6.1Hz),77.57,63.36,62.64,51.50(d,J=2.9Hz),21.63,14.02,13.33.HRMS(ESI)calcdfor C30H28FNNaO7S[M+Na+]:588.1463,found:588.1478.
实施例18
在N2氛围下,向装有磁子的玻璃封管中加入前述实施例1制备得到的5-氟多取代二氢吡咯衍生物纯品III-1(0.2mmol),2.0ml NH3的1,4-二氧六环溶液(0.4M),50℃下搅拌7h后,反应完成,直接减压旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=3:1)得到氨基取代二氢吡咯衍生物IV(119mg,98%)。
白色固体.Mp 152-154℃.1H NMR(400MHz,CDCl3)δ7.93(d,J=8.2Hz,2H),7.30(d,J=8.0Hz,4H),6.96(brs,2H),6.73(brs,2H),4.75(s,1H),4.39(q,J=7.1Hz,2H),4.03–3.83(m,2H),3.79–3.43(m,2H),2.42(s,3H),1.38(t,J=7.1Hz,3H),0.94(brs,3H),0.81(t,J=7.1Hz,3H).13C NMR(126MHz,CDCl3)δ167.84,163.65,144.40,137.95,137.80,130.81,129.41,127.26,121.48,80.31,77.20,63.25,62.33,58.97,51.35,21.49,14.14,13.82,13.12.HRMS(ESI)calcd for C26H29BrN2NaO8S[M+Na+]:631.0720,found:631.0725.
实施例19
在氮气氛围下,向装有4A分子筛(100mg)及碳酸钾(0.4mmol)的干燥反应管中注入4-甲基苯硫酚(0.24mmol)的N,N-二甲基甲酰胺溶液(2.0mL),室温下搅拌半个小时,将前述实施例1制备得到的5-氟多取代二氢吡咯衍生物纯品III-1(0.2mmol)加入上述混合液中,在50℃下继续搅拌3h。反应完成,用5.0mL水淬灭,乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后,经硫酸镁干燥,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=5:1)得到对甲基苯硫酚取代二氢吡咯衍生物V(140mg,98%)。
无色油状物.1H NMR(400MHz,CDCl3)δ8.18(d,J=8.4Hz,2H),7.38(d,J=8.6Hz,2H),7.24(d,J=8.2Hz,2H),6.99(d,J=8.4Hz,6H),4.95(s,1H),4.46(q,J=7.1Hz,2H),4.01–3.56(m,4H),2.38(s,3H),2.27(s,3H),1.43(t,J=7.1Hz,3H),1.05(t,J=7.2Hz,3H),0.85(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ167.98,164.34,161.97,147.75,144.23,138.02,137.24,136.33,131.06,130.78,129.67,129.61,129.33,129.03,121.95,115.73,80.22,77.20,63.31,62.50,60.18,54.97,21.47,20.95,13.83,13.68,13.38.HRMS(ESI)calcd for C33H34BrNNaO8S2[M+Na+]:738.0801,found:738.0795.
实施例20
在氮气氛围下,向装有4A分子筛(100mg)及碳酸钾(0.4mmol)的干燥反应管中注入苯酚(0.4mmol)的N,N-二甲基甲酰胺溶液(2.0mL),室温下搅拌半个小时,将前述实施例1制备得到的5-氟多取代二氢吡咯衍生物纯品III-1(0.2mmol)加入上述混合液中,在50℃下继续搅拌4h。反应完成,用5.0mL水淬灭,乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后,经硫酸镁干燥,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=5:1)得到苯酚取代二氢吡咯衍生物VI(136mg,99%)。
无色油状物.1H NMR(400MHz,CDCl3)δ7.97(d,J=8.3Hz,2H),7.43(d,J=8.0Hz,2H),7.31-7.25(m,3H),7.22(d,J=8.3Hz,2H),7.09(t,J=7.4Hz,2H),7.03(d,J=8.0Hz,2H),4.89(s,1H),4.60-4.44(m,2H),3.99–3.33(m,4H),2.38(s,3H),1.49(t,J=7.1Hz,3H),1.06(t,J=7.2Hz,3H),0.65(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ167.78,164.20,161.98,156.68,155.75,144.70,136.70,136.22,131.10,129.44,129.29,128.99,123.53,122.05,115.67,91.58,77.02,63.37,62.58,59.81,52.21,21.51,13.98,13.47,13.36.HRMS(ESI)calcd for C32H32BrNNaO9S[M+Na+]:708.0873,found:708.0870.
实施例21
于室温条件下,将前述实施例1制备得到的5-氟多取代取代二氢吡咯衍生物纯品III-1(0.2mmol)溶解于DMF(2.0mL)中,向其中加入四丁基醋酸铵(0.5mmol),H2O(10μL)50℃下搅拌,直到III-1几乎反应完全,用5.0mL水淬灭,乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后,经硫酸镁干燥,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=4:1)得到内酰胺衍生物VII(117mg,96%)。
无色油状物.1H NMR(400MHz,CDCl3)δ8.03(d,J=8.4Hz,2H),7.45(d,J=8.5Hz,2H),7.33(d,J=8.2Hz,2H),7.05(d,J=8.5Hz,2H),4.45-4.37(m,2H),4.33(d,J=11.7Hz,1H),4.23–3.88(m,4H),4.02(d,J=11.7Hz,1H),2.44(s,3H),1.37(t,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H),1.05(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ166.82,165.99,165.74,165.30,145.67,134.44,131.71,131.64,130.32,130.08,129.03,123.15,74.84,63.21,63.06,62.51,52.06,49.01,21.69,13.87,13.86,13.49.HRMS(ESI)calcd forC26H28BrNNaO9S[M+Na+]:632.0560,found:632.0571.
实施例22
在氮气氛围下,向玻璃封管中逐次加入前述实施例1制备得到的5-氟多取代二氢吡咯衍生物纯品III-1(0.2mmol),苯酚(0.2g),HBr(40%水溶液,0.24mL),冰醋酸(0.8mL),90℃下反应1h后,旋蒸除去冰醋酸,向剩余物中加入5.0mL水,乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后,经硫酸镁干燥,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=3:1)得到脱去3位酯基的内酰胺衍生物VIII(60mg,56%)。
无色油状物.1H NMR(400MHz,CDCl3)δ8.05(d,J=8.2Hz,2H),7.42(d,J=8.3Hz,2H),7.34(d,J=8.1Hz,2H),6.99(d,J=8.3Hz,2H),4.42(q,J=7.1Hz,2H),4.12–3.94(m,2H),3.91-3.81(m,1H),2.84(dd,J=8.4,5.7Hz,2H),2.45(s,3H),1.39(t,J=7.1Hz,3H),1.01(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ171.70,166.96,164.90,145.35,135.10,134.47,131.60,129.98,129.89,128.96,122.69,77.08,63.29,62.70,46.10,36.15,21.71,13.91,13.46.13C NMR DEPT 135(126MHz,CDCl3)δ131.69,130.06,129.98,129.04,63.36,62.76,46.19,36.25,21.77,13.98,13.53.HRMS(ESI)calcd for C23H24BrNNaO7S[M+Na+]:560.0349,found:560.0356.
实施例23
于室温条件下,将前述实施例1制备得到的5-氟多取代取代二氢吡咯衍生物纯品III-1(0.2mmol),LiCl(0.25mmol)放入盛有磁子的干燥反应管中,向其中注入2.0mLDMF作为反应溶剂,在O2氛围下升温至165℃,搅拌,1.5h,直到III-1反应完全,用5.0mL水淬灭,乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后,经硫酸镁干燥,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=4:1)得到5-氟多取代吡咯衍生物IX(58mg,76%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ10.11(s,1H),7.48(d,J=8.3Hz,2H),7.19(d,J=8.3Hz,2H),4.14(q,J=7.1Hz,4H),1.15(t,J=7.1Hz,3H),1.08(t,J=7.1Hz,3H).19F NMR(282MHz,CDCl3)δ-119.37.13C NMR(101MHz,CDCl3)δ161.87(d,J=4.9Hz),160.83(d,J=1.9Hz),150.01(d,J=281.4Hz),132.11,131.77,130.41,130.20,121.70,111.14,97.31(d,J=3.2Hz),61.08,60.12,13.97,13.81.HRMS(ESI)calcd for C16H15BrFNNaO4[M+Na+]:406.0061,found:406.0075.
实施例24
于70℃条件下,将前述实施例1制备得到的5-氟多取代二氢吡咯衍生物纯品III-1(0.2mmol)溶解于6.0mL乙醇中,向其中加入NaOH固体(1.0mmol),搅拌1h后,旋去溶剂,向浓缩液中加入少量二氯甲烷,水洗,经硫酸镁干燥后,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=3:1)得到5-乙氧基取代的吡咯衍生物X(67mg,82%)。
白色固体.Mp 108-110℃.1H NMR(400MHz,CDCl3)δ9.24(s,1H),7.45(d,J=8.4Hz,2H),7.15(d,J=8.4Hz,2H),4.33(q,J=7.0Hz,2H),4.08(q,J=7.0Hz,2H),4.05(q,J=7.0Hz,2H),1.46(t,J=7.0Hz,3H),1.05(t,J=7.0Hz,3H),1.03(t,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ163.24,160.90,151.19,133.66,131.64,131.55,130.00,121.06,111.53,100.51,69.36,60.45,59.58,14.95,13.87,13.81.HRMS(ESI)calcd forC18H20BrNNaO5[M+Na+]:432.0417,found:432.0420.
实施例25
在氮气下,将前述实施例1制备得到的5-氟多取代二氢吡咯衍生物纯品III-1(0.945mmol)苯硼酸(0.86mmol),K2CO3(1.72mmol)放入装有磁子的封管中,抽换气三次,向其中注入THF(2mL)和H2O(1mL),95℃搅拌13h后,冷却到室温,用5.0mL水淬灭,乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后,经硫酸镁干燥,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=3:1)得到5-氟多取代二氢吡咯衍生物XI(549mg,95%)。
白色固体.Mp 68-70℃.1H NMR(300MHz,CDCl3)δ8.11(d,J=7.6Hz,2H),7.57(d,J=7.6Hz,2H),7.53(d,J=8.6Hz,2H),7.39(d,J=8.6Hz,2H),7.50–7.30(m,5H),4.94(d,J=5.7Hz,1H),4.50(q,J=6.8Hz,2H),4.29–3.89(m,2H),3.90–3.56(m,2H),2.47(s,3H),1.49(t,J=7.1Hz,3H),1.11(t,J=7.1Hz,3H),0.99(t,J=7.2Hz,3H).19F NMR(282MHz,CDCl3)δ-96.66.13C NMR(101MHz,CDCl3)δ167.26,163.66,161.98(d,J=5.6Hz),155.91(d,J=294.7Hz),145.31,140.89,140.39,136.37,134.89,129.46,129.06,129.05,128.67,127.32,126.89,126.60,86.14(d,J=3.5Hz),77.62,63.41,62.61,60.25,50.68(d,J=1.1Hz),21.61,13.98,13.93,13.22.HRMS(ESI)calcd for C32H32FNNaO8S[M+Na+]:632.1725,found:632.1734.
实施例26
在氮气下,将前述实施例1制备得到的5-氟多取代二氢吡咯衍生物纯品III-1(0.5mmol),苯乙炔(2.5mmol),Pd(PPh3)2Cl2(0.01mmol),CuI(0.02mmol),放入装有磁子的封管中,抽换气三次,向其中注入THF(0.75mL)和Et3N(0.2mL),60℃搅拌32h后,冷却到室温,用5.0mL水淬灭,乙酸乙酯(5.0mL*3次)萃取。有机相用饱和食盐水洗涤后,经硫酸镁干燥,旋去溶剂,将粗产品直接用硅胶快速柱色谱纯化(石油醚:乙酸乙酯=5:1)得到5-氟多取代二氢吡咯衍生物XII(183.6mg,58%)。
黄色油状物.1H NMR(400MHz,CDCl3)δ8.08(d,J=7.8Hz,2H),7.52(dd,J=6.5,3.1Hz,2H),7.45(d,J=8.3Hz,2H),7.37(d,J=8.5Hz,2H),7.34(dd,J=5.0,1.9Hz,3H),7.16(brs,2H),4.88(d,J=5.6Hz,1H),4.52-4.44(m,2H),4.24–3.91(m,2H),3.85–3.63(m,2H),2.47(s,3H),1.46(t,J=7.1Hz,3H),1.08(t,J=7.1Hz,3H),1.04(t,J=7.2Hz,3H).19FNMR(282MHz,CDCl3)δ-96.44.13C NMR(101MHz,CDCl3)δ167.25,163.56,161.89(d,J=5.7Hz),156.12(d,J=295.0Hz),145.42,136.35,136.15,136.14,131.55,131.21,129.54,129.15,129.14,128.33,123.17,123.00,89.91,88.98,85.97(d,J=3.4Hz),77.55,63.54,62.80,60.34,50.75,21.70,14.03,13.99,13.41.HRMS(ESI)calcd for C34H32FNNaO8S[M+Na+]:656.1725,found:656.1734.
本发明不局限于以上实施例。在不违背发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (8)
1.一种5-氟多取代二氢吡咯衍生物的制备方法,其特征在于,在无机碱的作用下,含三氟甲基烯类化合物与酰胺丙二酸二乙酯类化合物发生环化反应得到所述5-氟多取代二氢吡咯衍生物;所述制备方法的反应过程如反应式(1)所示,
反应式(1);
其中,R1为酯基、羰基、炔基;R2为芳基、杂芳基、烷基、氢;PG为Ac,Ts,Cbz,Ns;
其中,所述羰基为苯甲酰基。
2.如权利要求1所述的制备方法,其特征在于,所述酯基为乙氧羰基,所述羰基为苯甲酰基,所述炔基为苯基乙炔基;所述芳基为苯基、4-溴苯基、4-甲氧基苯基、4-氯苯基、2-氯苯基、4-硝基苯基、4-氰基苯基、4-三氟甲基苯基、2-萘基,所述杂芳基为2-呋喃基、2-噻吩基,所述烷基为异丁基。
3.如权利要求1或2所述的制备方法,其特征在于,所述有机溶剂是N,N-二甲基甲酰胺。
4.如权利要求1或2所述的制备方法,其特征在于,所述有机溶剂的用量为8.0~10.0mL/mmol酰胺丙二酸二乙酯类化合物。
5.如权利要求1或2所述的制备方法,其特征在于,所述无机碱选自于碳酸钾、碳酸钠。
6.如权利要求1或2所述的制备方法,其特征在于,所述环化反应在0℃-50℃条件下进行。
7.如权利要求1或2所述的制备方法,其特征在于,所述环化反应的反应时间为4~12小时。
8.如权利要求1或2所述的制备方法,其特征在于,所述含三氟甲基烯类化合物、酰胺丙二酸二乙酯类化合物、碱的摩尔比为三氟甲基烯类化合物:酰胺丙二酸二乙酯类化合物:碱=3.0-1.0:1.0-2.0:1.0-2.0。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610070648.5A CN105481748B (zh) | 2016-02-01 | 2016-02-01 | 5-氟多取代二氢吡咯衍生物及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610070648.5A CN105481748B (zh) | 2016-02-01 | 2016-02-01 | 5-氟多取代二氢吡咯衍生物及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105481748A CN105481748A (zh) | 2016-04-13 |
CN105481748B true CN105481748B (zh) | 2018-05-15 |
Family
ID=55669070
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610070648.5A Expired - Fee Related CN105481748B (zh) | 2016-02-01 | 2016-02-01 | 5-氟多取代二氢吡咯衍生物及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105481748B (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107459475B (zh) * | 2016-06-02 | 2019-09-27 | 中国科学院理化技术研究所 | 一种可见光催化合成吡咯-4-酮类衍生物的方法 |
CN107324982B (zh) * | 2017-06-01 | 2020-07-14 | 华东师范大学 | 1-三氟甲基-四取代环戊烯衍生物及其制备方法和应用 |
CN111233666A (zh) * | 2020-01-16 | 2020-06-05 | 山东师范大学 | 一种高效合成三氟甲基化合物的方法、三氟甲基化合物及应用 |
CN114685344A (zh) * | 2020-12-29 | 2022-07-01 | 中国科学院福建物质结构研究所 | 一种3-氰基二氢吡咯类化合物及其制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101423488A (zh) * | 2008-12-01 | 2009-05-06 | 华东师范大学 | 一种二氢吡咯衍生物的制备方法 |
CN102351769A (zh) * | 2011-08-05 | 2012-02-15 | 中国科学技术大学 | 手性2,5-二氢吡咯衍生物及其合成方法和生物活性 |
CN104592181A (zh) * | 2015-01-29 | 2015-05-06 | 华东师范大学 | 2-氟多取代4h-吡喃衍生物及其制备方法 |
-
2016
- 2016-02-01 CN CN201610070648.5A patent/CN105481748B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101423488A (zh) * | 2008-12-01 | 2009-05-06 | 华东师范大学 | 一种二氢吡咯衍生物的制备方法 |
CN102351769A (zh) * | 2011-08-05 | 2012-02-15 | 中国科学技术大学 | 手性2,5-二氢吡咯衍生物及其合成方法和生物活性 |
CN104592181A (zh) * | 2015-01-29 | 2015-05-06 | 华东师范大学 | 2-氟多取代4h-吡喃衍生物及其制备方法 |
Non-Patent Citations (2)
Title |
---|
DBU-catalyzed tandem additions of electron-deficient 1,3-conjugated enynes with 2-aminomalonates: a facile access to highly substituted 2-pyrrolines;Xiuzhao Yu, et al.,;《Chem. Commun.》;20121231;第48卷;第4003页table 2,右栏化学式 * |
The nucleophilic 5-endo-trig cyclization of gem-difluoroolefins with homoallylic;Junji Ichikawa et al.,;《Chem. Commun.》;20000918;第1887-1888页 * |
Also Published As
Publication number | Publication date |
---|---|
CN105481748A (zh) | 2016-04-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105481748B (zh) | 5-氟多取代二氢吡咯衍生物及其制备方法 | |
CN101111462B (zh) | 氟代衍生物的生产方法 | |
CN101066945B (zh) | 一种合成3-位取代内酰胺类化合物的方法 | |
CN106573920A (zh) | 用于在流感病毒感染中使用的吲哚 | |
CN105960400A (zh) | 氨磺酰基噻吩酰胺衍生物及其作为药物用于治疗乙型肝炎的用途 | |
DE60008524T2 (de) | Furanonderivate als inhibitoren von cathepsin s | |
CN102803260A (zh) | 被取代的多环性氨基甲酰基吡啶酮衍生物 | |
CN106543065B (zh) | 一种4-三氟甲基-2,4-二取代-2,5-二氢吡咯衍生物及其制备方法和应用 | |
KR20130143084A (ko) | 마크로락탐의 제조 방법 및 중간체 | |
CN109336887A (zh) | 一种苯并咪唑并手性杂环类化合物及其制备方法和应用 | |
CN108689903A (zh) | 一种布瓦西坦的新的制备方法 | |
Han et al. | A convergent route to substituted azetidines and to Boc-protected 4-aminomethylpyrroles | |
CN109640657A (zh) | 制备4-烷氧基-3-(酰基或脂族饱和烃基)氧基吡啶甲酰胺的方法 | |
CN105899487B (zh) | 5-羟基哌啶-2-甲酸的制造方法 | |
WO2021201036A1 (ja) | ヒドロキシピロリジン誘導体およびその医薬用途 | |
CN103755708B (zh) | 一种吲哚或吡咯并嘧啶衍生物的制备方法 | |
CN105732648B (zh) | 一种吡咯并呋喃的含氮杂环化合物及合成方法 | |
CN107324982B (zh) | 1-三氟甲基-四取代环戊烯衍生物及其制备方法和应用 | |
CN103755587A (zh) | 4-多氟烷基-2,4-二取代吡咯衍生物及其制备方法 | |
CN102186817B (zh) | (羟烷基)吡咯衍生物的阻转异构体 | |
CN104884436B (zh) | 苯并氮杂衍生物及其医药用途 | |
CN110054637A (zh) | 一种制备苯并磺内酰胺类含手性四氢吡啶骨架的不对称合成方法 | |
CN107033206A (zh) | 6‑甲基7位脱氮嘌呤核苷类化合物及其用途 | |
Aslam et al. | Direct lactonization of α-amino γ, δ-unsaturated carboxylic acid esters via olefin activation: stereo-and regioselective production of homoserine lactone scaffolds having contiguous stereocenters | |
CN107417548A (zh) | 可比司他中间体及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180515 |