CN1315811C - Pyrimidine derivatives and preparing method thereof - Google Patents
Pyrimidine derivatives and preparing method thereof Download PDFInfo
- Publication number
- CN1315811C CN1315811C CNB2003101066402A CN200310106640A CN1315811C CN 1315811 C CN1315811 C CN 1315811C CN B2003101066402 A CNB2003101066402 A CN B2003101066402A CN 200310106640 A CN200310106640 A CN 200310106640A CN 1315811 C CN1315811 C CN 1315811C
- Authority
- CN
- China
- Prior art keywords
- amino
- bromo
- pyrimidine
- methylpyrimidine
- independently selected
- 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 - Lifetime
Links
- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 27
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title claims description 16
- 238000000034 method Methods 0.000 title description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 17
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 17
- 125000002252 acyl group Chemical group 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 150000002148 esters Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 29
- 239000000460 chlorine Substances 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 150000003222 pyridines Chemical class 0.000 claims description 18
- VTSWSQGDJQFXHB-UHFFFAOYSA-N 2,4,6-trichloro-5-methylpyrimidine Chemical compound CC1=C(Cl)N=C(Cl)N=C1Cl VTSWSQGDJQFXHB-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 10
- -1 2-amino-5-bromo-pyrimidine-4-ylmethyl Chemical group 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- GHCFWKFREBNSPC-UHFFFAOYSA-N 2-Amino-4-methylpyrimidine Chemical compound CC1=CC=NC(N)=N1 GHCFWKFREBNSPC-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- TVEASXPERATMLF-UHFFFAOYSA-N (2-amino-5-bromopyrimidin-4-yl)methyl acetate Chemical compound NC1=NC=C(C(=N1)COC(C)=O)Br TVEASXPERATMLF-UHFFFAOYSA-N 0.000 claims description 3
- ZPHPSXRQSGYUHB-UHFFFAOYSA-N (2-amino-5-bromopyrimidin-4-yl)methyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC1=NC(N)=NC=C1Br ZPHPSXRQSGYUHB-UHFFFAOYSA-N 0.000 claims description 3
- VRRXMULARLFPHQ-UHFFFAOYSA-N (2-amino-5-bromopyrimidin-4-yl)methyl prop-2-enoate Chemical compound NC1=NC=C(Br)C(COC(=O)C=C)=N1 VRRXMULARLFPHQ-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- UBBMXAOOKMFWJA-UHFFFAOYSA-N 5-bromo-4-(phenylmethoxymethyl)pyrimidin-2-amine Chemical compound NC1=NC=C(Br)C(COCC=2C=CC=CC=2)=N1 UBBMXAOOKMFWJA-UHFFFAOYSA-N 0.000 claims description 3
- UTTWHHWRBBKMAC-UHFFFAOYSA-N 5-bromo-4-(tribromomethyl)pyrimidin-2-amine Chemical compound NC1=NC=C(Br)C(C(Br)(Br)Br)=N1 UTTWHHWRBBKMAC-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 3
- SRDYUVUFFRQPEE-UHFFFAOYSA-N NC1=NC(=C(C(=N1)N=[N+]=[N-])Br)C Chemical compound NC1=NC(=C(C(=N1)N=[N+]=[N-])Br)C SRDYUVUFFRQPEE-UHFFFAOYSA-N 0.000 claims description 3
- OLDXASKAIPWIMZ-UHFFFAOYSA-N NC1=NC(=C(C(=N1)OC(C)C)Br)C Chemical compound NC1=NC(=C(C(=N1)OC(C)C)Br)C OLDXASKAIPWIMZ-UHFFFAOYSA-N 0.000 claims description 3
- WPSAFRPHGABYHP-UHFFFAOYSA-N NC1=NC(=C(C(=N1)OC1=C(C=CC=C1)[N+](=O)[O-])Br)C Chemical compound NC1=NC(=C(C(=N1)OC1=C(C=CC=C1)[N+](=O)[O-])Br)C WPSAFRPHGABYHP-UHFFFAOYSA-N 0.000 claims description 3
- HVKGXLSVUYIKMJ-UHFFFAOYSA-N NC1=NC(=C(C(=N1)OC1=CC=C(C=C1)[N+](=O)[O-])Br)C Chemical compound NC1=NC(=C(C(=N1)OC1=CC=C(C=C1)[N+](=O)[O-])Br)C HVKGXLSVUYIKMJ-UHFFFAOYSA-N 0.000 claims description 3
- KNZDWHKELRAQNJ-UHFFFAOYSA-N NC1=NC=C(Br)C(COC(=O)C=2C=CC=CC=2)=N1 Chemical compound NC1=NC=C(Br)C(COC(=O)C=2C=CC=CC=2)=N1 KNZDWHKELRAQNJ-UHFFFAOYSA-N 0.000 claims description 3
- CKYQMPHPSISTHM-UHFFFAOYSA-N NC1=NC=C(C(=N1)COC(CC(C)C)=O)Br.O1C(CCCC1)C(=O)N Chemical compound NC1=NC=C(C(=N1)COC(CC(C)C)=O)Br.O1C(CCCC1)C(=O)N CKYQMPHPSISTHM-UHFFFAOYSA-N 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 3
- 229910052801 chlorine Inorganic materials 0.000 claims 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 12
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract 2
- 229940079593 drug Drugs 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 231100000956 nontoxicity Toxicity 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- 239000007787 solid Substances 0.000 description 39
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- UQVORCPILRMHFZ-UHFFFAOYSA-N 5-bromo-4-(phenoxymethyl)pyrimidin-2-amine Chemical compound NC1=NC=C(Br)C(COC=2C=CC=CC=2)=N1 UQVORCPILRMHFZ-UHFFFAOYSA-N 0.000 description 2
- LPQVTZJEIXYDQA-UHFFFAOYSA-N 5-bromo-4-methylpyrimidin-2-amine Chemical compound CC1=NC(N)=NC=C1Br LPQVTZJEIXYDQA-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YUUVHXFOIWPQHO-UHFFFAOYSA-N NC1=NC(=C(C(=N1)C1=CC=CC2=CC=CC=C12)Br)CN Chemical compound NC1=NC(=C(C(=N1)C1=CC=CC2=CC=CC=C12)Br)CN YUUVHXFOIWPQHO-UHFFFAOYSA-N 0.000 description 2
- ZZWVUBRUVMIXKY-UHFFFAOYSA-N NC1=NC(=C(C(=N1)C=1SC=CC1)Br)C Chemical compound NC1=NC(=C(C(=N1)C=1SC=CC1)Br)C ZZWVUBRUVMIXKY-UHFFFAOYSA-N 0.000 description 2
- REDFUJBDMKJMTI-UHFFFAOYSA-N NC1=NC(=C(C(=N1)OC1=CC2=CC=CC=C2C=C1)Br)C Chemical compound NC1=NC(=C(C(=N1)OC1=CC2=CC=CC=C2C=C1)Br)C REDFUJBDMKJMTI-UHFFFAOYSA-N 0.000 description 2
- WKGDHBDATUBVJY-UHFFFAOYSA-N NC1=NC(=C(C(=N1)OC1=CC=CC2=CC=CC=C12)Br)C Chemical compound NC1=NC(=C(C(=N1)OC1=CC=CC2=CC=CC=C12)Br)C WKGDHBDATUBVJY-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 1
- 150000004782 1-naphthols Chemical class 0.000 description 1
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HFZWRUODUSTPEG-UHFFFAOYSA-N 2,4-dichlorophenol Chemical compound OC1=CC=C(Cl)C=C1Cl HFZWRUODUSTPEG-UHFFFAOYSA-N 0.000 description 1
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- AYASTOBWUFFCEK-UHFFFAOYSA-N CC(CC(=O)O)C.O1C(CCCC1)C(=O)N Chemical compound CC(CC(=O)O)C.O1C(CCCC1)C(=O)N AYASTOBWUFFCEK-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 102000003858 Chymases Human genes 0.000 description 1
- 108090000227 Chymases Proteins 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 1
- 229940122858 Elastase inhibitor Drugs 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- NWJBDXQSTJKWDQ-UHFFFAOYSA-N NC1=NC(=C(C(=N1)C1=CC=CC=C1)Br)CN Chemical compound NC1=NC(=C(C(=N1)C1=CC=CC=C1)Br)CN NWJBDXQSTJKWDQ-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000008847 Serpin Human genes 0.000 description 1
- 108050000761 Serpin Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000006035 Tryptophane Substances 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- GPKUICFDWYEPTK-UHFFFAOYSA-N methoxycyclohexatriene Chemical group COC1=CC=C=C[CH]1 GPKUICFDWYEPTK-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YMXOXAPKZDWXLY-QWRGUYRKSA-N tribenuron methyl Chemical group COC(=O)[C@H]1CCCC[C@@H]1S(=O)(=O)NC(=O)N(C)C1=NC(C)=NC(OC)=N1 YMXOXAPKZDWXLY-QWRGUYRKSA-N 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Abstract
The present invention provides a pyrimidine derivative and a preparation method thereof. The pyrimidine derivative is a pyrimidine derivative disclosed in a general formula (I) and a non-toxicity salt and in vivo hydrolyzable ester thereof. In the general formula (I), R1 and R2 are independently selected from H and acyl, R3 is selected from H and halogen atoms, R4 and R5 are independently selected from H and halogen atoms, and X is independently selected from H, halogen atoms, SCN, N3, O, S and N. When X is independently selected from the O, S and N, an R6 substituted group exists, and R6 represents H, alkyl, substituted aryl, substituted heteroaryl, substituted thick heteroaryl, acyl; the pyrimidine derivative can be used for preparing medicines.
Description
Technical field
The present invention relates to a kind of pyrimidine derivatives with and preparation method thereof.
Background technology
Pyrimidine derivatives is the broad-spectrum compound of a class, can be used for preparing medicine or weedicide, for example:
1, disclosing general formula (W) in CN1406229A is useful as cell cycle kinase inhibitors.
The compound of this specification sheets report general formula (W) representative significantly suppresses the effect of cell-cycle kinases, demonstrates the selectivity to CDK2, CDK4, CDK6, and suppresses FAK.These characteristics with the treatment of abnormal cells cycle and cell increment disease states associated in be considered to valuable.
2, open flat 5-286946 number, special table flat 7-505876 number, special table flat 7-505877 number and J.Med.Chem. the spy,
38, disclosing pyrimidines in 98 (1995) is useful as elastase inhibitor.
3, in WO98/24806 number, it is useful disclosing as serpin.
4, in WO96/33974 number and WO98/09949 number, it is useful disclosing as inhibitors of chymase.
5, it is useful disclosing as weedicide in US4601747 number, US4746353 number, EP41623 number, US4459408 number.
As seen, pyrimidine derivatives can be widely used in the preparation medicine.The invention provides a kind of new pyrimidine derivatives with and preparation method thereof, can be used to prepare medicine.
Summary of the invention
The invention provides a kind of new pyrimidine derivatives with and preparation method thereof, can be used to prepare medicine.
The technical solution adopted for the present invention to solve the technical problems is:
Pyrimidine derivatives of the present invention and preparation method thereof is characterized in that, its be the pyrimidine derivatives shown in the general formula (I) with and non-toxic salt, body in hydrolyzable ester:
In the formula: R
1, R
2Be independently selected from H and acyl group; R
3Be selected from H and halogen atom; R
4, R
5Be independently selected from H and halogen atom; X is independently selected from H, halogen atom, SCN, N
3, O, S; When X is independently selected from O, S, there is R
6Substituting group, R
6Expression H, alkyl, substituted aryl, substituted heteroaryl, the thick heteroaryl of replacement, acyl group.
Aforesaid pyridine derivatives, wherein pyridine derivatives with and non-toxic salt, body in hydrolyzable ester be the compound shown in the general formula (I-A):
In the formula: R
4, R
5Be independently selected from H and halogen atom.
Aforesaid pyridine derivatives, wherein pyridine derivatives with and non-toxic salt, body in hydrolyzable ester be the compound shown in the general formula (I-B):
In the formula: R
4, R
5Be independently selected from H and halogen atom.
Aforesaid pyridine derivatives is characterized in that, described pyridine derivatives with and non-toxic salt, body in hydrolyzable ester be the compound shown in the general formula (I-C):
In the formula: R
4, R
5Be independently selected from H and halogen atom; X is independently selected from H, halogen atom, SCN, N
3, O, S; When X is independently selected from O, S, there is R
6Substituting group, R
6Expression H, alkyl, substituted aryl, substituted heteroaryl, the thick heteroaryl of replacement, acyl group.
Aforesaid pyridine derivatives, wherein pyridine derivatives with and non-toxic salt, body in hydrolyzable ester be selected from:
2-(4-brooethyl-pyrimidine-2-base) isoindole-1, the 3-dimethyl diketone;
2-(4-two brooethyls-pyrimidine-2-base) isoindole-1, the 3-dimethyl diketone;
2-amino-5-bromo-4-methylpyrimidine;
2-amino-5-bromo-4-brooethyl pyrimidine;
2-amino-5-bromo-4-dibromo methylpyrimidine;
2-amino-5-bromo-4-trisbromomethyl pyrimidine;
2-amino-5-bromo-4-azido methyl pyrimidine;
2-amino-5-bromo-4-thiocyanogen methylpyrimidine;
2-amino-5-bromo-4-oxymethylpyrimidine;
4-(2-amino-5-bromo-pyrimidine) thiomethyl alcohol;
2-amino-5-bromo-4-methoxy methyl yl pyrimidines;
2-amino-5-bromo-4-(ethoxymethyl) yl pyrimidines;
2-amino-5-bromo-4-isopropoxy methylpyrimidine;
2-amino-5-bromo-4-allyloxy methylpyrimidine;
2-amino-5-bromo-4-benzyloxymethyl pyrimidine;
2-amino-3-" 4-(2-amino-5-bromo pyrimi piperidine-4-methoxyl group)-phenyl " propionic acid;
2-amino-5-bromo-4-phenoxymethyl pyrimidine;
2-amino-5-bromo-4-is to the tolyloxy methylpyrimidine;
2-amino-5-bromo-4-(o-methyl-benzene oxygen base) methylpyrimidine;
2-amino-5-bromo-4-(4-methoxyl group phenoxy group) methylpyrimidine;
2-amino-5-bromo-4-(2-nitro-phenoxy) methylpyrimidine;
2-amino-5-bromo-4-(4-nitrophenoxy) methylpyrimidine;
2-amino-5-bromo-4-(2,4 dichloro benzene base) methylpyrimidine;
2-amino-5-bromo-4-(1-naphthyloxy) methylpyrimidine;
2-amino-5-bromo-4-(2-naphthyloxy) methylpyrimidine;
2-amino-5-bromo-4-thiophenyl methylpyrimidine;
Acetate (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Phenylformic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Toluylic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Vinylformic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Lauric acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
(2R)-uncle's 2-fourth oxanamide-3 Methylbutanoic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
2-amino-5-bromo-4-" (N, N-diisopropylaminoethyl)-methyl " pyrimidine;
2-amino-5-bromo-4-phenyl amino methylpyrimidine;
2-amino-5-bromo-4-(1-naphthyl) amino methylpyrimidine;
2-" (2-amino-5-bromo pyrimi piperidine-4-methyl) amino "-3 Methylbutanoic acid
2-" (2-amino-5-bromo pyrimi piperidine-4-methyl) amino "-3 methylvaleric acid acid
2-" (2-amino-5-bromo pyrimi piperidine-4-methyl) amino "-3-(1H-indol-3-yl) propionic acid
Or hydrolyzable ester in the non-toxic salt of above-claimed cpd, body.
The preparation method of pyridine derivatives of the present invention is characterized in that: the compound shown in the described general formula (I-A), by 2-(4-methyl-pyrimidine-2-base) isoindole-1,3-diketone (II-A) bromination reaction obtains.
The preparation method of pyridine derivatives of the present invention is characterized in that: the compound shown in the described general formula (I-B) obtains by 2-amino-4-methylpyrimidine (II-B) bromination reaction.
The preparation method of pyridine derivatives of the present invention is characterized in that: the compound shown in the general formula (I-C) is obtained by the reaction of compound shown in compound shown in the general formula (I-B) and the general formula (II-C).
When X is independently selected from O, S, there is R
6Substituting group, R
6Expression H, alkyl, substituted aryl, substituted heteroaryl, the thick heteroaryl of replacement, acyl group.
The preparation method of aforesaid pyridine derivatives, wherein reaction solvent is methylene dichloride, chloroform, tetracol phenixin, methyl alcohol, methyl-sulphoxide, N, one solvent or mixed solvent in dinethylformamide, dioxane, acetic acid, the water; Bromizating agent can be NBS or liquid bromine; Temperature of reaction remains on 20-170 ℃.
The application of pyridine derivatives of the present invention in the preparation medicine.
The invention has the beneficial effects as follows that compound structure is reasonable, the raw material range of employing is extensive, and the preparation method is easy, and the synthesis technique cost is low, and product meets the requirement of environmental friendliness and Green Chemistry.
Embodiment
The inventor finds that through big quantity research 2-amino-4 methylpyrimidine derivative general formula (I) has good biological activity, can directly use as medicine or weedicide, perhaps can be used as the intermediate of useful medicine or weedicide.
In the formula: R
1, R
2Be independently selected from H and acyl group; R
3Be selected from H and halogen atom; R
4, R
5Be independently selected from H and halogen atom; X is independently selected from H, halogen atom, SCN, N
3, O, S; When X is independently selected from O, S, there is R
6Substituting group, R
6Represent H, alkyl, can replace aryl, can replace heteroaryl, can replace thick heteroaryl, acyl group.
In order to reach synthetic purpose, I have taked the method shown in the reaction process 1.
Reaction process 1
In reaction process 1, R
1, R
2Be independently selected from H and acyl group; R
3Be selected from H and halogen atom; R
4, R
5Be independently selected from H and halogen atom; X is independently selected from H, halogen atom, SCN, N
3, O, S; When X is independently selected from O, S, R
6Represent H, alkyl, can replace aryl, can replace heteroaryl, can replace thick heteroaryl, acyl group.
In reaction process 1, bromide reagent can be NBS or liquid bromine, the solvent that is responded all can be methylene dichloride, chloroform, tetracol phenixin, methyl alcohol, methyl-sulphoxide, N, dinethylformamide, dioxane, acetic acid, water one or mixing, and temperature of reaction remains on 20-170 ℃.
Hydrolyzable ester also is to belong to this in general formula provided by the present invention (1) pharmacologically acceptable salts or the body
Within the invention scope.
The compounds of this invention can be crystalline state material or solvation material (such as hydrate), and the material of two states all belongs within the scope of the invention, and the solvation method is known to widely in the prior art, repeats no more.
Below by embodiment the present invention is described in detail, but the present invention is not limited to these embodiment, the reagent of not mentioning among the embodiment is buied from the market and is used with former state, and except as otherwise noted, all temperature all are degree centigrade.
The preparation of embodiment 1:2-amino-5-bromo-4-brooethyl pyrimidine.
Weighing 2-amino-4-methylpyrimidine 1.09g (about 0.01mol) places the 100ml round-bottomed flask, adds 40ml methylene dichloride or acetic acid, and to wherein adding 0.76ml liquid bromine (about 0.015mol), reaction solution is red-brown again.Temperature of reaction remains between the 20-80 degree.Stir after 0.5-2 hour, add the alkali lye neutralization.CH
2Cl
2Extraction is with saturated NaCl washing extraction liquid.Dry (anhydrous Na
2SO
4).Be spin-dried for back column chromatography (40g silica gel H, 2%CH
3OH/CH
2Cl
2Wash-out) gets white solid 1.4g.Productive rate 52%[
1H] NMR (200MHz, CD
3Cl): δ 8.31 (s, 1H, Pm), 5.09 (br.s, 2H, NH2), 4.36 (s, 2H, CH2) .mp.184 ℃ (decomposition)
Can prepare compound 2-amino-5-bromo-4-methylpyrimidine by this routine described method, 2-amino-5-bromo-4-brooethyl pyrimidine, 2-amino-5-bromo-4-dibromo methylpyrimidine, 2-amino-5-bromo-4-trisbromomethyl pyrimidine, 2-(4-brooethyl-pyrimidine-2-base) isoindole-1,3-dimethyl diketone, 2-(4-two brooethyls-pyrimidine-2-base) isoindole-1, the 3-dimethyl diketone is the equivalent of corresponding change bromine.
The preparation of embodiment 2:2-amino-5-bromo-4-thiocyanogen methylpyrimidine.
Weighing 2-amino-5-bromo-4-brooethyl pyrimidine 100mg (0.37mmol), 214mg potassium thiocyanate (1.48mmol) places the 25ml round-bottomed flask, adds 10ml N, dinethylformamide, backflow 1-5hr.In system, add H then
2O, with methylene dichloride or ethyl acetate extraction, the extraction liquid anhydrous Na
2SO
4Drying, be spin-dried for after column chromatography (silica gel H 15g, 30% ethyl acetate/petroleum ether wash-out) separate white solid 50mg.Productive rate 55%.[
1H]NMR(300MHz，CDCl
3)：δ8.331(s，1H，Pm)，5.160(br.s，2H，NH2)，4.283(s，2H，CH2)。Mp.159 ℃ (decomposition).
When if compound (II-C) is salt or mineral alkali, can adopt this routine method.For example (II-C) reacts when being sodiumazide and obtains 2-amino-5-bromo-4-azido methyl pyrimidine; Reaction obtains 2-amino-5-bromo-4-oxymethylpyrimidine when (II-C) being sodium hydroxide; Reaction obtains 4-(2-amino-5-bromo-pyrimidine) thiomethyl alcohol when (II-C) being Sodium sulfhydrate.
The preparation of embodiment 3:2-amino-5-bromo-4-methoxy methyl yl pyrimidines.
Weighing 2-amino-5-bromo-4-brooethyl pyrimidine 100mg (0.37mmol) places the 50ml round-bottomed flask that claims to have 20ml methyl alcohol, add 12mg metal Na (about 0.52mmol), backflow 1-2 hour, wash solid residue with water after being spin-dried for, separate (silica gel H 15g, 3%CH through column chromatography
3OH/CH
2Cl
2) must white solid 60mg.Productive rate 73%.TLC(3％CH
3OH/CH
2Cl
2)Rf＝0.3。[
1H]NMR(300MHz，CD
3Cl)：δ8.258(s，1H，Pm)，5.20(br.s，1H，NH2)，4.51(s，2H，CH2)，3.53(s，3H，CH3)。mp.211-215℃。
When if compound (II-C) is hydroxyl or sulfhydryl compound, can adopt this routine method just to use suitable alkali instead.For example (II-C) reacts when being ethanol and obtains 2-amino-5-bromo-4-(ethoxymethyl) yl pyrimidines; Send out when (II-C) being Virahol and should obtain 2-amino-5-bromo-4-isopropoxy methylpyrimidine; Send out when (II-C) being vinyl carbinol and should obtain 2-amino-5-bromo-4-allyloxy methylpyrimidine; Send out when (II-C) being phenylcarbinol and should obtain 2-amino-5-bromo-4-benzyloxymethyl pyrimidine; Send out when (II-C) being tyrosine and should obtain 2-amino-3-" 4-(2-amino-5-bromo pyrimi piperidine-4-methoxyl group)-phenyl " propionic acid; Send out when (II-C) being phenol and should obtain 2-amino-5-bromo-4-phenoxymethyl pyrimidine; Send out when (II-C) being p-cresol and should obtain 2-amino-5-bromo-4-the tolyloxy methylpyrimidine; Send out when (II-C) being ortho-cresol and should obtain 2-amino-5-bromo-4-(o-methyl-benzene oxygen base) methylpyrimidine; Send out when (II-C) being p methoxy phenol and should obtain 2-amino-5-bromo-4-(4-methoxyl group phenoxy group) methylpyrimidine; Send out when (II-C) being o-nitrophenol and should obtain 2-amino-5-bromo-4-(2-nitro-phenoxy) methylpyrimidine; Send out when (II-C) being p-nitrophenol and should obtain 2-amino-5-bromo-4-(4-nitrophenoxy) methylpyrimidine; Send out when (II-C) being 2,4 dichloro phenol and should obtain 2-amino-5-bromo-4-(2,4 dichloro benzene base) methylpyrimidine; Send out when (II-C) being the 1-naphthols and should obtain 2-amino-5-bromo-4-(1-naphthyloxy) methylpyrimidine; Send out when (II-C) being beta naphthal and should obtain 2-amino-5-bromo-4-(2-naphthyloxy) methylpyrimidine; Send out when (II-C) being benzenethiol and should obtain 2-amino-5-bromo-4-thiophenyl methylpyrimidine.
The preparation of embodiment 4:2-amino-5-bromo-4-phenyl amino methylpyrimidine.
In the 25ml round-bottomed flask, add 1ml aniline, 255mg (1.84mmol) anhydrous K
2CO
3(1.84mmol), 100mg2-amino-5-bromo-4-brooethyl pyrimidine (0.37mmol), 10ml N, dinethylformamide, backflow 1-5hr.In system, add H then
2O, with methylene dichloride or ethyl acetate extraction, the extraction liquid anhydrous Na
2SO
4Drying, be spin-dried for after column chromatography (silica gel H 15g, 30% ethyl acetate/petroleum ether wash-out) separate white solid 20mg, productive rate 19%.[
1H]NMR(300MHz，CD
3Cl)：δ8.268(s，1H，Pm)，7.258-7.199(m，2H，Ph)，6.780-6.731(m，3H，Ph)，5.155(br.s，2H，NH2)，5.086(br.s，1H，NH)，4.306(s，2H，CH2)。Mp.160 ℃ of decomposition.
If compound (II-C) when being aminated compounds, can adopt this routine method.For example (II-C) be (N, reaction obtains 2-amino-5-bromo-4-" (N, N-diisopropylaminoethyl)-methyl " pyrimidine during the N-Diisopropylamine; Reaction obtains 2-amino-5-bromo-4-(1-naphthyl) amino methylpyrimidine when (II-C) being naphthalidine; Reaction obtains 2-" (2-amino-5-bromo pyrimi piperidine-4-methyl) amino "-3 Methylbutanoic acid when (II-C) being Xie Ansuan; (II-C) be that Isoleucine reaction obtains 2-" (2-amino-5-bromo pyrimi piperidine-4-methyl) amino "-3 methylvaleric acid acid (II-C) and reacts when being tryptophane and obtain 2-" (2-amino-5-bromo pyrimi piperidine-4-methyl) amino "-3-(1H-indol-3-yl) propionic acid.
Embodiment 5: the preparation of acetate (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester.
Weighing 2-amino-5-bromo-4-brooethyl pyrimidine 100mg (0.37mmol), 121mg sodium acetate (1.48mmol) place the 25ml round-bottomed flask, and 10ml adds N, dinethylformamide, backflow 1-5hr.In system, add H then
2O, with methylene dichloride or ethyl acetate extraction, the extraction liquid anhydrous Na
2SO
4Drying, be spin-dried for after column chromatography (silica gel H 15g, 30% ethyl acetate/petroleum ether wash-out) separate white solid 30mg.Productive rate 32%.[
1H]NMR(CDCl
3)：δ8.26(s，1H，Pm)，5.1(br.s，2H，NH2)，5.09(s，2H，CH2)，2.17(s，3H，CH3)。mp.195-196℃。
If compound (II-C) when being carboxylic acid cpd, can adopt this routine method.For example (II-C) reacts when being phenylformic acid and obtains phenylformic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester; Reaction obtains toluylic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester when (II-C) being toluylic acid; Reaction obtains vinylformic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester when (II-C) being vinylformic acid; Reaction obtains lauric acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester when (II-C) being lauric acid; Reaction obtains (2R)-uncle 2-fourth oxanamide-3 Methylbutanoic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester when (II-C) being (2R)-uncle 2-fourth oxanamide-3 Methylbutanoic acid.
Table 1: the compound materialization data of general formula (I-C) expression
| Numbering | R 4 | R 5 | X | R 6 | Proterties | Mp./℃ |
| 1 | H | H | H | - | White solid | 170-175 |
| 2 | H | H | Br | - | White solid | 184 * |
| 3 | H | Br | Br | - | White solid | 133 * |
| 4 | Br | Br | Br | - | White solid | 123 * |
| 5 | H | H | SCN | - | White solid | 159 * |
| 6 | H | H | N 3 | - | White solid | 127-129 |
| 7 | H | H | O | CH 3(CH 2) 10C＝ O | White solid | 96-97 |
| 8 | H | H | O | PhC＝O | White solid | 150-152 |
| 9 | H | H | O | H 2C＝CHC＝O | White solid | 136-138 |
| 10 | H | H | O | CH 3C＝O | White solid | 195-196 |
| 11 | H | H | O | PhCH 2C＝O | White solid | 125-126 |
| 12 | H | H | O | Boc-Val | White solid foam | 35-38 |
| 13 | H | H | O | CH 3 | White solid | 211-215 |
| 14 | H | H | O | (CH 3) 2CH | White solid | 148-150 |
| 15 | H | H | O | CH 3CH 2 | White solid | 158-192 |
| 16 | H | H | O | CH 2Ph | White solid | 151-153 |
| 17 | H | H | O | H 2C＝CH | White solid | 139-140 |
| 18 | H | H | S | H | White solid | 212 * |
| 19 | H | H | O | H | Faint yellow solid | 159-162 |
| 20 | H | H | O | P-methylphenyl | White solid | 224 * |
| 21 | H | H | O | The 1-naphthyl | White solid | 165-167 |
| 22 | H | H | O | The 2-naphthyl | White solid | 197-200 |
| 23 | H | H | O | Ph | White solid | 196-198 |
| 24 | H | H | O | P-nitrophenyl | White solid | 195-198 |
| 25 | H | H | O | The ortho-nitrophenyl base | White solid | |
| 26 | H | H | O | P-methoxyphenyl | White solid | 200-204 |
| 27 | H | H | S | Ph | White solid | 164-166 |
| 28 | H | H | O | The 2,4 dichloro benzene base | White solid | 147-149 |
| 29 | H | H | O | O-methyl-phenyl- | White solid | 138-140 |
| 30 | H | H | N | ((CH 3) 2CH) 2 | White solid | 81-84 |
| 31 | H | H | NH | Ph | White solid | 160 * |
| 32 | H | H | NH | The 1-naphthyl | White solid | 203-205 |
Annotate:
*Expression is decomposed
Table 2: the compound materialization data of general formula (I-A) expression
| Numbering | R 4 | R 5 | Proterties | Mp./℃ |
| 33 | H | Br | White solid | 166 |
| 34 | H | H | White solid | 176-178 |
Table 3: compound
1H NMR data
| Numbering | NMR |
| 1 | [ 1H]NMR(200MHz，CD 3Cl)：δ8.19(s，1H，Pm)，5.00(br.s，2H， NH2)，2.41(s，3H，CH3) |
| 2 | [ 1H]NMR(200MHz，CD 3Cl)：δ8.31(s，1H，Pm)，5.09(br.s，2H， NH2)，4.36(s，2H，CH2) |
| 3 | [ 1H]NMR(200MHz，CD 3Cl)：δ8.31(s，1H，Pm)，6.80(s，1H，CH)， 5.31(s，2H，NH2) |
| 4 | [ 1H]NMR(200MHz，CD 3Cl)：δ8.41(s，1H，Pm)，5.29(s，2H，NH2) |
| 5 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.331(s，1H，Pm)，5.160(br.s， 2H，NH2)，4.283(s，2H，CH2) |
| 6 | [ 1H]NMR(300MHz，CDCl 3)：δ8.309(s，1H，Pm)，5.174(br.s， 2H，NH2)，4.370(s，2H，CH2) |
| 7 | [ 1H]NMR(200MHz，CDCl 3)：δ8.25(s，1H，Pm)，5.10(br.s， 2H，NH2)，5.08(s，2H，CH2-Pm)，2.42(t，2H，J＝7.3Hz， O＝C-CH2)，1.23-1.65(m，18H，-(CH2) 9)，0.85(t，3H，J＝6.3Hz， CH3) |
| 8 | [ 1H]NMR(200MHz，CDCl 3)：δ8.28(s，1H，Pm)，8.08-8.12(m， 2H，Ph)，8.44-8.58(m，3H，Ph)，5.32(s，2H，CH2)，5.05 (br.s，2H，NH2) |
| 9 | [ 1H]NMR(200MHz，CDCl 3)：δ8.26(s，1H，Pm)，5.86-6.46(m， 3H，-CH＝CH2)，5.16(s，2H，CH2)，5.10(br.s，2H，NH2) |
| 10 | [ 1H]NMR(CDCl 3)：δ8.26(s，1H，Pm)，5.1(br.s，2H，NH2)， 5.09(s，2H，CH2)，2.17(s，3H，CH3) |
| 11 | [ 1H]NMR(200MHz，CDCl 3)：δ8.2(s，1H，Pm)，7.23-7.33(m， 5H，Ph)，5.10(s，2H，CH2-Pm)，4.62(br.s，2H，NH2)，3.74 (s，2H，CH2-Ph) |
| 12 | [ 1H]NMR(300MHz，CDCl 3)：δ8.249(s，1H，Pm)，5.243(br.s， 2H，NH2)，5.177(s，2H，CH2)，5.087(d，1H，J＝9.38Hz，C(O)-CH)， 2.349-2.242(m，1H，CH)，1.453(s，9H，O(CH3) 3)，1.044-0.950 (dd，6H，J 1＝J 2＝7.04Hz，(CH3) 2) |
| 13 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.258(s，1H，Pm)，5.20(br.s， 1H，NH2)，4.51(s，2H，CH2)，3.53(s，3H，CH3) |
| 14 | [ 1H]NMR(200MHz，CD 3Cl)：δ8.246(s，1H，Pm)，5.152(br.s， 2H，NH2)，4.492(s，2H，CH2)，3.75(q，2H，J＝6.2Hz)， 1.259-1.228(d，6H，J＝6.2Hz) |
| 15 | [ 1H]NMR(200MHz，CD 3Cl)：δ8.228(s，1H，Pm)，5.151(br.s， 2H，NH2)，3.658-3.586(q，2H，J＝7.2Hz，CH2)，1.297-1.229 (t，3H，J＝6.8Hz，CH3) |
| 16 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.259(s，1H，Pm)，7.417-7.240 (m，5H，Ph)，5.179(br.s，2H，NH2)，4.698(s，2H，CH2-Pm)， 4.540(s，2H，CH2-Ph) |
| 17 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.259(s，1H，Pm)，5.988-5.929 (m，1H，-CH＝)，5.369-5.238(2H，m，＝CH2)，5.224(br.s， 2H，NH2)，4.534(s，2H，CH2)，4.177-4.158(d，2H，J＝5.86Hz) |
| 18 | [ 1H]NMR(200MHz，DMSO-d)：δ8.26(s，1H，Pm)，6.87(br.s， 2H，NH2)，3.78(s，2H，CH2)，1.2(br.s，1H，SH) |
| 19 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.262(s，1H，Pm)，5.170(br.s， 1H，NH2)，3.538(s，2H，CH2)，1.758(br.s，1H，OH) |
| 20 | [ 1H]NMR(DMSO-d6)：δ8.34(s，1H，Pm)，6.83-7.07(dd，4H， Ph，)，6.95(br.s，2H，NH2)，4.93(s，2H，CH2)，2.23(s， 3H，CH3) |
| 21 | [ 1H] and NMR (300MHz, DMSO-d6): δ 8.387 (s, 1H, Pm), (8.180-8.155 d, 1H, naphthalene nucleus), (7.885-7.860 d, 1H, naphthalene nucleus), (7.551-7.381 4H, m, naphthalene nucleus), (7.016 s, 1H, naphthalene nucleus), 6.991 (br.s, 2H, NH2) |
| 22 | [ 1H] NMR (300MHz, DMSO-d6): δ 8.380 (s, 1H, Pm), 7.858-7.192 (m, 7H, naphthalene nucleus), 7.032 (br.s, 2H, NH2), 5.103 (s, 2H, CH2) |
| 23 | [ 1H]NMR(200MHz，DMSO-d6)：δ8.30(s，1H，Pm)，7.20(m， 4H，Ph)，6.97(m，3H，1H-Ph，NH2)，4.96(s，2H，CH2) |
| 24 | [ 1H]NMR(200MHz，DMSO-d6)：δ8.36(s，1H，Pm)，8.22、8.18、 7.19、7.15(dd，4H，J＝8Hz，Ph)，7.00(br.s，2H，NH2)，5.17 (s，2H，CH2) |
| 25 | [ 1H]NMR(200MHz，DMSO-d6)：δ8.35(s，1H，Pm)，7.14-7.85 (m，4H，Ph)，6.99(br.s，2H，NH2)，5.16(s，2H，CH2) |
| 26 | [ 1H]NMR(200MHz，DMSO-d6)：δ8.31(s，1H，Pm)，6.97(br.s， 2H，NH2)，6.64-6.66(dd，4H，Ph)，4.68(s，2H，CH2)， 3.66(s，3H，CH3) |
| 27 | [ 1H]NMR(200MHz，DMSO-d6)：δ8.30(s，1H，Pm)，7.30-7.38 (m，5H，Ph)，7.07(br.s，2H，NH2)，5.71(s，2H，CH2) |
| 28 | [ 1H]NMR(300MHz，DMSO-d6)：δ8.362(s，1H，Pm)，7.589-7.580 (d，1H，Ph)，7.381-7.343(dd，1H，Ph)，7.173-7.143(d，1H， Ph)，6.994(br.s，2H，NH2)，5.083(s，2H，CH2) |
| 29 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.328(s，1H，Pm)，7.167-6.833 (m，4H，Ph)，5.171(br.s，2H，NH2)，5.059(s，2H，CH2)， 2.289(s，3H，CH3) |
| 30 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.268(s，1H，Pm)，7.258-7.199 (m，2H，Ph)，6.780-6.731(m，3H，Ph)，5.155(br.s，2H， NH2)，5.086(br.s，1H，NH)，4.306(s，2H，CH2) |
| 31 | [ 1H]NMR(300MHz，CD 3Cl)：δ8.268(s，1H，Pm)，7.258-7.199 (m，2H，Ph)，6.780-6.731(m，3H，Ph)，5.155(br.s，2H， NH2)，5.086(br.s，1H，NH)，4.306(s，2H，CH2) |
| 32 | [ 1H]NMR(300MHz，CDCl 3): δ 8.319 (s, 1H, Pm), (8.017-6.660 m, 7H, naphthalene nucleus), 5.215 (br.s, 2H, NH2-Pm), 4.460 (s, 2H, CH2), 1.8 (br.s, 1H, the NH-naphthalene nucleus) |
| 33 | [ 1H]NMR(300MHz，CDCl 3)：δ9.047(d，1H，J＝5.28Hz，6-H-Pm)， 8.022-70994(m，2H，Ph)，7.875-7.858(d，J＝5.28Hz，1H，5-H-Pm)， 7.852-7.825(m，2H，Ph)，6.560(s，1H，CH) |
| 34 | [ 1H]NMR(300MHz，CDCl 3)：δ8.937(d，1H，J＝4.8Hz，6-H-Pm)， 8.016-7.988(m，2H，Ph)，7.847-7.819(m，2H，Ph)，7.573 (d，1H，J＝4.8Hz，5-H-Pm)，4.538(s，2H，CH2) |
The mensuration of weeding activity
Supplying in the biological activity test of test agent above-mentioned, with weedicides such as commercial tribenuron-methyls as reference, this compounds of topology discovery has good removing activity and kills the grass spectrum, and wherein the biological activity of weedicides such as compound 4,14,31 etc. and commercial tribenuron-methyl is suitable.
The above, it only is preferred embodiment of the present invention, be not that the present invention is done any pro forma restriction, every foundation technical spirit of the present invention all still belongs in the scope of technical solution of the present invention any simple modification, equivalent variations and modification that above embodiment did.
Claims (8)
1, a kind of pyrimidine derivatives is characterized in that, its be the pyrimidine derivatives shown in the general formula (I) with and pharmacologically acceptable salts:
In the formula: R
1, R
2Be independently selected from H and acyl group; R
3Be selected from H and halogen atom; R
4, R
5Be independently selected from H and halogen atom; X is independently selected from halogen atom, SCN, N
3, O and S; When X is independently selected from O, S, there is R
6Substituting group, R
6Expression H, alkyl, chlorine or methyl or methoxy or nitro substituted aryl, acyl group.
2, pyrimidine derivatives according to claim 1 is characterized in that, described pyridine derivatives with and pharmacologically acceptable salts be the compound shown in the general formula (I-B):
In the formula: R
4, R
5Be independently selected from H and halogen atom.
3, pyrimidine derivatives according to claim 1 is characterized in that, described pyridine derivatives with and pharmacologically acceptable salts be the compound shown in the general formula (I-C):
In the formula: R
4, R
5Be independently selected from H and halogen atom; X is independently selected from halogen atom, SCN, N
3, O and S; When X is independently selected from O, S, there is R
6Substituting group, R
6Expression H, alkyl, chlorine or methyl or methoxy or nitro substituted aryl, acyl group.
4, according to claim 1 or 2 or 3 described pyrimidine derivatives, it is characterized in that, described pyridine derivatives with and pharmacologically acceptable salts be selected from:
2-amino-5-bromo-4-brooethyl pyrimidine;
2-amino-5-bromo-4-dibromo methylpyrimidine;
2-amino-5-bromo-4-trisbromomethyl pyrimidine;
2-amino-5-bromo-4-azido methyl pyrimidine;
2-amino-5-bromo-4-thiocyanogen methylpyrimidine;
2-amino-5-bromo-4-oxymethylpyrimidine;
4-(2-amino-5-bromo-pyrimidine) thiomethyl alcohol;
2-amino-5-bromo-4-methoxy methyl yl pyrimidines;
2-amino-5-bromo-4-(ethoxymethyl) yl pyrimidines;
2-amino-5-bromo-4-isopropoxy methylpyrimidine;
2-amino-5-bromo-4-allyloxy methylpyrimidine;
2-amino-5-bromo-4-benzyloxymethyl pyrimidine;
2-amino-3-" 4-(2-amino-5-bromo pyrimi piperidine-4-methoxyl group)-phenyl " propionic acid;
2-amino-5-bromo-4-is to the tolyloxy methylpyrimidine;
2-amino-5-bromo-4-(o-methyl-benzene oxygen base) methylpyrimidine;
2-amino-5-bromo-4-(4-methoxyl group phenoxy group) methylpyrimidine;
2-amino-5-bromo-4-(2-nitro-phenoxy) methylpyrimidine;
2-amino-5-bromo-4-(4-nitrophenoxy) methylpyrimidine;
2-amino-5-bromo-4-(2,4 dichloro benzene base) methylpyrimidine;
Acetate (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Phenylformic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Toluylic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Vinylformic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Lauric acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
(2R)-uncle's 2-fourth oxanamide-3 Methylbutanoic acid (2-amino-5-bromo-pyrimidine-4-ylmethyl) ester;
Or the pharmacologically acceptable salts of above-claimed cpd.
5, the preparation method of pyrimidine derivatives as claimed in claim 2 is characterized in that: the compound shown in the described general formula (I-B) obtains by 2-amino-4-methylpyrimidine (II-B) bromination reaction:
In the formula: R
4, R
5Be independently selected from H and halogen atom.
6, the preparation method of pyrimidine derivatives as claimed in claim 3 is characterized in that: the compound shown in the general formula (I-C) is obtained by the reaction of compound shown in compound shown in the general formula (I-B) and the general formula (II-C):
In the formula: R
4, R
5Be independently selected from H and halogen atom; X is independently selected from halogen atom, SCN, N
3, O and S; When X is independently selected from O, S, there is R
6Substituting group, R
6Expression H, alkyl, chlorine or methyl or methoxy or nitro substituted aryl, acyl group.
7, according to the preparation method of claim 5 or 6 described pyridine derivatives, it is characterized in that: reaction solvent is methylene dichloride, chloroform, tetracol phenixin, methyl alcohol, methyl-sulphoxide, N, one solvent or mixed solvent in dinethylformamide, dioxane, acetic acid, the water; Bromizating agent is NBS or liquid bromine; Temperature of reaction remains on 20-170 ℃.
8, the application of the described pyridine derivatives of claim 1 in the preparation medicine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07196780A (en) * | 1993-12-29 | 1995-08-01 | Showa Denko Kk | Poly(alkyl substituted-2,5-pyrimidin-diyl) and its production |
| CN1406229A (en) * | 2000-03-01 | 2003-03-26 | 阿斯特拉曾尼卡有限公司 | Pyrimidine compounds |
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- 2003-10-16 CN CNB2003101066402A patent/CN1315811C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07196780A (en) * | 1993-12-29 | 1995-08-01 | Showa Denko Kk | Poly(alkyl substituted-2,5-pyrimidin-diyl) and its production |
| CN1406229A (en) * | 2000-03-01 | 2003-03-26 | 阿斯特拉曾尼卡有限公司 | Pyrimidine compounds |
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