GB2099813A - Pyridine-or pyridine-amino compounds - Google Patents
Pyridine-or pyridine-amino compounds Download PDFInfo
- Publication number
- GB2099813A GB2099813A GB8124353A GB8124353A GB2099813A GB 2099813 A GB2099813 A GB 2099813A GB 8124353 A GB8124353 A GB 8124353A GB 8124353 A GB8124353 A GB 8124353A GB 2099813 A GB2099813 A GB 2099813A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- salt
- mixture
- solution
- formula
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 76
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000003277 amino group Chemical group 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 9
- 125000005110 aryl thio group Chemical group 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 238000003379 elimination reaction Methods 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- 101000742868 Rattus norvegicus Retinoblastoma-associated protein Proteins 0.000 claims 2
- 230000008030 elimination Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 246
- -1 carbamoyloxymethyl Chemical group 0.000 description 120
- 239000000243 solution Substances 0.000 description 103
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 95
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 87
- 229940093499 ethyl acetate Drugs 0.000 description 82
- 235000019439 ethyl acetate Nutrition 0.000 description 82
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 74
- 238000006243 chemical reaction Methods 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 45
- 238000000034 method Methods 0.000 description 45
- 239000002904 solvent Substances 0.000 description 44
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 40
- 239000007864 aqueous solution Substances 0.000 description 37
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 230000002829 reductive effect Effects 0.000 description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
- 229960004132 diethyl ether Drugs 0.000 description 28
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- 238000001914 filtration Methods 0.000 description 26
- 239000010410 layer Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000002244 precipitate Substances 0.000 description 24
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000000843 powder Substances 0.000 description 21
- 238000001816 cooling Methods 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 230000002411 adverse Effects 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 229910052783 alkali metal Inorganic materials 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 125000001589 carboacyl group Chemical group 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 150000004682 monohydrates Chemical class 0.000 description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- GAEXNJCVRMLMDX-UHFFFAOYSA-N ethyl 2-(4-formamidopyrimidin-2-yl)acetate Chemical compound CCOC(=O)CC1=NC=CC(NC=O)=N1 GAEXNJCVRMLMDX-UHFFFAOYSA-N 0.000 description 5
- KFWXMEFMJAQBJR-UHFFFAOYSA-N ethyl 2-(6-formamidopyridin-2-yl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=CC=CC(NC=O)=N1 KFWXMEFMJAQBJR-UHFFFAOYSA-N 0.000 description 5
- RYBBDPRLAIWHRI-UHFFFAOYSA-N ethyl 2-(6-formamidopyridin-2-yl)acetate Chemical compound CCOC(=O)CC1=CC=CC(NC=O)=N1 RYBBDPRLAIWHRI-UHFFFAOYSA-N 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- RIONGWNSXXUZSI-UHFFFAOYSA-N 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid;hydrochloride Chemical compound Cl.CON=C(C(O)=O)C1=CC=CC(N)=N1 RIONGWNSXXUZSI-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000011369 resultant mixture Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- MYMKYRIJWXAQQG-UHFFFAOYSA-N 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=NC=CC(N)=N1 MYMKYRIJWXAQQG-UHFFFAOYSA-N 0.000 description 3
- NXVRBXUUZSHHRK-UHFFFAOYSA-N 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CC=C(NC=O)N=C1 NXVRBXUUZSHHRK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- QFNGLPDYXLHFQS-UHFFFAOYSA-N ethyl 2-(4-chloro-6-formamidopyrimidin-2-yl)acetate Chemical compound CCOC(=O)CC1=NC(Cl)=CC(NC=O)=N1 QFNGLPDYXLHFQS-UHFFFAOYSA-N 0.000 description 3
- UATNWYBPCQYTNR-UHFFFAOYSA-N ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate Chemical compound CCOC(=O)C(=NOC)C1=NC=CC(NC=O)=N1 UATNWYBPCQYTNR-UHFFFAOYSA-N 0.000 description 3
- UIOWFARLANYOME-UHFFFAOYSA-N ethyl 2-(4-formamidopyrimidin-2-yl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=NC=CC(NC=O)=N1 UIOWFARLANYOME-UHFFFAOYSA-N 0.000 description 3
- AJIPGVQKXQFJNX-UHFFFAOYSA-N ethyl 2-(6-aminopyridin-2-yl)acetate Chemical compound CCOC(=O)CC1=CC=CC(N)=N1 AJIPGVQKXQFJNX-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- OTKFCIVOVKCFHR-UHFFFAOYSA-N (Methylsulfinyl)(methylthio)methane Chemical compound CSCS(C)=O OTKFCIVOVKCFHR-UHFFFAOYSA-N 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- XTQHXWJMHOAKCK-UHFFFAOYSA-N 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=NC=CC(NC=O)=N1 XTQHXWJMHOAKCK-UHFFFAOYSA-N 0.000 description 2
- BPCFWKRESKTDGF-UHFFFAOYSA-N 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid Chemical compound ON=C(C(O)=O)C1=CC=CC(NC=O)=N1 BPCFWKRESKTDGF-UHFFFAOYSA-N 0.000 description 2
- SVDIMZGAXIXJPS-UHFFFAOYSA-N 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CC=CC(NC=O)=N1 SVDIMZGAXIXJPS-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- QUXLCYFNVNNRBE-UHFFFAOYSA-N 6-methylpyridin-2-amine Chemical compound CC1=CC=CC(N)=N1 QUXLCYFNVNNRBE-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 229920000388 Polyphosphate Polymers 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
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- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
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- 235000011010 calcium phosphates Nutrition 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- QKWRPFSDVREMOD-UHFFFAOYSA-N ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate Chemical compound CCOC(=O)C(=NOC)C1=NC(N)=CC(Cl)=N1 QKWRPFSDVREMOD-UHFFFAOYSA-N 0.000 description 2
- TXRFPCUZRJMHQE-UHFFFAOYSA-N ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate Chemical compound CCOC(=O)CC1=NC(N)=CC(Cl)=N1 TXRFPCUZRJMHQE-UHFFFAOYSA-N 0.000 description 2
- NYQGNDGYSOIOML-UHFFFAOYSA-N ethyl 2-(4-amino-6-phenylsulfanylpyrimidin-2-yl)-2-methoxyiminoacetate Chemical compound CCOC(=O)C(=NOC)C1=NC(N)=CC(SC=2C=CC=CC=2)=N1 NYQGNDGYSOIOML-UHFFFAOYSA-N 0.000 description 2
- GYVLBYPRDQGLKU-UHFFFAOYSA-N ethyl 2-(4-chloro-6-formamidopyrimidin-2-yl)-2-oxoacetate Chemical compound CCOC(=O)C(=O)C1=NC(Cl)=CC(NC=O)=N1 GYVLBYPRDQGLKU-UHFFFAOYSA-N 0.000 description 2
- ORRVPWMZOBSPHD-UHFFFAOYSA-N ethyl 2-(4-formamidopyrimidin-2-yl)-2,2-dihydroxyacetate Chemical compound CCOC(=O)C(O)(O)C1=NC=CC(NC=O)=N1 ORRVPWMZOBSPHD-UHFFFAOYSA-N 0.000 description 2
- ADAQTWCTDHYVNY-UHFFFAOYSA-N ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=NO)C1=NC=CC(NC=O)=N1 ADAQTWCTDHYVNY-UHFFFAOYSA-N 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000004508 fractional distillation Methods 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 2
- 239000004137 magnesium phosphate Substances 0.000 description 2
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 2
- 229960002261 magnesium phosphate Drugs 0.000 description 2
- 235000010994 magnesium phosphates Nutrition 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- NZNPCVMHAMJJJC-UHFFFAOYSA-N methyl 2-(2-formamidopyrimidin-4-yl)acetate Chemical compound COC(=O)CC1=CC=NC(NC=O)=N1 NZNPCVMHAMJJJC-UHFFFAOYSA-N 0.000 description 2
- TWYHWPARYAKHBK-UHFFFAOYSA-N methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate Chemical compound CON=C(C(=O)OC)C1=NC(NC=O)=CC(OC)=N1 TWYHWPARYAKHBK-UHFFFAOYSA-N 0.000 description 2
- PYQRUDYLXHRTQU-UHFFFAOYSA-N methyl 4-aminopyrimidine-2-carboxylate Chemical compound COC(=O)C1=NC=CC(N)=N1 PYQRUDYLXHRTQU-UHFFFAOYSA-N 0.000 description 2
- KZRZHJNHBQTQHU-UHFFFAOYSA-N methyl 4-formamidopyridine-2-carboxylate Chemical compound COC(=O)C1=CC(NC=O)=CC=N1 KZRZHJNHBQTQHU-UHFFFAOYSA-N 0.000 description 2
- LVKIKXMWEDRICX-UHFFFAOYSA-N methyl 4-formamidopyrimidine-2-carboxylate Chemical compound COC(=O)C1=NC=CC(NC=O)=N1 LVKIKXMWEDRICX-UHFFFAOYSA-N 0.000 description 2
- LPMIVIOTPQVDGX-UHFFFAOYSA-N methyl 6-formamidopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(NC=O)=N1 LPMIVIOTPQVDGX-UHFFFAOYSA-N 0.000 description 2
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- NUXCOKIYARRTDC-UHFFFAOYSA-N o-ethylhydroxylamine;hydron;chloride Chemical compound Cl.CCON NUXCOKIYARRTDC-UHFFFAOYSA-N 0.000 description 2
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- IEWFXYBKEKZBIR-UHFFFAOYSA-M potassium;2-(4-aminopyrimidin-2-yl)-2-oxoacetate Chemical compound [K+].NC1=CC=NC(C(=O)C([O-])=O)=N1 IEWFXYBKEKZBIR-UHFFFAOYSA-M 0.000 description 2
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- DMJIOPFUBQBBNA-UHFFFAOYSA-N 6-methyl-n,n-bis(trimethylsilyl)pyridin-2-amine Chemical compound CC1=CC=CC(N([Si](C)(C)C)[Si](C)(C)C)=N1 DMJIOPFUBQBBNA-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- SGCDUDVQGBGWCR-UHFFFAOYSA-N C=1C=CC(NC=O)=NC=1C(C(=O)O)=NOC1=CC=CC=C1 Chemical compound C=1C=CC(NC=O)=NC=1C(C(=O)O)=NOC1=CC=CC=C1 SGCDUDVQGBGWCR-UHFFFAOYSA-N 0.000 description 1
- UJEQHOSXUPLTDQ-UHFFFAOYSA-N CC(C)ON=C(C(O)=O)C1=CC=CC(NC=O)=N1 Chemical compound CC(C)ON=C(C(O)=O)C1=CC=CC(NC=O)=N1 UJEQHOSXUPLTDQ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- XNPOFXIBHOVFFH-UHFFFAOYSA-N N-cyclohexyl-N'-(2-(4-morpholinyl)ethyl)carbodiimide Chemical compound C1CCCCC1N=C=NCCN1CCOCC1 XNPOFXIBHOVFFH-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- OBGLBOWBCVQXBA-UHFFFAOYSA-N O.COC(=O)C(=O)C1=CC=NC(NC=O)=N1 Chemical compound O.COC(=O)C(=O)C1=CC=NC(NC=O)=N1 OBGLBOWBCVQXBA-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
- 229910001485 alkali metal perchlorate Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 description 1
- 150000008049 diazo compounds Chemical group 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- AXZAYXJCENRGIM-UHFFFAOYSA-J dipotassium;tetrabromoplatinum(2-) Chemical compound [K+].[K+].[Br-].[Br-].[Br-].[Br-].[Pt+2] AXZAYXJCENRGIM-UHFFFAOYSA-J 0.000 description 1
- MEBOQHVMVIQHKU-UHFFFAOYSA-N disodium ethanolate methanolate Chemical compound [Na+].[Na+].C[O-].CC[O-] MEBOQHVMVIQHKU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- YDVDYMHZOQYOJP-UHFFFAOYSA-N ethyl 2-(4-chloro-6-formamidopyrimidin-2-yl)-2-methoxyiminoacetate Chemical compound CCOC(=O)C(=NOC)C1=NC(Cl)=CC(NC=O)=N1 YDVDYMHZOQYOJP-UHFFFAOYSA-N 0.000 description 1
- BOPPSRGQAVIGSO-UHFFFAOYSA-N ethyl 2-amino-2-iminoacetate;hydrobromide Chemical compound Br.CCOC(=O)C(N)=N BOPPSRGQAVIGSO-UHFFFAOYSA-N 0.000 description 1
- SSWRFXWOCJHUSL-UHFFFAOYSA-N ethyl 3-ethoxyprop-2-enimidate;hydrochloride Chemical compound Cl.CCOC=CC(=N)OCC SSWRFXWOCJHUSL-UHFFFAOYSA-N 0.000 description 1
- YHDZCFILDSOJRF-UHFFFAOYSA-N ethyl 4-aminopyrimidine-2-carboxylate Chemical compound CCOC(=O)C1=NC=CC(N)=N1 YHDZCFILDSOJRF-UHFFFAOYSA-N 0.000 description 1
- YMHWNLAAGMXNJR-UHFFFAOYSA-N ethyl 4-formamidopyrimidine-2-carboxylate Chemical compound CCOC(=O)C1=NC=CC(NC=O)=N1 YMHWNLAAGMXNJR-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- MCYSCULAEIIHJN-UHFFFAOYSA-N methyl 2-(2-aminopyrimidin-4-yl)acetate Chemical compound COC(=O)CC1=CC=NC(N)=N1 MCYSCULAEIIHJN-UHFFFAOYSA-N 0.000 description 1
- OMVXCAOWENKKRT-UHFFFAOYSA-N methyl 2-(2-formamidopyrimidin-4-yl)-2-oxoacetate Chemical compound COC(=O)C(=O)C1=CC=NC(NC=O)=N1 OMVXCAOWENKKRT-UHFFFAOYSA-N 0.000 description 1
- IIHVCFOYFWVIDF-UHFFFAOYSA-N methyl 2-(4-amino-6-methoxypyrimidin-2-yl)acetate Chemical compound COC(=O)CC1=NC(N)=CC(OC)=N1 IIHVCFOYFWVIDF-UHFFFAOYSA-N 0.000 description 1
- NSDCNAZSMAEVQJ-UHFFFAOYSA-N methyl 2-(4-formamido-6-methoxypyridin-2-yl)acetate Chemical compound COC(=O)CC1=CC(NC=O)=CC(OC)=N1 NSDCNAZSMAEVQJ-UHFFFAOYSA-N 0.000 description 1
- ZYMAJOYJUQDHKL-UHFFFAOYSA-N methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)acetate Chemical compound COC(=O)CC1=NC(NC=O)=CC(OC)=N1 ZYMAJOYJUQDHKL-UHFFFAOYSA-N 0.000 description 1
- BYGJOWFAAPMXFZ-UHFFFAOYSA-N methyl 2-(6-chloro-2-formamidopyrimidin-4-yl)-2-methoxyiminoacetate Chemical compound CON=C(C(=O)OC)C1=CC(Cl)=NC(NC=O)=N1 BYGJOWFAAPMXFZ-UHFFFAOYSA-N 0.000 description 1
- WAGIEIDUCOCTGK-UHFFFAOYSA-N methyl 2-(6-chloro-2-formamidopyrimidin-4-yl)acetate Chemical compound COC(=O)CC1=CC(Cl)=NC(NC=O)=N1 WAGIEIDUCOCTGK-UHFFFAOYSA-N 0.000 description 1
- YHOVYZINCVIRGK-UHFFFAOYSA-N methyl 4-aminopyridine-2-carboxylate Chemical compound COC(=O)C1=CC(N)=CC=N1 YHOVYZINCVIRGK-UHFFFAOYSA-N 0.000 description 1
- OHIHEJTUXNQOPM-UHFFFAOYSA-N methyl 6-aminopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(N)=N1 OHIHEJTUXNQOPM-UHFFFAOYSA-N 0.000 description 1
- DZFLVLARSXMHTI-UHFFFAOYSA-N methyl 6-formamidopyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(NC=O)N=C1 DZFLVLARSXMHTI-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 1
- FBYQSNVERBVQMX-UHFFFAOYSA-N n-[2-(2-methylsulfinylpropanethioyl)pyridin-4-yl]formamide Chemical compound CS(=O)C(C)C(=S)C1=CC(NC=O)=CC=N1 FBYQSNVERBVQMX-UHFFFAOYSA-N 0.000 description 1
- GRZOAFQYBHMVRH-UHFFFAOYSA-N n-[5-(2-methylsulfinylpropanethioyl)pyridin-2-yl]formamide Chemical compound CS(=O)C(C)C(=S)C1=CC=C(NC=O)N=C1 GRZOAFQYBHMVRH-UHFFFAOYSA-N 0.000 description 1
- FRGFOHNRMCLYEQ-UHFFFAOYSA-N n-[6-(2-methylsulfinylpropanethioyl)pyridin-2-yl]formamide Chemical compound CS(=O)C(C)C(=S)C1=CC=CC(NC=O)=N1 FRGFOHNRMCLYEQ-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- AQFWNELGMODZGC-UHFFFAOYSA-N o-ethylhydroxylamine Chemical compound CCON AQFWNELGMODZGC-UHFFFAOYSA-N 0.000 description 1
- FDVFCJYDSZGNLJ-UHFFFAOYSA-N o-propylhydroxylamine;hydrochloride Chemical compound Cl.CCCON FDVFCJYDSZGNLJ-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 229910001487 potassium perchlorate Inorganic materials 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- SNBYSHHMYDYWST-UHFFFAOYSA-N s-methyl 2-(2-formamidopyridin-4-yl)-2-oxoethanethioate Chemical compound CSC(=O)C(=O)C1=CC=NC(NC=O)=C1 SNBYSHHMYDYWST-UHFFFAOYSA-N 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
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Abstract
Compounds of the formula (1):- <IMAGE> wherein subject to certain provisos, R<1>a is amino or a protected amino group, R<1>b and R<1>c are each hydrogen, halogen, lower alkoxy or arylthio, R<14> is carboxy or a protected carboxy group, X is lower alkylene or a group of the formula: <IMAGE> in which R<6> is hydrogen or an organic amino residue which may have suitable substituent(s), and Z is N or CH, or salts thereof are useful as intermediates in the preparation of cephalosporanic acid derivatives.
Description
SPECIFICATION
Pyridine- or pyrimidine-amino compounds
The present invention relates to a compound of the formula (1):-
wherein R' is amino or a protected amino group, Rb and R1 are each hydrogen, halogen, lower alkoxy or arylthio,
R14 is carboxy or a protected carboxy group, Xis lower alkylene or a group of the formula:
in which Re is hydrogen or an organic residue which may have suitable substituent(s), and
Z is N or CH, or a salt thereof.
The compounds of the present invention are useful as intermediates in the preparation of cephalosporanic acid derivatives having the formula
wherein R1 is a group of the formula:
in which Ra Rb, Rc and Z are each as defined above,
R1 is hydrogen or lower alkoxy;
R3 is hydrogen or lower alkyl
R4 is hydrogen, halogen, carbamoyloxymethyl lower alkyl, lower alkoxy, lower alkanoyloxymethyl, lower alkanoylthiomethyl, or heterocyclic- thiomethyl which may have suitable substituent(s);
R5 is carboxy or its derivative; and
X is as defined above: and non-toxic pharmaceutically acceptable salts thereof. Such compounds form the subject of our copending Patent Application published under No. 2010840.
In the compounds of the present invention the partial structure represented by the formula:
(i.e. (I) in which X is
is to be understood to include both of the geometrical structures represented by the formula:
Accordingly, with regard to the compounds having the above mentioned partial structure, the compounds having the geometrical structure shown by the formula (A) are referred to as "syn isomer" and the other compounds having the alternative one shown by the formula (A') as "anti isomer" in this specification.
Some of the compounds of the present invention can be prepared, for example, from the known compounds (A-1), (B-1), (C-1a) and (D-1a) by the Processes A to Q as illustrated by the following reaction schemes or a simllar manner therato.
The compounds (A-1). (B-1), (C-la) and (D-1 a) are disclosed, for example, in the following literatures.
Compound (A-I):
(Journal of Organic Chemistry, Vol. 27, page 3608)
Compound (B-i):
(Journal of the Americal Chemical Society,
Vol. 69, page 2657 (1949)).
Compound (C-1a) :
(Chemical Abstract Vol. 54, 6709) (Chemical Abstract Vol. 52, 731 3g) (Chemical Abstract Vol. 53, 71 62c) (Journal für Praktische Chemie Reihe 4,
Vol. 13,page58, 1961)
Compound (D-1a)
(Abstracts of the 9th Congress of Heterocyclic
Chemistry, page 146, Fukuoka, Japan, 1976)
Process A:
of a salt thereof of a salt thereof
(A - 1) (A-2) (A-3)
Process B :
Process C:
Proccss D:
Process E:
Process F :
Process G::
or a salt thereof or a salt thereof or a salt thereof
(A-1) (B-1) (B-2)
or a salt thereof or a salt thereof
(C-1) (C-2)
or a salt thereof or a salt thereof
(D-1) (D-2)
(E-4) (E-2)
or a salt thereof or a saltthereof
(F-1) (F-2)
our a salt thereof or a salt thereof (G-1) (G-2)
Process H :
Process I:
Process J :
Process K:
Process L:
Process M: Process N:
or a salt thereof or a salt thereof
(N-1) (N-2)
Process 0:
Process P:
Process Q::
or a salt thereoF or a salt thereoF
(P-1) (P-2)
or a salt thereof or a salt thereof
(Q-1) (Q-2) wheroin Ra, Rb, Rc, R8, R14, and Z are esch es deflned above and R1 is a protected amino group
R6, is an organic residue which may have suitable substituent(s),
R8 is halogen,
R9 is a protected carboxy group,
R10 is lower alkyl,
R11 is lower alkoxy or arylthio,
R12 is hydrogen or lower alkyl,
R13 is a protected carboxy group, or a group of the formula
in which X4 is lower alkylene, and R6 and R14 are each as defined above,
R15 is hydrogen or halogen,
X1 is lower alkylene or a group of the formula:
in which R6 is as defined above,
X2 is lower alkylene, or a group of the formula: -CO- or
in which R6 is as defined above, and
X3 is a group of the formula:: -CO- or
in which R6 is as defined above.
In the above and subsequent description of the present specification, suitable examples and
illustration of the various definitions which the present invention Intends to include within the scope thereof are explained in detail as follows.
The term "lower" is intended to mean a group having 1 to 6 carbon atoms, unless otherwise provided.
Suitable "protective group" in the terms "a protected amino group"
may include an acyl and the other conventional protective group such as ar(lower)alkyl (e.g.,
benzyl, trityl, diphenylmethyl, etc.), substituted phenylthio (e.g. 2-nitrophenylthio, etc.), substituted
aralkylidene (e.g. 4-nitrobenzylidene, etc.), substituted alkylidene (e.g. 1 -methoxycarbonyl-2propylidene, etc.), substituted lower cycloalkylidene (e.g. 2-ethoxycarbonylcyclohexylidene, etc.), and the like.And suitable acyl group may be the ones derived from carboxylic, sulfonic or carbamic acid, and more particularly substituted or unsubstituted carbamoyl, aliphatic acyl, and acyl having an aromatic ring (referred to as aromatic acyl) or heterocyclic ring (referred to as heterocyclic acyl.)
Suitable examples of the aliphatic acyl may be lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl, sudcinyl, pivaloyl, etc.); lower cycloalkanecarbonyl (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl, etc.); lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxy
carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxy
carbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower cycloalkyl(lower)alkoxycarbonyl (e.g., 1 -cyclopropylethoxycarbonyl, etc.); lower alkoxyalkanoyl (e.g., methoxyacetyl, ethoxyacetyl, methoxy
propionyl, etc.); and lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl,
etc.).
Suitable examples of the aromatic acyl may be ar(lower)alkanoyl (e.g., phenylacetyl, phenyl
propionyl, etc.); ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.);
arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); and aroyl (e.g., benzoyl, toluoyl, naphthoyl, phthaloyl,
indancarbonyl, etc.).
Suitable examples of the heterocyclic acyi may be heterocyclic(lower)alkanoyl (e.g., thienylacetyl, fu rylacetyl, pyrrolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, piperazinylacetyl, etc.); heterocyclicoxycarbonyl (e.g. 8-quinolyloxycarbonyl; etc.); heterocycliccarbonyl (e.g., thenoyl, furoyl, nicotinoyl, isonicotinoyl, pyrrolecarbonyl, pyrrolidinecarbonyl, tetrahydropyranecarbonyl, etc.); heterocyclic (lower)a Ikoxycarbonyl (e.g. 2-pyridylmethoxycarbonyl, etc.).
Suitable substituted or unsubstituted carbamoyl may include carbamoyl, lower alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), arylcarbamoyl (e.g., phenylcarbamoyl, etc.), ar(lower)alkylcarbamoyl (e.g., benzylcarbamoyl, tritylcarbamoyl, etc.), lower alkanoylcarbamoyl (e.g., formylcarbamoyl, acetylcarbamoyl, etc.), mono(or di or tri)halo(lower)alkanoylcarbamoyl (e.g., chloroacetylcarbamoyl, trichloroacetylcarbamoyl, etc.), and the like.
The "acyl" as stated above may optionally have 1 to 3 suitable substituent(s) such as halogen
(e.g., chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy, lower alkyl, lower alkenyl, acyl[preferably mono(or di or tri)halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.)], aryl (e.g., phenyl, tolyl, etc.), or the like.
Preferable examples of said "protective group" in the terms "a protected amino group" are acyl,
and more preferably lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), mono(or di or tri)halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.) and lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxyca rbonyl, isopropoxycarbonyl, butoxyca rbonyl, tert-butoxyca rbonyl, pentyloxycarbonyl, tertpentyloxycarbonyl, hexyloxycarbonyl, etc.).
Suitable "lower alkyl" may include straight or branched saturated aliphatic hydrocarbon residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, and the like, and preferably one having 1 to 4 carbon atoms.
Suitable "organic residue which may have suitable substituent(s)" may include:
lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tertpentyl, hexyl, etc.);
mono(or di or tri)halo(lower)alkyl (e.g., chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc.);
lower alkenyl (e.g., vinyl, 1 -propenyl, allyl, q -methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.);
lower alkynyl (e.g., ethynyl, 1 -propynyl, propargyl, 1 -methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.);
aryl (e.g., phenyl, tolyl, xylyl, cumenyl, naphthyl, etc.);;
ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.); and the like.
halo(lower)alkanoyl(e.g. chloroacetyl, dichloroacetyl, etc.); and the like.
Suitable "lower alkoxy" may be straight or branched and include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like, and preferably one having 1 to 4 carbon atoms.
Suitable "halogen" may be chlorine, bromine, iodine or fluorine.
Suitable "lower alkylene" may include methylene, ethylene, trimethylene, 1-methylethylene, etc., preferably one having 1 to 3 carbon atoms and the most preferably methylene.
Suitable "carboxy derivative" includes protected carboxy such as èsterified carboxy. And suitable examples of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1cyclopropylethyl ester, etc.);
lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); loweralkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyi ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1 methoxy ethyl ester, etc.); lower alkylthioalkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.); mono(or di or tri)-halo(lower)alkyl ester (e.g., 2iodoethyl ester, 2,2,2-trichioroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethylester, proionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis( methoxyphenyi) methyl ester, 3 ,4-di methoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkyl silyl ester; lower alkylthioester (e.g. methylthioester, ethylthioester, etc.) and the like.
Suitable "a protected carboxy group" may include esterified carboxy as aforementioned.
Suitable "arylthio" may include phenylthio, tolylthio, xylythio, mesitylthio and the like.
Process A:
The compound (A-3) or a salt thereof can be prepared by reacting the compound (A-i) or a salt thereof with the compound (A-2).
The present reaction is usually carried out in the presence of a base in a conventional solvent which does not adversely influence the reaction. Suitable base includes, for example, an inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxide (e.g. magnesium hydroxide and calcium hydroxide), alkali metal carbonate (e.g. sodium carbonate and potassium carbonate), alkaline earth metal carbonate (e.g. magnesium carbonate and calcium carbonate), alkali metal bicarbonate (e.g. sodium bicarbonate and potassium bicarbonate), alkaline earth metal phosphate (e.g. magnesium phosphate and calcium phosphate), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate and dipotassium hydrogen phosphate) or an organic base such as alkali metal acetate (e.g. sodium acetate and potassium acetate), alkali metal alkoxide (e.g. sodium methoxy, sodium ethoxide and sodium propoxide), trialkylamine (e.g. trimethylamine and triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo (4,3,0)5-nonene, 1,4-diazabicyclo (2,2,2)octane and 1,5-diazabicyclo (5,4,0)-5-undecene.
The reaction temperature is not Critical and the reaction can be carried out under cooling or at ambient temperature.
Process B:
The compound (B-2) or a salt thereof can be prepared by reacting the compound (A-i) or a salt thereof with the compound (B-i) or a salt thereof.
The present reaction is substantially the same as Process A, and accordingly the reaction conditions (e.g. a base, reaction temperature, solvent, etc.) can be referred to those of Process A.
Process C:
The compound (C-2) or a salt thereof can be prepared by reacting the compound (C-i) or a salt thereof with carbon dioxide.
The present reaction is usually carried out in the presence of a base such as alkyl lithium (e.g.
butyl lithium, etc.) or the like in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling or at ambient temperature.
Process D:
The compound (D-2) or a salt thereof can be prepared by reacting the compound (D-i) or a salt thereof with an halogenating agent
Suitable halogenating agent may include a conventional one used for halogenation of hydroxy group such as phosphorus compound (e.g., phosphoryl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, etc.) or the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under warming to heating.
Process E:
The compound (E-2) can be prepared by subjecting a compound (E-l) to dehalogenative reduction. The dehalogenative reduction to be used in this process is a conventional one such as a catalytic reduction (.e.g, palladium on carbon, palladium black, spongy palladium, etc.) and the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.
Process F:
The compound (F-2) or a salt thereof can be prepared by reacting the compound (F-i) or a salt thereof with a nucleophile selected from alkanol and arenethiol or a salt thereof.
The present reaction is usually carried out in the presence of a base as aforementioned in Process
A in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling or at ambient temperature.
Process G:
The compounci(G-2) or a salt thereof can be prepared by reacting the compound (G-i) or a salt thereof with a carboxy protective agent.
Suitable agent to be used in this reaction may include conventional ones such as lower alkyl
halide (e.g. methyliodide, etc.) di(lower)alkylsulfate (e.g. dimethylsulfate, etc.), diazo(lower)alkane (e.g.
diazomethane, etc.), lower alkanol (e.g. methanol, ethanol, etc.) or the like.
The present reaction is usually carried out in the presence of an acid such as an organic or an
inorganic acid, for example, formic acid, trifluoroacetic, benzenesulfonic acid, p-toluenesulfonic acid,
hydrochloric acid or the like in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling to heating.
Process H:
The compound (H-2) can be prepared by reacting the compound (H-i) with a compound of the formula: RlaSCH2SORlo.
The present reaction is usually carried out in the presence of a base as aforementioned Process A in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out under cooling to under heating.
Process I:
The compound (1-1) can be prepared by reacting the compound (H-2) with an acid and/or acid anhydride such as acetic acid and/or acetic anhydride. The reaction can preferably be carried out in the presence of alkali metal perchlorate (e.g. sodium perchlorate, potassium perchlorate, etc.), alkaline earth metal perchlorate (e.g., magnesium perchlorate, calcium perchlorate, etc.) and the like, and an acid such as an organic carboxylic acid (e.g., formic acid, etc.).
The reaction temperature is not critical and the reaction is preferably carried out under warming to heating.
Process J:
The compound (J-2) or a salt thereof can be prepared by subjecting the compound (J-1) to elimination reaction of the carboxy-protective group.
The elimination reaction is carried out by a conventional method, such as hydrolysis or reduction.
These methods may be selected depending on the kind of the protecting group to be eliminated.
The hydrolysis may include a method being conducted in the presence of an acid (referred to as acidic hydrolysis hereinafter) base (referred to as hasi hydrolysis hereinafter) or hvdrazine.
Suitable acid for the acidic hydrolysis includes an organic or an inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. Preferable acid is one which can easily be removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acid suitable for the reaction can be selected according to the kind of protective group to be eliminated, and the elimination reaction can be carried out in the presence or absence of a solvent.
Suitable solvent includes a conventional organic solvent, water or a mixture thereof. When the hydrolysis is carried out in the presence of trifluoroacetic acid, the reaction may be carried out in the presence of anisole.
The basic hydrolysis is preferably applied for eliminating the protective group. Suitable base includes, for example, an inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxide (e.g. magnesium hydroxide and calcium hydroxide), alkali metal carbonate (e.g., sodium carbonate and potassium carbonate), alkaline earth metal carbonate (e.g., magnesium carbonate and calcium carbonate), alkali metal bicarbonate (e.g., sodium bicarbonate and potassium bicarbonate), alkaline earth metal phosphate (e.g. magnesium phosphate and calcium phosphate), alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate and dipotassium hydrogen phosphate) or an organic base such as alkali metal acetate (e.g., sodium acetate and potassium acetate), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, and sodium propoxide), trialkylamine (e.g., trimethylamine and triethylamine), picoline, Nmethylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo (4,3,0)-5-nonene, 1 ,4-diazabicyclo(2,2,2)octane or 1 ,5-diazabicyclo(5,4,0)-5-undecene. The basic hydrolysis is often carried out in water or a hydrophilic or moistened organic solvent or a mixture thereof. Suitable reductive elimination reaction may include, for example, reduction with an alkali metal borohydride (e.g., sodium borohydride).
The reaction temperature is not critical and may be suitably selected in accordance with the kind of the protective group to be eliminated and the method to be applied, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly elevated temperature.
Process K:
The compound (K-2) or a salt thereof can be prepared by reacting the compound (K-i) or a salt thereof with an amino-protective agent.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvents may be used in a mixture with water. The reaction can be usually carried out under cooling.
When the carboxylic acid is used as the amino-protective agent in a form of the free acid or salt in this reaction, the reaction is preferably carried out in the presence of a condensing agent such as a carbodiimide compound (e.g., N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N1-(4-diethylamino-cyclohexyl) carbodiimide, N,N'-diethylcarbodiimide,
N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylamino-propyl) carbodiimide, etc.), a ketenimine compound (e.g., N,N'-carbonylbis(2-methylimidazole), pentamethylene-ketene-N-cyclohexylimine, diphenylketene-N-chclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g.
ethoxyacetylene), p-chlorovinyiethyl ether, a sulfonic acid ester of N-hydroxybenzotriazole derivative (e.g., 1 -(4-chlorobenzenesulfonyloxy)-6-chloro-1 H-benzotriazole, etc.), a phosphorus compound (e.g., trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, triphenylphosphine, etc.), thionyl chloride, oxalyl chloride, N-ethyl-benzisoxazolium salt, Nethyl-5-phenylisoxazolium-3-sulfonate, a reagent (referred to as so-called "Vilsmeier reagent") formed by the reaction of an amide compound such as dimethylformamide, diethylacetamide, N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like.
Process L:
The compound (L-2) can be prepared by oxidizing the compound (L-1).
The present oxidation reaction is conducted by a conventional method which is applied for the transformation of so-called activated methylene group into carbonyl group. That is, the present oxidation is conducted by a conventional method such as oxidation by using selenium dioxide or the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is preferably carried out under warming to heating.
Process M:
The compound (M-2) or a salt thereof can be prepared by reacting the compound (M-1) or its hydrate or a salt thereof with a compound of the formula: R6~ONH2 or a salt thereof.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, and when a salt of the compound of the formula: R6-0NH is used in the reaction, the reaction is preferably carried out in a presence of a base as aforementioned in Process A.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.
Process N:
The compound (N-2) or a salt thereof can be prepared by subjecting the compound (N-i) or a salt thereof to elimination reaction of the amino-protective group.
The present reaction can be carried out in substantially the same manner as that of Process J.
Accordingly, the detailed explanation therefor is to be referred to said Process J.
Process 0:
The compound (0-2) or a salt thereof can be prepared by reacting the compound (0-1) or a salt thereof with a nitrosating agent.
Suitable nitrosating agent may include a conventional one such as alkali metal nitrite (e.g., sodium nitrite and potassium nitrite) and the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is preferably carried out under cooling or at ambient temperature.
Process P:
The compound (P-2) or a salt thereof can be prepared by reacting the compound (P-i) or a salt thereof with a substituting agent capable for substituting a hydrogen atom of the hydroxy in the compound (P-i) by R6' group.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
When the substituting agent is diazo compound, the reaction can be carried out under cooling or at ambient temperature.
Process O: The compound (0-2) or a salt thereof can be prepared by reacting the compound (Q-1) or a salt thereof with a halogenating agent.
Suitable halogenating agent may include a conventional one used for halogenation of an aromatic ring such as chlorine, bromine and the like.
The present reaction is usually carried out in a conventional solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction can be carried out at ambient temperature.
It is to be noted that, in the aforementioned reactions and/or the post-treatment of the reaction mixture, the aforementioned geometric isomer may be occasionally transformed into the other geometric isomer and such case is also included in the scope of the present invention.
The following examples are given for the purpose of illustrating the present invention.
Example 1
(1) A 1 5% n-hexane solution (636 g.) of n-butyllithium was added to a solution of 6-amino-2methylpyridine (64.8 g.) in tetrahydrofuran (500 ml.) at -20 to -300C over one hour, and stirred at -8 to -i 00C for 30 minutes. To the solution was added trimethylsilylchloride (161.7 g.) at --1 5 to -50C over 40 minutes, and the resultant solution was stirred at room temperature overnight. The solution was filtered through by a column packed with silica gel (180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure.The residue was purified by fractional distillation to give 6-[N,N-bis(trimethylsilyl)-amino-2-methyípyridine (117.6 g.), b.p. 95 to 97 C/5-6 mm.
N.M.R. # ppm (CCI4): 0.13 (18H, s), 2.35 (3H, s), 6.43 (1 H, d, J=8Hz), 6.60 (1 H, d, J=8Hz), 7.25 (1H, t, J=8Hz).
(2) A 15% n-hexane solution (338.6 g.) of n-butyllithium was dropwise added to a solution of 6 [N,N-bls(trimethylsilyl)aminol-2-methylpyridine (100 g.) in anhydrous tetrahydrofuren (30 ml.) at -20 to -30 C over one hout and the solution was stirred at 20 to 23 C for one hour,The resultant solution was added in small portions to crushed dry ice (1 kg.) under stirring, and stirred till a room temperature. After removing tetrahydrofuran from the solution under reduced pressure, absolute ethanol (1 1) was added to the residue. 30% Ethanol solution (660 ml.) of hydrochloric acid was dropwise added to the soslution at -5 to -10 C, nd further hydrogen chloride gas was bubbled at 0 to 5 C for 30 minutes and then the solution was stirred at 1 C overmight.After removing ethanol frum the resultant solution, the residue was dissolved in water, and washed with ethyl acetate 3 times. The solution was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give the crude product (54 g.). The product was purified by column chromatography on silica gel (1 kg.) with an eluent (ethyl acetate+benzene) to give ethyl 2-(6aminopyridin-2-yl)acetate (30.2 g.), mp 66 to 680C.
I.R. ## : 3430, 3340, 3200, 1730, 1645, 1480, 1190 cm-1 N.M.R. a ppm (CDCI3): 1.25 (3H, t, J=6Hz), 3.67 (2H, s), 4.20 (2H, q, J=6Hz), 5.33 (2H, broad s),
6.43 (1 H, d, J=8Hz), 6.62 (1 H, d, J=8Hz), 7.40 (1 H, t, J=8Hz).
Example 2
Acetic anhydride (16.6 ml.) and 98% formic acid (7.32 ml.) were mixed at room temperature and stirred at 50 to 660C for 30 minutes. The solution was dropwise added to a solution of ethyl 2-(6aminopyridin-2-yl)acetate (26.5 g.) in ethyl acetate (250 ml.) at 20 to 230C over 30 minutes, and stirred at the same temperature for one hour. Cool water was added to the resultant solution and shaked sufficiently. The ethyl acetate layer was separated, washed with water, an aqueous solution of sodium bicarbonate and water in turn, dried and concentrated under reduced pressure to give ethyl 2 (6-formamidopyridin-2-yl)acetate (28 g.), mp 35 to 38 C.
I.R. ## : 3250, 3100-, 1738, 1690, 1580, 1480, 1305, 1277 cm-1 n.M.R. # ppm (DMSO-do) : 1.17 93H, t, J=8Hz), 3.75 (2H, s), 4.08 (2H, q, J=8Hz), 6.85 (0.5H,
broad d, J=8Hz), 7.95 (0.5H, broad s), 7.08 (1H, d, J=8Hz), 7.73 (1H, t, J=8Hz), 8.33 (0.5H,
broad s), 9.25 (0.5H, broad d), 10.58 (1 H, broad s).
Example 3
(1) To a soiutlon of ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g.) in dioxane (260 ml.) was added selenium dioxide (16.65 g.) in small portions at 85 to 900C over one hour and stirred at the same temperature for one hour. After cooling the resultant solution the dioxane layer was separated and concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and treated with activated charcoal and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp 124 to 1 260C.
I.R. ## : 3220, 3100, 1737, 1720, 1690, 1273, 1233 cm-1 N.M.R. a ppm (DMSO-d6): 1.34 (3H, t, J=8Hz), 4.44 (2H, q, J=8Hz), 7.33 (0.65H, broad s), 7.8- 8.2 (0.35H), 7.84 (1H, d, J=8Hz). 8.09 (1H, t, J=8Hz), 8.44 (0.35H, broad s), 9.22 (0.65H,
broad s), 10.85 (1H, broad s).
(2) 2N Sodium hydroxide solution [solvent:water(1 part)+ethanol (4 parts)] (14.87 ml.) was added to a solution of ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (6.00 g.) in ethanol (180 ml.) at room temperature and stirred at the same temperature for 20 minutes. Methoxyamine hydrochloride (2.71 g.) was added to the resultant solution, stirred at room temperature for 1.5 hours and then concentrated to a small volume under reduced pressure. The precipitates were collected by filteration washed with ethyl acetate and water, dissolved in methanol and then treated with activated charcoal.
The solution was concentrated under reduced pressure and then the precipitates were collected by filtration to give 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (3.63 g.), mp 170 to 171 C (dec.).
I.R. PmuajXol 3230, 3132, 1745, 1680, 1575, 1450, 1320, 1208, 1O32cm1 N.M.R. 8 ppm (DMSO-d6): 3.70 (3H, s), 6.90 (0.6H, broad d), 7.9 (0.4H, broad s), 7.10 (1 H, d, J=8Hz), 7.75 (1H,t, J=8Hz). 8.38 (0.4H, broad s), 9.25 (0.6H, broad d), 10.58 (1H, broad d).
Example 4
To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (4.4 g.) in ethanol (44 ml.) was added 2N sodium hydroxide solution [solvent:water (1 part)+ethanol (4 parts)] (15.9 ml.) at 18 to 200C over 30 minutes, and then the solution was stirred at room temperature for one hour. After 1 N hydrochloric acid (31.7 ml.) was added to the solution, the solution was concentrated under reduced pressure. The residue was extracted with hot ethyl acetate (500 ml.) and the extract was concentrated under reduced pressure. The residue was washed with ethyl acetate to give 2-(6-formamidopyridin-2-yl)acetic acid (2.5 g.), mp 125 to 1 260C (dec.).
I.R. ## : 3270, 1720, 1655, 1575, 1460 cm-1
N.M.R. a ppm (DMSO-d6+D20): 3.70 (2H, s), 6.9 and 7.9 (1 H, m), 7.10 (1'H, d, J=8Hz), 7.75 (1 H, t,J=8Hz), 9.25 and 8.38 (iH, broad s).
Example 5
A suspension of 2(6-formamldopyrldin-2-yl]-2-methoxylminoacetic acid (1.5 g.) and conc.
hydrochloric acid (0.77 g.) in methanol (30 ml.) was stirred at room temperature for 45 minutes. After concentrating the resultant solution under reduced pressure, the residue was washed with diethyl ether. The precipitates were collected by filtration to give 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (1.63 g.), mp 100 to 1050C.
I. R. vNmuaixol: 3400-31 50, 1730, 1670, 1245, 1050, 803 cm 1 N.M.R. 8 ppm (DMSO-d6): 4.13 (3H, s), 6.89 (1 H, d, J=8Hz), 7.22 (1 H, d, J=8.5Hz), 7.95 (1 H, dd, J=8.5Hz, 8Hz).
Example 6
Bis(trimethylsilyl)acetamide (1.61 g.) was added to a stirred suspension of 2-(6-aminopyridin-2yl)-2-methoxyiminoacetic acid hydrochloride (410 mg.) in ethyl acetate (5 ml.) all at once, and stirred at 400C for 50 minutes. Trifluoroacetic anhydride (1.3 g.) was dropped into the solution at 0 to -50C over 30 minutes, and then the solution was stirred at the same temperature for 3 hours. Ethyl acetate (10 ml.) and water (3 ml.) were added to the resultant solution. The solution was washed with water and a saturated aqueous solution of sodium bicarbonate in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-(6-trifluoroacetamidopyridin-2-yl)-2-methoxy- iminoacetic acid (470 mg.), mp 194 to 1 950C.
I.R. ## : 3350, 1680-1670, 1600, 1380, 1040, 850, 810 cm-1
Example 7
1 N Sodium hydroxide (27.5 ml.) was added to a stirred solution of ethyl 2-(6-formamidopyridin- 2-yl)-glyoxylate (5.55 g.) in ethanol (100 ml.) at room temperature, and the solution was stirred at the same temperature for 30 minutes. To the solution was added hydroxylamine hydrochloride (1.9 g.) all at once, and the solution was stirred at room temperature for 2 hours. After removing ethanol from the resultant solution under reduced pressure, ethylacetate was added to the residue, and then the solution was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2 with 10% hydrochloric acid.The precipitates were collected by filtration, washed with water and dried to give 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), mp 190 to 1 920C (dec.).
I.R. pNUaixol: 3120, 1700, 1665, 1620 cm-1
Example 8
A mixture of 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), dichloroacetyl chloride (7.6 g.) and methylene chloride (100 ml.) was stirred at room temperature for 5 hours. The precipitates were collected by filtration, washed with diethyl ether and dried to give 2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (4.6 g.), mp 88 to 90 C.
R. ## : 1800, 1720, 1620 cm-1
Example 9
A mixture of acetic anhydride (32.7 g.) and formic acid (16.2 g.) was stirred at 50 to 600C for 30 minutes. The solution was added to a suspension of methyl 2-(2-aminopyrimidin-4-yl)acetate (17.93 g.) in ethyl acetate (300 ml.) at room temperature over 10 minutes, and the solution was stirred at room temperature for 3 hours. After removing the insoluble substance by filtration, water (300 ml.) was added to the filtrate, and then the mixture was adjusted to pH 7 with sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal, and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g.), mp 103 to 107 C.
I.R. ## : 300-3400 (multiple), 1740, 1703, 1600, 1567 cm-1
N.M.R. 8 ppm (DMSO-d6): 3.70 (3H, s), 3.90 (2H, s), 7.25 (1 H, d, J=5Hz), 8.60 (1 H, d, J=5Hz),
9.43 (1 H, d, J=1OHz), 11.07 (1 H, broad d, J=1 OHz) Example 10
(1) Selenium oxide (9.92 g.) was added to a solution of methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.52 g.) in dioxane (200 ml.) at 90 to 950C over 20 minutes, and stirred at the same temperature for an hour. After cooling the resultant solution, the solution was filtered through a column packed with silica gel (20 g.), washed with dioxane and concentrated under reduced pressure. The residue was dissolved in acetone and filtered, and then the filtrate was concentrated under reduced pressure.The residue was triturated with chloroform to give a crude product (8.2 g.). The product was added to ethyl acetate, heated and an insoluble material was filtered out. The filtrate was cooled, and the precipitates were collected by filtration to give methyl 2-(2-formamidopyrimidin-4-yl)glyoxylate (5.55 g.). The product was recrystallized from ethyl acetate (saturated with water) to give mono hydrate thereof, mp 143 to 1440 C.
Anal. Calcd. for C8H,N304 H20 C H N
Calcd. 42.30 3.99 18.50
Found 42.22 3.95 18.34 I.R. ## 3270, 3200, 1750, 1710, 1597. 1585. 1416, 1233 cm-1 N.M.R. a ppm (DMSO-d6) : 3.65 (3H, s), 7.30 (2H, s), 7.40 (1 H, d, J=5Hz), 8.63 (1 H, d, J=5Hz),
9.33 (1 H, d, J=1OHz), 10.95 (1 H, bd, J=1 OHz).
(2) 4N sodium hydroxide (10.85 ml.) was added to a solution of methyl 2-(2-formamidopyrimidin-4-yl)glyoxylate mono hydrate (4.55 g.) in methanol (60 ml.), and the solution was stirred for an hour. To the solution was added methoxylamine hydrochloride (1.82 g.) little by little, and the solution was stirred at room temperature for 30 minutes, and then under ice cooling for 30 minutes.
The precipitates were collected by filtration, and dissolved in water. The insoluble substance was filtered out. The filtrate was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and concentrated under reduced pressure. The precipitates were collected by filtration to give 2-(2formamidopyrimidin-4-yl)-2-methoxyiminoacetic acid (0.63 g ). The methanol solution obtained above was concentrated under reduced pressure, and the residue was dissolved in water. The aqueous solution was treated with activated charcoal, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure.The precipitates were collected by filtration to give the same object compound (0.73 g.), total yield 1.36 g, mp 180 to 1 820C (dec.).
I.R. ## : 3300-2400 (multiple), 1750, 1870, 1590, 1573, 1408, 1240, 1048 cm-1
N.M.R. # ppm (DMSO-d6): 4.00 (3H, s), 7.47 (1 H, d, J=5Hz), 8.60 (1 H, d, J=5Hz), 9.23 (1 H, d, J=1 OHz) 11.02 (1 H, broad d, J=1 OHz).
Example 11
1 N Sodium hydroxide solution (8.5 ml.) was added to a stirred solution of ethyl 2-(6-formamidopyridin-2-yl)-glyoxylate (1.9 g.) in ethanol (30 ml.) at room temperature and stirred at the same temperature for 30 minutes. After adding ethoxylamine hydrochloride (912 mg.) to the solution, the solution was stirred at room temperature for 4 hours. The resultant solution was concentrated under reduced pressure, and ethyl acetate and an aqueous solution of sodium bicarbonate were added to the residue. The aqueous layer was separated and ethyl acetate was added to the solution. The solution was adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated under reduced pressure.The residue was triturated with a mixture of diethyl ether and petroleum ether to give 2-(6-formamidopyridin-2-yl)-2-ethoxyiminoacetic acid (920 mg.), mp. 155 to 1 560C (dec.).
I. R. i'mNuaIxcI:325O, 1740, 1650cm1
N.M.R. ppm (DMSO-d6): 1.3 (3H, t, J=7Hz), 4.3 (2H, q, J=7Hz), 6.8-8.2 (3H, m), 9.4 H, broad d), 10.5 (1 H, broad d)
Example 12
(1) A mixture of formic acid (20 g.) and acetic anhydride (41.3 g.) was stirred for 30 minutes at 500C and thereto was added methyl 4-amino-2-pyridinecarboxylate (11 g.) at ambient temperature, and then the mixture was stirred for 2 hours at 70-750C. After the removal of the solvent from the reaction mixture, the residue was recrystallized from ethanol (160 ml.) to give a pale yellow powder of methyl 4-formamido-2-pyridinecarboxylate (8.3 g.), mp. 185 to 1 86.50C.
I. R. i'Nmua0I: 3200-3300, 1 690, 1 675, 1 585, 1 570, 1495, 1420, 1260, 990, 860, 840 cm 1 (2) To a mixture of methyl 4-formamido-2-pyridinecarboxylate (9.9 g.), methyl methylthiomethyl sulfoxide (6.82 g.) and N,N-dimethylformamide (200 ml.) was added 50% sodium hydride (7.92 g.) with stirring at 1 00C and the stirring was continued for further 10.5 hours at 450C. After the removal of N,N-dimethylformamide from the reaction mixture, to the residue was added a cold mixture of ethyl acetate and diluted hydrochloric acid. The ethyl acetate layer was separated and the remaining aqueous layer was further extracted with ethyl acetate. The combined extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and the solvent was distilled off.
The residue (6.0 g.) was washed with a mixture of ethyl acetate and diethyl ether, collected by filtration and then dried to give the brownish yellow powder of 4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (1.96 g.), mp. 132 to 132.50 C. After the concentration of the filtrate, the precipitates were collected by filtration, washed with diethyl ether and then dried to give the same compound (1.11 g.). Total yield: 3.07 g.
I. R. pNLI: 3200-3225, 1 680, 1580, 1290. 1170, 1020, 845 cm (3) After stirring a mixture of acetic anhydride (14 ml.) and formic acid (136 ml.) for 10 minutes at 40 to 50 C, 4-formamido-2-(2-mothanesulfinyl-2-methylthloacetyl)pyrldlne (3.7 g.) was added thereto, and then the stirring was continued at 650C for 30 minutes. To the mixture was added sodium periodate (0.872 g.), and the mixture was stirred for 1 5 minutes. After the removal of the solvent from the reaction mixture, the residue was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium bicarbonate, aqueous sodium thiosulfate and water successively, and then dried over anhydrous magnesium sulfate.The solvent was distilled off and the residue was washed with diethyl ether, collected by filtration and then dried to give a pale yellow powder of S-methyl 2-(4formamidopyridin-2-yl)thioglyoxylate (1.96 g.), mp. 145 to 1480 C.
I. R. vNmuaixal: 3150-3300, 1690 1670, 1585, 1570, 1500, 1420, 1265, 990, 860, 835, 746 cm (4) A mixture of S-methyl 2-(4-formamidopyridin-2-yl)thioglyoxylate (1.07 g.), methanol (20 ml.) and 1N aqueous solution of sodium hydroxide (5.7 ml.) was stirred for 50 minutes at ambient temperature to give a solution containing 2-(4-formamidopyridin-2-yl)glypxylic acid. To the solution was added O-methylhydroxylamine hydrochloride (438 mg.), and the mixture was stirred for an hour at ambient temperature. After the removal of the solvent from the reaction mixture, to the residue was added water (5 ml.), and the mixture was washed with ethyl acetate and then water was distilled off.
The remaining water in the residue was azeotropically removed with ethanol and benzene in turn to give a ple brown powder of 2-(4-formamidopyrldin-2-yl)-2-methoxylminoacetic acid (syn isomer0 (960 mg.).
N.M.R. # p ppm (DMSO-d6+D20): 3.93 (3H, s), 7.6 (1 H, broad) 8.1 (broad s) 8.55 (broad s) (1 H) 8.45 (1 H, broad s) Example 13
(1) A mixture of formic acid (559.3 g.) and acetic anhydride (1033.4 g.) was stirred for 30 minutes at 40 to 50 C and thereto was added methyl 6-amino-2-pyridinecarboxylate (616 g.) at 400C, and then the mixture was stirred for 1 hour at 800 C. After the removal of the solvent from the reaction mixture, the residue was dissolved in a mixture of benzene and n-hexane and then filtered.
Thus obtained precipitates were recrystallized from benzene (2 1.) to give methyl 6-formamido-2
pyridinecarboxylate (647.8 g.), mp. 134 to 1 360C.
Element analysis:
C N H
Calcd. (%) 53.33 4.48 15.55
Found (%) 53.37 4.40 15.58 l.R. PmuajxOl: 3200, 1740, 1700 cm-1
(2) To a mixture of methyl 6-formamido-2-pyridinecarboxylate (435.7 g.), methyl methylthiomethyl suifoxide (300 g.) and N,N-dimethylformamide (2.2 1.) was added 50% sodium hydride (348 g.) with stirring under ice-cooling, and the mixture was stirred for 30 minutes at ambient temperature. To the reaction mixture was added benzene (4.41.) under ice-cooling and the precipitates were collected by filtration. The precipitates were added to a mixture of methylene chloride (3 1.), ice (2 kg.) and concentrated hydrochloric acid (730 ml.). The mixture was adjusted to pH 7 with sodium bicarbonate and then extracted with methylene chloride. The extract was dried over magnesium sulfate and the solvent was distilled off. The residue was crystallized in diethyl ether, collected by filtration and then dried to glve 6-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (430 g.), mp. 130 to 13200.
I.R. ## : 3250, 3150, 3050, 1710, 1690, 1600, 1510 cm-1
N.M.R. a ppm (d6-acetone+D20): 2.30 (3H, s), 2.88 (3H, s), 6.00 (1 H, s), 7.7-8.2 (3H, m)
(3) A mixture of 6-formamldo-2-(2-methanesulflnyl-2-mathylthioacetyl)pyridine (424 9.), sodium periodate (100 9.) in acetic acid (2.1 1.) was stirred for 30 minutes at 70 C. After the removal of the solvent from the reaction mixture, to the residue were added water (5 I.) and sodium thiosulfate (116 g.), and then the mixture was adjusted to pH 7 with sodium bicarbonate.The precipitates were collected by filtration, washed with water and then dried to give S-methyl 2-(6-formamidopyridin-2yl)thioglyoxylate (246.4 9.), mp. 163 to 1 650C. Further, the same compound (12 g.) was obtained from the aqueous layer by extraction with ethyl acetate.
I.R. ## : 3250, 3150, 3080, 1700, 1670, 1595, 1580, 1510 cm-1
N.M.R. Sppm (acetone-d6+D2O) : 2.57 (3H, s), 7.77-8.27 (3H, m)
(4)-a A mixture of S-methyl 2-(6-formamidopyridin-2-yl)thioglyoxylate (4.48 g.), methanol (20 ml.) and 1 N aqueous solution of sodium hydroxide (20 ml.) was stirred for 50 minutes at ambient temperature to give a solution containing 2-(6-formamidopyridin-2-yl)glyoxylic acid. To the solution was added O-propylhydroxylamine hydrochloride (2.23 g.), and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was adjusted to pH 7 with hydrochloric acid and the methanol was distilled off.The remaining aqueous mixture was washed with ethyl acetate, and ethyl acetate was added thereto and then adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and then the solvent was distilled off. Thus obtained product was washed with a mixture of diethyl ether and diisopropyl ether and then dried to give 2-(6-formamidopyridin-2-yl)-2-propoxyiminoacetic acid (syn isomer) (1.76 g.), mp. 140 to 1420C (dec.).
R. ## : 3250, 3100, 2600, 1755, 1670, 1620, 1580 cm-1 N.M.R. S ppm (acetone-d6+D20): 0.96 (3H, t, J=7Hz), 1.56-1.84 (2H, m), 4.2 (2H, t, J=7Hz), 7.0-8.32 (3H, m)
Similarly, the following compounds were obtained.
(4)-b (2-(6-Formamidopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer), mp.
183 to 1 840C (dec.)
I.R. ## : 3200, 1760, 1680 cm-1
N.M.R. 8 ppm (DMSO-d6): 4.78, 5.07 (2H, ABq, J=9Hz), 7.0-8.2 (3H, m), 9.0-9.3 (1 H, m),
10.76 (1H, m)
(4)-c 2-(6-Formamidopyridin-2-yl)-2-isopropoxyiminoacetic acid (syn isomer), mp. 140 to 1500C (dec.) I.R. ## : 3300, 2600, 1750, 1670, 1620, 1580, 1510 cm-1 N.M.R. # ppm (acetone-d6+D20): 1.3 (6H, d, J=6Hz), 4.36-4.64 (1 H, m), 6.92-8.28 (3H, m)
(4)-d 2-Allyloxyimino-2-(6-formamidopyridin-2-yl) acetic acid (syn isomer), mp. 1400C (dec.).
I.R. ## : 3250, 3100, 2600, 1760, 1670, 1620, 1580 cm-1
N.M.R. Sppm (acetone-d6+D2O): 4.67-4.9 (2H, m), 5.17-5.6 (2H, m), 5.8-6.52 (lH, m).
7.0-8.33 (3H, m)
(4)-e 2-(6-Formamidopyridin-2-yl)-2-propargyloxyiminoacetic acid (syn isomer), mp. 145 to 150 C (doc.).
I.R. ## : 3350, 3250, 3100, 2600, 1755, 1685, 1620, 1580, 1510 cm-1
N.M.R. 8 ppm (acetone-d6+D20): 3.04 (1 H, t, J=2Hz), 4.88 (2H, d, J=2Hz), 7.0-8.28 (3H, m)
(4)-f2-Butoxyimino-2-(6-formamidopyrldin-2-yl)-acetic acid (syn isomer), mp. 129 to 1310C (dec.).
I.R. ## : 3150, 1755, 1670 cm-1 N.M.R.# ppm (DMSO-d6) : 0.7-1.9 (7H, m), 4.20 (2H, t, J=6Hz), 7.0-8.1 (3H, m), 10.7 (1H,
broad d)
(4)-g 2-lsobutoxyimino-2-(6-formamidopyridin-2-yl)-acetic acid (syn isomer), mp. 153 to 1 550C (dec.).
I.R. ## : 3250, 3150, 1750, 1680, 1620, 1580 cm-1 N.M.R. 8 ppm (acetone-d6+D20): 0.96 (6H, d, J=6Hz), 1.88-2.16 (1 H, m), 4.0 (2H, d, J=6Hz) 7.0-8.28 (3H, m)
(4)-h 2-(6-Formamidopyridin-2-yl)-2-phenoxyiminoacetic acid (syn isomer), mp. 148 to 150 C (dec.).
I.R. ## : 1730, 1660, 1560 cm-1
N.M.R. Sppm (DMSO-d6): 6.80-8.2 (8H, m), 10.80 (1 H, d, J=8Hz).
Example 14
(1) Methyl 6-formamido-3-pyridinecarboxylate, mp. 218 to 2200C was obtained according to the similar manner to that of Example 12(1)
I.R. ## : 3100, 3020, 1710, 1605, 1540 cm-1 N.M.R. a ppm (DMSO-d6+D20): 3.84 (3H, s), 8.12-8.84 (3H, m)
(2) 2-Formamido-5-(2-methanesulfinyl-2-methylthioacetyl)pyridine, mp. 125 to 1 270C was obtained according to the similar manner to that of Example 1 2(2).
I.R. ## : 3200, 1710, 1660, 1600, 1545 cm-1 (3) S-Methyl 2-(6-formamidopyridin-3-yl)thloglyoxylate, mp. 152 to 1 540C was obtained according to the similar manner to that of the Preparation Example 1-2(3) by using acetic acid instead of acetic anhydride and formic acid.
I.R. ## : 3250. 3150, 3050. 1730. 1680. 1600. 1590, 1510 cm-1
N.M.R. 8 ppm (acetone-d6+D20): 2.47 (3H, s), 8.35-9.17 (3H, m)
(4) A mixture of S-methyl 2-(6-formamldopyrldin-3-yl)thioglyoxylate (13 g.), methanol (50 ml.),
1 N aqueous solution of sodium hydroxide (58 ml.) and water (1 50 ml.) was stirred at ambient temperature for 30 minutes. To the mixture was added O-methylhydroxylamine hydrochloride (4.85 g.) and then stirred for an hour. The reaction mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate, and the methanol was removed by distillation under reduced pressure. The remaining aqueous solution was washed with ethyl acetate and thereto was added ethyl acetate.The resultant mixture was adjusted to pH 2 with 10% hydrochloric acid and thereto was added sodium chloride, and the mixture was stirred for a while. The precipitates were collected by filtration washed with diispropyl ether and then dried to give 2-(2-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (syn isomer) (2.0 g.), mp. 159 to 161 C (dec.).
I.R. ## : 1735. 1665, 1590, 1550 cm-1
N.M.R. Sppm (DMSO-d6): 4.00 (3H, s), 7.8-8.5 (3H, m), 10.87 (tH, d, J=6Hz)
On the other hand, the ethyl acetate layer was separated from the filtrate and the remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, dried over magnesium sulfate and then the solvent was distilled off to give powder of 2-(6formamidopyridin-3-yl)-2-methoxyiminoacetic acid (a mixture of syn and anti isomers), Thus obtained powder was dissolved in an aqueous solution of sodium bicarbonate and then adjusted to pH 2 to 3 with 10% hydrochloric acid.The precipitates were collected by filtration and then dried to give 2-(6formamidopyridin-3-yl)-2-methoxyiminoacetic acid (anti isomer) (1.45 g.), mp. 168 to 1 700 C (dec.).
I. R. vNmuaixal: 1 705, 1 605, 1 535 cm-1 N.M.R.3 ppm (DMSO-d): 4.00 (3H, s) 7.8-8.5 (3H, m), 10.80 (1 H, d, J=7Hz)
Further, the mother liquor was adjusted to pH 3 to 4 with an aqueous solution of sodium bicarbonate. The resultant solution was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and then the solvent was distilled off to give further 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (syn isomer) (2.5 g.).
Example 15
(1) Methyl 2-formamido-4-pyridine mp. 196 to 1 970C was obtained according to the similar manner two that of Example 12 (1) I.R. ## : 3100. 1740, 1710, 1580, 1540 cm-1 N.M.R. Sppm (DMSO-d6): 3.92 (3H, s), 7.48-8.6 (3H, m)
(2) 2-Formamido'-4-(2-methanesulfinyl-2-methylthioacetyl)pyndine, mp. 123 to 1 250C was obtained according to the similar manner to that of Example 12(2).
I,.R. ## : 3150, 3050, 1690, 1610, 1565 cm-1
(3) S-Methyl 2-(2-formamidopyridin-4-yl)thioglyoxylate, mp. 165 to 1 670C was obtained according to the similar manner to that of Example 12(3) using acetic acid instead of acetic anhydride and formic acid.
I.R. ## : 3250, 3100, 1710, 1680, 1610, 1565, 1520 cm-1 N.M.R. 8 ppm (CDCl3+D20): 2.48 (3H, s), 7.5-8.6 (3H, m)
(4) 2-(2-Formamidopyridin-4-yl)-2-methoxyiminoacetic acid (syn isomer), mp. 170 to 1 720C (dec.) was obtained according to the similar manner to that of Example 12(4) via 2-(2-formamidopyridin-4-yl)-glyoxylic acid.
I.R. ## : 2500, 1710, 1640, 1615, 1600, 1520 cm-1
N.M.R. a ppm (DMSO-d6+D20): 4.02 (3H, s), 7.0-8.6 (3H, m)
Example 16
(1) A mixture of ethyl 2(4-amlno-6-hydroxypyrlmldin-2-yl)acetate (15.8 g.) and phosphoryl chloride (75 ml.) was stirred for 4 hours under heating at 80 to 900 C. The resultant solution was allowed to cool and phosphoryl chloride was distilled off. The remaining oily substance was poured into a mixture of ice-water (200 ml.) and ethyl acetate (200 ml.). The resultant mixture was neutralized with an aqueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then the solvent was distilled off.The resultant residue was washed with diisopropyl ether and then dried to give pale brown crystals of ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate (8.1 g.), mp. 127 to 1 280C.
I.R. ## : 3250-3400, 1700, 1650, 1520-1580, 1320, 1160-1210, 860, 840 cm-1 (2) Ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (oil) was obtained according to the similar manner to that of Example 12(1)
I.R. ## : 2800-3600, 1680-1730, 1560, 1140-1190, 1020 cm-1
N.M.R. ss ppm (CDCl3):: 1.30 (3H, t, J=8Hz), 3.92 (2H, s), 4.23 (2H, q, J=8Hz), 8.3-9.3 (1 H, broad), 9.4-10.4 (2H, broad)
(3) To a solution of ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (2.3 g.) and sodium acetate (0.93 g.) in 80% ethanol (50 ml.) was added 10% palladium on carbon (0.2 g.), and the mixture was stirred under a hydrogen atmosphere for 8 hours at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated. To the residue were added ethyl acetate and a small amount of water and the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with water and dried over magnesium sulfate and then the solvent was distilled off.Thus obtained oily substance (2.2 g.) was purified by column chromatography on silica gel (40 g.) using mixture of benzene and ethyl acetate as an eluent to give a pale brown solid of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (1.3 g.), mp. 80 to 930C.
I.R. ## : 1710, 1670, 1530, 1310, 1170, 840 cm-1
N.M.R. 8 ppm (CDCl3): 1.23 (3H, t, J=8Hz), 3.78 (2H, s), 4.33 (2H, q, J=8Hz), 6.5-8.3 (1 H,
broad), 8.37 (1 H, d, J=5Hz), 9.15 (1 H, broad s), 9.45 (1 H, broad s)
(4) To a solution of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (7.0 g.) in acetic acid (34 ml.) was added dropwise a solution of sodium nitrite (4.1 g.) in water (12 ml.) over a 15 minutes period with stirring at 10 C. and the stirring was continued at the same temperature for an hour and at ambient temperature for another an hour. After cooling the reaction mixture in an ice bath, water (50 ml.) was added thereto.The precipitates were collected by filtration and washed successively with water and diethyl ether and then dried to give a quantitative yield of a powder of ethyl 2-(4formamidopyrimidin-2-yl)-2-hydroxyiminoacetate, mp. 164 to 1 800C (dec.).
N.M.R. 8 ppm (DMSO-d6): 1.30 (3H, t, J=8Hz), 4.40 (2H, q, J=8Hz), 7.5 (1 H, broad), 8.73 (1 H, d, J=6Hz), 9.05 (1 H, broad s)
(5) Ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate (7.0 g) was dissolved in dioxane (200 ml.) under heating and the resultant solution was cooled to ambient temperature in an ice bath, and then thereto was added a solution of diazomethane in diethyl ether with stirring until complete consumption of the starting materials.The reaction mixture was concentrated to give a brown oil, which was purified by column chromatography on silica gel (140 g.) using benzene as an developing solvent and a mixture of benzene and ethyl acetate (3:1) as an eluent to give a pale brown semisolid of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxy-iminoacetate (4.4 g.).
I. R. pFIlam: 3500-3600 (shouldor), 2900-3400, 1680--1740, 1560, 1500, 1250, 1020, 840 1 N.M.R. 8 ppm (CDCl3): 1.40 (3H, t, J=8Hz), 4.17 (3H, s), 4.47 (2H, q, J=8Hz), 7.5-8.6 (1 H,
broad), 8.73 (1 H, d, J=6Hz), 8.9 (1 H, broad)
(6) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.3 g.) and 1 ON aqueous solution of sodium hydroxide (6.1 ml.) in ethanol (100 ml.) was stirred for 3 hours at ambient temperature. To the reaction mixture was gradually added concentrated hydrochloric acid with stirring, whereby said mixture was adjusted to pH 3.The precipitates were collected by filtration and washed successively with ethanol and diethyl ether and then dried to give white crystals of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid.
I.R.v(nujol) : 2500-3300, 1550-1650, 1240, 1000-1040 cm-1
N.M.R. Sppm (D20-NaHCO3): 4.05 (3H, s), 6.67 (1 H, d, J=6Hz), 8.18 (1 H, d, J=6Hz)
The filtrate and washings are combined together and the solvents were distilled off. The residue was pulverized in diethyl ether, collected by filtration and then dried to give further the same compound.
(7) 2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (brown powder), mp. 64 to 700C (dec.) was obtained according to the similar manner to that of the Example 1 2(1)
N.M.R. a ppm (DMSO-d6): 4.02 (3H, s), 7.1-7.9 (1 H, broad) 8.73 (1 H, d, J=6Hz), 8.9 (1 H, broad).
Example 17
(1) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (2.95 g.), selenium dioxide (1.73 g.) in dimethylsulfoxide (30 ml.) was stirred under heating at 50 to 520C for an hour and at 70 to 720C for another 0.5 hours. The reaction mixture was cooled to ambient temperature and filtered, and then the filtered precipitates were washed with ethyl acetate. The filtrate and-washings were combined together and concentrated to the volume of about 5 ml. under reduced pressure below 100 C. The residue was poured into water (50 ml.), and the mixture was stirred for 10 minutes. The resultant mixture was filtered and the filtered precipitates were washed with water. The filtrate and washings were combined together and adjusted to pH 7 with an aqueous solution of sodium bicarbonate.The mixture was washed with ethyl acetate and saturated with sodium chloride and then extracted with a mixture of ethyl acetate and ethanol (2:1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off to give a deep yellow oil of a mixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate, i.e. ethyl 2-(4-formamidopyrimidin-2-yl)-2,2-dihydroxyacetate (2.4 g.).
(2) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (2.95 g.), selenium dioxide (1.87 g.) and N,N-dimethyl formamide (15 ml.) was stirred for an hour under heating at 700 C. The reaction mixture was cooled to ambient temperature and filtered and then the filtered precipitates were washed with a small amount of N,N-dimethylformamide. The filtrate and washings were combined together and the solvent was distilled off. The residue was poured into water (60 ml.) and the resulting mixture.
was stirred for 10 minutes. The mixture was adjusted to pH 6 to 7 with an aqueous solution of sodium bicarbonate and filtered to separate insoluble substances, which were washed with water. The filtrate and washings were combined together and washed successively with diethyl ether and ethyl acetate.
The aqueous mixture was saturated with sodium chloride and then extracted with a mixture of chloroform and ethanol (1:1) (60 ml.x4). The extract was dried over magnesium sulfate and the solvent was distilled off. The resulting oily substance (2.2 g.) was dissolved in ethyl acetate (10 ml.) and subjected to column chromatography on silica gel (15 g.) using ethyl acetate as an eluent. The eluates containing the desired compound were collected and then the solvent was distilled off. The resulting oily substance (1.5 g.) was dissolved in a small amount of ethyl acetate and then crystallized from diisopropyl ether-to give pale yellow crystals of a mixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate, i.e. ethyl 2-(4-formamidopyrimidin-2-yl)-2,2-dihydroxyacetate (0.6 g.), mp. 74 to 78"C.
I.R. 1)NmuaixaI:32OO34O0, 1755,1690-1710,1595, 1580,1280,1250,1215, 1135,1100, 1030, 850 cam~' N.M.R. a ppm (DMSO-d): 1.1 6 (1.8H, t, J=7Hz), 1.26 (1.2H, t, J=7Hz), 4.10 (1.2H, q, J=7Hz)
4.42 (0.8H, q, J=7Hz), 6.97 (1.2H, broad s), 7.0-7.8 (1 H, m), 8.64 (0.6H, d, J=6Hz), 8.90 (0.4H, d, J=6Hz), 8.8-9.6 (1 H, m), 11.15 (1 H, broad s)
(3) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate obtained in
Example 14(a) was dissolved in ethanol (30 ml.) and thereto was added dropwise 1 N ethanol solution of potassium hydroxide (11 ml.) under ice-cooling with stirring, and then stirring was continued for 2 hours at ambient temperature. The reaction mixture was filtered and the filtered precipitates were washed successively with a small amount of ethanol and diethyl ether and then dried to give a brown powder of potassium 2-94-aminoprimidin-2-yl)glyoxylate (0.4 g.).The flltrate and washings were combined together and concentrated to the volume of about 15 ml. and to the residue was added diethylether (20 ml.). the preclpltates were collected by filtration nd washed successively with a small amount of ethanol and diethyl ether to give further a pale brown powder of a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate (0.8 g.).
Total yield: 1.2 g.
I.R. ## : 3380, 3200, 1715, 1665, 1600, 1245, 940, 750 cm-1
N.M.R. a ppm (D20):
6.64 (d, J=6Hz) 6.74 (d, J=6Hz) (1 H) 8.13 (d,J=6HZ) ) (1H) 8.24 (d, J=6Hz) (1 H) (4) To a solution of O-methylhydroxylamine hydrochloride (0.25 g.) in methanol (6 ml.) was added a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate with stirring at ambient temperature, and the mixture was stirred for 4 hours. The reaction mixture was allowed to stand overnight at ambient temperature, filtered, and the filtered precipitates were washed with ethanol.After the filtrate and washings were combined together, the solvents were distilled off. The resultant oily substance was pulverized in acetone (1 5 ml.) and collected by filtration. Thus obtained powder was washed successively with acetone and diethyl ether and then dried to give a pale brown powder of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (290 mg.).
R. ## : 3100-340, 2500-2900, 1540-1600, 1250. 990-1040 cm-1 N.M.R. a ppm (D20+NaHCO3): 4.05 (3H, s), 6.63 (1.H, d, J=6Hz), 8.13 (1 H, d, J=6Hz)
Example 18
(1) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)acetate (crystal) was obtained according to the similar manner to that of Example 12(1)
I.R. ## : 3200, 3140, 1730, 1700, 1540-1580, 1500, 1420, 1380, 1350, 1270, 1240,
1140, 840, 770, 740 cm-1
(2) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl) 2-hydroxyiminoacetate, mp. 1 to 1 120C was obtained according to the similar manner to that of Example 16(4)
I.R. ## : 3200, 1740, 1700, 1675, 1570, 1560, 1380, 1270, 1240, 1180, 1045, 860, 810,
750 cm-1
N.M.R. # ppm (DMSO-d6) : 3.90 (3H, s). 7.57 (1H, s) 9.23 (1H, d, J=9Hz), 11.40 (1H, d, J=9Hz),
13.28 (1H, s)
(3) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl )-2-methoxyiminoacetate (powder), mp. 165 to 1 72.50C was obtained according to the similar manner to that of Example 16(5)
I.R. ## : 3150, 1750, 1700, 1670. 1645, 1420, 1380, 1270 1250, 1040, 955. 795, 735
N.M.R. s ppm (DMSO-d6): 3.93 and 4.14 (6H, sJ, 7.59 (1H, s), 9.26 (1 H, d, J=9Hz), 11.50(1 H, d,
J=9Hz)
(4) 2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid (powder) was obtained according to the similar manner to that of Example 16(6) I.R. ## : 3350, 3200. 1695-1740. 1660, 1365, 1030 cm-1
N.M.R. 8 ppm (DMSO-d6+D20):
3.80 (3H, s),
8.16 (s) 6.77 (s) # (1H) (5) 2-(2-Formamido-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid (powder), mp. 138 to 1 420C (dec.) was obtained according to the similar manner to that of Example 12(1)
I.R. # : 3400.3325, 3200, 1740, 1695, 1670, 1550, 1385, 1250, 1040, 820 cm-1 N.M.R.# ppm (DMSO-d6) :: 4.05 (3H, s)
6,87 (s) 6.93 (s) # (1H) 9.38 (1H, d, H=9Hz)
11.11 (1H,d,J=9Hz)
Example 19
(1) A 1 5% n-hexane solution (636 g.) of n-butyllithium was added to a solution of 2-amino-6methylpyridin (64.8 g.) in tetrahydrofuran (500 ml.) at -20 to -300C over one hour, and stirred at -8 to - 10 C for 30 minutes. To the solution was added trimethylsllylchloride (161.7 g.) at-15 to-5 C over 40 minutes, and the resultant solution was stirred at room temperature overmlght. The solsution was filtered through by a column packed with silica gel (180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure.The residue was purified by fractional distillation to give a 2-[N,N-bls(trimethylsllyl)amlnol-8-methylpyrldine (117.6 g.). b.p. 95 to 97 C/5-6 mmHg.
N.M.R. # ppm (CCl4) : 0.13 (18H, s), 2.35 (3H, s0, 6.43 (1H, d, J=8Hz), 6.60 (1H, d, J=8Hz), 7.25
(1 H, t, J=8Hz)
(2) A 1 5% n-hexane solution (338.6 g.) of n-butyllithium was dropwise added to a solution of 2 [N,N-bis(trimethylsilyl)amino]-6-methylpyridine (100 g.) in anhydrous tetrahydrofuran (300 ml.) at -20 to - 30 C over one hour and the solution was stirred at 20 to 23 C for one hour. The tesultant solution was added in small portions to cruashed dry ics (1 kg.) under stirring, and stirred till a room temperature.
After removing tetrahydrofuran from the solution under reduced pressure, absolute ethanol (1 I.) was added to the residue. 30% Ethanol solution (660 ml.) of hydrochloric acid was dropwise added to the solution at-5 to -1 00C, and further hydrogen chloride gas was bubbled at O to 50C for 30 minutes and then the solution was stirred at 10 C overnight. After removing ethanol from the resultant solution, the residue was dissolved in water, and washed with ethyl acetate 3 times. The solution was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give the crude product (54 g.).The product was purified by column chromatography on silica gel (1 kg.) with an eluent (ethyl acetate+ benzene) to give ethyl 2-(6-aminopyridin-2-yl)acetate (30.2 g.), mp. 66 to 68 C.
I.R. ## : 3430, 3340. 3200. 1730, 1645, 1480. 1190 cm-1
N.M.R. a ppm (CDCl3): 1.25 (3H, t, J=6Hz), 3.67 (2H, s). 4.20 (2H, q, J=6Hz), 5.33 (2H, broad s),
6.43 (1H, d, J=8Hz), 6.62 (1H, d, J=8Hz), 7.40 (1H, t, J=8Hz)
(3) Ethyl 2-(6-formamidopyridin-2-yl)acetate, mp. 35 to 380C was obtained according to the similar manner to that of Example 12(1) I.R. ## : 3250, 3100. 1738, 1690, 1580, 1460, 1305, 1277 cm-1 N.M.R. 8 ppm (DMSO-d): 1.17 (3H, t, J=8Hz). 3.75 (2H, s), 4.08 (2H, q, J=8Hz), 6.85 (0.5H,
broad d, J=8Hz). 7.95 (0.5H, broad s), 7.08 (1 H, d, J=8Hz). 7.73 (1 H, t, J=8Hz). 8.33 (0.5H.
broad s). 9.25 (0.5H, broad d), 10.58 (1 H, broad s).
(4) To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g.) in dioxane (260 ml.) was added selenium dioxide (16.65 g.) in small portions at 85 to 900C over one hour and stirred at the same temperature for one hour. After cooling the resultant solution the dioxane layer was separated and concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and treated with activated charcoal and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp. 124 to 126 C.
I.R. ## : 3220, 3100, 1737, 1720, 1690, 1273, 1233 cm-1 N.M.R. 8 ppm (DMSO-d8): 1.34 (3H, t, J=8Hz), 4.44 (2H, q, J=8Hz), 7.33 (0.65H, broad s), 7.8- 8.2 (0.35H), 7.84 (1 H, d, J=8Hz). 8.09 (1 H, t, J=8Hz), 8.44 (0.35 H, broad s), 9.22 (0.65H,
broad s), 10.85 (1H, broed s)
(5) 2-(6-Formemldopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer), mp. 170 to 171 C (dec.) was obtained according to the similar manner to that of the Example 1 2(4) via 2-(6 formamidopyridin-2-yI)-glyoxylic acid.
I.R. ## : 3230, 3132. 1745, 1680, 1575, 1450, 1320, 1208, 1032 cm-1 N.M.R. 8 ppm (DMSO-d6): 3.70 (3H, s), 6.90 (O.6H, broad d), 7.9 (0.4H, broad 5), 7.10 (1 H, d, J=8Hz), 7.75 (1 H, t, J=8Hz), 8.38 (0.4H, broad s), 9.25 (0.6H, broad d), 10.58 (1 H, broad d)
(6) A mixture of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (5.0 g.) and concentrated hydrochloric acid (2.34 9.) in methanol (50 ml.) was stirred for 40 minutes at ambient temperature.
After the removal of methanol from the reaction mixture under reduced pressure, the residue was pulverized in diethyl ether, collected by filtration and then dried to give a pale brown powder of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer) (5.2 g.).
N.M.R. 8 ppm (DMSO-d6+D2O) : 4.10 (3H, s), 6.84 (1 H, d, J=7Hz), 7.23 (1H, d, J=1 0Hz), 7.99 (1 H, dd, J=7Hz, OHz) (7) To a mixture of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer), acetic acid (350 ml.) and water (10 ml.) was introduced chloride gas for 1.5 hours. After the removal of the excess of the chlorine gas by bubbling air into the reaction mixture, the solvent was distilled off. The residue was pulverized in diethyl ether and collected by filtration. After the addition of water and ethyl acetate to the resultant powder (9.8 g.), the aqueous layer was separated and washed with ethyl acetate. The ethyl acetate layer and washings were combined together, and further extracted with water.The aqueous layers were combined together and adjusted to pH 4 with 1 N aqueous solution of sodium hydroxide, and then the solvent was distilled off under reduced pressure.
The remaining water in the residue was azeotropically removed with benzene three times to yield brownish powder which was dried in a desiccator to give 2-(6-amino-3-chloroyridin-2-yl)-2-methyoxy- iminoacetic acid (syn isomer) (3.27 g.).
N.M.R. 8 ppm (DMSO-d6+D20): 3.81 (3H, s), 6.50 (1 H, d, J=9Hz), 7.48 (1 H, d, J=9Hz)
Further the remaining ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off. The residue was washed with diethyl ether and then dried to give 2-(6-amino-3,5dichloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (2.4 g.), mp. 139 to 1440 C.
N.M.R. 8 ppm (DMSO-d6): 3.96 (3H, s), 6.2-7.1 (2H, broad), 7.83 (1 H, s)
(8)-a) 2-(3-Chloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (powder), mp. 1 51 to 1 540C was obtained according to the similar manner to that of Example 12(1)
I.R. ## : 3200, 1740, 1680, 1580, 1290, 1250, 1140,1 050, 840 cm-1
(8)-b)2-(3,5-Dichloro-6-formamidopyridin-2-yl)-2-methoxyiminocetlc acid (syn isomer)
[powder), mp. 164 to 165 C was obtained according to the similar manner to that of Example 12(1)
I.R. ## : 3250, 2300-2600, 1712, 1565, 1410, 1250, 1035 cm-1
N.M.R. 8 ppm (DMSO): 4.02 (3H, s), 8.29 (1 H, s), 9.05 (1 H, d, J=1OHz), 10.77 (1 H, d, J=1 OHz).
Example 20
(1) To a solution of ethyl 3-ethoxyacrylimidate hydrochloride (4.0 g.) and 1 -ethoxycarbonyl- formamidine hydrobromide (4.4 g.) in methanol (110 ml.) was added dropwise a solution of sodium metal (1 g) In methanol (110 ml) at 0 C. The reaction mlxture was stirred for an hour at 0 to 5 C and for addltional 4 hours et ambient tomperature. The solsution was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate five times. All organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give methyl 4-aminopyrimidine-2-carboxylate (1.33 g.), which was recrystallized from ethyl acetate, mp. 140-142.5 C.
I.R. ## : 3450, 3300, 3180, 1730, 1630, 1585, 1540 cm-1
N.M.R. ss ppm (DMSO-d): 3.81 (3H, 5), 6.64 (1 H, H, d, J=6Hz), 7.23 (2H, S) 8.16 (1 H, d, J=6Hz).
(2) To a solution of 2-chlorocrylonitrile (437 mg) and 1-ethoxycarbonylformamide hydrobromide
(985 mg) in ethanol (5 ml) was added dropwise triethylamlne (1.01 g.) at 0 C. The reaction mlxture was stirred for 4 hours at ambient temperature and evaporated to dryness. The residue was dissolved in a mixture of ethyl acetate and water, and extracted with ethyl acetate three times. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give othyl-4-amlnopyrimldine-2-carboxylate (480 mg), which was recrystallized from a mixture of ethyl acetate and benzene, mp. 101-104 C.
I.R. ## : 3450, 3300, 3180, 1730, 1630, 1580, 1540 cm-1.
N.M.R. 8 ppm (DMSO-d6): 1.30 (3H, t, J=7Hz), 4.30 (2H, q, J=7Hz), 6.60 (1 H, d, J=6Hz), 7.31 (2H, S). 8.20 (1 H, d, J=6Hz).
The following compound was obtained according to the similar manner to that of Step (2) above by using triethylamine or sodium carbonate as a base.
Methyl 4-aminopyrimidine-2-carboxylate.
I.R. ## ; 3450, 3300, 3180, 1730, 1630, 1585, 1540 cm-1,
(3) A mixture of formic acid (100 g) and acetic anhydride (204 g) was stirred for half an hour at ambient temperature. To the solution was added ethyl 4-aminopyrimidine-2-carboxylate (30 g) and the mixture was stirred for 1.5 hours at 70 to 750C and then evaporated to dryness. The residue was trifurated with ethanol, collected by filtration nd washed with ethanol to give ethyl 4-formamidopyridilne-2-carboxylate (20.0 g), mp 205-208 C.
I. R. pNmuaixo(: 3100, 1720, 1630. 1570, 1 520 cm N.M.R. 8 ppm (DMSO-d6): 1.37 (3H, t, J=7Hz), 4.40 (2H, q, J=7Hz), 7.73 (1 H, broad s), 8.83 (1 H,
d, J=4Hz), 9.00 (1 H, broad s), 11.40 (1 H, broad s).
The following compound was obtained according to the similar manner to that of Step (3) above
Methyl-4-formamidopyrimidine-2-carboxylate, mp. 234-236 C.
I.R. ## : 3100, 1735, 1710, 1640, 1570, 1530, 1510 cm-1.
N.M.R. # ppm (DMSO-d6) : 3.93 (3H, s), 7.73 (1H, broad s), 8.82 (1H, d, J=5Hz), 9.00 (1H, broad
s), 11.40 (1H, broad s).
(4) To a solution of methyl 4-formamidopyrimidine-2-carboxylate (1.3 g.) and methyl methylthiomethyl sulfoxide (0.89 g.) in N,N-dimethylformamide (10 ml) was added 50% sodium hydride (1.0 g) at 1 oac under stirring and the stirring was continued for 1.5 hours at ambient temperature. The mixture was cooled in an ice bath and thereto was added methylene chloride (30 ml). The precipitate which was collected by filtration was added portionwise to a mixture of methylene chloride (50 ml), ice water and concentrated hydrochloric acid (2.1 ml) under stirring. The methylene chloride layer was separated out and the aqueous layer was extracted with methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness.
The residue was triturated with diethyl ether, filtered and washed with diethyl ether to give 4formamido-2-(2-methanesulfonyl-2-methylthioacetyl)pyrimidine (1.2 g).
I.R. ## : 1690, 1560, 1450, 1370 cm-1
N.M.R. 8 ppm (DMSO-d6): 2.23 (s) 4 (3H)
2.73 (s) 5,35 (s)
2.93 (s) # (3H) 6.07 (s) # (1H), 7.67 (1H, broad s), 8.82 (1H, d, J=5Hz)
9.17 (1H, broad s), 11.40 (1H, broad s)
The same compound as the object compound of Example 20 (4) was obtained from the following compound according to the similar manner thereto.
Ethyl 4-formamidopyrimidine-2-carboxylate.
(5) A mixture of formic acid (4.82 g) and acetic anhydride (9.7 g) was stirred for half an hour at ambient temperature. To the solution was added 4-formamido-2-(2-methanesulfinyl-2-methyithio- acetyl)pyrimidine (2.6 g) and the mixture was stirred for 1.5 hours at 50 C and then for an hour with an addition of sodium periodate (610 mg) at the same temperature. The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate (50 ml) and an aqueous solution (20 ml) of sodium chloride. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness.The residue (2.0 g) was subjected to column chromatography over silica gel (13g) using a mixture of ethyl acetate and benzene (1:1 by-volume) as an eluent. The fractions containing a desired compound were collected, evaporated to dryness and crystallized from a small amount of ethyl acetate to give pure product of S-methyl 4-formamidopyrimidine-2-thioglyoxylate (840 mg), mp 112-114 C.
I.R. ## : 3480, 3380, 1715, 1680, 1585 cm-1.
N.M.R. ppm (DMSO-d6): 2.17 (3H, s), 7.20 (1 H, broad s), 8.12 (1H, d, J=6Hz). 9.17 (1H, broad s),
11.08 (1H,d,J=7Hz).
(6) To a suspension of S-methyl 4-formamidopyrimidine-2-thioglyoxylate (3.0 g) in water (26 ml) was added dropwise 1N aqueous solution (12 ml) of sodium hydroxide at ambient temperature and the mixture was stirred for half an hour at the same temperature.
To the solution was added an aqueous solution of ethoxyamine prepared by ethoxyamine hydrochloride (1.3 g), water (10 ml) and sodium bicarbonate (1.12 g). The reaction mixture was stirred for half an hour at ambient temperature and adjusted to pH 4 with 1 N hydrochloric acid (1.5 ml). The solution was stirred for 10 minutes at ambient temperature and adjusted to pH 3 with 1 N hydrochloric acid and then washed with ethyl acetate. The aqueous layer was salted out, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was driedover magnesium sulfate and evaporated to dryness. The crystallized residue ws washed with n-hexane to give 2-athoxylmino-2-(4formamidopyrimidin-2-yl)acetic acld (syn lsomer) (2.22 g), mp. 130-135 C (dec.).
I.R. pNmuaiXl 3250,1720,1630 1605,1570 cm 1.
N.M.R. a ppm (DMSO-d6): 1.28 (3H, t, J=7Hz), 4.32 (2H, q, J=7Hz), 7.4-7.7 (1 H, m), 8.72 (1 H,
d, J=6Hz), 8.8-9.1 (1H, m), 11.37 91H, d, J=6Hz).
The following compounds were obtained according to the similar manner to that of Step (6) above.
2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer), mp. 1 65-1 660C (dec.).
I. R. pNmuajxol 3400,3250,3150,1740, 1700, 1570cm1.
N.M.R. a ppm (DMSO-d6): 4.00 (3H, s), 7.53 (1 H, broad s), 8.72 (1 H, d, J=6Hz), 8.87 (1 H, broad s), 11.23 (1 H, d, J=6Hz).
2-(4-Formamidopyrimidin-2-yl)-2-propoxyiminoacetic acid (syn isomer), mp - 145-148 C (dec.).
I.R. ## : 3150, 3100, 3050, 1750, 1690, 1615, 1570, 1540 cm-1.
2-Allyloxyimino-2-(4-formamidopyrimidin-2-yl) acetic acid (syn isomer), mp 120-1 220C (dec.).
I.R. ## : 3250, 3100, 1710, 1630, 1570, 1515 cm-1.
2-Benzyloxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer), mp 75-77 0C.
I.R. ## : 3250, 3050, 1720, 1630, 1570 cm-1.
Example 21
(1) A mixture of ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (24.3 g) and selenium dioxide (16.65 g) in N,N-dimethylformamide (243 ml) was stirred for an hour at 70 to 750C. The precipitated solid was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed with water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diisopropyl ether to give a powder of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate (17.74 g).
This product (1 g) was recrystallized from ethyl acetate (10 ml) to afford the purified product (570 mg), mp 114-11 70C.
I. R. ';Nxo1: 3400, 3230-3100,1760, 1720-1 680, 1 580-1 550, 1250, 1200, 850, 730 cm-1
(2) To a mixture of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate (10.6 g) and methoxyamine hydrochloride (3.34 g) in ethanol (200 ml) was added an aqueous solution (60 ml) of sodium bicarbonate (3.36 g) and the mixture was stirred for 2 hours at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to give oily product (10.8 g).
This product was subjected to column chromatography over silica gel (11 8 g) using benzene as an eluent.
The fractions contained a desired compound were collected, and evaporated, and resultant oily product (5.6 g) was crystallized from diethyl ether to give ethyl 2-(6-chloro-4-formamidopyrimidin-2yl)-2-methoxyiminoacetic acid (syn isomer), mp. 11 6-11 90C.
I.R. ## : 3400, 1750, 1725, 1685, 1495, 1270, 1030 cm-1, N.M.R. #. ppm (CDCl3) : 1.35 (3H. t, J=7Hz), 4.09 (3H, s), 4.40 (2H, q, J=7Hz), 6.5-83. (1H, broad), 8.3-9.0 (1 H, broad), 9.2 (1 H, broad s).
Example 22
A mixture of ethyl 2-(4-formamidopyrimidine-2-yl)acetate (50.0 g) and selenium dioxide (31.87 g) in N,N-dimethylformamide (240 ml) was stirred for an hour at 70 to 750C and cooled to ambient temperature.
The precipitated solid was filtered off and the filtrate was evaporated in vacuo to give an oily product. The oil was added to water (750 ml) under stirring, adjusting to pH7 with an aqueous solution of sodium bicarbonate. The precipitated yellow substance was filtered off and washed with water. The filtrate and washings were combined and thereto was added methoxyamine hydrochloride (19.59 g).
The mixture was adjusted to pH4 with an aqueous solution of sodium bicarbonate and stirred for 3 hours at ambient temperature. The aqueous reaction mixture was extracted with ethyl acetate and the extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give ethyl 2-(4-fiormamidopyrimidin-2-yl)-2-methoxyiminocacetate (syn isomer) (31 g) as a brownish oil.
N.M.R. a ppm (CDCI3): 1.36 (3H, t, J=7Hz), 4.12 (3H, s), 4.42 (2H, q, J=7Hz), 6.5-8.2 (1 H, broad), 8.66 (1 H, d, J=6Hz), 8.8-10.0 (2H, broad).
Example 23
(1) To a solution of ethyl 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (30.8 g) in ethanol (308 ml) was added 1 N alcoholic solution (550 ml) of potassium hydroxide and the mixture was stirred for 3.5 hours at ambient temperature. The reaction mixture was cooled in an ice bath and adjusted to pH 3 with concentrated hydrochloric acid (53 ml). The resultant solid was filtered and washed with ethanol (60 ml), water (100 ml), acetone (100 ml) to give a crude product (28.8 g.). This product (1 g) was recrystallized from water (10 ml) to give a purified product of 2-(4-aminopyrimidin2-yl)-2-methoxyiminoacetic acid (dihydrate, syn isomer) (0.4 g), mp. 1 78-1 830C (dec.).
The following compound was obtained according to the similar manner to that of Example 23(1).
(2) 2-(4-Amino-6-chloropyrimidin-2-yi)-2-methoxyiminoacetic acid (syn isomer).
I. R. vNmuaixol: 3480, 3380, 3200, 1640, 1610--1580, 1530, 1040, 720 cm 1.
N.M.R. a ppm (D20): 4.10 (3H, s), 6.76 (1H, s).
Example 24
To a solution of ethyl 2-(4-chloro-6-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (17 g) in ethanol (255 ml) was added dropwise phosphoryl chloride (14.7 g) under cooling in an ice bath. The mixture was stirred for 1.5 hours at ambient temperature and evaporated to dryness.
The residue was dissolved in a mixture of ethyl acetate and water and adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The organic layer was separated out, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with n-hexane to give ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (9.99 g), mp 138-142 C.
I.R. ## : 3500, 3380, 3200, 1735, 1640, 1575, 1535, 1040 cm-1.
N.M.R. # ppm (DMSO-d6) : 1.30 (3H, t, J=7Hz), 4.03 (3H, s). 4.30 (2H, q, J=7HJz), 6.53 (1H,s ),
7.5 (2H, broad s)
Example 25
(1) To a solution of ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate (21.5 g) in methanol (200 ml) was added a solution of sodium metal (7.25 g) in methanol (130 ml) and the mixture was refluxed for 3.5 hours. The reaction mixture was cooled in an ice-salt bath and saturated with dry hydrogen chloride and then allowed to stand overnight at ambient temperature. The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate and a cold aqueous solution of sodium bicarbonate. The organic layer was separated out, washed with water, dried over anhydrous magnesium sulfate and evaporated to give methyl 2-(4-amlno-6-methoxy-pyrimidin-2-yl)acetate (14.2 g), mp 91-94 C,.
I.R. ## : 3480, 3390, 3210, 1738, 1660, 1600 cm-1
N.M.R. oz ppm (DMSO-d6): 3.66 (5H, s), 3.82 (3H, s), 5.68 (1H, s), 6.66 (2H, broad s).
(2) To a solution of thiophenol (2.55 g) in N,N-dimethylformamide (20 ml) was added 50% sodium hydride (1.1 g) under cooling in an ice bath and the mixture was stirred for 20 minutes at 0 C to 50C. To the mixture was added ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and the mixture was stirred for 6 hours at ambient temperature. The resultant mixture was poured into cold water, adjusted to pH 7 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of chloroform and ethyl acetate (3:1 by volume) as an eluent.The fractions containing the object product were collected and evaporated to give ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (460 mg), mp 154-156 C.
I.R. ## : 3450, 3280, 3160, 1720, 1620, 1550, 1520, 1300, 1040, 1025, 700 cm-1 N.M.R.# ppm (CDCl3) : 1.34 (3H, t, J=7Hz). 4.05 (3H, s), 4.27 92H, g. J=7Hz) 5.2 (2H, broad s).
5.84 (1H, s), 7.2-7.7 (5H, m).
Example 26
Methyl 2-(4-formamido-6-methoxypyridin-2-yl)acetate (13.9 g) was obtained by reacting methyl 2-(4-amino-6-methoxypyrimidin-2-yl)acetate (14 g) with formic acid (14.7 g) and acetic anhydride (30.4 g) according to the similar manner to that of Example 20(3) mp. 61-630C.
N.M.R. a ppm (DMSO-d6): 3.73 (3H, s), 3.87 (2H, s), 3.96 (3H, s), 6.1-7.8 (1 H, broad), 8.1-9.8 (1 H, broad), 10.87 (1 H, d, J=6Hz).
Example 27
Methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (12.47 g) was obtained by reacting methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)acetate (12.24 g) with selenium dioxide (6.94 g) and then methoxyamine hydrochloride (4.51 g) according to the similar manner to that of Example 22
I.R. ## : 3300, 1750, 1720, 1660, 1590, 1565, 1210, 1035 cm-1.
Example 28 2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (8.22 g) was obtained by reacting methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (12.0 g) with 1 N ethanolic solution (187 ml) of potassium hydroxide according to the similar manner to that of Example 23 mp. 127-1 290C (dec.).
I.R. Pmuajx l 3420, 3380, 1650, 1615,1590, 1250, 1050, 1025cm1 N.M.R. # ppm (DMSO-d6+D20): 3.78 (3H, s), 3.95 (3H, s), 5.78 (1 H, s).
Example 29
2 (4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (130 mg) was obtained by reacting ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyimino-acetate (syn isomer) (247 mg) with 1N aqueous solution (1.8 ml) of sodium hydroxide according to the similar
manner to that of Example 23 mp. 136-1 380C (dec.).
R. ## : 3300, 1650, 1600, 1560, 1150, 1040, 750 cm-1.
Claims (2)
1. A compound of the formula:
wherein
Ra is amino or a protected amino group,
Rb and Rc are each hydrogen, halogen, lower alkoxy or arylthio,
R14 is carboxy or a protected carboxy group,
X is lower alkylene or a group of the formula:
in which R6 is hydrogen or an organic residue which may have suitable substituent(s), and
Z is N or CH, or a salt thereof, provided that:
a) Ra is a protected amino group when Z is CH, X is lower alkylene, R14 is carboxy or protected
carboxy, Rb is hydrogen or halogen and
Rc is hydrogen; or
b) Ra is a protected amino group when Z is N, Z is
R14 is a protected carboxy group Rb is hydrogen and Rc is hydrogen.
1. A compound of the formula:
wherein R1 is amino or a protected amino group.
Rb and R1 are each hydrogen, halogen, lower alkoxy or arylthio,
R14 is carboxy or a protected carboxy group, Xis lower alkylene or a group of the formula:
in which R6 is hydrogen or an organic residue which may have suitable substituent(s), and
Z is N orCH, or a salt thereof.
2.A process for preparing the compound of claim 1 which comprises (1) reacting a compound of the formula:
wherein
R2a, Rb, Rc, R14 and Z are each as defined in claim 1 or a salt therenf, with a compound of the formula : R6-ONH2 wherein
R6 is as defined in claim 1 or a salt thereof, to give a compound of the formula:
wherein
Rat Rb, Rc, R6, R14a nd Z are each as defined above; or
(2) reacting a compound of the formula:
wherein
Ra, Rb, Rc, R14 and Z are each as defined above, or a salt thereof, with a nitrosating agent to give a compound of the formula:
wherein
Ra, Rb, Rc, R14 and Z are each as defined above; or
(3) reacting a compound of the formula:
wherein
Ra, Rb, Rc, R14 and Z are each as defined above, or a salt thereof, with a substituting agent capable for substituting a hydrogen atom of the hydroxy by R6' group, in which R6' is an organic residue which may hve suitable substituent(s). to glve a compound of the formula:
wherein
Rat Rb, Rc, R6', R14 and Z are each as defined above, or a salt thereof; or
(4) reacting a compound of the formula:
wherein
Ra, R6 and R14 are each as defined above, or a salt thereof, with halogenating agent to give a compound of the formula:
wherein
R8 is halogen, R15 is hydrogen or halogen, and
Ra, R6 and R14 are each as defined above, or a salt thereof; or
(5) subjecting a compound of the formula:
wherein
R,a is a protected amino group, and
X is as defined in claim 1,
Rb R', R'4 and Z are each as defined above, or a salt thereof, to elimination of the amino-protective group to give a compound of the formula:
wherein Rb, Rc, R14, X and Z are each as defined above, or a salt thereof; or
(6) reacting a compound of the formula:
wherein
Rb Rc R14 X and Z are each as defined above, or a salt thereof with an amino protective agent to give a compound of the formula:
wherein Ral, Rb, Rc, R14, X and Z are each as defined above, or a salt thereof.
New Claims or Amendments to Claims filed on 12/5/82.
Superseded Claims 1
New or Amended Claims :-
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4735277 | 1977-11-14 |
Publications (2)
Publication Number | Publication Date |
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GB2099813A true GB2099813A (en) | 1982-12-15 |
GB2099813B GB2099813B (en) | 1983-06-02 |
Family
ID=10444650
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8124353A Expired GB2099813B (en) | 1977-11-14 | 1978-11-10 | Pyridine- or pyrimidine-amino compounds |
Country Status (3)
Country | Link |
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JP (1) | JPS61143360A (en) |
BE (1) | BE871889A (en) |
GB (1) | GB2099813B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1600969A (en) * | 1977-01-07 | 1981-10-21 | Acf Chemiefarma Nv | Heterocyclic compounds |
-
1978
- 1978-11-09 BE BE191631A patent/BE871889A/en not_active IP Right Cessation
- 1978-11-10 GB GB8124353A patent/GB2099813B/en not_active Expired
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1985
- 1985-10-30 JP JP60245092A patent/JPS61143360A/en active Granted
Also Published As
Publication number | Publication date |
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BE871889A (en) | 1979-05-09 |
JPS61143360A (en) | 1986-07-01 |
JPS6218550B2 (en) | 1987-04-23 |
GB2099813B (en) | 1983-06-02 |
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