CN117903065A - Synthesis method of 2-sulfonyl pyrimidine-4-carboxamide compound II - Google Patents
Synthesis method of 2-sulfonyl pyrimidine-4-carboxamide compound II Download PDFInfo
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- CN117903065A CN117903065A CN202410091674.0A CN202410091674A CN117903065A CN 117903065 A CN117903065 A CN 117903065A CN 202410091674 A CN202410091674 A CN 202410091674A CN 117903065 A CN117903065 A CN 117903065A
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- Prior art keywords
- pyrimidine
- solvent
- compound
- solution
- reaction
- Prior art date
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- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000001308 synthesis method Methods 0.000 title claims description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 title abstract 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 107
- 239000002904 solvent Substances 0.000 claims abstract description 79
- 150000001408 amides Chemical class 0.000 claims abstract description 66
- 239000000758 substrate Substances 0.000 claims abstract description 57
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 54
- -1 amino compound VII Chemical compound 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 230000009471 action Effects 0.000 claims abstract description 34
- 230000001590 oxidative effect Effects 0.000 claims abstract description 33
- 239000003513 alkali Substances 0.000 claims abstract description 32
- 239000003960 organic solvent Substances 0.000 claims abstract description 31
- 239000007800 oxidant agent Substances 0.000 claims abstract description 31
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims abstract description 30
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract description 30
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 29
- 150000008282 halocarbons Chemical group 0.000 claims abstract description 24
- 238000006482 condensation reaction Methods 0.000 claims abstract description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 99
- 238000006243 chemical reaction Methods 0.000 claims description 55
- 239000000243 solution Substances 0.000 claims description 55
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- 230000035484 reaction time Effects 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 12
- 230000000996 additive effect Effects 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910000077 silane Inorganic materials 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- 239000012973 diazabicyclooctane Substances 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 239000007821 HATU Substances 0.000 claims description 5
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 4
- OOWSDKUFKGVADH-UHFFFAOYSA-N 1-diphenylphosphoryloxy-2,3,4,5,6-pentafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 OOWSDKUFKGVADH-UHFFFAOYSA-N 0.000 claims description 3
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 3
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 claims description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 3
- BVXMSQWCZAGNTO-UHFFFAOYSA-N 3,5-dinitrobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 BVXMSQWCZAGNTO-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 claims description 3
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 claims description 3
- ZJAFQAPHWPSKRZ-UHFFFAOYSA-N 4-nitrobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=C([N+]([O-])=O)C=C1 ZJAFQAPHWPSKRZ-UHFFFAOYSA-N 0.000 claims description 3
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 3
- 229910019213 POCl3 Inorganic materials 0.000 claims description 3
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012317 TBTU Substances 0.000 claims description 3
- VORIUEAZEKLUSJ-UHFFFAOYSA-M [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylidene]-dimethylazanium;trifluoroborane;fluoride Chemical compound [F-].FB(F)F.C1=C(Cl)C=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 VORIUEAZEKLUSJ-UHFFFAOYSA-M 0.000 claims description 3
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 claims description 3
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 claims description 3
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 3
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 238000009987 spinning Methods 0.000 claims description 3
- RKFZTABXZXYIOJ-UHFFFAOYSA-N tert-butyl 1-[(2-methylpropan-2-yl)oxy]-1h-isoquinoline-2-carboxylate Chemical compound C1=CC=C2C(OC(C)(C)C)N(C(=O)OC(C)(C)C)C=CC2=C1 RKFZTABXZXYIOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 10
- 230000002194 synthesizing effect Effects 0.000 claims 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 102000029749 Microtubule Human genes 0.000 description 3
- 108091022875 Microtubule Proteins 0.000 description 3
- 210000004688 microtubule Anatomy 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a synthetic method of a 2-sulfonyl pyrimidine-4-carboxamide compound II, which comprises the steps of substituting halogenated hydrocarbon II and thiourea III in an organic solvent to prepare an isothiourea intermediate IV, then reacting with aldehyde acrylic acid V in water and the organic solvent or only water as a solvent under the action of alkali to generate a pyrimidine intermediate VI, then carrying out condensation reaction with an amino compound VII in a solution to prepare an amide substrate VIII, and finally oxidizing in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, wherein the total yield is more than 31%. The invention has simple and quick synthetic route, high efficiency, low cost and high yield, and is suitable for large-scale popularization and use.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a synthesis method of a 2-sulfonyl pyrimidine-4-carboxamide compound II.
Background
The 2-sulfonyl pyrimidine-4-carboxamide compound II is a novel antitumor lead compound targeting colchicine site microtubules, and has very important significance in antitumor treatment. Microtubules have become an important target for research and development of current brand new targeted anticancer drugs. Microtubule stabilizing agents at the colchicine site have taken an important role in clinical tumor treatment and thus have great market and development potential. However, the current domestic synthesis method of the 2-sulfonyl pyrimidine-4-carboxamide compound II is still not mature, so that a simple, economical and efficient compound synthesis method is developed, thereby breaking through the synthesis technology of high-barrier targeted antitumor drugs, reducing the production cost and further enriching the preparation process.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a simple, convenient, efficient and low-cost synthesis method of the 2-sulfonyl pyrimidine-4-carboxamide compound II.
In order to solve the technical problems, the technical scheme of the invention is as follows:
A synthetic method of a 2-sulfonyl pyrimidine-4-carboxamide compound II, wherein the 2-sulfonyl pyrimidine-4-carboxamide compound II is,
In the formula 1, the components are mixed,
R 1 is monosubstituted or disubstituted at any substitutable position on the benzene ring where it is located, and is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid and derivatives thereof, amide and heterocyclic compounds;
R 2 is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid, derivatives and amides thereof;
R 3 is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid, derivatives thereof, amides and heterocyclic compounds;
The synthesis method of the 2-sulfonyl pyrimidine-4-carboxamide compound II comprises the following steps of,
Wherein the compound with the structure of formula II is halohydrocarbon; the compound with the structure shown in the formula III is thiourea; the compound with the structure shown in the formula IV is an intermediate IV, wherein the intermediate IV is isothiourea; the compound with the structure of the formula V is aldehyde acrylic acid; the compound with the structure shown in the formula VI is an intermediate VI, wherein the intermediate VI is pyrimidine; the compound of the structure of formula VII is an amino compound; the compound with the structure of the formula VIII is an amide substrate; the compound with the structure of the formula I is a 2-sulfonyl pyrimidine-4-carboxamide compound II;
The halogenated hydrocarbon and thiourea are substituted by S N to prepare an isothiourea intermediate IV, then the isothiourea intermediate IV is reacted with aldehyde acrylic acid in water and an organic solvent or only water as a solvent to generate a pyrimidine intermediate VI, then the pyrimidine intermediate VI is condensed with an amino compound in solution to prepare an amide substrate, and finally the amide substrate is oxidized in a solvent to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II under the action of an oxidant.
Preferably, when the halogenated hydrocarbon and the thiourea are substituted by the solvent S N to prepare the isothiourea intermediate IV, the halogenated hydrocarbon and the thiourea are uniformly dispersed by the solvent, then the temperature is raised to 96 ℃ and stirring is continued for 2 hours, the solvent is removed by reduced pressure distillation of the reaction solution, and the isothiourea intermediate IV is obtained by washing the filter cake with ethyl acetate alkane for multiple times and collecting the filter cake.
When the halogenated hydrocarbon and the thiourea are substituted by S N < 2 > in a solvent to prepare the isothiourea intermediate IV, the molar ratio of the halogenated hydrocarbon to the thiourea is 1.0-5.0:1.
When the halogenated hydrocarbon and the thiourea are substituted by a solvent S N to prepare an isothiourea intermediate IV, the solvent is one or more of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile and n-hexane;
When a plurality of solvents are mixed, the composition ratio of the mixed solvents is 1:0.1-0.9 by volume.
When the halogenated hydrocarbon and the thiourea are substituted by S N < 2 > in a solvent to prepare the isothiourea intermediate IV, the reaction temperature is 0-150 ℃ and the reaction time is 0.5-24 h.
Preferably, when the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the isothiourea intermediate IV and the aldehyde acrylic acid are uniformly dispersed by using water and an organic solvent or only water as solvents, then alkali is slowly dripped to control for 1 hour, then the temperature is naturally raised to room temperature, and the reaction is continued for 12 hours; the filtrate after filtration was adjusted to pH 3 with 1M aqueous hydrochloric acid in ice bath, extracted several times with ethyl acetate, each time with ethyl acetate, and the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate and the solvent was removed by spinning to give pyrimidine intermediate VI.
Preferably, when the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the alkali is inorganic alkali or organic alkali;
the inorganic base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide;
the organic base is one of triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine, potassium tert-butoxide, sodium tert-butoxide and DBU, DMAP, DABCO.
When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the mol ratio of the isothiourea intermediate IV to the aldehyde acrylic acid to the alkali is 1.0-5.0:1:0.2-2.0.
When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the ratio of water to the organic solvent in a mixed solution formed by water and the organic solvent is 1.0-0:1.0-0;
Wherein the organic solvent is one or more of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol and trifluoroethanol.
When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the reaction temperature is-10-40 ℃ and the reaction time is 2-36 h.
Preferably, when the pyrimidine intermediate VI and the amino compound undergo condensation reaction in a solution to prepare an amide substrate, the pyrimidine intermediate VI and the amino compound are uniformly dispersed in the solution, and then a condensing agent and an additive are sequentially added into the reaction system; after the completion of the dropping, the mixture was stirred at room temperature for 12 hours, and then the solution was removed and separated by a silica gel column to obtain an amide substrate.
Preferably, when the pyrimidine intermediate VI and the amino compound undergo condensation reaction in a solution to prepare an amide substrate, the condensing agent is one of MsCl、TsCl、POCl3、(COCl)2、T3P、CDI、NDSC、PivCl、ECF、IBCF、EEDQ、IIDQ、BBDI、TCT、DMTMM、CDMT、EDCI、EDC、DIC、DCC、PyBOP、PyBrOP、PyClOP、PyAOP、PyClU、BOPCl、DppCl、DEPC、DPP、DPC、FDPP、TDBTU、TBTU、HCTU、HBTU、HATU、TSTU、CIP、TOTU、TCTU、TPTU、TNTU、COMU、TFFH、HDMA、CITU.
When the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the additive is one of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine and DBU, DMAP, DABCO, HOBt, DIPEA.
When the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the molar ratio of the pyrimidine intermediate VI to the amino compound to the condensing agent to the additive is 1:1-7:0-7.
When the pyrimidine intermediate VI and an amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the solution is one or more of tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, acetone, 1, 2-dichloroethane, dichloromethane, chloroform, normal hexane, cyclohexane, toluene and carbon tetrachloride;
when the solution is a mixed solution of a plurality of mixed solutions, the composition ratio of the mixed solution is 1:0.1-0.9 by volume.
When the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in the solution to prepare the amide substrate, the reaction temperature is 0-100 ℃ and the reaction time is 0.5-24 h.
Preferably, when the amide substrate is oxidized in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, the amide substrate is uniformly dispersed by the solvent, the oxidant is added into the amide substrate in batches after precooling, and then the mixture is naturally warmed to room temperature and stirred for 3 hours; after the TLC detection reaction is finished, the reaction solution is quenched by saturated sodium thiosulfate solution and saturated sodium bicarbonate solution, the reaction solution is extracted by ethyl acetate, the organic phases are combined, the solvent is removed by reduced pressure distillation after being dried by anhydrous sodium sulfate, and then the 2-sulfonyl pyrimidine-4-carboxamide compound II is obtained by recrystallization in the ethyl acetate solution.
Preferably, when the amide substrate is oxidized in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, the oxidant is one of trifluoro-peroxyacetic acid, 3, 5-dinitroperoxybenzoic acid, p-nitro-peroxybenzoic acid, m-chloroperoxybenzoic acid, peroxyformic acid, peroxybenzoic acid, peroxyacetic acid, hydrogen peroxide and tert-butyl hydrogen peroxide.
When the amide substrate is oxidized in a solvent under the action of an oxidant to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II, the molar ratio of the amide substrate to the oxidant is 1:1.0-5.0.
Preferably, when the amide substrate is oxidized in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, the solvent is water and an organic solvent or only an organic solvent;
The solvent is one or more of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol, trifluoroethanol, isopropanol, acetone, n-hexane and water;
when the dissolving agent is a mixed solution of a plurality of mixed materials, the composition ratio of the mixed solution is 1:0.1-0.9 by volume.
When the amide substrate is oxidized in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, the reaction temperature is between-20 and 60 ℃ and the reaction time is between 1 and 50 hours.
The invention has the advantages that: the invention provides a synthetic method of a 2-sulfonyl pyrimidine-4-carboxamide compound II, which comprises the steps of substituting halogenated hydrocarbon II and thiourea III in an organic solvent to prepare an isothiourea intermediate IV, then reacting with aldehyde acrylic acid V in water and the organic solvent or only water as a solvent under the action of alkali to generate a pyrimidine intermediate VI, then carrying out condensation reaction with an amino compound VII in a solution to prepare an amide substrate VIII, and finally oxidizing in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, wherein the total yield is more than 31%.
Detailed Description
The invention is described in further detail below in connection with the detailed description.
The 2-sulfonyl pyrimidine-4-carboxamide compound II of the invention is,
In the formula 1, the components are mixed,
R 1 is monosubstituted or disubstituted at any substitutable position on the benzene ring where it is located, and is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid and derivatives thereof, amide and heterocyclic compounds;
R 2 is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid, derivatives and amides thereof;
R 3 is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid, derivatives thereof, amides and heterocyclic compounds;
The synthesis method of the 2-sulfonyl pyrimidine-4-carboxamide compound II comprises the following steps of,
Wherein the compound with the structure of formula II is halohydrocarbon; the compound with the structure shown in the formula III is thiourea; the compound with the structure shown in the formula IV is an intermediate IV, wherein the intermediate IV is isothiourea; the compound with the structure of the formula V is aldehyde acrylic acid; the compound with the structure shown in the formula VI is an intermediate VI, wherein the intermediate VI is pyrimidine; the compound of the structure of formula VII is an amino compound; the compound with the structure of the formula VIII is an amide substrate; the compound with the structure of the formula I is a 2-sulfonyl pyrimidine-4-carboxamide compound II;
The halogenated hydrocarbon and thiourea are substituted by S N to prepare an isothiourea intermediate IV, then the isothiourea intermediate IV is reacted with aldehyde acrylic acid in water and an organic solvent or only water as a solvent to generate a pyrimidine intermediate VI, then the pyrimidine intermediate VI is condensed with an amino compound in solution to prepare an amide substrate, and finally the amide substrate is oxidized in a solvent to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II under the action of an oxidant.
The invention provides a synthetic method of a 2-sulfonyl pyrimidine-4-carboxamide compound II, which comprises the steps of substituting halogenated hydrocarbon II and thiourea III in an organic solvent to prepare an isothiourea intermediate IV, then reacting with aldehyde acrylic acid V in water and the organic solvent or only water as a solvent under the action of alkali to generate a pyrimidine intermediate VI, then carrying out condensation reaction with an amino compound VII in a solution to prepare an amide substrate VIII, and finally oxidizing in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, wherein the total yield is more than 31%.
When the halogenated hydrocarbon and thiourea are substituted by the solvent S N to prepare the isothiourea intermediate IV, the halogenated hydrocarbon and thiourea are uniformly dispersed by the solvent, then the temperature is raised to 96 ℃ and stirring is continued for 2 hours, the solvent is removed by reduced pressure distillation of the reaction liquid, and the filter cake is collected after washing the filter cake with ethyl acetate alkane for multiple times to obtain the isothiourea intermediate IV. When the halogenated hydrocarbon and thiourea are substituted by S N < 2 > in the solvent to prepare the isothiourea intermediate IV, the molar ratio of the halogenated hydrocarbon to the thiourea is 1.0-5.0:1; the solvent is one or more of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile and n-hexane; when a plurality of solvents are mixed, the composition ratio of the mixed solvents is 1:0.1-0.9 by volume. When the halogenated hydrocarbon and thiourea are substituted by S N < 2 > in the solvent to prepare the isothiourea intermediate IV, the reaction temperature is 0-150 ℃ and the reaction time is 0.5-24 h.
When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the isothiourea intermediate IV and the aldehyde acrylic acid are uniformly dispersed by using water and an organic solvent or only water as solvents, then alkali is slowly dripped to control the dripping time for 1 hour, and then the temperature is naturally raised to room temperature to continue the reaction for 12 hours; the filtrate after filtration was adjusted to pH 3 with 1M aqueous hydrochloric acid in ice bath, extracted several times with ethyl acetate, each time with ethyl acetate, and the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate and the solvent was removed by spinning to give pyrimidine intermediate VI.
Wherein the alkali is inorganic alkali or organic alkali; the inorganic base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide; the organic base is one of triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine, potassium tert-butoxide, sodium tert-butoxide and DBU, DMAP, DABCO. The molar ratio of the isothiourea intermediate IV to the aldehyde acrylic acid to the alkali is 1.0-5.0:1:0.2-2.0; the ratio of water to the organic solvent in the mixed solution formed by the water and the organic solvent is 1.0-0:1.0-0; wherein the organic solvent is one or more of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol and trifluoroethanol. When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the reaction temperature is-10-40 ℃ and the reaction time is 2-36 h.
When the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the pyrimidine intermediate VI and the amino compound are uniformly dispersed in the solution, and then a condensing agent and an additive are sequentially added into the reaction system; after the completion of the dropping, the mixture was stirred at room temperature for 12 hours, and then the solution was removed and separated by a silica gel column to obtain an amide substrate.
Wherein, when the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in a solution to prepare the amide substrate, the condensing agent is one of MsCl、TsCl、POCl3、(COCl)2、T3P、CDI、NDSC、PivCl、ECF、IBCF、EEDQ、IIDQ、BBDI、TCT、DMTMM、CDMT、EDCI、EDC、DIC、DCC、PyBOP、PyBrOP、PyClOP、PyAOP、PyClU、BOPCl、DppCl、DEPC、DPP、DPC、FDPP、TDBTU、TBTU、HCTU、HBTU、HATU、TSTU、CIP、TOTU、TCTU、TPTU、TNTU、COMU、TFFH、HDMA、CITU. The additive is one of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine and DBU, DMAP, DABCO, HOBt, DIPEA. The molar ratio of the pyrimidine intermediate VI to the amino compound to the condensing agent to the additive is 1:1-7:0-7.
When an amide substrate is prepared by condensation reaction of a pyrimidine intermediate VI and an amino compound in a solution, the solution is one or more of tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, acetone, 1, 2-dichloroethane, dichloromethane, chloroform, N-hexane, cyclohexane, toluene and carbon tetrachloride; when the solution is a mixed solution of a plurality of mixed solutions, the composition ratio of the mixed solution is 1:0.1-0.9 by volume. When the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in the solution to prepare the amide substrate, the reaction temperature is 0-100 ℃ and the reaction time is 0.5-24 h.
When the amide substrate is oxidized in a solvent under the action of an oxidant to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II, the amide substrate is uniformly dispersed by the solvent, the oxidant is added into the amide substrate in batches after precooling, and then the mixture is naturally warmed to room temperature and stirred for 3 hours; after the TLC detection reaction is finished, the reaction solution is quenched by saturated sodium thiosulfate solution and saturated sodium bicarbonate solution, the reaction solution is extracted by ethyl acetate, the organic phases are combined, the solvent is removed by reduced pressure distillation after being dried by anhydrous sodium sulfate, and then the 2-sulfonyl pyrimidine-4-carboxamide compound II is obtained by recrystallization in the ethyl acetate solution.
The oxidant is one of trifluoro peracetic acid, 3, 5-dinitroperoxybenzoic acid, p-nitro peroxybenzoic acid, m-chloroperoxybenzoic acid, peroxyformic acid, peroxybenzoic acid, peroxyacetic acid, hydrogen peroxide and tert-butyl hydrogen peroxide. When the amide substrate is oxidized in a solvent under the action of an oxidant to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II, the molar ratio of the amide substrate to the oxidant is 1:1.0-5.0. The solvent is water and organic solvent or organic solvent only; the solvent is one or more of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol, trifluoroethanol, isopropanol, acetone, n-hexane and water; when the dissolving agent is a mixed solution of a plurality of mixed materials, the composition ratio of the mixed solution is 1:0.1-0.9 by volume. When the amide substrate is oxidized in a solvent to generate the 2-sulfonyl pyrimidine-4-formamide compound II under the action of an oxidant, the reaction temperature is between-20 and 60 ℃ and the reaction time is between 1 and 50 hours.
In the S N substitution reaction of the invention, the molar ratio of the halohydrocarbon to the thiourea is 1.0-5.0:1, so that the reaction can be smoothly carried out. The reaction solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile and n-hexane can be a single solvent or a mixed solvent, and the composition ratio of the mixed solvent is 1:0.1-0.9 by volume. The solvents have wide sources, are cheap and easy to obtain, and are convenient to recycle. Suitable reaction temperatures and reaction times are in the range from 0 to 150℃and from 0.5 to 24 hours, respectively. In the S N 2 substitution reaction, the solvent is ethanol, so that the effect is excellent, and the source is wide and low in cost; the molar ratio of the halohydrocarbon to the thiourea is the best material ratio of 1:1, and the reaction can be successfully completed; the reaction temperature is preferably controlled to be 80-100 ℃ to complete the reaction; the reaction time is 1-2 h, and the effect is optimal.
In the Biginelli-type reaction, the molar ratio of the isothiourea intermediate IV to the aldehyde acrylic acid to the alkali is 1.0-5.0:1:0.2-2.0, and the reaction can be successfully completed. The solvent for the reaction can be a single organic solvent or a mixed solvent of the single organic solvent and water in a certain proportion, and the organic solvent such as tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol and trifluoroethanol has wide sources, is cheap and easy to obtain and is convenient to recycle. Meanwhile, the ratio of water to organic solvent is 1.0-0:1.0-0, so that the reaction can be well carried out. The reaction temperature is controlled between-10 ℃ and 40 ℃. The reaction time is controlled between 2 and 36 hours, and the reaction is completed smoothly. In the Biginelli-type reaction, the base used is triethylamine optimally; the molar ratio of the isothiourea intermediate IV to the aldehyde acrylic acid to the alkali is optimal in the material ratio of 1:1:3, and the reaction can be smoothly carried out; the solvent is preferably water, and has wide sources and low cost; the most preferable reaction temperature is-5 to 5 ℃, and the materials are added, and the temperature is slowly increased to room temperature to complete the reaction; the reaction time is controlled to be optimal at 12 h.
In the condensation reaction, the molar ratio of the pyrimidine intermediate VI to the amino compound to the condensing agent to the additive is 1:1-7:0-7, so that the reaction can be smoothly carried out. The solution is one or more of tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, acetone, 1, 2-dichloroethane, dichloromethane, chloroform, N-hexane, cyclohexane, toluene and carbon tetrachloride, and can be a single solvent or a mixed solvent, wherein the composition ratio of the mixed solution is 1:0.1-0.9 by volume. The solvents have wide sources, are cheap and easy to obtain, and are convenient to recycle. Suitable reaction temperatures and reaction times are in the range from 0 to 100℃and from 0.5 to 24 hours, respectively. In the condensation reaction of the invention, the condensing agent is preferably HATU, and the effect is optimal; the additive is preferably DIPEA, and the catalytic effect is optimal; the molar ratio of the pyrimidine intermediate VI to the amino compound to the condensing agent to the additive is 1:1.5:1.3:1.3, so that the reaction can be smoothly carried out; the solvent is preferably dichloromethane, which is cheap and easy to obtain; most preferably, the reaction temperature is room temperature to complete the reaction; the reaction time is controlled to be optimal at 12 h.
In the oxidation reaction of the present invention, the oxidizing agent can well cause the oxidation reaction to occur. The molar ratio of the amide substrate to the oxidant is 1:1.0-5.0, so that the reaction can be smoothly carried out. The proper reaction temperature and reaction time for the oxidation reaction are respectively in the range of-20 to 60 ℃ and 1 to 50 hours. In the oxidation reaction, the oxidant used in the oxidation is preferably m-chloroperoxybenzoic acid, so that the effect is optimal; the molar ratio of the amide substrate to the m-chloroperoxybenzoic acid is 1:2.5, so that the reaction can be smoothly carried out; the solvent is dichloromethane, so that the source is wide, and the cost is low and the solvent is easy to obtain; the most suitable reaction temperature is charging at-5 ℃, and naturally heating to room temperature to complete the reaction; the most suitable reaction time is 3h.
Example 1
Preparation of isothiourea intermediate IV
Halogenated hydrocarbon II (11.92 mL,0.10 mol) and thiourea III (7.60 g,0.10 mol) were dispersed uniformly with 100mL ethanol, and then heated to 96℃and stirred for 2h. The reaction mixture was distilled off under reduced pressure to remove the solvent, and after washing the cake with 20mL of ethyl acetate for 4 times, the cake was collected to give 21.44g of crude isothiourea intermediate IV (white solid) in 97% yield.
Example 2
Preparation of pyrimidine intermediate VI
In a low-temperature bath at 0 ℃, the crude isothiourea intermediate IV (17.68 g,0.08 mol) and aldehyde acrylic acid (13.52 g,0.08 mol) are uniformly dispersed by 160mL of water, triethylamine (33.30 mL,0.24 mol) is slowly dripped into the mixture for 1 hour, and then the mixture is naturally warmed to room temperature for continuous reaction for 12 hours. The filtrate after filtration is adjusted to pH 3 by 1M hydrochloric acid aqueous solution under ice bath, extracted by ethyl acetate for 3 times, 200-300 mL of ethyl acetate is used each time, the combined organic phases are washed once by 200mL of saturated saline water, and then dried by anhydrous sodium sulfate, and the solvent is removed by rotation to obtain a pyrimidine intermediate VI crude product, wherein the brown yellow oily matter is 9.54g, and the yield is 40%.
Example 3
Preparation of amide substrate VIII
Crude pyrimidine intermediate VI (8.94 g,0.03 mol) was uniformly dispersed with amino compound (5.57 mL,0.045 mol) using 100mL dichloromethane. HATU (14.82, 0.039 mol) and DIPEA (6.43 mL,0.039 mol) were then added sequentially to the above reaction. After the dripping, stirring for 12 hours at room temperature. After removing the solution, the white powder was separated by a silica gel column to obtain 12.7g of compound (VIII) as a white solid in 96% yield.
1H NMR(400MHz,Chloroform-d)δ10.18(s,1H),8.71(s,1H),8.49(d,J=8.3Hz,1H),7.69–7.56(m,2H),7.47–7.36(m,1H),7.30–7.23(m,2H),7.06(dt,J=14.6,8.2Hz,2H),4.48(s,2H).
13C NMR(150MHz,Chloroform-d)δ169.28,161.89,161.17,160.24,159.26,150.72,134.50,133.04,130.97,130.94,129.60,129.54,126.32,126.29,126.25,126.21,125.78,124.89,124.29,124.27,123.23,123.20,123.10,120.21,120.01,115.69,115.55,77.21,77.00,76.79,29.09,29.06.
Example 4
Preparation of 2-sulfonylpyrimidine-4-carboxamide Compound II
Amide substrate VIII (8.82 g,0.02 mol) was uniformly dispersed with 90mL of methylene chloride in an ice bath, and after pre-cooling for 10min, m-chloroperoxybenzoic acid (85%) (10.15 g,0.05 mol) was added thereto in portions, followed by natural warming to room temperature and stirring for 3h. After completion of the TLC detection, the reaction mixture was quenched with 30mL of a saturated sodium thiosulfate solution and 30mL of a saturated sodium bicarbonate solution, the organic phases were combined with ethyl acetate extraction reaction mixture (100 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, followed by 7.94g of a white solid of 2-sulfonylpyrimidine-4-carboxamide compound II recrystallized from an ethyl acetate solution in 84% yield.
1H NMR(400MHz,Chloroform-d)δ10.12(s,1H),9.09(s,1H),8.43(d,J=8.3Hz,1H),7.74–7.61(m,2H),7.49(td,J=7.5,1.8Hz,1H),7.34(ddt,J=7.9,5.4,2.5Hz,2H),7.17(td,J=7.6,1.2Hz,1H),7.01(ddd,J=9.7,8.3,1.3Hz,1H),4.87(s,2H).
13C NMR(150MHz,Chloroform-d)δ162.59,162.03,161.46,160.38,157.90,152.11,133.86,133.08,133.02,133.00,131.56,131.50,126.50,126.47,125.59,124.85,124.83,124.75,123.60,115.86,115.71,113.77,113.68,77.21,77.00,76.79,51.78,51.76.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention, and are intended to be included within the scope of the appended claims and description.
Claims (10)
1. A method for synthesizing a 2-sulfonyl pyrimidine-4-carboxamide compound II is characterized in that:
the 2-sulfonyl pyrimidine-4-carboxamide compound II is,
In the formula 1, the components are mixed,
R 1 is monosubstituted or disubstituted at any substitutable position on the benzene ring where it is located, and is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid and derivatives thereof, amide and heterocyclic compounds;
R 2 is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid, derivatives and amides thereof;
R 3 is hydrogen, halogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, silane, carboxylic acid, derivatives thereof, amides and heterocyclic compounds;
The synthesis method of the 2-sulfonyl pyrimidine-4-carboxamide compound II comprises the following steps of,
Wherein the compound with the structure of formula II is halohydrocarbon; the compound with the structure shown in the formula III is thiourea; the compound with the structure shown in the formula IV is an intermediate IV, wherein the intermediate IV is isothiourea; the compound with the structure of the formula V is aldehyde acrylic acid; the compound with the structure shown in the formula VI is an intermediate VI, wherein the intermediate VI is pyrimidine; the compound of the structure of formula VII is an amino compound; the compound with the structure of the formula VIII is an amide substrate; the compound with the structure of the formula I is a 2-sulfonyl pyrimidine-4-carboxamide compound II;
The halogenated hydrocarbon and thiourea are substituted by S N to prepare an isothiourea intermediate IV, then the isothiourea intermediate IV is reacted with aldehyde acrylic acid in water and an organic solvent or only water as a solvent to generate a pyrimidine intermediate VI, then the pyrimidine intermediate VI is condensed with an amino compound in solution to prepare an amide substrate, and finally the amide substrate is oxidized in a solvent to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II under the action of an oxidant.
2. A process for the synthesis of 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 1, characterized in that: when the halogenated hydrocarbon and the thiourea are substituted by the solvent S N to prepare the isothiourea intermediate IV, the halogenated hydrocarbon and the thiourea are uniformly dispersed by the solvent, then the temperature is raised to 96 ℃ and stirring is continued for 2 hours, the solvent is removed by reduced pressure distillation of the reaction liquid, and the filter cake is collected after the filter cake is washed by ethyl acetate alkane for multiple times to obtain the isothiourea intermediate IV.
3. A process for the synthesis of 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 2, characterized in that: when the halogenated hydrocarbon and the thiourea are substituted by S N < 2 > in a solvent to prepare an isothiourea intermediate IV, the molar ratio of the halogenated hydrocarbon to the thiourea is 1.0-5.0:1;
When the halogenated hydrocarbon and the thiourea are substituted by a solvent S N to prepare an isothiourea intermediate IV, the solvent is one or more of tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile and n-hexane;
When a plurality of solvents are mixed, the composition ratio of the mixed solvents is 1:0.1-0.9 by volume;
When the halogenated hydrocarbon and the thiourea are substituted by S N < 2 > in a solvent to prepare the isothiourea intermediate IV, the reaction temperature is 0-150 ℃ and the reaction time is 0.5-24 h.
4. A process for the synthesis of 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 1, characterized in that: when the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the isothiourea intermediate IV and the aldehyde acrylic acid are uniformly dispersed by using water and an organic solvent or only water as solvents, then alkali is slowly dripped to control for 1 hour, and then the temperature is naturally raised to room temperature to continue the reaction for 12 hours; the filtrate after filtration was adjusted to pH 3 with 1M aqueous hydrochloric acid in ice bath, extracted several times with ethyl acetate, each time with ethyl acetate, and the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate and the solvent was removed by spinning to give pyrimidine intermediate VI.
5. The method for synthesizing 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 4, wherein: when the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the alkali is inorganic alkali or organic alkali;
the inorganic base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide;
The organic base is one of triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine, potassium tert-butoxide, sodium tert-butoxide and DBU, DMAP, DABCO;
When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the mol ratio of the isothiourea intermediate IV to the aldehyde acrylic acid to the alkali is 1.0-5.0:1:0.2-2.0;
When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the ratio of water to the organic solvent in a mixed solution formed by water and the organic solvent is 1.0-0:1.0-0;
wherein the organic solvent is one or more of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol and trifluoroethanol;
When the isothiourea intermediate IV reacts with aldehyde acrylic acid to generate a pyrimidine intermediate VI under the action of alkali, the reaction temperature is-10-40 ℃ and the reaction time is 2-36 h.
6. A process for the synthesis of 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 1, characterized in that: when the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the pyrimidine intermediate VI and the amino compound are uniformly dispersed in the solution, and then a condensing agent and an additive are sequentially added into the reaction system; after the completion of the dropping, the mixture was stirred at room temperature for 12 hours, and then the solution was removed and separated by a silica gel column to obtain an amide substrate.
7. A process for the synthesis of 2-sulfonylpyrimidine-4-carboxamide compound II as claimed in claim 11, characterized in that: when the pyrimidine intermediate VI and an amino compound undergo condensation reaction in a solution to prepare an amide substrate, the condensing agent is one of MsCl、TsCl、POCl3、(COCl)2、T3P、CDI、NDSC、PivCl、ECF、IBCF、EEDQ、IIDQ、BBDI、TCT、DMTMM、CDMT、EDCI、EDC、DIC、DCC、PyBOP、PyBrOP、PyClOP、PyAOP、PyClU、BOPCl、DppCl、DEPC、DPP、DPC、FDPP、TDBTU、TBTU、HCTU、HBTU、HATU、TSTU、CIP、TOTU、TCTU、TPTU、TNTU、COMU、TFFH、HDMA、CITU;
When the pyrimidine intermediate VI and an amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the additive is one of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, diethylamine, diisopropylethylamine, pyridine, piperidine and DBU, DMAP, DABCO, HOBt, DIPEA;
When the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the molar ratio of the pyrimidine intermediate VI to the amino compound to the condensing agent to the additive is 1:1-7:0-7;
When a pyrimidine intermediate VI and an amino compound are subjected to condensation reaction in a solution to prepare an amide substrate, the solution is one or more of tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, acetone, 1, 2-dichloroethane, dichloromethane, chloroform, normal hexane, cyclohexane, toluene and carbon tetrachloride;
When the solution is a mixed solution of a plurality of mixed solutions, the composition ratio of the mixed solutions is 1:0.1-0.9 by volume;
when the pyrimidine intermediate VI and the amino compound are subjected to condensation reaction in the solution to prepare the amide substrate, the reaction temperature is 0-100 ℃ and the reaction time is 0.5-24 h.
8. A process for the synthesis of 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 1, characterized in that: when the amide substrate is oxidized in a solvent under the action of an oxidant to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II, the amide substrate is uniformly dispersed by the solvent, the oxidant is added into the amide substrate in batches after precooling, and then the temperature is naturally raised to room temperature, and the mixture is stirred for 3 hours; after the TLC detection reaction is finished, the reaction solution is quenched by saturated sodium thiosulfate solution and saturated sodium bicarbonate solution, the reaction solution is extracted by ethyl acetate, the organic phases are combined, the solvent is removed by reduced pressure distillation after being dried by anhydrous sodium sulfate, and then the 2-sulfonyl pyrimidine-4-carboxamide compound II is obtained by recrystallization in the ethyl acetate solution.
9. The method for synthesizing 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 8, wherein: when the amide substrate is oxidized in a solvent under the action of an oxidant to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II, the oxidant is one of trifluoro peracetic acid, 3, 5-dinitroperoxybenzoic acid, p-nitro peroxybenzoic acid, m-chloroperoxybenzoic acid, peroxyformic acid, peroxybenzoic acid, peroxyacetic acid, hydrogen peroxide and tert-butyl hydroperoxide;
when the amide substrate is oxidized in a solvent under the action of an oxidant to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II, the molar ratio of the amide substrate to the oxidant is 1:1.0-5.0.
10. The method for synthesizing 2-sulfonylpyrimidine-4-carboxamide compound II according to claim 8, wherein: when the amide substrate is oxidized in a solvent under the action of an oxidant to generate a 2-sulfonyl pyrimidine-4-carboxamide compound II, the solvent is water and an organic solvent or only the organic solvent;
The solvent is one or more of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform, acetonitrile, ethanol, methanol, trifluoroethanol, isopropanol, acetone, n-hexane and water;
When the dissolving agent is a plurality of mixed solutions, the composition ratio of the mixed solutions is 1:0.1-0.9 by volume;
When the amide substrate is oxidized in a solvent under the action of an oxidant to generate the 2-sulfonyl pyrimidine-4-carboxamide compound II, the reaction temperature is between-20 and 60 ℃ and the reaction time is between 1 and 50 hours.
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