MXPA97008768A - Piridines sustitui - Google Patents
Piridines sustituiInfo
- Publication number
- MXPA97008768A MXPA97008768A MXPA/A/1997/008768A MX9708768A MXPA97008768A MX PA97008768 A MXPA97008768 A MX PA97008768A MX 9708768 A MX9708768 A MX 9708768A MX PA97008768 A MXPA97008768 A MX PA97008768A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- optionally substituted
- independently
- group
- compound
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 162
- 238000000034 method Methods 0.000 claims abstract description 63
- 230000002194 synthesizing Effects 0.000 claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 95
- 229910052739 hydrogen Inorganic materials 0.000 claims description 83
- 239000001257 hydrogen Substances 0.000 claims description 82
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 62
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 60
- 150000002431 hydrogen Chemical group 0.000 claims description 59
- 125000005843 halogen group Chemical group 0.000 claims description 46
- -1 phenyl- Chemical group 0.000 claims description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 239000011593 sulfur Substances 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 15
- 239000011630 iodine Substances 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 239000003638 reducing agent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004429 atoms Chemical group 0.000 claims description 9
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 230000003287 optical Effects 0.000 claims description 8
- QYKIQEUNHZKYBP-UHFFFAOYSA-N vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000808 adrenergic beta-agonist Substances 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 241001649081 Dina Species 0.000 claims description 4
- 101710034456 MT-CO1 Proteins 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 3
- 101710040931 PTGS1 Proteins 0.000 claims description 3
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000004001 thioalkyl group Chemical group 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- UDHXJZHVNHGCEC-UHFFFAOYSA-N Chlorophacinone Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)C(=O)C1C(=O)C2=CC=CC=C2C1=O UDHXJZHVNHGCEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000002941 palladium compounds Chemical class 0.000 claims description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims 3
- 229960001663 sulfanilamide Drugs 0.000 claims 3
- LCZDCKMQSBGXAH-AWEZNQCLSA-N 3-[[3-[(2S)-2-amino-2-carboxyethyl]-5-methyl-2,6-dioxopyrimidin-1-yl]methyl]-5-phenylthiophene-2-carboxylic acid Chemical compound O=C1C(C)=CN(C[C@H](N)C(O)=O)C(=O)N1CC1=C(C(O)=O)SC(C=2C=CC=CC=2)=C1 LCZDCKMQSBGXAH-AWEZNQCLSA-N 0.000 claims 2
- 235000008733 Citrus aurantifolia Nutrition 0.000 claims 2
- 241000234435 Lilium Species 0.000 claims 2
- 235000015450 Tilia cordata Nutrition 0.000 claims 2
- 235000011941 Tilia x europaea Nutrition 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 239000004571 lime Substances 0.000 claims 2
- 239000000758 substrate Substances 0.000 claims 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 210000001268 Chyle Anatomy 0.000 claims 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N Hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims 1
- 235000013382 Morus laevigata Nutrition 0.000 claims 1
- 244000278455 Morus laevigata Species 0.000 claims 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N Roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 claims 1
- HSUIVCLOAAJSRE-UHFFFAOYSA-N bis(2-methoxyethyl) benzene-1,2-dicarboxylate Chemical group COCCOC(=O)C1=CC=CC=C1C(=O)OCCOC HSUIVCLOAAJSRE-UHFFFAOYSA-N 0.000 claims 1
- 239000002131 composite material Substances 0.000 claims 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims 1
- 125000001145 hydrido group Chemical group *[H] 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 206010012601 Diabetes mellitus Diseases 0.000 description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 5
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 210000004369 Blood Anatomy 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N benzohydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 3
- 210000000577 Adipose Tissue Anatomy 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229960004592 isopropanol Drugs 0.000 description 3
- 235000020997 lean meat Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- QARVLSVVCXYDNA-UHFFFAOYSA-N Bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000577218 Phenes Species 0.000 description 2
- 210000002307 Prostate Anatomy 0.000 description 2
- 241000750042 Vini Species 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000883 anti-obesity agent Substances 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 201000002028 prostate disease Diseases 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 230000004648 relaxation of smooth muscle Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- CVCQAQVBOPNTFI-AAONGDSNSA-N (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)oxane-2,4,5-triol;sulfuric acid Chemical compound OS(O)(=O)=O.N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O.N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O CVCQAQVBOPNTFI-AAONGDSNSA-N 0.000 description 1
- KDXFYIPBNUUBPT-UHFFFAOYSA-N (5-bromopyridin-2-yl)carbamic acid Chemical compound OC(=O)NC1=CC=C(Br)C=N1 KDXFYIPBNUUBPT-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 101700082949 ACOX1 Proteins 0.000 description 1
- 102000017910 Adrenergic receptor family Human genes 0.000 description 1
- 108060003345 Adrenergic receptor family Proteins 0.000 description 1
- 208000006673 Asthma Diseases 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- 210000000621 Bronchi Anatomy 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
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- 206010058108 Dyslipidaemia Diseases 0.000 description 1
- 102000019460 EC 4.6.1.1 Human genes 0.000 description 1
- 108060000200 EC 4.6.1.1 Proteins 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 210000003405 Ileum Anatomy 0.000 description 1
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- 102000004895 Lipoproteins Human genes 0.000 description 1
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- 241000124008 Mammalia Species 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 241001139947 Mida Species 0.000 description 1
- 210000002464 Muscle, Smooth, Vascular Anatomy 0.000 description 1
- HBZDMVSJHVZHKC-UHFFFAOYSA-N N-(5-bromo-3-methylpyridin-2-yl)acetamide Chemical compound CC(=O)NC1=NC=C(Br)C=C1C HBZDMVSJHVZHKC-UHFFFAOYSA-N 0.000 description 1
- VCZKTIKPEDMZNW-UHFFFAOYSA-N O=S(=O)=S Chemical compound O=S(=O)=S VCZKTIKPEDMZNW-UHFFFAOYSA-N 0.000 description 1
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- 208000008589 Obesity Diseases 0.000 description 1
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- 241001595582 Octolasmis cor Species 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N Phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M Potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- JLKDVMWYMMLWTI-UHFFFAOYSA-M Potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 description 1
- SQGYOTSLMSWVJD-UHFFFAOYSA-N Silver nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M Sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N Sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
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- 206010044565 Tremor Diseases 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
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- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 230000003466 anti-cipated Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001502 aryl halides Chemical group 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- CPMYJFQEVDMCPY-UHFFFAOYSA-N benzyl N-(5-acetylpyridin-2-yl)carbamate Chemical compound N1=CC(C(=O)C)=CC=C1NC(=O)OCC1=CC=CC=C1 CPMYJFQEVDMCPY-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 239000012043 crude product Substances 0.000 description 1
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- 238000006731 degradation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-O diphenylazanium Chemical compound C=1C=CC=CC=1[NH2+]C1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-O 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical class CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 235000020828 fasting Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N fe2+ Chemical group [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000002650 habitual Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000002218 hypoglycaemic Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZZDSDJFYOYWDGW-UHFFFAOYSA-N lithium;sodium;boron(1-) Chemical compound [Li+].[B-].[B-].[Na+] ZZDSDJFYOYWDGW-UHFFFAOYSA-N 0.000 description 1
- 239000004579 marble Substances 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- 150000002829 nitrogen Chemical group 0.000 description 1
- IQZPDFORWZTSKT-UHFFFAOYSA-N nitrosulphonic acid Chemical compound OS(=O)(=O)[N+]([O-])=O IQZPDFORWZTSKT-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- KDLHZDBZIXYQEI-OIOBTWANSA-N palladium-103 Chemical compound [103Pd] KDLHZDBZIXYQEI-OIOBTWANSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 230000000291 postprandial Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- 239000001230 potassium iodate Substances 0.000 description 1
- 235000006666 potassium iodate Nutrition 0.000 description 1
- 229940093930 potassium iodate Drugs 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000012191 relaxation of muscle Effects 0.000 description 1
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- BQCADISMDOOEFD-UHFFFAOYSA-N silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
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- 239000004332 silver Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- UKNAYQWNMMGCNX-UHFFFAOYSA-N sodium;[hydroxy(phenyl)methyl]-oxido-oxophosphanium Chemical compound [Na+].[O-][P+](=O)C(O)C1=CC=CC=C1 UKNAYQWNMMGCNX-UHFFFAOYSA-N 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
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- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to certain compounds of the formula I, which are useful in the synthesis of certain α-adrenergic receptor agonists, the invention also relates to a process for carrying out the compounds of formula (I) and to compounds of the formula (II) ), in which R1, R2 and R4 are as defined herein, which are useful in the synthesis of the compounds of formula I, the invention also relates to a process for synthesizing a compound of formula II, the invention is further refers to processes for synthesizing compounds of formula (Z *), in which R1, R2 and Y * are as defined in this document
Description
SUBSTITUTE PIRIDINS
BACKGROUND OF THE INVENTION
The present invention relates to certain compounds of formula (1), shown below, which are useful in the synthesis of certain β-adrenoreceptor agonists having the general formula Z
LÜ
(Z) 5
wherein R1 and R2 are as defined in the document for the compound of formula (I) and Y *, Y2 and Y3 are any chemical substances that can be bound to the atoms to which they are attached and , Y2 e? 3 and confer β-adrenergic receptor activity, and as such have utility as hypoglycemic and anti-obesity agents, is preferably hydrogen. In PCT Publication No. WO 94/29290 published on December 22, 1994, examples of such 5 substituents and of the resulting β-adrenergic receptor agonists can be found. The invention also relates to a process for synthesizing the fopnula compounds (I) and compounds of the formula (TI), defined below, which are useful in the synthesis of compounds of formula (T). The invention also relates to methods for synthesizing a compound of formula b (TI). The invention further relates to methods for synthesizing compounds of formula (Z *), defined below. Β-adrenergic receptor agonists also possess utility to increase the deposition of lean meat and / or improve the ratio between lean meat and fat in
LO animals eat them. F3 adrenergic receptor agonists also have utility in the treatment of intestinal motility tri-, depression, prostate disease, dyslipidemia and inflammatory pathway disorders.
L5 respiratory, such as asthma and obstructive pulmonary disease. The diabetes mellitus disease is characterized by metabolic defects in the production and / or utilization of carbohydrates, which lead to the inability to maintain
appropriate levels of blood sugar. The result of these defects is an elevated blood glucose level or hyperglucernia. Research in the treatment of diabetes has focused on attempts to normalize fasting and postprandial blood glucose levels. The current 5 treatments include the administration of exogenous insulin, the oral administration of drugs, and di et al therapies. Lipoprotein diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone that regulates the use of carbohydrates, Type-I diabetes, or non-insulin-dependent diabetes, often it occurs with normal or even high levels of Lina and appears to be the result of the inability of the tissues to respond appropriately to insulin.Most Type II diabetics are also obese The β-adrenergic receptor agonists decrease blood glucose levels in an effective way, when administered orally to patients with hyperglucernia or diabetes, and agonists of the β-adrenergic receptors also reduce the body weight or decrease in weight gain when administered to mammals or poultry The ability of β-adrenergic receptors agonists to affect weight gain is due to the activation of ß-adrenergic receptors it is the metabolism of adipose tissue. The ß-adrenergic receptors have been classified into subtypes ßi, 2 and (33. ß-receptor agonists promote the activation of adenyl cyclase.) Activation of ßi receptors involves increases in heart rate, which increase activation of receptor-is β2 induces the rL ation of the muscular-skeletal tissue, which causes a drop in blood pressure and the start of smooth muscle tremors.It is known that the activation of the receptor-is β3 is im1 polysis (the degradation of + ngl i cep two of adipose tissue in glycerol and free fatty acids) and the rate e abolica (energy expenditure) and, therefore, promotes the loss of fat mass. Therefore, compounds that stimulate β-receptors are useful as contributors to obesity and can also be used to increase the content of lean meat in edible animals. In addition, the compounds that are β3 receptor agonists have hypoglycemic or diabetic activity, but the mechanism of this effect is unknown. Until recently, it was thought that ß3 ~ adrenergic receptors were found predominantly in adipose tissue, it is known that receptor-is 3 are located in such diverse tissues as the intestine (3. Clin .. Invest. , 9_1, 344 (1993)) and the brain (Eur. 3. Pharrn., 219, 193 (1992)).
It has been shown that the stimulation of receptor 3 causes the relaxation of smooth muscle in the colon, in the trachea and in the bronchi. Life Sciences 4 (19), 1411 (1989); Br. J. Pharm.,
J12, 55 (1994); Br. 3. Pharmacol., 110, 1311 (1993). For example, it has been maintained that the stimulation of the receptor-ß3 induces the relaxation of the guinea pig ileum con-tred with histarnin, 3. Pharrn. Exp. Ther., 260, 1, 192 (1992). The ß3 receptor is also expressed in the human prostate. Because the receptor is immutated (.3 causes the relaxation of muscles in which the expression of receptor 3 has been demonstrated (by exertion, the intestine) , a practitioner of the art could envisage the relaxation of smooth muscle of the prostate, therefore, β3 agonists will be useful for the prevention or prevention of prostate disease Examples of β-adrenergin agonists can be found. Those which can be synthesized using the compounds of lopnula (I), in PCI Publication No. UO 94/29290, published on December 22, 1994, in United States Patent Application Mo. 08 / 312,027, filed September 26, 1994, in PCT Patent Application No. PCT / IB95 / 00344, filed on January 10, 1995 and in United States Provisional Patent Application No. 60 / 015,216, submitted on April 1996, of which all are assigned to the of this document. With respect to the process for synthesizing a compound of formula (II), defined hereinafter, of the present invention, the chemical literature indicates that the addition of aplo halides (eg, bromobenzene, PhBr) to a living ether is generally carried out. of formula (LV) (see below) (for example n-butiL viml ether, when R¿ is n-buyl), to produce a mixture of regioisorneproduct addition products that result from the addition of the remainder I apply to any of the olefmic carbon atoms of the thousand ether (HalLberg and Daves, Ohemiral Revie? s, Vol 89, 1909, page 1413) "Thus, with romobenzene and n-hutil vinyl ether, the addition products can rep- esentai e co or PhCH-OHOGu and PhO (OBu) - CII2. The PhCH-uHOBu product comes from what is called a beta-apion, in which the apr group is added to the olefinic carbon atom dis + to the oxygen atom of the vinyl ether. The product PhCÍOBu. = CH2 proceeds from what is called an aliphatic phase, in which the aryl graph is added to the circumference of the olefinic crystal or to the oxygen atom of the ether-matrix. is well documented (when the aryl halide is substituted with electron acceptor groups, such as the nitro group (eg, 4-bromo-J-nitrobenzene), the addition to the vinyl ether proceeds in such a way that it preferentially forms the product of beta-arylation, O2NC6H4CH-CHOBU, generally exceeding the beta-alpha and alpha-leveling ratio of the 1 (Hallberg, Daves and Andersson, Journal of Organic Chernistry, VoJ .. 52, 1907, 3529)., The chemistry of the pyridms is often presented and considered comparable with that of the corresponding nitrobenzenes, because of the significant electron deficiency of these ring sis + ems, produced by the ring nitrogen atom in the case of the pins dynas and by the su + ituyen + e nitro in the case of nitro benzene (pareh, Advanced Organic Che istry, 3a. Edition, 1985, page 461; Acheson, The Chernistry of Hetercyclic Compounds, L96O, page J67), So the pipdins and the corr-spondiont os are still loga'-, (te ru + robenconc experi en many of the same reactions that are common in benzene chemistry , such as a substitution of aromatic aromatics, and many of the same reactions that are common in benzene chemistry, such as an electrofusic substitution, for a habitual specialist in the technique it will be evident that, for In the case of the present invention, the product of the appendix is required (represented by formula II, to obtain the desired compounds of formula (I) after the hydrolysis of the vimlico ether. in the art it could not be anticipated that puridium halides, such as those of formula (TIT), would produce useful amounts of the products of the fa-arylation of fopnu 1 to (II).
BRIEF DESCRIPTION OF THE INVENTION
The invention relates to compounds having the formula (1)
(!) to the raceinic mixtures -onant polynoms and the optical isomers of said co-npue'- < or, in the Rl so it selects between the group composed of NR3 -00-au? J? (O? -C? o), -NR3 -002- lqu? l? (C? Cío >, ~ NR3 -002 - (Cl-I2) a - (leni the optionally substituted fabric), -NR3 -00- (CH2) a (optionally substituted fem), -NR3 -SO2 -allo? (C? - NR3 -SO2 ~ (CH2) a "(optionally substituted flush) and -MR3 -00-per-f 1 uoro i ui lo (0? -0¿); R2 is selected from the group consisting of - hydrogen, amino, nitro, alkylamino (Oi-Oß), fluoro, OF3, alkyl (O1-C4), akoxy (C1-). -NR3 ~ oo-alqu? Jo (C? -C? o). NR3 -CO2 -al qui J o (C? -Cio) / -NR3 -G? - (CH2) a- (optionally substituted), -NR3-C0- (CH2) a ~ (fem is optionally substituted) , -NR3-S02-altju? Lo (C? -Cio) -NR3 -SO2 - (CH2) a - (optionally substituted phenyl) and -NR3 -00- perf luoroalkyl (C? ~ C¿); a, whenever it appears, it is independently 0, 1, 2, 3 or 4, R3, each time it appears, is independently selected from the group consisting of hydrogen and alkyl (Ci- Cß), and the optionally substituted ferrous group is optionally substituted with one, two or three suceptors, and each substituent is independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, CF3, sulphanaride, alkyl ( C1-C4), (C1-C4) alkoxy, carboxy, hydroxyalkyl, alkoxycarbon (C1-C4), thioalkyl (C1-C4), sulfonyl, sulfonyl and amino;
with the proviso that a cc "position of (I n in. D not N- (5 ace t i -? -inet i l ~ 4 - ?? p di m 1) ace + arn? da, 3- acet i 1 4
(?? valoi larní no) pin dina or 3 -: -: et? l -7 - (ivaloil r í no) pi p di na. preferred compound of formula (1), referred to as "Group A", are compounds of formula (I) in the
(Rl is selected from the group consisting of NR3--0Q2- (CI-.2) a- (optionally substituted phene), -NR3 -co- (OH2) a (phene optionally substituted), - NR3- Ü -al qui l (C? -Cio), NR3-O2 - (CH2) a - (phenyl or optionally substituted) and -NR3 -COperf J uoroalkyl (C? -O4); and:? 2 the group consisting of hydrogen, alkyl (Ci-C *) and alkoxy (O1-O4) is selected.A preferred group of compounds of Group A, designated "Gr-upo W", are the compounds of Group A on those who
R is selected from the group consisting of -NR3 -CO2 - (CH2) a - (optionally substituted fem) and NR3-O-perfluoroalkyl (C? -). A preferred group of compounds of group B, designated "Group C", are the compounds of group B wherein R2 is selected from the group consisting of hydrogen, methyl, and methoxy. A preferred group of compounds of Group C, designated "Group D", are the Group C compounds in which Rl is selected from the group consisting of -NH-CO2 - (CH2) »- (femlo) and -NH-CO -CF3 A preferred group of compounds of group D, designated "Group E", are the compounds of Gr-upo D in which R-- is hydrogen. Of the Group F compounds, the acid ester (5-acet? J-? Pd? N-2- i J) -earharnLco and the N- (5 -ace- * i 1-pin) are especially preferred. d? n-2- l) - 2, 2, 2 -tp 11 uoro- [. a cot mida. Another group intended for compounds of formula (1), referred to as "Group F", are the compounds of formula (I) wherein R 1 is -NR 3 -00 -al qu i lo (Ci-CA) and R 2 is chyl ( C1 - C4). A preferred group of compounds of the group. , 0 called "? < ~ upo G", are the compounds of Group F pn which
R1 is -NH-CO-CH3 and R2 is methyl. Of the compounds of Group G, N- (5-acet? L-6-rnet? L-?? pd? N-2-? 1) -acet ai da, N- (3-acetyl) is especially preferred. ? l-5-rnet il -pu r? d? n-2-? 1) acetarn? and N- (5-acet 11 -3 -5 rnet 11-pyridm-2-1) -acetylamide. Another preferred group of compounds of formula (I) referred to as "Group H" are the compounds of formula (D in which Ri is -NH-C0-alkylene (C? -C4) and R2 is hydrogen. Of the compounds of Group H, N- (5-acetyl-? R? D? N-2-L) -acetamide and N- (5- acetyl-p? R-? d? n- 2-? l) -2, 2-d? rnet? 1-? ro? onar? da This invention also relates to compounds of the invention (II),
l (II)
They are useful in the synthesis of compounds of formula (1), as defined herein, where R 1 is selected from the group consisting of NR 3 -C 0 -alkyl (C 0 -C 3) -NR 3 -C02-alkyl (C? -C o), -NR3-002 - (OH2) a ~
(optionally substituted phenol), -NR3 -CO- (CH2) a- (optionally substituted phenyl), -NR3-SO2 -alkyl or (C? -Cio), -NR3 ~ SG2- (CH2) - (phenyl) Optionally, replace it) and -NR3-C0-per-fl uoro lqui lo (C? -CA); R2 is selected from the group consisting of hydrogen, ammo, nitro, at which the ino (Ci-Oß), fluoro, CF3, lqui lo (C? -0A), alC0Xl (C? -CA), -NR3 - CÜ-Alkyl (C? -Cio), -NR3-C02 A 1 qui 1 O (d -Cio) / -NR3 -0O2- (CH2) a- (optionally substituted phenyl), -NR3-C0- (CI-) l2) a ~ (optionally substituted fem), -NR3 ~ S02-alkyl (C? ~ C? o) -NR3 -SO2 - (OH2) a - (optionally substituted ferule) and -NR3 -CO-perfluoroalk? lo (C? -CA); where a, each time it appears, is independently 0, 1, 2, 3 or 4; R3, each time it appears, is independently selected from the group consisting of hydrogen and the one (C? -Ce); and the substituted phenyl group optionally substituted is optionally substituted with one, two or three substituents, and each substituent is independently selected from the group consisting of hydroxy, fluoro, chloro, iodo, bromo, CF3, sulphonane, alkyi (C? -CA), cox 1 (Ci -CA), carboxy, hydrox 1 to Iqu ilo, cox 1 carbo or lo (C? -C). T? oalqu? o (O? -CA), sulfonyl, sulphite and arnine; and R * is to the uilo (Ci -Cβ). The present invention also relates to a process for the preparation of a compound of formula (II)
(II)
(Thio comprises reacting a compound of formula (III)
with a liquid ether of formula (EV), CH2-CH0R, in the presence of a palladium compound or a palladium metal catalyst and a base; in which 1 J
? i is bromine, iodine, methanesul foni loxi or t r-i f luo omet anosul foni ox i; Ri < e selects from the group consisting of -NR3-00-alkyl (C -? - C? o). -NR3 -C02 -al qui lo (C? -Cío). -NR3 -C02 - < CH 2) a - (feru optionally substituted), -NR 3 -00- (CI-I 2) a-1 phenyl optionally substituted), -NR 3 -SO 2 -al < JUL (C? -CÍO), -NR3-S02- (CH2) a- (f oni lo optionally substituted) and -NR3-00-per-f luoroalqui lo (0? -CA); R2 is selected from the group consisting of aromatic hydrogen, nitro, Lamino alky (Oi-Cß), fluoro, CF3, aLqui Lo (C? -CA),
< acox (0? -CA), -NR3 -CO- aJqui Lo (0? -C? o), -NR3 -C02 -alkyl (Ci Cio) / -NR3 -C02- (CH2) a- (optionally substituted tenyl) ), -NR3 -00- (CH2) a • (optionally substituted phenyl), -NR3-SÜ2-alkyl (C? -Cio). -NR3 -SO2 - (OH2) «- (optionally substituted tenyl) and -NR3-C0-perfluoroalkyl (0? -CA); where a, each time (Thurs-oce, it is independently 0, 1, 2, 3 or 4; R3, each time it appears, is independently selected from the group consisting of hydrogen and alkyl (Ci -Cß); optionally substituted tenyl is optionally substituted with one, two or three substituents, and each substituent is independently selected from the group consisting of hydroxy, fluoro, chloro, iodo, bromo, CF3, sulphononide, alkyl (C? -CA), alkoxy (C1-C4), carboxy, hydroxyalkyl, alkoxycarbonyl (C? -CA), t? Oalkyl (C? -CA) / sulphonyl sulphide, sulphine vinyle, and R * os aTq ilo (I heard -Cß), with the condition of (th when it is Br, the reaction is carried out in the presence of a phosphine.) A procedure omitted from the immediately preceding procedure is a procedure in which Rl is
NHCOCl-I3, -NHCO-t-Bu, -NHCOCF3 O -NHC00-CH2-teni lo; and R2 is hydrogen, or motil. A procedure omitted from the immediately preceding procedure is a procedure in which? is Br and the reaction is also carried out in the presence of a fine phos compound. A preferred process of the immediately preceding process is a process in which the reaction is also carried out in the presence of a polar apr-otic solvent. A preferred procedure of the immedi-is a process in which the reaction of the compound of formula (III) with the vinyl ether of formula (IV), CH2-CH0R, is carried out at a temperature of about 20 ° C to about 130 ° C, The palladium catalyst is a palladium (II) compound and the fine is a fine trienol. A preferred method of the immediately preceding process is a procedure in which the reaction is carried out at a temperature of about 60 ° C to about 100 ° O, the phosphine is tol-tol-11-fos and the solvent is acetonitoplo The present invention also refers to a process for the preparation of a compound of formula (I),
(I) which comprises reacting a compound of formula (TI)
(»)
with an acid, in the presence of water; wherein 0 R1 is selected from the group consisting of -NR3-C0-aiquiloiCi-Cio) / -NR3 -CO2 -alkyloxyCi -Cio). -NR3 -CO2- (CH2) a- (optionally substituted phenyl), -NR3 -C0- (CH2) a- (optionally substituted fem), -NR3 -SO2 -alkyl (C? -Cio). ~ NR3-s? 2 ~ (CH2) a - (optionally substituted phenyl) and -NR3-C0- 5? Erfluoroalkyl (C? -CA); R2 is selected from the group consisting of hydrogen, aromo, Ib
nitro, alkylain or (Oi-Cß), fluoro, CF3, alkyl (C? -C), alkoxy ((II-CA), -NR3 -C0-alkyl (C? -0i0), -NR3-C02- Alkyl (d-Cyclo) -NR3 -CO2 - (CH2) a -'-fn-1-substituted ophyl), -NR3-00- (CH2) »- (optionally substituted phenyl), -NR3- Ü2- alkyl (C? -Cio) / - NR -SO2 - (OH2) a - (phenyl optionally substituted with 1 tuido) and -NR3 -CO-erf luoroalkyl (C? -OA); where a, each time it appears, you will independently 0, 1,, 3 or 4; R3, each time that echo-echo, is independently selected from the group consisting of hydrogen and to which Jo (0? -Cβ); the optionally substituted phenyl group is optionally substituted with one, two or three substituents, and each substitue * e is independently selected from the group consisting p. hydroxy, fluoro, chloro, iodo, bromo, CF3, sulfonary, alkylo (C? -CA), alkoxy (Ci -CA), carboxy, hydr-ox-1-alkyl, or coxi-carbon 1 lo (C? -CA), t? Oalqu? Lo (O? -CA), sulfonyl, sulfiniJo and arn L no; and R * is alkyl (C? -Cβ). A preferred method of the immediately preceding process is when the compound of formula (I) is benzyl ester of the acid (5-acet? Lp? R? D? N-2-? L) -carbarnico, N- (5-acet? Lp) ? pd? n-2-? l) -2, 2, 2-tri-fluoroacetar a, N- (5-acet? l ~ 6-rnet? lp? r? d? n-2-? l) - acetam? da, N- (3 -acet 11-5 -rnet? l ~ ?? pd? n-2-? l) -aceta? n? a, N- (5-acet? l-3-rnet? l-?? r?? n-2-? l) -acetanide, N- (5-acet? ip? r? dm-2-? l) -acetam? da or N- (5-acet? i- 1 /
?? r- 1 d i n- 2 - 11) - 2, 2 - d i inet 11 p rop. -.narní da. This invention also provides a process for the preparation of a corn: .. this of the formula (Z *),
(Z *)
the racemic mixtures and the optical isomers of said compounds, comprising (1) reacting a compound of formula (I),
0)
with a source of bromine, chlorine or iodine, to form a compound of formula (a),
(to)
(2) reacting a compound of formula (a) with a compound of formula H2 -Y2 * to form a compound of formula (71).
(Z1)
and (3) reacting a compound of formula (Z) with a reducing agent to form a compound of formula (Z *), the racene-enant-1 mixture and the optical isomers of said formula (Z). *), where X2 is 01, Br or I; R is selected from the group consisting of -NR3-C0-alkyl (C? -C? O). -NR3 -CO2 -alkyl (C? -Cio), -NR3 -C02 - (CH2)? - (optionally substituted phenyl), -NR3 -C0- (0H2) a - (optionally substituted phenol), - NR 3 -SO 2 -alkyl (Ci -Cio). -NR3-S02 ~ (CH2) a - (optionally substituted fem) and -NR3-C0-perf luoroalkyl (C? -CA); R 2 is selected from the group consisting of hydrogen, ammo, nitro, alkylamine (C? -C8) / fluoro, CF3, alkyl Lo (G? -CA), alkoxy (CI-CA). -NR3-CO-alkyl (O? -C? O), -NR3-C0 -al quilo? Ci-C10). ~ NR3-C02- (CH2) ~ (optionally substituted), -NR3-C0- (CH2) a - (optionally substituted phenyl), -NR3-S02-alkyl (C? -Cio). -NR3 -SO2 - (CH2) a - (phenyl optionally substituted) and -NR3 -CO-μerf J uoroalqui Jo (Ci -C) - where a, each time it appears, is independently 0, 1, 2, 4; R3, each time (ten parts), is independently selected from the group consisting of hydrogen and alkyl (C ~ Cß), and the optionally substituted phenyl group is optionally substituted with one, two or three substituents, and each substituent. It is selected independently from the group consisting of hydroxy, fluoro, chlorine, iodine, bromine, OF3, sulfonamics, alkyl (C? -CA), alkox-1 (Ci -CA), carboxy 1, hydroxyalkyl, alkoxycarbonyl (C? -CA), t? Oalkyl (C? -CA), sullyl, sulfinyl and aromo; Y2 * is
where Qi is oxygen, nitrogen or sulfur; 02 is carbon or nitrogen; 03 is hydrogen, - (CH2) n -femlo, -alqu? Lo (C? -Cio), - (CH2) n -NG1G2, - (CH2) n -C02G3, - (CH2) n -C0-NG1 G2, - (CH2) n -0G3, - (CH2) n ~ 503G3, - (CH2) n -S02 -alkyl (Ci-Cß). - (CH2) n - 02 NGl G2 or a het orooust selected from the group consisting of - (OH2) n - in i lo, - (OH2) n -pirp i di lo, - (CI-I2 ) n - i razi ni lo, (OH2) n - i oxazol ilo, (CH2> n -oxazol lio, (CH2) n - * lazol 1 lo, - (C..2) n (1.2, -oxadi azole) ilo), - (CH2) n - 1 mi dazol 1 lo, - (CH2) n -t pazol ilo y - (CI-I2) n -tet razol 1 lo; where one of the nitrogen atoms of the ring said - (CH2) n - uni dazo li lo - (CH2) n tnazolyl and - (CH2) n-tetrazolyl may be optionally substituted with optionally substituted alkyl ((.? - Cß) alkyl independently with one or more carbon atoms. halo, where each heterocyclic compound may optionally be substituted on one or more of the carbon atoms of the ring, with one or more substituents being independently selected from the group consisting of alkyl (C? ~ Cß). independently substituted with one or more halo atoms, halo nitro, cyano, - (CH2) n -NG G2, - (CH2) n-C02G3, - (CH2) n "C 0-NG G2, - (CH2) n "0G3, - (CH2) n - SO2 G3, - (CH2) n ~ SO2 alkyl (C? -Cß) or - (CH2) n ~? O2NGiG; wherein a phenyl radical of said - (CH 2) n -pheni may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl (Ci-Cβ) optionally independently substituted with one or more halo, hydroxy atoms , alkoxy, (Ci-Cß) optionally substituted independently with one or more halo, alkyl tio (C? ~ Ce), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n -NG1G2, - ( CH2) n -C02G3, - (CH2) n -CO-NG1 G2, - (CH2) n -0G3, - (CH) n -O3 G3, - (CH2) n-S02 -alkyl (C? -C6), - (CH2) n "S02 G1 G2; - (CH2) n ~ NG3 -S02 G3 and - > CH2) n" NG3-SÜ2 NG * G2; Q * is - 0 0H2) n -CN, - (011) n - 'J2 G3, - (0H2 n-'iOsG3, - (CH2 Jn -SÜ2"To the quilo (C? -C6), - (CH2) n "S02 I 31 2, (0H2 'n -CI-I2 OH, - (CH2) n - C lO, -. CH2) n - 00" G3, - (CH2) n -CONO 1 r ^ a het cr oci cio selected from - (CH2) n -t lazole 1 lo, -'CH2) n -oxazolyl, - (CH2) n -nnidazolyl, - (OH2) n-tpazol 1I0, -CH2) n-1,, -oxad? azole -, - (OH2) n - 1 oxazoli 1 or, - (OH2) n - et razolilo and - (CH2) n -pirazol 1 lo; where one of the nitro jeno atoms of the said ring - (OH2) n - iiru dazol lio, - (CH2) n - nazol ± lo and -ÍCH2> n - tet razol 1 it can be substituted with alkyl (C? ~ Cß) optionally substituted 1 ndependient eme e with one M atom halo wherein each of said heterocycles may optionally be substituted, in one or more of the ring conditions, with one or more substituents selected i dependently between the group consisting of hydrogen, alkyl (Ci-Cβ) optionally substituted independent with one or more halo atoms, - (CH2) n -C0-NG1G2, - (CH2) n -CO2G3, halo, nitro, cyano, - (CH2) n -00-NG1G2, - (CH2) n ~ 0G3 , -lCH2) n- "SO3G3, - (CH2) n ~ S? 2 -alkyl (C? ~ Cß) O - (CH2) n -SO2 NGl G; QS is hydrogen, or (Ci-Cβ) alkyl optionally substituted independently with one or more halo atoms; O6 is a covalent bond, oxygen or sulfur; O7 is hydrogen, or (Ci-C) alkyl optionally substituted independently with one or more halo atoms; Qβ and Q 9 are independently an oxygen, oxygen, sulfur, NH or -N-alkyl (Ci-Cβ) bond; 010 is - (CH2) n-0R9, - (CH) "--C02 H, - (CH2) n -C0R11, - (CH2) n ~ S02 R9 RIO - (CH2) n-NR9S? 2R8, - (CH2 ) n -P (0) (0R «) (0R5), - (CH2) n -0- (CH2) m -C02H, lCI.2) n-0- (CH2 Jm- (ORH, - (C42) n "O - (CH2) m - P (O) (0R) (0R5), (CH2) n-0 (CH) mL? 2N 9R10 or - 1 CH2) n - lCH2) m -NR9S02R8; R * and R5 are each, independently, hydrogen, or alkyl (Ci-Oß), and R6 V 7 c- < on each, independently, hydrogen, halo, alkyl (Ci-Cß), nitro, cyano, t r1 f1 uorome ilo , SO2 R8, S02 NR9 Rlo NR9 RI O. COR l, C02 -R9, leoxy (Ci-Cß) NR9 S02 R8, NR C0RH, NR9C02R9 OR OR9; where G and G2, each time they appear, are each independently hydrogen, alkyl (Ci-Cß) optionally substituted independently with one or more halo, alkoxy (Ci -Cs) to the one Jo (Ci-Cß) or cycloal (| u Gl, and G2 together with the nitrogen at which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms can optionally be replaced by oxygen, geno or sulfur, G3 each time it appears, is independently hydrogen, or alkyl (Ci-Cß), R8, each time it appears, is independently alkyl (Ci-Oß) or alkoxy (C? ~ Cß); and R10, each time they appear, are independently hydrogen, alkyl (Ci-Cß), cyclohexane (C3-C8) or alkoxy (Ci-β) alkyl (Ci-Cß); Rii, each time it appears, is independently hydrogen, alkyl (Oi-Cß), NR9Ri °, cycloalkyl (C3-O8) or alkoxy (Ci-Cß) alkyl (Ci-Cß), where R9 and Rio are as defined above, rn, each time ece, is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; with the proviso that: (1) when O9 is 0 or S, then n is not 0; (?) when Ql is oxygen or sulfur, then (,) 3 is absent; and (3) when O2 is nitrogen, then O5 is absent. A preferred method of the immediately preceding process is when R1 is -NHCOCHj ,, -NHCO- -Bu, -NHCOCF3 or ~ NH000-CH2-femlo; and R2 is hydrogen, or methyl. This invention also provides another method for the preparation of a compound of the formula (Z *),
(Z *)
of the racernic-enantiomepca mixtures and of the optical isomers of said compounds, comprising, (1) reacting a compound of the formula (I),
(I)
as a source of bromine, chlorine or iodine, to form a compound of formula (a), (a)
(2) reacting a compound of formula (a) with a mild reducing agent to form a compound of formula (c),
and (3) reacting a compound of formula (c) with a base and H2N-Y2 *? ar-a to form a compound of formula (Z *), wherein
X2 is Cl, Br or I; Rl is selected from the group consisting of
~ NR3-CO- (C1-C10) alkyl, -NR3 -CO2 - alkyl or (C1-C10), -NR3 ~ C2- (CH2) a ~ (optionally substituted phenyl), -NR3-CO (Ol-te) »- (optionally substituted phenyl), -NR 3 -SO 2 - (CH 2) a - (optionally substituted phenyl) and -NR 3 -CO-perfluoroalkyl (CI-CA);
R 2 is selected from the group consisting of hydrogen, aromo, nitro, alkylamino (Ci-Cß), fluoro, CF 3, alkyl (CI-CA) alkoxy
(CI-CA), -NR3-C0-alk (C1-C10), -NR3 -CO2- (CH2) a- (optionally substituted femlo), -NR3-CO- (CH2) - (optionally substituted phenyl) , -NR3-S02- (C1-C10) alkyl, -NR3-SO2 (CH2) a- (optionally substituted phenyl) and -NR3 -CO ~? Erfluoroalkyl (CI-CA);
K
where a, each time it appears is independently 0, 1, 2, 3, or 4; R3, each time it appears, is independently selected from the group consisting of hydrogen and alkyl (Ci-Cß); and optionally substituted phenyl is optionally substituted with one, two or three substituents, and each substituent is independently selected from the group consisting of hydroxy, fluoro, chloro, iodo, bromo, CF3, sulphamide, alkyl ( 0I -0A), carhoxy, hydroxyalkyl, alkoxylcarbon (CI -CA), thioalkyl (CI -OA), sulfonyl, sulfamium, ammonium; Y2 * is
where O1 is oxygen, nitrogen or sulfur; O2 is carbon or nitrogen; O3 is hydrogen, - (CH2) n -phenyl, -alkyl (C1-C10), - (CH) n ~ NGlG2, ~ (CH2) n ~ C02 G3, - (CH) n -CO-NG * G2, - (CH2) n ~ 0G3, - (CH2) n-03G3, - (CH2) n-S02 -alkyl (Ci-Cß), - (CH2) n "S02NGl G2 or a heterocycle selected from the group consisting of - - ( CH2) np? R? D? Lo, - (CH2) n -piprnidil, - (CH2) n -pirazini lo, (CH2) n-diosxazolil, - (CH2) n-oxazole?, - (CH2) n - tlazol lyo, (CH2) n- (l, 2,4-oxad? aolol), - (CH2) n -imidazolyl, - (CH2) ..- tpazolyl and - (CH2) n-tetrazolyl, where one of the atoms of 2 b
nitrogen of said ring (OH2) n-pnidazole Lyo, - (CI-I2) n -triazolyl / - (OH2) n -tetrazole 1 can be substituted opc 1 on 1 me nt e co n alkyl (01 - Cß ) oc 1 or na 1 ment sust you gone independently with one or more halo atoms; wherein each of heterocyclic dLChos can be optionally substituted on one or more of said carbon atoms of the ring, with one or more substitutes independently selected from the group consisting of alkyl (Oi-Cβ), optionally substituted or independently with one or more atoms of halo, halo, nitro, cyano, (CH2) n -NG1 G2, - (CH2) n "C02 G3, - (CH2) n - CO - NG1 G2, (CH2) n - 0 (. 3, - (Cl-b) n -SO3G3, - (CH2) n -S02 -alkyl (Ci-Cß) V- (O-fe) .. -SO2NGIG2; wherein the radical femlo of said - (CH2) n - The emf may optionally be substituted with one or more substituents independently selected from the group consisting of (Ci-Cß) alkyl optionally substituted independently with one or more halo, hydroxy, akoxy (Ci-Cβ) optionally substituted independently with one or rings of halo, alkyl 10 (Ci-Cß), fluoro, chloro, bromo, iodo, cyano, nitro, (CH2) n -NG1G2, - (CH2) n ~ C02G3, - (CH2) n ~ C0 ~ NG1G2, ~ (CH2) n- OG3, - (CH2) n-S03G3, - (CH2) n -SO2 -alkyl (C? -C6), - (CH2) n -SO2 NG * G2; - (CH2) n-NG3 -SO2-G3 and - (CH2) n ~ NG3 -S02NG1 G2; 0 * is - (CH2) n-CN, - (CH2) B-002G3, - (CH2) n - 03G3, - (CH2) n ~ S02 -alkyl (C? ~ Cß), - (CH2) n -SO2NGIG2 , - (CH2) n-CH20H, ~ (CH2) n "CHO, - (CH2) n" C0-G3, - (CH2) n -CONGiG2, or a heterocycle selected from - (CH2) n -thiazolyl, - ( CH2) n -oxazolyl, - (CH2) n -nitridazole 1I0, ~ (CH2) n ~ friazoJil, - (CH2) n-1. , 4-Oxad? Azole, - (CH2) n -isoxazolyl, - (01-12) n - * e * razo 111 or y - (CH2) n - P 11 '¿or 111 o; where one of the nitrogen rings of the said ring (OH2 Jn - uni dazol LJO. (CH2) nt pazol 1I0 and - (CH2) n - * or * razol 1 can be optionally substituted by al ( juic (Ci-Cß) optionally substituted independently with one or more halo atoms, where each of said atoms may be optionally substituted on one or more of the ring carbon atoms, by one or more substituents selected independently in the group consisting of hydrogen, alkyl (Ci -Cβ) opcLonalrnent or independently substituted with one or more halo atoms, - (CH2) n-00-NGlG2, - (CH2) n - C 2 2 G3, halo, nitro, cyano, - (0112) n - 00 - NG G2, - (CH2) n ~ 0G3, - (CH2) n-cJ? 3G3, - (CH2) n -S02 -al qui J or (Ci Cß) or - (CH2) n -SO2NGIG2; O5 is hydrogen, or (Ci-Cß) alkyl optionally substituted independently with one or more halo atoms, Q6 is a covalent bond, oxygen or sulfur, O7 is hydrogen, or alkyl (C? ~ Cß) optionally substituted independently with one or more halo volumes; O8 and O9 are, i dependently, a covalent bond, oxygen, sulfur, NH or -N-alkyl (Ci-Cß); 010 is - (CH2) m-0R9, - (CH2) n -OO2H, - (CH2) n -CORH, - (CH2) n-S02NR R10, - (CH2) n "NR9 O2 R8, - (CH2) n -P (0) (0R *)
(0RS), - (CH2) n-0 - (CH2) m -C02 H, - (CH2) n ~ 0 - (CH2) n -CORL 1, - (CH2) n -0 - (CH2) mP (0 ) (OR *) (0R5), - (CH2) n-0 - (CH2) m ~ .02 NR9 RIO O - (CH2) n "0 - (CH2) m-S0 NR R10 0 - (CH2) r. -0- (CH2) m ~ NR9 S02 R8; R * and RS are each, independently, hydrogen, or alkyl (Ci-Cß); and R6 and R7 are each, independently, ludrogen, halo, alkyl Cß), nitro, cyano, t-pfluorornethyl, SO2R8, 20
(, () 2NR9R10, NR9R10, OORH, 00R2 R9, alkoxy (C? - (ß), NR9 S02 R8, NR (.0Rii, NR9C02R9 or OR9; where Gl and G2, each time they appear, are each independently , hydrogen, alkyl (Gi-Cβ) optionally independently substituted with one or more halo, cox L (Ci-Cß) alkyl (Ci-Cß) or cycloalkyl (C3-C8), Gl and G2 together with nitrogen to which they are bonded form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms may be replaced optic canvas with nitrogen or sulfur oxygen; O3, each time it appears, is independently hydrogen , or alkyl (C? ~ 0ß); R8, each time it appears, is independently alkyl (Oi-Cß) or alkoxy (Ci-Cß) alkyl (C ~ Cß); R9 and Ri °, each time they appear, are independently hydrogen, alkyl (Ci-Cß), cycloalkyl (C3-C8) or alkoxy (Ci-Cß) alkyl (C? -Cß); R11, each time appended, is independently hydrogen, alkyl (Ci-Cß) ), NR Rio, cycloalkyl (C3-C8) ) or alkox1 (Ci-Cß) alkyl (Ci-Cß); where R9 and R or are as defined above; rn, each time it appears, it is independently an integer from 1 to 6; and n, each time it appears, is independently 0 or an integer from 1 to 6; with the conditions that: (1) when O9 is 0 or S, then n is not O; (2) when O1 is oxygen or sulfur, then O3 is absent; and (3) when O2 is nitrogen, then Qs is absent. A preterm procedure of the immediately preceding process is a process in which R is -NHCOCH 3, -NHCO-t-Bu, -NHCOCF 3 or -NHCOO-CH 2 -phenyl and R 2 is > q
hydrogen, or methyl .. Otr-o compound that is useful in the synthesis of a compound of formula (C), os a compound (Je the formula
(to)
where Rl is selected from the group consisting of Qc -NR3-CO-alkyl (C? ~ C? o), -NR3 -CO2 -alkyl (C? -Cio), -NR3 -CO2 - (CH2) a- (optionally substituted phenyl), -NR3-C02 - (CH2) a- (optionally substituted phenyl), ~ NR3 ~ CO-alkyl (C? -Cio), - NR3 ~ S02-alkyl ( C? -Cio), -NR3 -SO2 - (CH2) a (optionally substituted phenyl) and -NR3 -CO2-perfluoroalkyl (C? -CA); R2 is selected from the group consisting of arnino hydrogen, nitro, alkylaryn (C? -C8), fluoro, OF3, alkyl (C? -CA), alkoxy (C? -? A), -NR3 - CO-alkyl (C? -C? O). -NR3 -CCfc -alchiioiCi-Cio), -NR3-C02 ~ (CH2) a ~ (optionally substituted phenyl), -NR3 -CO2 - (CH2) a - (optionally substituted phenyl), -NR3-S02-alkyl (C? -Cio), -NR3 -SO2 - (CH2) a (optionally substituted fem) and -NR3 -CO2-perfluoroalkyl (C? -CA); where a, every time it appears, it is independently
0, 1, 2, 3 or 4;
R3, each time it appears, is independently selected from the group consisting of hydrogen and alkyl (Oi-Oß); and the optionally substituted alkyl group is optionally present with one, two or three substituents, and each substituent. The constituent is independently selected from the group consisting of hydroxy, fluoro, doro, iodine, bromine, CF3, sulfonaini, alkaline (0? -CA), cox! (Ci -CA). carboxy, hydroxyl Lalkyl, alkoxylcarbonyl (C? -OA), tioal (jui I0.C1 -CA), sulfonyl, sulfinyl and ammo; and X2 is 01, Br- or I .. A compound which is preferred among the immediately preceding group of compounds of formula (a), are compounds where R1 is -NHCOCH3, -NHCO-t-Bu, -NHCOCF-3 0 -NHCOO-CH2-phenyl and R2 is hydrogen, or methyl. Those skilled in the art will appreciate that the compounds of formulas (I), (II), (TU) and (Z *) can contain-at least one chiral center. Accordingly, the compounds of formula (T), (IT), (111) and (Z *) can exist and be isolated on the optically active and racernic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention embraces racernic, optically active, polynuclear and stereoisophatic forms, or mixtures thereof, it being well known in the art how to prepare optically active forms. For example, by resolution of the racernic form by reclassification technique, by synthesis from optically active starting materials, by chiral synthesis or by cold separation using a phase that is acceptable to 1. F_n In this descriptive specification and in the appended claims, the terms "alkyl" and "lco" are radicals of each ineal and branched, but (It should be understood that references to individual radicals such as "propyl" or "propoxL" encompass only the straight chain radical ("normal"), specifically referring to the chain isomers?? n? f? <such as "isopropyl" or "i sopropox i"
Detailed description
In the discussion shown below, common chemical abbreviations and acronyms have been used: BOC (tert-but ox icarboml i); CBZ (encyloxycaronyl); T? F
(tetrahydrofurane); DMF (dirnet íl form, i da); NMP (N-? Net? I-2-pioli dona); DMfíC (N, N-d? Rnet? Lacetarn? Da); DME (dirne tox L -ethane (;
DMSO (dunet ilsuloxido); ÍFfi (acid tpf luoroacet i co).
"Lower", as used herein, (eg, when referring to an alkyl group or a lower alkanol), means a group having one to four carbon atoms. The term "reaction inert solvent" refers to any solvent or combination of solvents that does not interact with starting materials, reagents, intermediates or products of a form adversely affecting
the reaction or the performance of the desired product. A process for the manufacture of a compound of formula (E) as defined above is provided, as a feature of the invention and is illustrated by the following procedure, in which the meanings of the generic radicals are as follows: Previously, it has been indicated that the procedure be indicated. The procedure can be carried out in general as shown in Method 1
ESQUE? R I
I If not available in the market, the starting materials necessary for the following processes can be obtained by conventional organic chemistry techniques known to those skilled in the art, techniques that are analogous to the synthesis of known compounds, or techniques that are analogous to the procedures described below or the procedures described in the examples.
A compound of formula (El) can be synthesized by the treatment of a compound (formula (III) with a vinyl ether of the formula UV), OH2-CHOR *, (where Ri, R *, and? Are as previously defined) in the presence of a base, a phosphine and a palladium catalyst, to produce a compound of formula Ul). The reaction is carried out typically by stirring in a polar solvent such as an ether (eg, rHF, dioxane, DME), a lower thanamethylene, a polar aprotic solvent such as DMF-, NMP, DMttO or a mixture of these dissolvents, especially acetorutrilo. Suitable bases for the reaction include lower tpalqulamines, sodium or potassium carbonate, or sodium or potassium bicarbonate, t r et 1 larn 1 na being particularly preferred. Suitable fine phos es include phospho-naphthanes such as trifeni-1-phosphine and d-phenol-2-pip-di-phosph-a, with n-ortho-tolu-lphosph-1a being particularly preferred. The palladium catalyst can be split between palladium on carbon or another solder when it is iodine, and when X is not iodine, the palladium catalyst is selected from a variety of salts and palladium complexes, such as palladium chloride. (TI), palladium (0) t.etraquisí riferulf o fi na), palladium chloride (11) b? S (t r-? Phenyl phosphine), palladium (0) b? S (lead-acetone dibencí), palladium (0) bisienzorutp lo), or diringer of palladium chloride and aillo, with palladium acetate being especially preferred
(II). The reaction is typically carried out at a temperature of:) /.
approximately 2 ° C) or approximately 150 ° C, a ternper-atur-a of approximately b () "or approximately 110 ° C. being particularly suitable. A compound of formula Ul) can be converted into a compound of formula U ) by treatment with an acid on the presence of water (water may already be present in the acid, in which case it is not necessary to add more water). Generally, prior isolation and / or purification of a compound of formula (II) is not required. Acids that may be used include sulfuric acid, p-chloroacetic acid, t-ritluoroacetic acid, oxalic acid, citric acid, nitrosulphonic acid, sodium or potassium bisulfate., the hydrochloric acid being particularly suitable. The reaction is typically carried out by stirring a compound (E formula) with an acid, in the presence of optional water, in the presence of a polar cosolvent such as an ether, an alcohol to the lower uilic, an ester to the chylic. or a mixture of these solvents The reaction is typically carried out at a temperature of about -20 ° C to about 50 ° C. Conventional methods and / or techniques of purification and separation known to those skilled in the art can be used to isolate The compounds of this invention such techniques include all types of chromatography (HPLC, column chromatography using common adsorbents such as silica gel and chromatography?
of fa layer), recp stalization and difor-encial extraction techniques (ie, 11 qui do-1 fluid) "ls' / le addition of acids of the compounds of the present invention may be useful to help the puri tion of said compounds, as indicated in the description of this document. The acid addition salts of the compounds of the present invention are easily prepared by reacting the basic forms with the appropriate acid. When you leave a monobasic acid (for example, the hydrochloride, the broinhi drato, the p-toluenosul fonat or the acetate), the hydrogenated form of a dbasic acid (for example, the bisulfate the succinate) or the If a dihydrogenated product of a teribasic acid (for example, dibiphosphate or citrate) is used, at least one molar equivalent is used, and usually a rnolar excess of the acid. However, when salts such as sulphate, hernissuccine, are desired, T osfato or phosphate, the appropriate and exact chemical equivalents of acid are generally used. The free base and the acid are usually combined in a co-solvent in which the desired salt is precipitated, or can be isolated in another way by concentration and / or addition of a non-solvent The compounds of formula (1) can be used to prepare ß-adrenergic receptor agonists that have the general formula (Z), (Z)
(I agree with the following general procedure, in which Rl and R2 on (have not been defined in this document or pair the compound of lopnula (I), and Y, Y2 < "Y3 < -on. Ualquior substituent (juimico) that can be united to those who are united and with the activity of receptor 3-adrenergic, and as they have utility as hypoglycemic and anti-obesity agents, examples of such substituents and the resulting β-adrenergic receptor agonists, in PCT Publication No. UO < H / 292 < 30, published on December 22, 19 < H. Preferred embodiments of formulations of formula (Z ) are composed ?, of formula (Z *),
(Z *) if
in Ja; e? i and Y3 are, each, hydrogen, or Y2 * as it has been defined: earlier. The acetyl side chain of a compound of formula (E) is brominated with a bromine source such as elemental bromine, phenyl phenyl-ammonium pbromide or perpuretine of papdino brornhydrate and hydrogen bromide in acetic acid, to prepare the compound (a) in X2 is Br. The reaction is completed in a period of 1 to 5 hours and is generally carried out at a temperature of approximately 0 ° C at the temperature of the lens, being preferred temperature amblen4-e.
(to)
The reaction can also be performed using the analogous chlorine reagents to prepare the compound (a) with an acetyl group substituted with chlorine, where X2 is 01. The acetyl side chain of a compound of formula (I) can be chlorinated with a source of chlorine, such as chlorine gas dissolved in acetic acid, trichloro-trichloroacetic acid and sulfuric acid in acetic acid, or chlorotn-rnethylsilane and dirnethiis sulfoxide in acetonitrile, to prepare the compound (a) with a substituted acyl group with chlorine, where X2 is 01. The acetal chain of a compound of formula (E) can also be iodinated with an iodine source, such as iodine and a soluble silver (T) salt, for example nitrate silver in methanol, N-yodosucmimide in acetic acid, or potassium iodate and potassium iodide in sulfuric acid, to prepare the compound (a) with an acetyl group substituted with iodine, where X2 is E. Fl. compound (a) can be sequentially admixed reduce to form the compu this (Z), or compound (a) can be reduced and treated with a base to form an epoxy compound (c),
(c)
which is then aminated to also prepare the compound (Z). The use of reducing agents chiral.es in this sequence allows the preparation of specific stereoisomers, since the carbon atom is carried to the hydroxyl in the compound (Z) is asymmetric. In the reaction of the compound (a), to prepare the compound (Z), the starting material is placed in a. < -)
d i so 1 ve rite a p ro t i. ol as a ce ton linio and aro i na enex ce so (ie, NHY Y3, with the preferred amine being H2NY2 *, producing a compound of formula (Z *)) and stirring (during a period of 10 hours). minutes to 2 hours.The solvent is removed and the residue with the activated acetone int rmedia of formula (/.i), for example
(Z1)
wherein Y2 * is as defined above, which can be isolated but which is normally not dissolved, is dissolved in a protic solvent such as alcohol and combined with a mild reducing agent, preferably sodium borohydride, at a temperature of about 0 ° C to about 10 ° C for about 15 minutes to about 2 hours. The product is isolated using known techniques. The compound (a) can also be converted to the epoxide (c) by using a mild reducing agent such as sodium borohydride, lithium borohydride and the like, the reducing agents will produce a random mixture (ie, these isomers). a reducing agent - this reospecific such as R-alpine-borane, which prepared the R-isomer of the substantial epoxide without the S-isomer. The reaction is carried out in a solvent inert to a 41)
0 ° 0 temperature at room temperature, preferably at room temperature, the reaction is generally completed p? a period of 1 to 10 days. F.1 progress of the reaction is generally continued by taking aliquots of the reaction mixture and analyzing them with r-spectra in the presence of starting material by the use, for example, of thin layer chromatography. When necessary, more reducing agent can be added. The reaction mixture is then treated with a base, such as a hydroxide (alkali metal), preferably sodium hydroxide, in a protic solvent such as an alcohol, in the presence of a tertiary amine, or with an excess of amine reactant. (ie-, HNY2 Y3, the amine being intended to be l-feNY2 * and producing a compound of formula (Z *)) The reaction is generally completed in a period (approximately 0.5 to approximately 24 hours and a temperature of 0 ° 0 at ambient temperature, preferably at room temperature Epoxide (c) is aminated using the excess of amine reacting in an alcohol heated to a temperature of about 50 ° C at the temperature The reaction is generally completed in a period of about 1 to about 24 hours.If compound (c) is prepared in a stereospecific manner, the optical purity of the product, compound (Z), will be retained. invention is illustrated by the following Examples However, it should be understood that the invention is not limited to the specific details of such examples.
EXAMPLE 1 N- (5-flcetyl-p? R? Din-2-IL) -acetam? Da
A mixture of 1.0? g (5 mole) of N- (..-- bromo - ?? p di n-2 - 11) -acetamide, 1.00 g (10 mrnol) of butyl vini l ter-, 0.245 g (0.0 marble) of t po-tol i 1 f osf i na, 0.090 g (0.4 mol) of palladium acetate and 1, 10 rnl (7.9 mol) Je tpeti lamina in 10 ml of acetonitoplo containing 15 The hydroquinone was heated to reflux for approximately 1 h. The reaction mixture was then cooled, concentrated and the residue was suspended in 10 ml of 6 M hydrochloric acid and stirred for approximately 15 minutes. It was diluted with 40 ml of ethyl acetate, adjusted to pH 8 with 6 M sodium hydroxide solution and the aqueous phase was saturated with sodium chloride.The ethyl acetate layer was separated, dried and concentrated, the residue was chromatographed on silica gel (2: 1 ethyl acetate-hexanes), to yield 0.578 g of N- (5 ~ acetii -p? pd? n-2-? l) -acetar ida in the form of white needles, mp 146-1 7 ° C (recrystallization solvent = 1: 4 ethanol-hexanes); 1 H NMR (from ute noel oro forma): 6 = 8.82 (s a, 1H), 8.21 (rn, 3H), 2.56 (s, 3H), 2.22 (s, 3H) ,; MS (NH3C1): rn / z = 179 (MH +).
2
EXAMPLE 2 N- (5-ñcet? L-p rid? N-2-? L) -2,2-d? Met? L-prop? Onam? Da
A solution of 5.00 g (28.9 rnmoles) of 2-arnmo-b-bromopyridine in 20 ml of di-chloro-methane was sequentially added with 3.50 g (34.6 mmol) of triethylamine followed by - 3.50 g (29.2 rnmoles) (Te chloride prnet i lacet i lo "the reaction mixture is filtered af) roxándarnente after 1 hour and ol fitrado evaporated to get an oil? This was crystallized from hexanes, fi ltered and evaporated to yield 3.36 g of N- (5-bromo or -dri-2? 2) -2,2-dirnet LJ. -propionarnide in the form of white crystals, mp 57-59 ° C. iH NMR (deuteriochloro form) 6 = 8.28 (d, ÍH), 8.16 (d, ÍH), 7.96 (a, IH), 7.75 (d of d, ÍH), 1.29 (s, 9H),: MS (NH3C1): m / z = 257, 259 (M + H +, isotopes of Br) Following the procedure of Example 1, the title compound was obtained from 3.84 g (15 mrnol) of N- (5-bromo-β-ridi n-2- l l) -2, 2-d ?rnet ?l -propionarnide, 15 rnl of acetoni * rilo, 3.15 rnl (22.5 mol) of triethylamine, 3.90 ml (30 mol) d e butyl vimJ ether, 135 ing (0.6 rnmoles) of palladium acetate and "367 rng (1.2 mrnols) of tri-o-tolylphosphm, to produce 2.63 of the title product in the form of white rhombs after the recrystallization of the crude product without chromatography, mp 113 ~ 115 ° C (solvent of the recrystallization = 2-propanol); H NMR (deuteriochloroforrne): d
= 8.84 (el, ÍH), 8.32 (d, ÍH), 8.23 (d of d, JH), 8.20 (a, 1H), 2.59 (s, 3H), 1, 34 (s, 9H), Lll (NH 3 C 1). in / Z - 221 (H *)
EXAMPLE 3 N- (5-ftcetyl-6-methyl-pyrid? N-2-? L) -acetam? Da
Following the procedure < ] Example 1, the compound of the itule was obtained from 1.15 g (5 rnrols) of N- (5-b-rom -6-met-1 -pin din-2-yl) -acetarnide, 10 mg of aceten 11 rilo, 1, 10 mi (7.5 mrnoles) of t riet i lam m, 1.00 g (10 immoles) of viral buti 1 ether, 90 ing (0.4 mrnols) of palladium acetate and
245 rng (0.8 mol) of t po-ol i 1 f osf i na, to produce 0.92 g of the title compound in the form of white flakes after chromatography (2: 1 hexanes-acefat ethyl), p. F. 2Q1-202 ° C (recrystallization solvent-2-propanol); iH NMR (J met j sul fox idode): o - 8.27 (d, IH), 8, 0J (d, 1H), 2.59
(s, 3H), 2.53 (s, 3H), 2.11 (s, 3H); MS (NH 3 Cl): rn / z 0 193 (H +).
EXAMPLE 4 N- (3-flcetyl-5-methyl-p? Ridin-2-yl) -acetamide
Following the procedure of Example 1, the title compound was obtained from 1.15 g (5 mmoles) of N- (3-bromo-5-met? L-par? D? N ~ 2-? L) acetal amide, 10 rnl of acetoni tplo, 1.10 rnl (7.5 rnmoles) of triethiiarnine, 1.00 g (10 mol) of butii viml ether, 90 rng (0.4 mol) of palladium acetate and 245 ing (0.8 mrnoles of * poto 1 il phosphine, to produce 0.50 g of the compound (Jel itulo in the form of a white solid two times the chromatography (2: 1 ethyl acetate; hexanes), p.f ".99-1 () 0 ° C (recrystallization solvent = 2-propanol); iH NMR (deu te ri oc paroro formmo): d = 11, 08 (a, 1H), 8, 41 (d, Hl),, 94
(d, ÍH), 2.63 (s, 3H), 2.35 (s, 3H), 2.34 (s, 31-1); MS (H301): rn / z = 193 (MH + = -) "
EXAMPLE 5 N- (5-Cetyl? -5-met? L-pyridin-2-id -acetamide
Following the procedure of Example 1, the title compound was obtained from 0.478 g (2.1 mmol) of N- (5-b? -omo-5-met? L-?? pd? N-2-? l) -acetarnide, 5 ml of acetom tplo, 0.32 g (3.2 rnrols) of tpetilarní na, 0,42 g (4,2 mrnols) of butyl vini l ether, 38 ing (0,17 rnrnols) of palladium acetate and 103 mg (0.33 mmol) of tp-o-toluo l phosph, to yield 0.162 g of the title product as a white sol after chromatography (2: 1 ethyl acetate). hexanes), pf 115-116 ° C (recrystallization solvent - ethyl acetate); 1 HOUR
NMR (deuteriochlor form): or = 8.26 (d, HH), 7.79 (a, 1H), 7.68 (d, HH), 2.24 (s, 9H) ,; MS (NH3Cl): rn / z = 193 (MH +).
4 I ''.
EXAMPLE 6 (5-Acetyl-pyridin-2-yl) -carbamic acid benzyl ester
Following the procedure of Example 1, the title was obtained from 1.50 g (5 mole) (Je ester benzyl) of the acid (5-brorno-p? R? clm-2-Ll) -carbarnic, 10 rnl of acetomeril, 1, 10 ml (7.5 mrnoles) of rie ti lamí na, 1, 00 g (10 pmol), butyl L vinyl ether, 90 g (0) , 4 rnrnoles) of palladium acetate v 245 ing (0,0 mol) of * i -ot oi i Fos fos, for production - 0,89 g of the product of the title in the form of white needles after the recpstalisation of the product gross without chroma ography, mp 186 ° C (dec.) (recrystallization solvent = ethyl acetate); 1 H NMR (d unet ulsuLfoxido-d6): d = 10.76 (sa, ÍH), 8.85 (d, ÍH), 8.25 (d of d, ÍH), 7.96 (d, 1H), 7.41 (rn, 5H), 5.19 (s, 2H), 2.54 (s, 3H); EM
(NH3C1): rn / z = 271 (MH +).
EXAMPLE 7 N- (5-ñ -ethyl-pyridin-2-yl) -2,2, 2-trif luoro-acetamide
Following the procedure of Example 1, the title compound was obtained from 1.34 g (5 mrnols) of N- (5-brorno-r? D? N-2-? L) -2, 2, 2-tr? Fluoro-acet.arn? Da, 10 rnl of acetoni + plo, 1.10 ml (7.5 mmoles) of t-petilarnin, 1,00 g (10 rnmoles) of butii vinyl ether, 90 mg (0, 4 mmoles) of palladium acetate and 245 rng (0.8 mmoles) tr? - tol? L phosphma, to produce 40
1. 01 g of the title product in the form of white holes after the end of the gross product s n chromography, p. F. 147-149 ° C (recrystalline solvent Lzation-ethyl acetate); 1 H NMR (deutep or gold torm): d --- 0, '! H (d, ll-l), 0, 11 (d, ll-l), 7.91 (a, 1H), 7.87 ( d of d, 1H), 2.35 (,
3H); MS (NH3OI) :: in / z = 233 (MH +).
EXAMPLE 8 N- [5- (l-Butox? -vinyl) -pi idin-2-? LJ-acetam? Da
A mixture of J, 07 g (5 mol) of N- ('".- bromo-p? R-? (J? N-2-il) -acetami da, 1.00 g (10 mol) of butLi viml ether, 0.245 g (0.8 mrnoles) of * p -o-tol -lfosphine, 0.090 g (0.4 mmol) of palladium acetate and 1.10 nmol (7.9 mmoles) of t-riet ilarnin in 10 g. ml of acetone containing 15 g of hydroquinone, 3 g heated to reflux for about 18 hours, the reaction mixture was then cooled, concentrated and the residue was suspended in ether and water. or, washed with water and brine, dried and concentrated.The residue was chromatographed on a silica gel (6: 1 benzene-ethyl acetate) to yield 0.254 g of the title product as a colorless oil. which crystallize rapidly, mp 55-58 ° C (recrystallization solvent = hexane). NMR (deutepochloroform): d = 8.48 (rn, HH), 8.42 (sa, HH), 8.24 (m, ÍH), 7.93 (rn, ÍH), 4.60 (d, 1H), 4.23 (d, ÍH), 3.84 (t,
3H), 2.21 (s, 3H), 1.77 (rn, 2H), 1.48 (m, 2H), 0.97 (t, 3H), EM (ET) ': 111 / z-234 (+)
PREPARATION 1 N- (5-Bromo-p? Ridin-2? L) -acetamide
A solution of 25.0 g (144 mol) of 2 not yet brine in 50 ml of acetic acid and 250 rnl of acetic anhydride was heated to reflux for about 2 hours. The reaction mixture was then cooled and poured into 50 ml of water with stirring. After approximately 1 hour, the solution was adjusted to pH-10 with 50% sodium hydroxide solution and the precipitate was filtered, washed with water and dried to give * 26.5 g of the compound of the thule in the form of a white scaly solid, mp 175-176 ° C. 1 H NMR (deutenochlorofor.no): d = 8.29 (d, H), 8.12 (d, 1 H), 7.96 ( a, 1H), 7.78 (d of d,
1H), 2.19 (s, 3H). MS (El): rn / z 214, 216 (M +, is moles of Br) ..
PREPARATION 2 Benzyl ester of (5-bromo-pyridin-2-yl) -carbamic acid
A solution of 2 ~ ammo- -brornopipdma (6.92 g, 40 mol) and 6.22 g (48 rnrols) of diisopropylene iranma in 50 ml of chloroform was added dropwise to a solution of 8.19 g ( 48 rnnols) of benzyl chloroformate in 20 ml of chloroform at about 0 ° C, with stirring. A 40 was formed
voluminous white container. After about 15 minutes, the mixture was filtered, the precipitate was washed with chloroform and dried to yield 2, 0.0 g of the title product, mp 184 ° C (dec.). (Replant solvent - 2 propanol),. * H NMR (dimethylsulfoxide-de): d = 10.48 (sa, ÍH),
8.3"(d, ÍH), f, 9ü (d of d, ÍH), JQ1 (d, LH), 7.40 (m, 5H), 5 17 (s, 2H), I- (NH3C1 ): m / Z = 307, 309 (l 1+).
PREPARATION 3 N- (5-Bromo-p? R? Din-2-yl) -2, 2, 2-trifluoroacetamide
Anhydride p 1-ulacetic acid (4.20 g, 20 mmol) was added dropwise, with stirring, at 0C > C, to a mixture of 3.46 g (20 rnmoles) of 2 -am? No-5-bromo ?? pdine and 8.30 g (60 mmol) of powdered potassium carbonate in 25 ml of dichloromethane. After about 2 hours, the mixture was filtered, concentrated and chromatographed (silica gel, 2: 1 ethyl acetate-hexanes) to yield, after concentration, 1.50 g of the title product in Form of white crystals, p. f .. 70-72 ° C (recrystallization solvent
= 2-? Spanish). 1 H NMR (deutepochloroform): d = 8.60 (a, ÍH), 8.39 (d, 1H), 8.09 (d, ÍH), 7.88 (d of d, 1H), MS (NH3CI) : rn / z = 269, 271 (MH +).
PREPARATION 4 N- (5-Bromo-6-met? L-p? Rid? N-2-yl) -acetamide
Following the procedure of Preparation 1, the compound was obtained (Jel title from 5.00 g (26.5 mol) (Je-arn? No-5-bromo-6-met i ipin dina, 14 g of acetic anhydride and 14 ml of acetic acid, to yield 4.70 g of the title product in the form of white lobes, mp 156-157 sC; 1 H NMR (deutepochloroform). d - 8,11 (a H,), 7, 89 (d, 1H), /, r'4 (d, 1H), 2.51 (s, 3H), 2.16 (s, 3H), MS (NH3C1): m / z-229, 231 ( MH +).
PREPARATION 5 N- (3-Bromo-5-methyl-p? Ridin-2-yl) -acetamide
Following the procedure of Preparation 1, the title compound was obtained from 4.70 g (25.0 mmol) of 2-a? N? No-3-bromo-5-met? Lp? R? D? n, 12.8 g of acetic anhydride and 13 rnl of acetic acid, to produce 2.13 g of the title product in the form of white needles, mp. 65-66 ° C;
1 H NMR (deuteriochloroforrn): d = 8.34 (d, ÍH), 7.84 (d, 1H), 2.42 (s, 3H), 2.30 (s, 3H); MS (NH3CD: rn / z = 229, 231 (MH +).
PREPARATION 6 N- (5-Bromo-3-methyl-pyri din-2-yl) -acetamide
Following the procedure of Preparation 1, the title compound was obtained, starting from 2.00 g (10.7 mmoles) of 2-arn? No-5-bromo-3-met? l pyridm, 8 g of acetic anhydride and (! rnl (acetic acid, to yield 1.71 g in form (white solid, mp J09-110 ° C; iH NMR (eutenochloroform): or -8.47 (d, 1H ), 7.80 (d, IH), 2.25 (s, 3H), 2.19 (s, 3H), MS (NH3CI): m / Z-229, 231 (MH +).
Claims (1)
- NOVELTY OF THE INVENTION CLAIMS A compound of the formula 1 0) the raceinic-enantiomep mixtures and the optical isomers of said compound, in Ja (thi Rl is selected from the group consisting of -NR3-C0 ~ alkyl (C ? -C? O). -NR3 -002-to which (C? Cio). -NR-CO2 (CH2) a - (optionally substituted phenyl-) e, -NR3 -C0- (CH2) »- f (optionally substituted enyl), -NR3-S02-alkylo (C? -Cio), -NR3-SO2 - (CH2) a- (optionally substituted phenyl and -NR3 -CO-? erfluoroalkyl) (C? -C "); R2 is selected from the group consisting of hydrogen, arnine, nitro, alkalmolamine (C? ~ C8), fluoro, CF3, alkylo (C? ~ C¿), alkox 1 (Ci -C« ), -NR3-00-alkyl (C? ~ C? O), -NR3 -C02 -alk 1? (Ci -Cio), -NR3-C02- (CH2) a- (optional phenyl and substi tude) , -NR3 -C0- (CH2) «- (optionally substituted phenyl), -NR3 -SO2 ~ alkyl (C? -Cio), -NR3 -S02-ÍCH2)» - (optionally substituted phenyl) and - NR3-C02-perfluoroalkyl (C? -C4) where a, each time it appears, is i independently 0, 1, 2, 3 or 4; R3, each time it appears, is independently selected from the group consisting of hydrogen and alkyl (C? -Cβ); and the optionally substituted phenyl group is optionally substi tuted with one, two or three substituents, and each substi tute is independently selected from the group consisting of hydroxy, illino, chloro, iodo, bri- Like IF3, sulphonamide, al (jui lo (C? -CA), alkox i (Ci -CA), carbox i, hi drcxialquL lo, alkoxycarbon i lo (O? -CA), t loal qui lo (C? - CA), sulforilo, sulfinilo and arnino, with the proviso that a compound of formula (1) is not N- (5-acet? L-2-rnet? L-4 -pin dini 1) acetarn? Da, 3 -acet-l-4- (pi loi lamino) pin dina or 3-E. cetil -2- (pivaloi lamí no) pin dina 2.- A compound according to claim 1, wherein Rl is selected from the group consisting of NR3 -C? 2- (OH2) »- (optionally substi- tuted enyl), -NR3-C0- (OH2) a- (optionally substituted phenyl), -NR3 -SO2 -alkyl or (Ci- O10), -NR3-S02- (CH2) a ~ (optionally substituted phenyl) and -NR3-C0-perf luoroalkyl (C? -CA), and R2 is selected from the comp put by hydrogen, alkyl (C? -C) and alkox 1 (Ci -OA). 3.- A < is added according to the rei indication 2, wherein R is selected from the group consisting of -NR3-C? 2- (CH2) to ~ (optionally substituted enyl) and -NR3-C0-perfluoroalkyl (C? -CA). 4. A compound according to claim 3, wherein R2 is selected from the group consisting of hydrogen, methyl and methox 1. 5. A compound according to claim 4, wherein R1 is selected from the group consisting of group consisting of -NH-C? 2-CH2 ~ (phenol) and -NH-CO-CF3. V! 6. - A compound according to claim 5. wherein R2 is hydrogen. 7. Compound (Je according to claim 6, which is the benzyl ester of the acid (-ace * 11-pin di n-2-11) -carbarnico, or N- (5 -acet ij-pin di n - 2 - i J) - 2, 2.2-tpf uoroacetamide 8. A compound according to claim 1, wherein R 1 is -NR 3 -CO-alkyl (C 1 -CA) and R 2 is alkyl 1 or (Ci -CA) - A compound according to 1 and ivication 8 wherein R1 is -NH-OO-CH3 and R2 is methyl 10. A compound (Je according to claim 9, (Thu is N- (5-acet? 1-6 -methyl-? r-? dm-2 -11) -acetamide, N- (3-acet-11 -5-methyl-p-din) - 2- 11) -acetyl, or N- (5-acct 1 -3-? Net? L-pi pdi n-2-Ll) -acetamide 11. A compound according to claim J, in Rl is -NR3 -C0-alkyl (0? -CA) and R2 is hydrogen, 12. The compound according to claim 11, which is N- (5 ~ acet 11 -pi nd? n-2 -11) - acetarnide or N- (5-aeti-pi pdi n-2-yl) -2, 2-d? meth? -propionnide 13.- A compound of formula (El), (11) in which it is selected from the group consisting of -NR3 -!, 4 00-aJqu? Jo (C-? Cío), -NR3 -Cü2 -al qui l? (C -CÍO, -NR3 -C02 - (CH2) a ((in i 1 or opc i ona luriate substi t ui do) , - NR3 -CO2 - (CH2) a - (f in 11 or opene replaced lime canvas), -MR3 -SO2 - Ci-cycloalkyi), ~ NR3 -CO2 - (OH2) * - (foni optician lily) substituted) and -NR 3 -00- b perf 1 uoroal (jui lo (C -CA); R 2 is selected from the group consisting of hydrogen-nitro-nitroalkynyiO-Cs), fluor-o, OF 3, alkyl (C? A), alkox 1 (Ci -C), -NR3 -CO-alkylo (C? -Cio), -NR3 S () 2-alkylene (C? -Cio), -NR3 -C02- (CH2 ) a- (optionally feared subsumed), -NR3 -C0- (CH2) a - (optional phenyl 10 substi tude), -NR3-S02 -al "? U? Lo (C? -Cío). -NR3-S0 - (CH2) a - (foni optionally substituted) and -NR3 -CO-perfluoroalkyl (C? -CA); where a, each time it appears is independently 0, 1, 2, 3 or 4; R3, each time (thu appears, is independently selected from the group consisting of hydrogen and alkyl (C? -Cβ); Optionally substituted phenyl group is optionally substituted with one or two substituents, and each substituent is independently selected from the group consisting of hydroxy, fluoro, chloro, bromine iodine, OF3, sulphonamide, at which (C? -CA), alkoxy (Ci -CA) carboxy Hydroxyalkyl, alkoxycarbonyl (C? -CA), t? Oalkyl (C? -CA), sulfonyl, sulfinyl and arnine; and R * is to the quilo (Ci -Cß) .. 14.- A process for the preparation of a compound of formula (El), ?! =. (11) (Thu comprises, reacting a compound of formula (Lll) (III) with a vinyl ether LCo of formula (EV), OH2-CHOR *, in the presence of a palladium compound, or a catalyst- of palladium metal and a base; in which ? it is bromine, iodine, ine-anosulfomloxy or tri-fluoronantanosul-fonyloxy; R1 is selected from the group consisting of -NR3 -00-alkyl (C? -Cio). -NR3 -CO2 - (CH2)? - (feni optionally substituted lily), -NR -C0- (CH2) a - (phenyl opc miter canvas substitched), -NR3 -SO2 -alkylCCi -Cio), -NR3 - SO2 - (CH2) a - (phenyl) optional substrate) and -NR3-C0-per-fl uoroalkyl 1O (0I-CA); R 2 is selected from the group consisting of hydrogen, arnine, nitro, alkylamino (C? -Cβ), fluoro, OF3, alkyl or (C 1 -C 4), alkox 1 (Ci -CA), ~ NR 3 -CO-alk? (C? -Cio), -NR3 -C? 2-alkylene (C? -C? o), -NR3 -CO2 - (CH2) _. - (optionally substituted phenyl), -NR3 -00- (CH2) a - (phenyl optionally substituted), -NR3-SO2 -alkyl (C? -Cio), -NR3-S02- (CH2) a ~ (optionally substituted phenyl) and -NR3-C0-fi pepor uoroal what (C? -CA); where a, each time (thu appears, is independently 0, 1, 2, 3 or 4; R3, each time it appears, is independently selected in the group consisting of hydrogen and alkylo (C? -Ce) and the optionally substituted phenol group is optionally substituted with one or two substituents, and each substiuent is selected in either the group or the hydrochloride group or by hydroxy, chlorine or chlorine, iodine, bromine, CF3, sulphonated, to the one (C? -OA), to the ccxi (CI-CA), carboxy, hydrocarbon qui lo, alkoxycarbom 1 or (C? -CA), t oalqu (C? -CA), sulfonyl, sulfinyl and arnmo, and R? is alkyl (C? -C?), with the proviso that when? is Br, the reaction is carried out in the presence of a phosphine 15. A process according to claim 14, wherein R1 is -NHCOCH3, NHCO-t-Bu, NHCOCF3 or -NHCOO-CH2-phenyl, and R2 is hydrogen, or methyl. according to claim 15, wherein X is Br and the reaction is carried out a in the presence of a phosphine compound. 17. A process according to claim 16, wherein the reaction is carried out in the presence of a polar aprotic solvent *. 18. A process according to claim 17, wherein the temperature range is from about 20 ° C to about 130 ° C, the palladium catalyst is composed of palladium (II) and the phosphine is a t rían1 fos f1na. 19. - A procedure or according to claim 10, in which < The temperature range is about 100 ° C to about 100 ° C, the phosphine is thiol-tolyl fos and the solvent s = acetoni tp lo. 20. On pr-ocedirient for the preparation of a compound of formula (D, ) (comprising, reacting a compound of formula (11 (II) with an acid, in the presence of water; wherein R1 is selected from the group consisting of -NR3 -CO-alkyl (Ci-Cio), -NR3 -CO2 -alkyl (C? -C? <), -NR3 -CO2 -alkyl (CH2) a - (optionally substituted phenyl), -NR3 -C0- (CH2) a- (substituted phenyl ophthalmic lamp), -NR3-S02- (C1-C10) alkyl, -NR -SO2 - (CH2) »- ( optionally substituted phenyl) and -NR 3 -CO-perfluoroalkyl (C 1 -C 4); R2 < E selects from the group consisting of hydrogen, aromo, nitro, alkylammo (Ci-Cß), fluoro, CF3 alkyl (CI-CA), alkoxy (CI-CA), -NR3 -CO- (C1-C10) alkyl, -NR3 -CO2 -alkyl (C? ~ C? 0), -59 NR3 -OO2 - (CH2) a - (optionally substituted phenyl), NR3 -00- (OH2) a - (if not the substituted cpcionalrnent), -NR3-C0 ~ lqu? (0? -C10), -NR3-002- (CH2) a (femlo optionally substitute Jo) and Hi ^ -00-? erf 1 uoroalkyl (C1-O4); where a, each time it appears, is independently 0, 1, 2, 3 or 4; R3, each time it appears, 1 is set 1, 1, 2, 1, 2, 3, 3, 7, 7, 8, 9, 10, 11, 11, 11, 11, 11, 11, 11, 11, 11, 10, 10, 10, 10, 10, 10, 10 e with one, two or three substitutes, and each substrate is independently selected from the group consisting of hydroxy, fluoro, chloro, iodo, bromo, CF3, sulfonamide, alkyl (C1-C4), cox 1 (C1-C4), carboxy, hydroxyl qui lo (C1-C4), ioal quilo (CI-CA). sulfonyl, sullyl and arnino; and R * is alkyl (Oi-Cß). 21. A process according to claim 20, wherein the compound of formula (I) is benzyl ether of the acid (5-acet? I-? Pd? N-2-? L) -carbarni co, N- (5-acet? L- pi r? D? N-2 -11) -2, 2, 2-t pfluoro-acetarnide, N- (5 ~ acet? L-6-rnet? Lp? Pdi n ~ 2-yl) -acetate, N- (3-acet? L-5-methy1-?? r-? D? N-2-? 1) -acetamide, N- (5- acetyl-3--.net ? l - ?? r? d? n-2-? l) - ace tam ida, N, (ace ti 1- pin din-2-? l) -acetarnide or N- (acetyl-pa pd? n-2) - 11) -2, 2 -dirnetiipropionnide. 22. A process for the preparation of a compound of the formula (Z *), 54 < Z *) the r-acerní cas-enantiornep cas mixtures and the optical isomers of said compounds, which compr-ende, (1) reacting a compound of formula (1), (l) with a source of bromine, chlorine, or iodine, to form a compound of formula (a), (to) (2) reacting a compound of formula (a) with a compound of formula H2N-Y2 * to form a compound of hO (or i -mu l a (* 'i) (Z1) and (1) reacting a zorn tax of formula (Zl) with a reducing agent, to form a compound of formula (71), the raceini mixtures < as-onant promoters and the optical derivatives of said compound of formula (Z * •, in which X2 is 01, Br or I; R is selected from the group consisting of -NR3 -C0-alk? _ .o (Ci -Cio), -NR3 -OO2 ~ alkyl (0? -Cio) -NR3 -CO2 - (CH2) - (optionally substituted), -NR3-CO2 - (CH2) - (optionally substituted phenyl), -NR3-SO2- (C1-C10) alkyl, -NR3-C02- (0H2) - (optionally substituted fem), and -NR3 -00- pe rf luoroa 1 qu? lo (C? - C4) -NR3 - CO-perf luoroa 1 ju? Lo (0? -C4); R2 is selected from the group consisting of hydrogen, aromo, nitro, alkylamino (0? ~ C8), fluoro, OF3, alkyl (0? -C), (C1-C4) alkoxy, -NR3-CO-alkyl (C? -C?), -NR3 ~ C02 -alkyl (C? -Cio), -NR3- CO2 - (CH2) a - (optionally substituted phenyl), -NR3-00- (OH2) a- (optionally substituted phenyl), -NR3-S02 ~ alkyl (0? -Cio), -NR3 - SO2 - (CH2) a - (optionally substituted phenyl) and -NR3 -CO2 -perfluoroalkyl (C? -C4), where a, each time it appears, is independent ntemente 0, 1, 2, 3 or 4; R3, each time it appears, i is selectively selected from the group consisting of hydrogen and alkyl (C? -Cβ); and the optionally substituted phenyl group is optionally substituted with one, two or three substitions, and each substituent c, e independently selects from the group consisting of hydroXL, fluor-o, doro, iodine, bromine CF3, sul f onariu da, alqui lo (O? -CA), alkox 1 (Ci -CA), carboxy, hydro lalky, alkoxy car bon bon (O? -CA), thioalkyl (C? -C4), sulfonyl , sulfimlo and not yet; Y2 * is where O1 is oxygen, nitrogen or sulfur; O2 is carbon or nitrogen; O3 is hydrogen, - (CH2) n-phenyl, -alkyl (C? -Cio), - (CH2) n-NGlG2, - (CH2) n "C0203, - (CH2) n" 00 -NGl G2, - (CH2) n ~ 0G3, - (CH2) n-03G3, - (CH2) n -S02 -alkyl (Ci-β), - (CH2) n ~ ^ 02-NG'I G2 or a heterocycle selected from compound group p > or - (CH2) n -pyridyl, - (CH2) n -pi rimi dyl, - (CH2) n - ?? razinyl, (CH2) n-isoxazolyl, - (CH2) n -oxazolyl, - (CH2) n -thiazolyl, (CH2) n - (1, 2, 4-oxad? Aolol), - (CH2) n-irnidazolyl, - (CH2) ..- tpazolyl and - (CH2) n -tetr-azolyl; wherein one of the ring nitrogen atoms of said - (CH2) n -nitridazolyl, - (CH2) n-tpazolyl and - (CH2) n -tetrazolyl may optionally be substituted with optionally substituted alkyl (0? -C-) i dependently with one or more halo atoms; where each one hl of said heterocycles may be optionally substituted on one or more of the carbon atoms of the ring, with one or more subtitlers selected from the group consisting of -alkyl 1 or (Ci-β), optionally substituted 5 independently with one or more halo, halo, or ro arrangements, OlAn, (CH2) n -NG1G2, - (CH2) n - C02G3, - (CH2) n -CO-NG G2, - (OH2) ?. - 0G3, ~ (CH2) n-S03G3, - (CH2) n-O2 -al qui lo (Ci-C6), - (CH2) n -O2-NG G2; wherein the r-ad ica l phenyl of said - (CH2) n-fe i may be optionally substituted with one or more substituents lll selected independently from the group consisting of the optionally substituted (O? -C) independently with one or more atoms of halo, hydroxy, alkoxy (Ci -Cβ) optionally substituted independently with one or more halo environments, at < ju? lt? o (C? -Cß), fluoro, chloro, bromo, iodo, cyano, nitro, 15 (CH2) n ~ N0lG2, - (CH2) n "C02 G3, - (CH2) n -CO-NG1 G2, - (CH2) n-0G3, - (0H2) n - SO303, - (CH2) n - O2 -al qui 1 o (Oi -Cß), - (CH2) n - SO2 - NG * G2; (CH2) n -NG3 -S02-G3, and (CH2) n "G3 -S02-NGlG2; O * is - (CH2) n -CN, - (0H2) n -C02G3, - (CH2) n -S03G3, - (CH2) n ~ 02 -alkyl (Ci-06), - (CH2) n- ^ 02 -NG1G2, - (CH2) n -CH2 OH, - (CH2) n ~ CHO, - (CH2) n • C0 -G3, -20 (CH2) n -CONGiG2 or a heterocycle selected from ~ (CH2) n ~ thiazolyl, - (CH2) n -oxazolyl, - (CH2) n -niridazolyl, - (CH2) ..- tpazolyl, - (CH2) n-l, 2,4-oxadololol 1, (CH2) n -1 soxazolyl, - (CH2) n -tetr-azol 1 lo and - (CH2) n -pyrazolyl, where one of the bases of nitrogen of said ring - (CH2) n -? rn? dazol Lyo, - 25 (CH2) n -tpazolyl and - (CH2) n-tetrazolyl can be optionally substituted with the qu? (C? -C?) optionally replaced () i independently with one or more halo atoms; wherein, each of said heterocycles can be optionally substi tuted, in one or more of the atoms (ring carbon), with one more substi tutes independently selected from the group consisting of hydrogen, alkyl or (Ci-C)? wasteland independently and substi tuted independently with one or more halo atoms, - (0H2) n -CO-NGiG2, (OH2) n - C02G3, halo, nitro, cyano, (CH2) n-00-NG1G2, - (CH2) n -0G3, - (CH2) n - SO3G3, - (CH2) n - O2"A 1 or 11 O (Ol-Cß), - (CH2) n ~ O2 -NG * O2; 0 * is hydrogen, or at 11 o (d 06) optionally substituted i with one or more halo conditions, O6 is a covalent bond, oxygen or sulfur, O7 is hydrogen, or alkyl (C? -Cß) option Substi tuted independently with one or more halo atoms, O8 and O9 are, independently, a covalent bond, oxygen, sulfur, NH or -N-alkyl or (Ci-Cß); Qi ° is - (CH2) «. -OFF, - (CH2) n ~ C02H, - (CH2) n CORH, - (CH2) n -S02NR9R10. - (CH2) n ~ NR9 02 R8, - (CH2) n -μ (0) (0R «) (OR5), - (CH2) n -0- (CH2) mC02H, - (CH2) n - 0-CORl , - (CH2) n-0- (OH2) ??? P (0) (OR *) (0R5), - (CH2) n "O- (CH2) tn O2 NR9 R1 O- (CH2) n" 0- (CH2) m -NR S02 8; R * and Rs are each, independently, hydrogen, or alkylCi -Cβ); and R6 and R7 are each, independently, hydrogen, halo, alkyl (C? -Cβ), nitro, cyano, trifluoromethyl, S02 R8, S? 2NR R, NR Rio, CORH, 002 R9, alkoxy (C ? -Cβ), NR9S02R8, NR C0RH, R C02 9 or OR9; where G and G2, each time they appear, are each, independently, hydrogen, alkyl (C? -Cβ) optionally substituted independently with one or more halo, alkoxy (C? -Cβ) alkyl (C ? - h Cß) > If there is a lime (O3 - Cß), or O and G2 together with the element to which they are united for a man, the heterocyclic one has 3 to 7 atoms. car-bond, where one of said carbon atoms may be replaced by oxygen or nitrogen, or nitrogen or sulfur; G3, whenever it appears, is independently hydrogen, or alkyl (O? -Cβ); R8, each time (thu appears, is independently to whom (C? -C?) Or alkox? (O? -C?) Alkyl (C? ~ ß); R9 and R10, each voice appearing, are 1 ndep end 1 enternen te h 1 d 1 -ogeno, to 1 qui lo (Oí - Cß). c 1 c 1 or to 1 qu L lo (C3 -Cß) or alc? xi (Ci - Cß Jalqui lo (C? -Ce R1 L. each time it appears, is independently hydrogen, alkyl (C? -Cß), NR9Ri °, sky (C3-C) or alkoxy (Ci-C) alkyl (0? -Ce), where R9 and RIO are as previously defined, m, each time it appears, is independently an integer from 1 to 6, and n, whenever it appears, is independently 0, or an integer from 1 to 6; conditions that: (1) when O9 is 0 or S, then n is not 0, (2) when O1 is oxygen or sulfur, then O3 is absent, and (3) when Q2 is nitrogen, then O5 is absent. A process according to claim 22, wherein R1 is -NHCOCH3, -NHCO-t-Bu, -NHCOCF3 or -NHC00-CH2 ~ phenol and R2 is hydrogen, or methyl. 24.- A procedure for the preparation of a compound of the formula (Z *), b5 (z *) raceini mixtures cas-enant íornepcas and optónicos isomers of said compound comprising, (1) reacting a compound of the formula (T), (0 with a source of bromine, chlorine or iodine, to form a compound of formula (a), (to) (2) reacting a compound of formula (a) with a mild reducing agent to form a compound of formula (c), (5 (5 and (1) reacting a compound of formula (c) with a base and H2N-Y2 * to form a compound of formula (Z *), wherein X2 is Cl, Br or 1; R is selected ont r-e the group consisting of -NR3-C0-alkyl? IC1-C10), -NR3 -CO2 ~ al (JU110 (C1-C10), -NR3-C22- (CH2) «- (f eni the optionally substituted), -NR3 -00- (CH2) a - (phenyl optionally substitution), -NR3-SO2 -alkyl (C1-C10), NR3 -S- 2 ~ (CH2) a- (optionally substituted phenyl) and -NR3-C0-perfor-oal qui lo (CI -CA ); R 2 is selected from the group consisting of hydrogen, arnine, nitro, alkylamino (Ci-β), f luoro, CF 3, alkyl (C 1 -C 4), alkox 1 (Ci-C *), -NR 3 -00 -al (Ui l? (C? -C? O), -NR3-C? 2-alkyl? (C? ~ C? O), -NR3 -CO2 - (CH2) a - (optionally substituted phenyl), -NR3 -C0- (CH2) a- (optionally substituted phenyl), -NR3 -SO2 -alkyl (C? -Cio), -NR3-S02- (CH2) a ~ (optionally substituted enyl) and -NR3-C0 -perfl uoroal qui 1O (CI-CA), where a, each time it appears, is independently 0, 1, 2, 3 or 4, R3, each time it appears, is independently selected from the group consisting of hydrogen and alk? (C? ~ 0ß), and the optionally substituted phenyl group is optionally substituted with one, two or three substituents, and each substitute, and each substitute is independently selected from the group consisting of hydroxy, fluoro, chloro, iodo, bromo, CF3, sulfonarnide, alkyl (C? -CA), alkoxy (C? -CA), carboxy, hydroxyalkyl, alkox Lcar-bomlo (C? -CA), t? Oal? Lo (C? -CA), sulfoyl, sulfimyl and aromo; Y2 * is h? where Q is oxygen, nitrogen or sulfur; O2 is carbon or nitrogen; O3 is hydrogen; - (CH2) n - Pheni lo, to the quiloiCi -Cio), (OH2) n -NGlG2, - (CH2) n -CO2G3, - f CH2) n -CO-NG G2, - (CH2) n ~ 0C3, - (CH2) nc.03G3, - (CH2) n-02-alkyl (C? -Cβ), - (CH2) n "S02 NGl G2 or a heterocycle selected from the group consisting of - (CH? N n - pindyl, ~ (CH2) n -raprnidyl, - (CH2) n -pirazi n Lio, - (CH2) n -soxazolyl, - (CH2) n -oxazolyl, - (CH2) n -tlazole 1 lo, - (CH2) ) n ~ (1, 2, 4 -oxadiazolyl), - (CH2) n-irnidazolyl, - (CH2) n -t pazol Lio and - (CH2) n -t et razol 1 lo; where one of the nitrogen conditions of the said ring - (CH2) n -ipu dazolyl, - (CH2) n -tpazole 1 lo and - (CH2) n ~ tet razol ilo can optionally be substituted with (Ci-Cß) alkyl optionally substituted independently with one or more halo atoms, where each one of these have been sprayed on you can be replaced (optionally in one or several of the carbon atoms of the ring with one or several stents selected independently from the composite group) per alkyl (C? ~ Cß), optionally substituted independently by one or more halo, halo, nitro, cyano, - (CH2) n -NG G2, - (CH2) n -C02G3, - (CH2) atoms n ~ CO-NG1 G2, - (CH2) n "0G3, - (CH2) n '? .02 G3, - (CH2) n ~ 02 -alkyl (C? -Cβ) and - (CH2) n - SO2NGIG2; where the radical bB phenyl of said - (CH2) n-femlo can optionally be substituted with one or more substituents selected 1 ndependently from the group consisting of optionally substituted alkoxy (O? -Ce) independently with one or more alternatives of halo, hi roxi, 1C1-Cβ alkoxy) op > c? onal? nent independently substituted with one or more halo, alkyl? (C? -C?), fluoro, chloro, bromo, iodo, cyano, nitro, - (CH2) n -NGlG2, - (CH2) ) n - CO2 G3, - (CH2) n 00 - NGl G2, - (CH2) n -OG3, - (CH2) n - SO3 G3, - (0H2) n "CO2 - at 1 qull O (Ci - Cß) , - (CH2) n - S02 NG1 Q2 - (CH2) n - NG3 - S02 - C y (CH2 ln - NG3 -? 2 - NG1G2; Q4 s - (CH2) n -CN, - (0H2) n C02 G3, - (OH2) n - c < 03 tí3, - (CH2) n - O2 -alkyl (Ci-Cß), - (CH2) n -SO2 NGl G2, - (CH2) n CH2 OH, ~ ( CH2) n -CH0, - (CH2) n -C0-G3, - (CH2) n -GONG * G2, or a heterocycle selected from - (CH2) n -tlazole 1 lo, - (0H2) n'oxazolyl, - (CH2) n -imi dazolyl, - (CH2) n -triazole Lyo, - (CH2) n _ 1, 2, 4-oxad? Oazolol, - (CH2) n -isoxazolyl, - (CH2) n-tetrazolyl Y ~ (CH2) n -pyrazolyl; where one of the nitrogen atoms of the ring of said - (CI-I2) n-nnidazolyl, - (CH2) n -t riazole i and - (CH2) n te razolilo can be optionally substituted by alkyl (C) ? -Cβ) optionally substituted independently with one or more halo atoms; wherein each of said heterocycles may be optionally substituted on one or more of the carbon atoms of the ring, by one or more substituents independently selected from the group consisting of hydrogen, alkyl (C? -Cβ) optionally substituted independently with one or Halo atoms, - (CH2) n ~ C0- NGiG2, - (CH2) n -C02G3, halo, nitro, cyano, - (CH2) n -00-NGiG2, - (') < < ) (CH2) n -0G3, - (0H2) n "- 03G3, - (CH2) n - O2 ~ 1 quil O (CiCß) or - (OH2) n - ^ 02 NGlG2; Q5 is hydrogen, or which is optionally substituted independently with one or more halo atoms, O6 is a covalent bond, oxygen or sulfur, O7 is hydrogen, or optionally substituted (C? -C) alkyl with one or more halo atoms: O8 and O9 are independently, a covalent bond, oxygen, sulfur, NH or -N-alkylCHIC-Cß); Q1 is - (CH2) m -0R9, - (CH) n -CO2H , - (0H2) n -CORH, (CH2 1n ~ S02NR9RlO, - (CH2) n -NR9 S02 R8, - (CH2) n P (0) (0 41 (0R5), -ICH2) n -0- (CH2 ) »C02H, - (CH2) n" 0- (CH) m C0R11, - (0H2) r. -0- (CH2) m ~ P (0) (OR *) (0R5), - (CH2) n - 0- (0H) m 02NR R10 0 - (CH2) n ~ 0- (CH2) m -NR9S02 R8; R4 and Rs are each, independently, hydrogen, or alkyl (C? -0β), and R6 and R7 are each, independently, hydrogen, halo, alkyl (C? -Cβ), nitro, cyano, trifluoromethyl, SO2 R8, S? 2NR Ri °, NR Rio, CORH, CO 2 R9, alkox 1 (Ci-Cß), NR S02R8, NR9C0RH, NR C02R9 or OR9; where Gl and G2, each time they appear, are each, independently, hydrogen, alkyl (C? -Cβ) optionally independently substituted with one or more halo, alkoxy (C? -Cβ) alk? io (C? -Cβ) or (C3-C8) cycloalkyl, or G and G2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms, where one of said carbon atoms it may be replaced optionally by oxygen, nitrogen or sulfur; G3, each time it appears, is independently hydrogen, or alkyl (C? -Cβ); R8, each time it appears, is independently alkyl (C? -Cß) or alkoxy (C? - O) Cß) al (jui lo (O? -Cß); R9 and R °, each time (they appear, are independently hydrogen, alky1 or (C? -C?), C? Cloalkyl (C3 -C?) Or coxi ( Ci -Cß) alkyl (C? -Cß); 11, each time it appears, is independently hydrogen, alkyl (C? -Cß), NR9Ri °, ci-cloal (jui lo (C3 -Cß) or alkoxy (Ci -Cß) alkyl (C? -Cß), where R9 and R o are as defined above; rn, each time it appears, is independently an integer from 1 to 6; and n, each time it appears, is independently 0, or an integer from 1 to 6; with the conditions that: < 1) when O9 is 0 or S, then n is not 0; (2) when Q is oxygen or sulfur, then O3 is absent; and (3) when O2 is m + rogeno, then O5 is absent. 25. A process according to claim 24, wherein R1 is -NHCOCH3, -NHCO-t-Bu, -NHCOCF3 or -NHCOO-CH2-phenyl and R2 is hydrogen, or methyl. 26.- A compound of the formula (to) wherein R is selected from the group consisting of -NR3-CO ~ alkyl (C? -C? o), -NR3 -CO2 -alkyl (C? -Cio), -NR3 -CO2 - (CH2) ) a- (optionally substituted phenyl), ~ NR3 -C0- (CH2) a - (phenyl optionally substituted), -NR3 -S? 2 ~ to the chyle (Ci -Cio), -NR3-S02- (CH2) n - (optionally substituted phenyl) and -NR3 -CO- perfluoroalkyl (C? -04), P is selected from the group consisting of hydrogen, amino, nor t, to which L lam i no (O? - Cß), fluoro, 01-3, al (jui lo (C? -CA), at 1 cox L (OÍ -CA>, -NR3 -CO-alkyl (C? -Cio), -NR3 -CO2 -al 'Ci -Cio), -NR3 -CO2- (CH2) a- (optionally substituted phenyl), -NR3 -00- (CH2) a- (optionally having its ituido), -NR3-S02 -alkyl or ( Ci -Cio). -NR3-S02 - (CH2) t - (ftinyl optionally substituted) and -NR3 -00- perf luoroal qui lo (C? -CA); where a, each time (tho appears, is independently 0, 1, 2, 3 or 4; R3, each time (tho appears, is selected independently from the group consisting of hydrogen and alkylo (C? -Ge) and the optionally substituted femlo group is optionally substituted with one, two or three solvents, and each substituent is independently selected from the group consisting of hydroxy, fluoro, chloro, iodo, bromo, CF3, sultonami. Da, alkyl (C? -C4), alkoxy (Ci-C4), carboxy, hydroxy-alkyl, alkoxycarbon (C? -C4), t? oalkyl (C? -C4), sulfonyl, sulfinyl and aromo, and X2 is 01, Br or I. 27.- A compound according to claim 26, wherein Rl is -NHCOCH3, -NHC0-t-Bu, -NHCOCF3 or -NHC00-CH2-phen? it, and R2 is hydrogen, or methyl. n SUMMARY OF THE INVENTION The present invention relates to certain compounds of formula 1 0) which are useful in the synthesis of certain β-adrenergic receptor agonists; the invention also relates to a process for synthesizing the compounds of formula (I) and compounds of formula (II), (ll) wherein R1, R2 and * are as defined herein, which are useful in the synthesis of the compounds of formula I; The invention also relates to a method of synthesizing a compound of formula II; The invention also relates to processes for synthesizing compounds of formula (Z *) (Z *) where Rl, R2 and Y2 * are as defined in this document, P97 / 1148 PF / lss * ap? N * rnrnrn * l? M * blm * kca * arnrn. * fac * elt *
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3080296P | 1996-11-14 | 1996-11-14 | |
| US60/030,802 | 1996-11-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9708768A MX9708768A (en) | 1998-09-30 |
| MXPA97008768A true MXPA97008768A (en) | 1998-11-16 |
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