IE46787B1 - Esters and thiolesters of amino acids,processes for their production, and compositions including them - Google Patents
Esters and thiolesters of amino acids,processes for their production, and compositions including themInfo
- Publication number
- IE46787B1 IE46787B1 IE552/78A IE55278A IE46787B1 IE 46787 B1 IE46787 B1 IE 46787B1 IE 552/78 A IE552/78 A IE 552/78A IE 55278 A IE55278 A IE 55278A IE 46787 B1 IE46787 B1 IE 46787B1
- Authority
- IE
- Ireland
- Prior art keywords
- valine
- ester
- hydrogen
- phenoxybenzyl
- fluoro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 107
- 239000000203 mixture Substances 0.000 title claims description 58
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 150000002148 esters Chemical class 0.000 title abstract description 67
- 150000001413 amino acids Chemical class 0.000 title abstract description 8
- 150000007970 thio esters Chemical class 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- -1 methylenedioxy group Chemical group 0.000 claims description 282
- 239000001257 hydrogen Substances 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 37
- 125000004432 carbon atom Chemical group C* 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 26
- DLULJAUWRRKBML-JTQLQIEISA-N (2s)-2-[2-fluoro-4-(trifluoromethyl)anilino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(C(F)(F)F)C=C1F DLULJAUWRRKBML-JTQLQIEISA-N 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 241000238631 Hexapoda Species 0.000 claims description 13
- 241000607479 Yersinia pestis Species 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- YKSHSSFDOHACTC-JTQLQIEISA-N (2s)-2-[2-chloro-4-(trifluoromethyl)anilino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(C(F)(F)F)C=C1Cl YKSHSSFDOHACTC-JTQLQIEISA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 241000238876 Acari Species 0.000 claims description 6
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 241000255925 Diptera Species 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 3
- 125000005291 haloalkenyloxy group Chemical group 0.000 claims description 3
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 3
- 125000000232 haloalkynyl group Chemical group 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 claims description 2
- 241000254173 Coleoptera Species 0.000 claims description 2
- 241000258937 Hemiptera Species 0.000 claims description 2
- 241001466007 Heteroptera Species 0.000 claims description 2
- 241000257303 Hymenoptera Species 0.000 claims description 2
- 241000255777 Lepidoptera Species 0.000 claims description 2
- 241000238814 Orthoptera Species 0.000 claims description 2
- 241000916145 Tarsonemidae Species 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims 2
- 241001454295 Tetranychidae Species 0.000 claims 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims 1
- 230000000895 acaricidal effect Effects 0.000 abstract 1
- 230000000749 insecticidal effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 238
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 101
- 239000004474 valine Substances 0.000 description 101
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 94
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 87
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 76
- 238000006243 chemical reaction Methods 0.000 description 71
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- FBCHRMFAWNWJCU-JTQLQIEISA-N (2s)-2-(4-chloroanilino)-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(Cl)C=C1 FBCHRMFAWNWJCU-JTQLQIEISA-N 0.000 description 47
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- UJUNUASMYSTBSK-UHFFFAOYSA-N 1-(bromomethyl)-3-phenoxybenzene Chemical compound BrCC1=CC=CC(OC=2C=CC=CC=2)=C1 UJUNUASMYSTBSK-UHFFFAOYSA-N 0.000 description 42
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- 239000012267 brine Substances 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- 235000019441 ethanol Nutrition 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 33
- UEBARDWJXBGYEJ-UHFFFAOYSA-N 2-bromo-3-methylbutanoic acid Chemical compound CC(C)C(Br)C(O)=O UEBARDWJXBGYEJ-UHFFFAOYSA-N 0.000 description 32
- 229910000027 potassium carbonate Inorganic materials 0.000 description 29
- AJWAECPVBMQFSX-NSHDSACASA-N (2s)-3-methyl-2-(4-methylanilino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(C)C=C1 AJWAECPVBMQFSX-NSHDSACASA-N 0.000 description 27
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 24
- 239000002904 solvent Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000012259 ether extract Substances 0.000 description 15
- 159000000000 sodium salts Chemical class 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 14
- 239000005457 ice water Substances 0.000 description 13
- KZPLXTSZVZBJPO-JTQLQIEISA-N (2s)-2-(4-chloro-2-fluoroanilino)-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(Cl)C=C1F KZPLXTSZVZBJPO-JTQLQIEISA-N 0.000 description 12
- NZPWGWAEKDSVFN-JTQLQIEISA-N (2s)-3-methyl-2-[4-(trifluoromethyl)anilino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(C(F)(F)F)C=C1 NZPWGWAEKDSVFN-JTQLQIEISA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 11
- HNBHHMUCXASXEW-UHFFFAOYSA-N (3-phenoxyphenyl)methyl 2-bromo-3-methylbutanoate Chemical compound CC(C)C(Br)C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 HNBHHMUCXASXEW-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 9
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 9
- 238000012746 preparative thin layer chromatography Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- CAXWIGJTXJTLLU-JTQLQIEISA-N (2s)-2-(4-bromo-2-fluoroanilino)-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(Br)C=C1F CAXWIGJTXJTLLU-JTQLQIEISA-N 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 8
- 239000007795 chemical reaction product Substances 0.000 description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 8
- 230000007935 neutral effect Effects 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 101150041968 CDC13 gene Proteins 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 238000005192 partition Methods 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- XCAMLAFYNOLVPM-NSHDSACASA-N (2s)-2-(2,6-dimethylanilino)-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=C(C)C=CC=C1C XCAMLAFYNOLVPM-NSHDSACASA-N 0.000 description 6
- LYJVJCQYQYSJHU-NSHDSACASA-N (2s)-2-(2-fluoro-4-methylanilino)-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(C)C=C1F LYJVJCQYQYSJHU-NSHDSACASA-N 0.000 description 6
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- XZUCJVTXERYPQH-NSHDSACASA-N (2s)-2-(4-methoxyanilino)-3-methylbutanoic acid Chemical compound COC1=CC=C(N[C@@H](C(C)C)C(O)=O)C=C1 XZUCJVTXERYPQH-NSHDSACASA-N 0.000 description 5
- MBRPCSKHPRLQQQ-JTQLQIEISA-N (2s)-2-anilino-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=CC=C1 MBRPCSKHPRLQQQ-JTQLQIEISA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- CSFDTBRRIBJILD-UHFFFAOYSA-N 4-chloro-2-fluoroaniline Chemical compound NC1=CC=C(Cl)C=C1F CSFDTBRRIBJILD-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- CQVOILYSLSWABZ-NSHDSACASA-N (2s)-2-(2-fluoro-4-methoxyanilino)-3-methylbutanoic acid Chemical compound COC1=CC=C(N[C@@H](C(C)C)C(O)=O)C(F)=C1 CQVOILYSLSWABZ-NSHDSACASA-N 0.000 description 4
- XWTQCMHYIJEQPD-JTQLQIEISA-N (2s)-2-(4-chloro-3-fluoroanilino)-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=C(Cl)C(F)=C1 XWTQCMHYIJEQPD-JTQLQIEISA-N 0.000 description 4
- IUKZSVHIWMVLEQ-NSHDSACASA-N (2s)-3-methyl-2-(2-methylanilino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC1=CC=CC=C1C IUKZSVHIWMVLEQ-NSHDSACASA-N 0.000 description 4
- ZQEXBVHABAJPHJ-UHFFFAOYSA-N 2-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C(F)=C1 ZQEXBVHABAJPHJ-UHFFFAOYSA-N 0.000 description 4
- RMXZAXNAIMJGCX-UHFFFAOYSA-N 3-[2-fluoro-4-(trifluoromethyl)phenyl]-4-propan-2-yl-1,3-oxazolidine-2,5-dione Chemical compound O=C1OC(=O)C(C(C)C)N1C1=CC=C(C(F)(F)F)C=C1F RMXZAXNAIMJGCX-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 235000019445 benzyl alcohol Nutrition 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
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- 241001454293 Tetranychus urticae Species 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 240000006677 Vicia faba Species 0.000 description 1
- 235000010749 Vicia faba Nutrition 0.000 description 1
- 235000002098 Vicia faba var. major Nutrition 0.000 description 1
- VXSIXFKKSNGRRO-MXOVTSAMSA-N [(1s)-2-methyl-4-oxo-3-[(2z)-penta-2,4-dienyl]cyclopent-2-en-1-yl] (1r,3r)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropane-1-carboxylate;[(1s)-2-methyl-4-oxo-3-[(2z)-penta-2,4-dienyl]cyclopent-2-en-1-yl] (1r,3r)-3-[(e)-3-methoxy-2-methyl-3-oxoprop-1-enyl Chemical class CC1(C)[C@H](C=C(C)C)[C@H]1C(=O)O[C@@H]1C(C)=C(C\C=C/C=C)C(=O)C1.CC1(C)[C@H](/C=C(\C)C(=O)OC)[C@H]1C(=O)O[C@@H]1C(C)=C(C\C=C/C=C)C(=O)C1 VXSIXFKKSNGRRO-MXOVTSAMSA-N 0.000 description 1
- SZJQXQICJDHRJE-UHFFFAOYSA-N [3-(bromomethyl)phenyl]-phenylmethanone Chemical compound BrCC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 SZJQXQICJDHRJE-UHFFFAOYSA-N 0.000 description 1
- RYULULVJWLRDQH-UHFFFAOYSA-N [4-(bromomethyl)phenyl]-phenylmethanone Chemical compound C1=CC(CBr)=CC=C1C(=O)C1=CC=CC=C1 RYULULVJWLRDQH-UHFFFAOYSA-N 0.000 description 1
- 150000004729 acetoacetic acid derivatives Chemical class 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000001142 back Anatomy 0.000 description 1
- VEMKTZHHVJILDY-UXHICEINSA-N bioresmethrin Chemical compound CC1(C)[C@H](C=C(C)C)[C@H]1C(=O)OCC1=COC(CC=2C=CC=CC=2)=C1 VEMKTZHHVJILDY-UXHICEINSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 229960005286 carbaryl Drugs 0.000 description 1
- CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical compound C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- WCMMILVIRZAPLE-UHFFFAOYSA-M cyhexatin Chemical compound C1CCCCC1[Sn](C1CCCCC1)(O)C1CCCCC1 WCMMILVIRZAPLE-UHFFFAOYSA-M 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- OEBRKCOSUFCWJD-UHFFFAOYSA-N dichlorvos Chemical compound COP(=O)(OC)OC=C(Cl)Cl OEBRKCOSUFCWJD-UHFFFAOYSA-N 0.000 description 1
- 229950001327 dichlorvos Drugs 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000004495 emulsifiable concentrate Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 1
- QFIFUKSTZGHSFY-UHFFFAOYSA-N ethyl 2-(4-chloroanilino)-3,3-dimethylbutanoate Chemical compound CCOC(=O)C(C(C)(C)C)NC1=CC=C(Cl)C=C1 QFIFUKSTZGHSFY-UHFFFAOYSA-N 0.000 description 1
- IODMJRFLLIWQIX-UHFFFAOYSA-N ethyl 2-anilino-3-hydroxybutanoate Chemical compound CCOC(=O)C(C(C)O)NC1=CC=CC=C1 IODMJRFLLIWQIX-UHFFFAOYSA-N 0.000 description 1
- AKEFSKQAKBVCGG-UHFFFAOYSA-N ethyl 3,3,3-trichloro-2-oxopropanoate Chemical compound CCOC(=O)C(=O)C(Cl)(Cl)Cl AKEFSKQAKBVCGG-UHFFFAOYSA-N 0.000 description 1
- KJHQVUNUOIEYSV-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-oxopropanoate Chemical compound CCOC(=O)C(=O)C(F)(F)F KJHQVUNUOIEYSV-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 description 1
- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- FYQGBXGJFWXIPP-UHFFFAOYSA-N hydroprene Chemical compound CCOC(=O)C=C(C)C=CCC(C)CCCC(C)C FYQGBXGJFWXIPP-UHFFFAOYSA-N 0.000 description 1
- 229930000073 hydroprene Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 239000002949 juvenile hormone Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229930001540 kinoprene Natural products 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- UPRXAOPZPSAYHF-UHFFFAOYSA-N lithium;cyclohexyl(propan-2-yl)azanide Chemical compound CC(C)N([Li])C1CCCCC1 UPRXAOPZPSAYHF-UHFFFAOYSA-N 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229930002897 methoprene Natural products 0.000 description 1
- 229950003442 methoprene Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- LRTFPLFDLJYEKT-UHFFFAOYSA-N para-isopropylaniline Chemical compound CC(C)C1=CC=C(N)C=C1 LRTFPLFDLJYEKT-UHFFFAOYSA-N 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- HYJYGLGUBUDSLJ-UHFFFAOYSA-N pyrethrin Natural products CCC(=O)OC1CC(=C)C2CC3OC3(C)C2C2OC(=O)C(=C)C12 HYJYGLGUBUDSLJ-UHFFFAOYSA-N 0.000 description 1
- VJFUPGQZSXIULQ-XIGJTORUSA-N pyrethrin II Chemical class CC1(C)[C@H](/C=C(\C)C(=O)OC)[C@H]1C(=O)O[C@@H]1C(C)=C(C\C=C/C=C)C(=O)C1 VJFUPGQZSXIULQ-XIGJTORUSA-N 0.000 description 1
- 229940070846 pyrethrins Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000012066 reaction slurry Substances 0.000 description 1
- VEMKTZHHVJILDY-FIWHBWSRSA-N resmethrin Chemical compound CC1(C)[C@H](C=C(C)C)C1C(=O)OCC1=COC(CC=2C=CC=CC=2)=C1 VEMKTZHHVJILDY-FIWHBWSRSA-N 0.000 description 1
- 229940108410 resmethrin Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 150000003679 valine derivatives Chemical class 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000004563 wettable powder Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/44—Two oxygen atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
- C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
- C07C205/12—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Agronomy & Crop Science (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The new esters and thiolesters (thioesters) of amino acids are represented by the formula (A) W and R<1> to R<5> are defined in the preceding Claim 1. The said compounds have insecticidal and acaricidal properties.
Description
This invention relates to novel esters and . thiolesters of amino acids, synthesis thereof and the use of said esters and thiolesters and compositions containing said esters or thiolesters for the control of pests.
The esters and thiolesters of amino acids of the present invention are represented by the following generic formula (A); (A) wherein, W is oxygen or sulfur; R1 is oyoloalkyl, oycloalkenyl, with halo or lower alkyl, or the group '20 cycloalkenyl substituted in which t is zero, one, two, three or four; Y is independently selected from hydrogen, lower alkyl, lower haloalkyl, lower alkoxy, lower alkylthio, lower alkylcarbonyl, lower alkoxycarbonyl, lower acyloxy, halogen, cyano, nitro, and lower haloalkylthio; and Z is independently selected from the values of Y, cycloalkyl, and lower haloalkoxy; or Y and Z form a methylenedioxy group; R is hydrogen, lower alkyL, lower haloalkylcarbonyl, or formyl; R is alkyl of 2 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkenyl of 2 to 4 carbon atoms, or cycloalkyl of 3 or 4 carbon atoms; R^ is hydrogen or fluoro; and wherein, p is zero, one, two or three; fi R is hydrogen, cyano, methyl, trifluoromethyl, ethynyl, or -OS .
I ' nh2 R is halogen, lower alkyl, lower haloalkyl, lower . alkoxy, lower haloalkoxy, lower alkylthio, lower alkenyl, or lower haloalkenyl; β 7 R is hydrogen or together with R forms a lower alkylenedioxy bridge across adjacent ring carbon atoms; R? is hydrogen, lower alkanyloxy, lower alkynyl, lower alkynyloxy, lower haloalkynyl, lower alkylcarbonyl, arylcarbonyl, substituted arylcarbonyl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, aralkyl, substituted aralkyl, oycloalkyl, cycloalkalkyl, lower acyloxy, aryloxyearbonyl, lower alkoxycarbonyl, or lower haloalkenyloxy; R^° is hydrogen or lower alkyl; 1S 13 hydr°9en’ lower alkenyb lower alkynyl, or aralkyl; R12 and R13 taken together fora, an alkylene bridge having 1 to 4 carbon atoms or an alkenylene bridge having 2 to 4 carbon atoms; -346787 alkynyl, together R is hydrogen, lower alkyl, lower alkenyl, lower or aralkyl? is hydrogen or lower alkyl; R·*·5 is hydrogen, chloro, fluoro, or methyl; R17 is hydrogen, chloro, fluoro, methyl, or taken 16 ‘ * with R forms a carbon-carbon bond; R is phenyl or phenyloxy; R is hydrogen, halogen, methyl, or ethyl? R is allyl, propargyl, 3-butenyl, 3-butynyl, phenyl, or benzyl; and the salts thereof of strong inorganic acids or organic acids.
The compounds of the present invention represented by generic formula (A), are useful agents for the control of pests such as insects and acarids. Without any intention of being bound by theory and although the mode of action of the compounds of formula (A) as applied to the control of insects and acarids is not completely understood, the compounds of formula (A) appear to be effective for the control of insects and acarids by reason of mechanisms of the nature of the insect control agents known as pyrethrins and synthetic pyrethroids. As such, the organic moiety (R5) is selected from the organo groups generally associated with the formation of pyrethrin esters and synthetic pyrethroid esters. Typical of such organo groups (R5) are the groups shown in, for example, U.S. Patents 3,973,035, 3,973,036, 3,996,244 and 4,003,945, Offenlegungsschrift 26 47 366, and Republic of South Africa Application No. 76/4622.
Xn the description hereinafter and the appended claims, 1 20 each of R through R , W, Ϋ, Z, p, and t is as defined hereinabove, unless otherwise specified. . -446787 As a generally applicable method of synthesis, the compounds of formula (A) can be prepared by the reaction of a primary or secondary amine of formula (I) with a halo ester or thiolester of formula (II) (X is bromo, chloro, or iodo). - Η (I) R2 The reaction of an amine (I) and halo ester (II) is generally carried out neat or in an organic solvent such as hexamethylphosphoric triamide, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide at room temperature or above. The reaction generally proceeds rather slowly. It may be assisted by a catalyst such as a small amount of potassium iodide. A good review of the synthesis of amino acids and esters of amino acids is given in Methodicum Chimicum, Academic Press, New York, Vol. 6, pp 599-623 (1975).
The halo esters of formula II can be prepared from e the acid halide thereof (II, wherein WR represents a bromo or e chloro) by reaction with an alcohol (R -OH). The a-halosubstituted acid halide and α-halo-substituted acid can be prepared by halogenation, using molecular halogen, of (1) a mono-carboxylic acid, or (2) a malonic ester followed by saponification using, for example, the Hell-Volhard-Zelinsky reaction and procedures described in Org. Syn. Coll., Vol. 2, (1943); ibid., Vol. 3, 495, 523, 623, and 848 (1955); ibid., Vol. 4, 358 and 608 (1963); Org. Syn. 50, 31 (1970); and JACS 91, 7090 (1969). Other suitable methods include the -510 6787 reaction, of N-bromos.uccinimide or N-chlorosuccinimide with an acid halide (II, wherein WR5 represents bromo or chloro) following the procedures of Harpp et al., J. Org. Chem. 40, 3420 (1975) and references cited therein. A method suitable when olefinic unsaturation is present is alkylation of aceto acetates followed by halogenation of the anion, e.g. the sodium enolate, and deacetylation. Rathke et al., Tetrahedron letters No. 43, 3995 (1971) and Slotter et al., ibid., No. 40, 4067 (1972). The synthesis of α-chloro acids may be accomplished also by reacting the acid with molecular chlorine in the presence of ohlorosulfonic acid and chloranil as described by Ogata et al., J. Org. Chem. 40, 2960 (1975). They may also be prepared from α-hydroxy acids by conventional methods.
The compounds of formula (A) can be synthesized also by reacting an acid of formula (III), or the acid chloride or - 5 bromide thereof, with an alcohol or mercaptan HW-R .
R3 I C I4 R* II C - OH (III) The acid of formula (III) can be made from the halo 21 acid or lower alkyl ester of formula (IV) (R is hydrogen or lower alkyl) using the conditions described hereinabove by reaction with the amine of formula (I).
OR (IV) Following reaction of a halo ester of formula (IV) 21 wherein R Is lower alkyl with an amine of formula (I), the resulting amino ester of formula (V) 646787 1 11 21 N - C - C - Ok (V) is saponified by conventional methods to the amino acid of 5 formula (Ill) or a reactive derivative thereof such as the acid chloride, acid bromide or sin inorganic salt thereof such as the sodium or potassium salt.
The following terms, wherever used in the description herein and the appended claims, have the meaning defined below, 10 unless otherwise specified hereinafter.
The term lower alkyl refers to an alkyl group straight or branched, having a chain length of one to eight carbon atoms. The term lower haloalkyl refers to an alkyl group substituted with one to three halogen atoms such as chloromethyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 6-chlorohexyl and 2-fluoroethyl.
The term lower alkoxy refers to an alkoxy group, straight or branched, having a chain length of one to eight carbon atoms. The term lower alkylthio refers to an alkylthio group, straight or branched, having a chain length of one to eight carbon atoms and "haloalkylthio refers to an alkylthio group substituted by up to three halogen atoms.
The term lower alkenyl refers to an ethylenically unsaturated hydrocarbon group, straight or oranched, having a chain length of two to eight carbon atoms and one or two ethylenic bonds such as vinyl, allyl, 3-butenyl, 2-hexenyl, i-propenyl and 2,4-hexadienyl.
The term lower haloalkenyl refers to a lower alkenyl group substituted with one to three halogen atoms. The term lower alkenyloxy refers to an alkenyloxy group, straight or branched, of two to eight carbon atoms. The term lower haloalkenyloxy" refers to a lower alkenyloxy group substituted with one to three halogen atoms.
The term lower alkynyl refers to an alkynyl group, straight or branched, having a chain length of two to eight carbon atoms and one or two acetylenic bonds. The term lower haloalkynyl refers to a lower alkynyl group having one to three halogen atoms. The term lower alkynyloxy refers to an alkynyloxy group, straight or branched, of three to eight carbon atoms.
The term cycloalkyl refers to a cycloalkyl group of three to eight cyclic carbon atoms. The term cycloalk10 alkyl refers to a cycloalkyl group wherein one hydrogen atom is replaced by a lower alkyl group, the total number of carbon atoms being from four to twelve, such as cyclopropanemethyl, cyclobutaneethyl an(j cyclohexanemethyl.
The term aryl refers to the aryl group phenyl or naphthyl. The term aralkyl refers to a lower alkyl group in which a hydrogen atom of the alkyl group is substituted by an aryl group, the total number of carbon atoms being from seven to twelve, such as benzyl and phenethyl.
The terms substituted aryl and substituted aralkyl refer / 20 to an aryl group and an aralkyl group, respectively, substituted at one, two or three of the ring carbon atoms with a group selected from lower alkyl, lower haloalkyl, lower alkoxy, lower alkenyl, lower haloalkenyl, lower alkenyloxy, halogen, nitro, cyano and lower alkylthio.
The term lower haloalkoxy refers to a lower alkoxy group substituted with one to three halogen atoms.
The term lower acyloxy refers to a lower carboxylic acid acyloxy group of one to sxx carbon atoms, such as acetoxy.
The compounds of the present invention of formula (A) have one or more asymmetric carbon atoms. The present -846787 invention includes each of the optical isomers and racemic mixtures thereof. In the examples hereinafter, unless otherwise specified, the compound prepared is a racemic mixture.
Included within the present invention are salts of the compounds of formula A. The salts are formed from strong inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, p-benzenesulfonic acid, methanesulfonic acid and Lewis acids. Many of the compounds of formula A are oils which advantageously are converted into the salt for convenience of handling and formulating and superior stability. The salts are useful for the control of pests in the same way as the compounds of formula A, The compounds of the present invention of formula A are useful pest control agents, particularly for the control of insects and acarids. In the use of the compounds of formula A for combating insects and acarids for the protection of agricultural crops, for example soybeans, cotton and alfalfa, a compound of formula A, or mixtures thereof, together with a carrier is applied to the locus in a pesticidally effective amount. The carrier can be liquid or solid and include adjuvants such as wetting agents, dispersing agents and other surface active agents. The compounds of formula A can be used in formulations such as wettable powders, solutions, dusts, granules and emulsifiable concentrates.
Suitable solid carriers include naturaj. and synthetic silicates and clays, carbon or charcoal granules, natural and synthetic resins and waxes. Suitable liquid carriers include water, aromatic hydrocarbons, alcohols, vegetable and mineral oils and ketones, The amount of a compound of -94 6 7 8 7 formula A in the formulation can vary widely, generally within , the range of about 0.01 percent to about 90.0 percent, by weight.
As shown hereinafter, compounds within the present 5 invention are effective on many different insects and on acarids.
They are effective control agents for insects such as mosquitoes, flies, aphids, weevils and acarids such as the spider mite and ticks. Depending upon the particular combination of the substituents of formula A herein, they have a broad or relatively narrow spectrum of unusually high pesticidal activity on insects and acarids. Among the pests against which they -are pesti ci dally effective are insects of the order Lepidoptera, Orthoptera, Heteroptera, Homoptera, Diptera, Coleoptera or Hymenoptera, and acarids of the order Acarina including mites of the family Tetrahychidae or Tarsonemidae and ticks such as Omithodoros.
The compounds of the present invention can be used in combination with other pesticides such as the carbamates, phosphates and insect growth regulators, e.g. propoxur, carbaryl, *Naled, dichlorvos,'methoprene, kinoprene, hydroprene, cyhexatin 1 and resmethrin.
The following examples are provided to illustrate the practice of the present invention. Temperature is given in degrees Centigrade. RT means room temperature.
*Naled is a trade mark EXAMPLE 1 A. To α-bromoisovalerie acid (10 g, 0.055 mole) in 60 ml ether, cooled to 10®, is added dimethylformamide (DME) (2.8 ml, 0.0332 mole), followed by slow addition of thionylchloride (5.9 ml, 0.0828 mole). After about one hour at 24·, the acid chloride intermediate is isolated by decanting off the top ether layer from the oily residue and removing the ether under vacuum. To the acid chloride (0.055 mole) in 100 ml of ether, cooled to 10®, is added m-phenoxybenzyl alcohol (11.49 g, 0.0495 mole) followed by addition of pyridine (9 ml, 0.11 mole) over about 15 minutes. The resulting White slurry is stirred, at 24® for about 16 hours and then a trace of water is added to decompose excess acid chloride.
The ester is isolated by pouring reaction slurry into ice water (100 ml), acidifying with 2N sulfuric acid (60 ml) and extracting with ether (3x 100 ml). The combined ether extracts are washed with 10% sodium bicarbonate (10 ml), followed by water (2X 100 -ml) and brine (25 ml) and dried over calcium sulfate to give m-phenoxybenzyl α-bromoisovalerate in quantitative yield. nmr (CC14) 6 1.03 [m, 6, (CH^CH], 2.18 [m, 6, (CH3)2CH), 3.94 (d, 1, J = 8 Hz, Br-CH-^- ), and 5.11 ppm (s, 2, ArCH2O- ). IS (film) 1744 cm-1 (C=O).
B. To m-phenoxybenzyl α-broraoisovalerate (3 g, 0.0083 mole) in 6 ml of hexamethylphosphorictriamide (HMPT), 24®, is added aniline (0.0248 mole) followed by a catalytic amount of potassium iodide (28 mg). The reaction mixture is -114 6 7 8 7 heated, at 65®, for about 90 hours and then poured into ice-water f35 ml) and extracted with ether (3X 50 ml). The combined ether extracts are washed with 2N sulfuric acid, water (2X 50 ml) until neutral, and with brine followed by drying over calcium.sulfate. The product is concentrated under vacuum and isolated by preparative thin layer chromatography (TLC). m-Phenoxybenzyl ester of N-phenylvaline. nmr· (CDClg) δ 1.00 [m, 6, CH^CH], 2.Ό7 [m, 1, (CH3)2· CH], 3.95 [nt, 1, N-CH-C02-], 4.00 (m, 1, NH), and 5.13 ppm (s, 2, ArCHjO) . IR (film) 3400 cm-1 (s) (NH) and 1738 cm-1 (C=O).
EXAMPLE 2 To the m-phenoxybenzyl ester of N-phenylvaline (0.25 g) 15 in HMPT (1 ml) and tetrahydrofuran (1 ml), at 24°, is added methyl iodide (0.12 ml) followed hy potassium carbonate (0.092 g). The reaction mixture is heated at 60® for 4 days. The reaction is worked up by pouring into ice-water (5 ml) and extracting with ether (3X 10 ml). The combined ether extracts are washed with water (2X 10 ml) and hrine (IX 5 ml) and dried over calcium sulfate. The product is isolated and purified by preparative TLC to give the m-phenoxybenzyl ester of N-phenylN-methylvaline. nmr (CDC13) δ 0.92 [m, 6, (CH3)2CH], 2.3 [m, 1, (CH3)225 CH], 2.88 (s, 3, Cg3N), 3.96 (d, 1, N-CH-C02), and 5.08 ppm (s, 2, ArCH20). IR (film) 1740 (C=O).
EXAMPLE 3 A. To valine (11.7 g, 0.10 mole) in 88% formic acid (40 ml) is added acetic formylanhydride· (26.3 g, 0.30 mole) -1246787 over 0.5 hr at 5°, The reaction mixture is warmed to 24’ and stirred for 17 hours. The reaction is worked up by distilling off (bath temp. 45-50*) the solvent; excess anhydride and acetic acid, to give, as a white solid, N-formylvaline, recrystallized from hot ethanol, m.p. 143-145*.
B. To 8 g (0.055 mole) of the product of part A in 55 ml of HMPT is added m-phenoxybenzyl bromide (14.4 g, 0.055 mole) followed by anhydrous potassium carbonate (7.6 g, 0.055 mole). The reaction mixture is stirred, at 24®, for 48 hours and then worked up by pouring into ice-water (250 ml) and extracting with ether (3X 100 ml). The combined ether extracts are washed, with water (2X 100 ml) and brine (25 ml) and dried over calcium sulfate and evaporated under vacuum to give the m-phenoxybenzyl ester of N-formylvaline.
C. To the ester (25 g, 0.0835 mole) of part B, in 84 ml of anhydrous methanol, is added. IN methanolic HC1 (92 »1, 0.092 mole). The reaction mixture is stirred at 24® for 18 hours and then the methanol removed under vacuum. The residue is poured into ice-water (200 ml) followed by removal of neutral impurities with ether. The aqueous layer is made basic by addition of 10% sodium bicarbonate and then extracted with ether (3X 200 ml). The combined ether phases are washed with water (2X 200 ml) until neutral and brine (100 ml) and then dried over calcium sulfate, filtered and rotoevaporated to give the m-phenoxybenzyl ester of valine nmr (CDClj) δ 0.91 [m, 6, (CH3)2CH), 1.37 (bs, 2, NH2), 2.00 [m, 1, (CH3)2CH), 3.31 (d, 1, N-CH-g-), and 5.17 ppm (s, 2, ArCHjO-). IR (film) -^3400 cm1 (NH2), 1740 cm1 (C«O) . -134 6 7 8 7 EXAMPLE 4 To m-phenoxybenzyl α-bromoisovalerate (5 g, 0.0138 mole) in 9 ml of HMPT, at 24°, is added p-chloroaniline (5.27 g, 0.0413 mole) and a catalytic amount of potassium iodide (60 rag). The reaction mixture is stirred at 70" for four. days. The reaction is then poured into ice-water (30 ml) and 10 ml of 2N sulfuric acid which is extracted with ether (3X 30 ral). The combined ether extracts are washed with water (2X 30 ml) and brine (10 ml), dried over calcium sulfate, filtered and evaporated. The crude product is purified by preparative TLC to yield the m-phenoxybenzyl ester of N-(p-chlorophenyl)valine. nmr (CDC13)'5 0.99 [m, 6, (CHICHI, 2.03 [m, 1, (CH3)2CH], 3.93 (ra, 2, NH and N-CH-CO2), and 5.10 ppm (s, 2, ArCH20-). IR (film) 3410 cm-1 (s) (NH), and 1740 cm-1 (C=O).
EXAMPLE 5 To m-phenoxybenzyl α-bromoisovalerate (2 g, 0.0055 mole) in 4 ml of HMPT, at 24°, is added toluidine (1.77 g, 0.0165 mole) and potassium iodide (25 mg). The reaction mixture is stirred at 60° for five days, cooled, and poured into ice-water (20 ml) plus 10 ml of 2N sulfuric acid. The reaction is worked up as in·Example 4 yielding the m-phenoxybenzyl ester of N-(p-methylphenyl)valine. nmr (CDClj) δ 0.99 [m, 6, (CH^CH), 2.20 (s, 3, Cg3v .1 Ar), 3.90 (m, 2, NH and N-CH-CO,,) , and 5.11 ppm (s, 2, ArCHjO) IR (film) 3400 cm-1 (s) (NH), and 1740 cm-1 (C=0) .
The above procedure is repeated using anisdine in place of toluidine to yield the m-phenoxybenzyl ester of N- (p-methoxyphenyl) valine. -1446787 nmr (CDC13) <$ 0.98 [m, 6, (Cg3)2CH], .2.03 [m, 1, (CH3)2CH], 3.73 (s, 3, OCH3), 3.77 (m, 2, NH and N-CH-CO2), and 5.10 ppm (s, 2, ArCHjO-). IE (film) 3400 cm-1 (s) (NH), and 1740 cm’3- (OO).
EXAMPLE 6 A. To a-bromoisovaleric acid (5.18 g, 0.0286 mole) in 30 ml of ether, cooled to 10", is added 1.3 ml of DMF followed by slow addition of 3 ml of thionyl chloride (0.0429 mole). After one hour at 24*, the acid chloride is isolated in quantitative yield, by decanting off top the ether layer and removing the solvent and excess thionyl chloride under vacuum.
To the acid chloride (5.7 g, 0.0286 mole) in 30 ml of ether at 10* is added 5.38 g. of ra-phenoxybenzaldehyde cyanohydrin (0.0257 mole) followed by slow addition of 4.6 ml of pyridine over 10 minutes. The reaction mixture is stirred at 24’ for 17 hours and then a trace of water is added to destroy excess acid chloride. The reaction product is worked up by pouring into ice-water (50 ml) plus 2N sulfuric acid (30 ml) and extracting with ether (3X 30 ml). The combined ether extracts are washed with 10S sodium bicarbonate (10 ml), water (2X 50 ml) and brine (10 ml), dried over calcium sulfate and evaporated to yield m-phenoxy-a-cyanobenzyl a-bromoisovalerate. nmr (CDClj) 5'1.05 (m, 6, (CH3)2CH], 2.23 [m, 1, (CH,),CH), 4.06 (d, 1, J » 8 Hz, Br-CH-<;-) , and 6.41 ppm [s, 1, -1 0 ArCH(CN)O). IR (film) 1752 cm * (C»0). -154 6 7 8 7 B. To m-phenoxy-a-cyanobenzyl α-bromoisovalerate (2.0 g, 0.0052 mole) in 4 ml of HMPT, at 24°, is added aniline (1.5 g, 0.016 mole) and potassium iodide (21 mg).
The reaction is stirred at 65° for 90 hours and then cooled and poured into ice-water (20 ml) plus 2N sulfuric acid (10 ml) = The reaction is worked up as in Example 4 and purified by preparative TLC to give the m-phenoxy-a-cyanobenzyl ester of N-phenyIvaline. nmr (CDC13) 5 1.02. [m, 6, (CH^CH), 2.10 [m, 1, γ I (CHjJjCH], 4.0 (m, 2, -NH and ^N-CH-COj), and 6.33 ppm [s, 1, ArCH(CN)01. IR (film) 3400 cm-! (s) (NH) , 2260 cm_l (w) (C=N), 1758 cm-1 (C=0).
EXAMPLE 7 Following the procedure of Example 5, each of the compounds under column I is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the repsective ester under column II.
I 3,4,5-trimethoxyaniline 4-phenetidine 2.4- dimethoxyaniline 3.5- dimethoxyaniline 2-anisidine 4-ethylaniline 2.4.6- trimethylaniline 4-nitroaniline 2.4.6— trichloroaniline 4-fIuoroaniline 4—bromoaniline -1646787 3- chloro-2-methoxyaniline 2- chloro-4-methylaniline 2.6- dichloroaniline 4- chloro-2-nitroaniline 2.6- dichloro-4-nitroaniline 4-aminoacetophenone 3- arainobenzonitrile 2-aminobenzonitrile 2.6- dimethylaniline 2,5-dimethylaniline II The m-phenoxybenzyl ester of N-(3,4,5-trimethoxyphenyl)valine N-(4-ethoxyphenyl)valine N- (2,4-dimethoxyphenyl)valine N-(3,5-dimethoxyphenyl)valine N-(2-methoxyphenyl)valine N-(4-ethylphenyl)valine N- (2,4,6-trimethylphenyl)valine N-(4-nitrophenyl)valine N-(2,4,6-triohlorophenyl) valine N-(4-fluorophenyl)valine N-(4-bromophenyl)valine N-(3-chloro-2-methoxyphenyl) valine N-(2-chloro-4-methylphenyl)valine N-(2,6-diohlorophenyl)valine N-(4-chloro-2-nitrophenyl)valine N-(2,6-dichloro-4-nitrophenyl)valine N-(4-methyloarbonylphenyl)valine -1746787 N-(3-cyanophenyl)valine N—(2-eyanophenyl)valine K-(2,6-dimethylphenyl)valine N—(2r5-dimethylphenyl)valine 5 EXAMPLE 8 Following the procedure of Example 1, a-bromoisovaleric acid via the acid halide is reacted with the alcohols listed in column III to yield the respective ester under column IV.
III p-phenoxybenzyl alcohol m-benzylbenzyl alcohol p-propargylbenzyl alcohol 4- allyl-Z, 6-dimethylbenzyl alcohol p-allylbenzyl alcohol 2.6- dimethyl-4-propargylbenzyl alcohol a-ethynyl-3-trifluoromethylhenzyl alcohol - benzyl-3-furylmethyl alcohol a-cyano-5-benzyl-3-furylmethyl alcohol -propargylfurfuryl alcohol 2- methyl-5-propargyl-3-furylmethyl alcohol -propargyl-a-ethynylfurfuryl alcohol -benzyl-2-methyl-3-furylmethyl alcohol 3- methyl-2-propargyl-2-cyclopentene-l-one-4-ol 2-allyl-3-methyl-2-cyclopentene-l-one-4-ol 2-benzyl-2-eyelopentene-l-one-4-ol 3.4.5.6- tetrahydrophthalimidomethyl alcohol phthalimidomethyl alcohol 4- phenyl-3-chloro-2-butene-l-ol -propargyl-2-thiophenemethanol -184 6 7 8 7 -benzyl-2-thiophenemethanol -benzyl-3-thiophenemethanol IV p-phenqxybenzyl a-bromoisovalerate m-benzylbenzyl a-bromoisovalerate p-propargyl-benzyl a-bromoisovalerate 4- allyl-2,6-dimethylbenzyl a-bromoisovalerate p-allylbenzyl a-bromoisovalerate 2,6-dimethyl-4-propargyl-benzyl a-bromoisovalerate a-ethynyl-3~trifluoromethylbenzyl a-bromoisovalerate - benzyl-3-furylmethyl a-bromoisovalerate a-cyano-5~benzyl-3~furylmethyl a-bromoisovalerate -propargylfurfuryl a-bromoisovalerate 2-methyl-5-propargyl-3-furylmethyl a-bromoisovalerate -propargyl-a-ethynylfurfuryl a-bromoisovalerate 5-benzyl-2-methyl-3-furylmethyl a-bromoisovalerate 2- methyl-3-propargyl-4-oxo-2-cyclopentene-l-yl methyl a-bromoisovalerate 3-allyl-2-methyl-4-oxo-2-cyclopentene-l-yl methyl a-bromoisovalerate 3- benzyl-4-oxo-2-cyclopentene-l-yl methyl a-bromoisovalerate 3,4,5,6-tetrahydrophthalimidomethyl a-bromoisovalerate phthalimidomethyl a-bromoisovalerate 4-phenyl-3-chloro-2-butene-l-yl a-bromoisovalerate -propargyl-2-thiophenemethyl a-bromoisovalerate 5-benzyl-2-thiophenemethyl a-bromoisovalerate 5-benzyl-3-thiophenemethyl a-bromoisovalerate -19EXAMPLE 9 Each of the α-bromo ester intermediates listed under column IV is reacted with 4-chloroaniline using the procedure hereinabove, e.g. Example 1, 4 or 5, to yield the respective ester of N-(4-chlorophenyl)valine listed under column V.
V 4-phenoxybenzyl ester of N-(4-chlorophenyl)valine 3- benzylbenzyl ester of N-(4-chlorophenyl)valine 4-propargylbenzyl ester of N-(4-chlorophenyl)valine 4- ally1-2,6-dimethylbenzyl ester of N-(4-chlorophenyl) valine p-allylbenzyl ester of N-(4-chlorophenyl)valine 2,6-dimethyl-4-propargylbenzyl ester of N-(4-chloro 15 phenyl)valine u-ethynyl-3-trilfuoromethylbenzyl ester of N-(4chlorophenyl)valine - benzyl-3-furylmethyl ester of N-(4-chlorophenyl) valine 2q a-cyano-5-benzyl-3-furylmethyl ester of N-(4-chlorophenyl) valine -propargylfurfuryl ester of N-(4-chlorophenyl)valine 2-methyl-5-propargyl-3-furylmethyl ester of N-(4chlorophenyl)valine -propargyl-a-ethynylfurfuryl ester of N-(4-chlorophenyl) valine -benzyl-2-methyl-3-furylmethyl ester of N-(4-cnlorophenyl)valine 2-methyl-3-propargyl-4-oxo-2-cyclopentene-l-yl methyl ester of N-(4-chlorophenyl) valine -20— 3-allyl-2-methyl-4-oxo-2-cyclopentene-l-yl methyl ester of N-(4-chlorophenyl)valine 3- benzyl-4-oxo-2-cyclopentene-l-yl methyl ester of N-(4- chlorophenyl)valine 3,4,5,6-tetrahydrophthalimidomethyl ester of N-(4chlorophenyl)valine phthalimidomethyl ester of N-(4-chlorophenyl)valine 4- phenyl-3-chloro-2-butene-l-yl ester of N-(4-chlorophenyl) valine - propargyl-2-thiophenemethyl ester of N-(4-chlorophenyl)valine -benzyl-2-thiophenemethyl ester of N-(4-chlorophenyl) valine -benzyl-3-thiophenemethyl ester of N-(4-chlorophenyl) valine EXAMPLE 10 Following the procedure of Example 5, each of the amino compounds listed under column VI is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the respective N-substituted ester listed under column VII.
VI 2-chloro-6-methylaniline 4-chloro-2-methylaniline 4-chloro-3-trifluoromethylaniline 2-chloro-5-trifluoromethylaniline 2- trifluoromethylaniline 3- trifluoromethylaniline 3,5-dichloro-4-hydroxyaniline 4- chloro-3-nitroaniline -212.3- dichloroaniline 2-fluoroaniline f 2,6-diiodo-4-nitroaniline 3.4.5- trichloroaniline 4-ethoxycarbonylaniline 2- nitroaniline 3- nitroaniline 4- (n-butyl)aniline 4-cyclopropylaniline 2,3-dimethylaniline 4-isopropylaniline 3.5- dimethylaniline 2.4- dimethylaniline 4-hydroxyaniline 2-methylthioaniline 2.5- dichloraniline 3.4- methylenedioxyaniline 3.4- dimethoxyaniline 2.6- difluoroaniline 3,4-dichloroaniline VIX The m-phenoxybenzyl ester of N-(2-chloro-6-methylphenyl)valine N-(4-chloro-2-methylphenyl)valine N-(4-chloro-3-trifluoromethylphenyl)valine N-(2-chloro-5-trifluoromethylphenyl)valine N-(2-trifluoromethylphenyl)valine N-(3-trifluoromethylphenyl)valine N- (3,5-dichloro-4-hydroxyphenyl)valine N-(4-chloro-3-nitrophenyl)valine -2246787 Ν-(2,3-dichlorophenyl)valine N-(2-fluorophenyl)valine N-(2,6-diiodo-4-nitrophenyl)valine N-(3,4,5-trichlorophenyl) valine N-(4-ethoxycarbonylphenyl)valine N-(2-nitrophenyl)valine N-(3-nitrophenyl)valine N-(4-n-butylphenyl)valine N-(4-cyclopropylphenyl)valine N- (2,3-dimethylphenyl)valine N-(4-isopropylphenyl)valine N-(3,5-dimethylphenyl) valine N-(2,4-dimethylphenyl)valine N-(4-hydroxyphenyl)valine N-(2-methylthiophenyl)valine N- (2,5-dichlorophenyl)valine Nr(3,4-methylenedioxyphenyl)valine N- (3,4-dimethoxyphenyl)valine N-(2,6-difluorophenyl)valine N- (3,4-dichlorophenyl)valine EXAMPLE 11 The α-halo acid chloride listed in column VIII is reacted with m-phenoxybenzyl alcohol to prepare the respective α-halo ester in column IX according to procedures hereinabove such as Example 1.
VIII 2-bromo-3-methylpentanoyl chloride 2-bromo-4-methylpentanoyl chloride 2-bromobutanoyl chloride -2346787 2-bromohexanoyl chloride 2-bromo-3fchloropropanoyl chloride 2,5-dichloropentanoyl chloride /-chloro-4-trich!oromethylbutanoyl chloride IX 3-phenoxybenzyl 2-bromo-3-methylpentanoate 3-phenoxybenzyl 2-bromo-4-methylpentanoate 3-phenoxybenzyl 2-bromobutanoate 3-phenoxybenzyl 2-bromohexanoate 3-phenoxybenzyl 2-bromo-3-chloropropionate 3-phenoxybenzyl 2,5-dichloropentanoate 3-phenoxybenzyl 2,4,4,4-tetrachlorobutanoate Following the procedures hereinabove such as Example 4, 4-chloroaniline is reacted with each of the α-halo esters listed in column IX to yield the respective substituted amino ester of column X.
X 3-phenoxybenzyl ester of N-(4-chlorophenyl)isoleucine 3-phenoxybenzyl ester of N-(4-chlorophenyl)leucine 3-phenoxybenzyl ester of 2-(4-ohlorophenylamino) butanoic acid 3-phenoxybenzyl ester of 2-(4-chlorophenylamino) hexanoic acid. 3-phenoxybenzyl ester of 2-(4-chlorophenylamino)3-chloropropionic acid 3-phenoxybenzyl ester of 2-(4-chlorophenylamino)5-chloropentanoic acid 3-phenoxybenzyl ester of. 2-(4-chlorophenylamino)4,4,4-trichlorobutanoic acid -2446787 EXAMPLE 12 To the m-phenoxybenzyl ester of valine (2 g, 0.0067 mole) in methanol (30 ml) is added concentrated sulfuric acid to bring to about pH 6. Cyclohexanone (0.6 j, 0.006 mole) is then added followed by 3A molecular sieves and sodium cyanoborohydride (0.2? g, 0.004 mole). Additional sulfuric acid is added to keep pH at about 6. After about 24 hours, the reaction is worked up by removing methanol by rotoevaporation and the residue is poured into water and 10% sodium carbonate followed by extraction with ether. The combined ether extracts are filtered and concentrated and the product is isolated by preparatory TLC (10% ether/hexane) to yield the m-phenoxybenzyl ester of N-cyclohexylvaline. nmr (CTC13) ί 0.89 (m, 6, J - 7 H2, (CH3)2CH], 2.26 [m, 1, (CH3)2CH], 3.12 (m, 1,)n-CH-C-), and 5.15 ppm (a, ArCH2O). IR (film) 1736 cm-1 (C-O).
EXAMPLE 13 Each of the substituted aryl amines listed in column XI is reacted with m-phenoxybenzyl 2-bromoisovalerateS using the procedure of Example 4 to prepare the respective N-substituted compound in column XII.
XI 2.4- dichloroaniline 3-methoxyaniline 3.4- dimethylaniline 2,3,5,6-tetrachloroaniline 3-methylaniline 3.5- dichloroaniline 3° 3-acetoaniline -2546787 2-acetoaniline 2- methylaniline I It XII m-phenoxybenzyl ester of 5 N-(2,4-dichlorophenyl)valine N-(3-methoxyphenyl)valine N—(3,4-dimethylphenyl)valine N- (2,3,5,6-tetrachlorophenyl)valine N-(3-msthylphenyl)valine 10 N- (3,5-dichloropheny1)valine U-(3-acetophenyl)valine N-(2-acetophenyl)valine N-(2-methylphenyl)valine EXAMPLE 14 IS Following the process of Example 1, each of the alcohols listed in column XIII is reacted with the acid chloride of β-bromoisovaleric acid, to yield the respective ester in column XIV. xm 3- (2,2-dichlorovinyloxy)benzyl alcohol 3- (o-fluorophenoXy)benzyl alcohol 4- phenyl-2-butenyl alcohol 4—(4-methylphenoxy)-2-butynyl) alcohol 25 4-(4-methylpheny1)-2-butenyl alcohol 3-phenylcarbonylbenzyl alcohol l-ethynyl-2-methyl-2,5-hexadien-l-yl alcohol l-ethynyl-2-methyl-2-penten-l-yl alcohol l-ethynyl-2-methyl-3-phenyl-2-propen-l-yl alcohol l-ethynyl-3-phenyl-2-propen-l-yl alcohol 2,4,6-trimethylbenzyl alcohol XIV 3-(2,2-dichlorovinyloxy)benzyl α-bromoisovalerate 3- (o-fluorophenoxy)benzyl a-bromoisovalerate 4- phenyl-2-butenyl a-bromoisovalerate 4-(4-methylphenoxy)-2-butynyl a-bromoisovalerate 4-(4-methylphenyl)-2-butenyl a-bromoisovalerate 3-phenylcarbonylbenzyl a-bromoisovalerate a-ethynyl-2-methy1-2,5-hexadienyl a-bromoisovalerate a-ethynyl-2-methyl-2-pentenyl a-bromoisovalerate a-ethynyl-2-methyl-3-phenyl-2-propenyl a-bromoisovalerate a-ethynyl-3-phenyl-2-propenyl a-bromoisovalerate 2,4,6-trimethylbenzyl a-bromoisovalerate Following the procedures hereinabove such as Example , p-methylaniline is reacted with each of the α-bromo esters in column XIV to yield the respective ester of N-(p-methylphenyl)valine in column XV.
XV 3-(2,2-diohlorovinyloxy)benzyl ester of N-(p-methylphenyl) valine 3- (o-fluorophenoxy)benzyl ester of N-(p-methylphenyl) valine 4- phenyl-2-butenyl ester of N-(p-methylphenyl)valine 4-(4-methylphenoxy)-2-butynyl ester of N-(p-methylphenyl)valine 4-(4-methylphenyl)-2-butenyl ester of N-(p-methylphenyl) valine 3-phenylcarbonylbenzyl ester of N-(p-methylphenyl) 'valine a-ethynyl-2-methyl-2,5-hexadienyl ester of N-(pmethylphenyl)valine -2746787 a-ethynyl-2-methyl-2-pentenyl ester of N-(p-methylphenyl)valine a-ethynyl-2-methyl-3-phenyl-2-propenyl ester of M-(p-methylphenyl)valine a-ethynyl-3-phenyl-2-propenyl ester of N-(p-methylphenyl) valine 2,4,6-trimethylbenzyl ester of N-(p-methylphenyl)valine EXAMPLE 15 Each of the α-halo esters in column IX hereinabove is reacted with p-methylaniline to yield the respective 3-phenoxybenzyl ester of the p-methylphenyl amino acid in column XVI using the procedure of Example 5.
XVI 3-phenoxybenzyl ester of N-(p-methylphenyl)isoleucine 3-phenoxybenzyl ester of N-(p-methylphenyl)leucine 3-phenoxybenzyl ester of 2-(p-methylphenylamino) butanoic acid 3-phenoxybenzyl ester of 2-(p-methylphenylamino) hexanoic acid 3-phenoxybenzyl ester of 2-(p-methylphenylamino)3-chloropropionic acid 3-phenoxybenzyl ester of 2-(p-methylphenylamino)5-chloropentanoic acid 3-phenoxybenzyl ester of 2-(p-methylphenylamino)4,4,4-trichlorobutanoic acid EXAMPLE 16 Each of the α-bromo esters listed in column IV is reacted with p-methylaniline using the procedure of Example 5 -2846787 to yield the respective ester of N-(p-methylphenyl)valine in column XVII.
XVII 4-phenoxybenzyl ester of N-(p-methylphenyl)valine 3- benzylbenzyl ester of N-(p-methylphenyl)valine 4- propargylbenzyl ester of N-(p-methylphenyl)valine 4- allyl-2,6-dimethylbenzyl ester of N-(p-methylphenyl) valine p-allylbenzyl ester of N-(p-methylphenyl)valine 2,6-dimethyl-4-propargylbenzyl ester of N-(p-methylphenyl)valine a-ethynyl-3-trifluoromethylbenzyl ester of N-(pmethylphenyl)valine - benzyl-3-furylmethyl ester of N-(p-methylphenyl) valine a-cyano-5-benzyl-3-furylmethyl ester of N-(p-methylphenyl) valine -propargylfurfuryl ester of N-(p-methylphenyl)valine 2-methyl-5-propargyl-3-furylmethyl ester of N-(pmethylphenyl)valine -propargyl-a-ethynylfurfuryl ester of N-(p-methylphenyl) valine -benzyl-2-methyl-3-furylmethyl ester of N-(p-methylphenyl) valine 2- methyl-3-propargyl-4-oxo-2-oyclopentene-l-yl methyl ester of N- (p-methylphenyl) valine 3- allyl-2-methyl-4-oxo-2-cyclopentene-l-yl methyl ester of N-(p-methylphenyl) valine 3-benzyl-4-oxo-2-cyolopentene-l-yl methyl ester of N-(p-methylphenyl)valine -293,4,5,6-tetrahydrophthalimidomethyl estar of Ν-(ρmethylphenyl)valine phthalimidomethyl ester of N-(p-methylphenyl)valine 4- phenyl-3-chloro-2-butene-l-yl ester of N-(p5 methylphenyl)valine - propargyl-2-thiophenemethyl ester of N-(p-methylphenyl) valine -benzyl-2-thiophenemethyl ester of N-(p-methylphenyl) valine -benzyl-3-thiophenemethyl ester of N-(p-methylphenyl) valine EXAMPLE 17 A. Two grams of α-bromoisovaleric acid (0.011 mole) 15 dissolved in 10 ml of methanol is titrated to the phenolphthalein end point at 0° with 2N sodium hydroxide/methanol. The. alcohol is then removed and 10 ml of dimethylformamide and p-trifluoromethylaniline (3-54 g, 0.022 mole) added.
The reaction mixture is heated at 100° for 2 hours and left at room temperature about 18 hours. The reaction mixture is poured into 50 ml of 0.1N sodium hydroxide, washed with ether and the aqueous phase adjusted to pH 4 with cone. HG1 and then extracted with chloroform (3X). The extracts are combined and washed with.brine, dried, concentrated in a jotoevaparator and solvent removed under vacuum at about 50° to yield N-(p-trifluoromethylphenyl)valine.
B- A mixture of the acid of part A (1.84 g, 0.0071 mole) and potassium carbonate (1.95 g) in 10 ml of dry dimethylformamide is stirred at room temperature, under nitrogen, for 0.5 hours and then m-phenoxyben2yl bromide -3046787 (1.85 g, 0.0071 mole) is added at 0*. The reaction mixture is allowed to warm up to room temperature and is then stirred about 18 hours. The reaction is then worked up by pouring into ice-water and extracting with ether (3X). The ether extracts are combined and washed with water and brine, dried over calcium sulfate and evaporated under vacuum to yield the m-phenoxybenzyl ester of N-(p-trifluoromethylphenyl) valine. MS m/e 443 (M+, 5.9).
EXAMPLE 18 To a solution of a-bromoisovaleric acid (2 g, 0.110 mole) and 5 ml of methanol is added one. drop of phenolphthalein and then sufficient sodium hydroxide/methanol until adjusted to neutral pH. The solvent is then stripped off and p-chloroaniline (7 g, 0.055 mole) added. The mixture is melted in a 100* bath and stirred at 100* for 3 hours. The mixture is cooled and taken up in ether, and 10% aqueous sodium hydroxide is added. The aqueous pnase is acidified to pH 4 and extracted with ether. The ether extracts are combined and washed with brine, dried over sodium, sulfate and stripped to yield N-(p-chlorophenyl)valine.
Following the procedure of Example 1, part A, N—(p-chlorophenyl)valine is converted to the acid chloride and then reacted with m-phenoxybenzyl alcohol to yield the m-phenoxybenzyl ester of N-(p-chlorophenyl)valine.
EXAMPLE 19 Following the procedure of Example 17, N-(2-fluoro4-chlorophenyl)valine (0.79 g) is reacted with a-ethynyl-mphenoxybenzyl bromide (0.39 g) to yield the a-ethynyl-mphenoxyben2yl ester of N-(2-fluoro-4-chlorophenyl)valine, -3146787 MS m/e 451 (M+). N-(2-fluorO-4-chlorophenyl)valine is prepared from 2-fluoro-4-chloroaniline and α-bromoisovaleric acid using the procedure of Example 17.
EXAMPLE 20 Following the procedure of Example 5, m-phenoxybenzyl α-bromoisovalerate is reacted with each of the substituted phenyl amines in column XVIII to prepare the respective N-substituted valine in column XIX.
XVIII 4-chloro-3-methylaniline 4-bromo-3-methylaniline 3- bromo-4-methylaniline 3.4- dibromoaniline 3-bromo-4-chloroaniline 4- (t-butyl)aniline 4-nitro-3-trifluorome thylaniline 3.5- di(trifluoromethyl)aniline XIX m-Phenoxybenzyl ester of N- (4-chloro-3-methyIphenyl)valine N-(4-bromo-3-methyIphenyl) valine N—(3-bromo-4-methyIphenyl)valine N-(3,4-dibromophenyl)valine 25 N—(3-bromo-4-chlorophenyl)valine N-(4-t-butyIphenyl)valine N—(4-nitro-3-trifluoromethylphenyl)valine N-(3,5-ditrifluoromethyIphenyl)valine -3246787 EXAMPLE 21 Following the procedure of Example 1, each of m-(p-chlorophenoxy)benzyl alcohol, m-(p-methylphenoxy)benzyl alcohol, and m-(m-trifluoromethylphenoxy)benzyl alcohol is reacted with α-bromoisovaleric acid chloride to yield: m-(p-chlorophenoxy)benzyl a-bromoisovalerate; m-(p-methylphenoxy)benzyl α-bromoisovalerate; and m-(m-trifluoromethylphenoxy) benzyl α-bromoisovalerate. Each of the above α-bromo esters is reacted with p-methylaniline to yield: m-(p-chlorophenoxy)benzyl ester of N-(p-methylphenyl) valinet m-(p-methylphenoxy)benzyl ester of N-(p-methylphenyl)valine; and m-(m-trifluoromethylphenoxy)benzyl ester of N-(p-methylphenyl)valine.
EXAMPLE 22 To m-phenoxybenzyl α-bromoisovalerate (2 g, 0.0055 20 mole), 24a, is added 2,6-dimethylaniline (3.33 g, 0.0275 mole) followed by a catalytic amount of potassium iodide (20 mg).
The reaction mixture is heated at about 120° for 48 hours, and then poured into ice-water (20 ml) and 2N sulfuric acid (10 ml) and extracted with ether (3X 30 ml). The combined ether extracts are washed with water (2X 20 ml) until neutral and with brine (10 ml) followed by drying over calcium sulfate. The reaction product is concentrated under vacuum and isolated by preparative TLC to give m-phenoxybenzyl ester of N-(2,6dimethylphenyl)valine. MS m/e 403.2 (M+, 7.5). -3346787 EXAMPLE 23 i To m-phenoxybenzyl α-bromoisovalerate (2 g, 0.0055 mole), 24°, is added 2-methylaniline (2.95 g, 0.0275 mole) followed by a catalytic amount of potassium iodide (20 mg).
The reaction mixture is heated, 110-115°, for about 36 hours, and then poured into ice-water (30 ml) and 2N sulfuric acid (10 ml) and extracted with ether (3X 30 ml). The combined ether extracts are washed with water (2X 30 ml) until neutral and with brine (10 ml) followed by drying over calcium sulfate.
The reaction product is concentrated under vacuum, and isolated by preparative TLC to yield 3-phenoxybenzyl ester of N-(2methylphenyl)valine. MS m/e 389.2 (M+).
EXAMPLE 24 To α-bromoisovaleric acid (1.2 g, 0.00603 mole) in methanol (2 ml) at 5°, is added dropwise methanolic sodium hydroxide to the phenolphthalein end point. The sodium salt of the acid is isolated under vacuum, and to the acid salt is added 2,6-dimethylaniline (3.65 g, 0.03015 mole) and the slurry heated in a pressure vessel at about 150° for 12 hours.
Upon cooling, water (20 ml) is added to the reaction mixture and the excess 2,6-dimethylaniline extracted with ether (3X 20 ml). The aqueous base layer is acidified with 2N sulfuric acid to about pH 4 and the N-(2,6-dimethylphenyl)valine is extracted with ether (3X 20 ml). The combined ether layers are washed with water (2X 20 ml) until neutral and with brine (10 ml) followed by drying over calcium sulfate. The N-(2,6-dimethylphenyl)valine is isolated by concentration under vacuum.
To N-(2,6-dimethylphenyl)valine (1.07 g, 0.00486 mole) in THE:HMPT·(3 ml: 3 ml) at 24° is added m-phenoxybenzyl -344 6 787 bromide (1.28 g, 0.00486 mole) and potassium carbonate (0.670 g, 0.00486 mole), and the slurry is stirred at 24° for 16 hours.
The product is isolated by pouring the reaction mixture into ice-water (20 ml) and extracting with ether (3X 20 ml). The combined ether extracts are washed with water (2X 20 ml) and brine (10 ml) and dried over calcium sulfate. The product is concentrated under vacuum and purified by preparative TLC to give m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine, MS m/e 403.2 (M+).
EXAMPLE 25 Following the procedure of Example 17 or 24, 3-fluoro4-methylaniline is reacted with ct-bromoisovaleric acid to prepare N-(3-fluoro-4-methylphenyl)valine, which is reacted with α-ethynyl-m-phenoxybenzyl bromide to yield the a-ethynyl-mphenoxybenzyl ester of N-(3-fluoro-4-methylphenyl)valine, MS m/e 431 (M+).
N-(2-fluoro-4-methylphenyl)valine is prepared from α-bromoisovaleric acid and 2-fluoro-4-methylaniline and then reacted with α-ethynyl-m-phenoxybenzyl bromide to yield the α-ethynyl-m-phenoxybenzyl ester of N-(2-fluoro-4-methylphenyl) valine, MS m/e 431 (M+, 180).
EXAMPLE 26 To the m-phenoxybenzyl ester of N-(p-trifluoromethylphenyl)valine (1.57 g) in about 15 ml benzene, with stirring and under nitrogen, is added N-chlorosuocinimide (0.53 g). The reaction mixture is heated to reflux for about 2 hours. The reaction is cooled and partitioned between ether and water. Aqueous phase is back-extracted with ether. The combined -3546787 ether phases are washed with water and brine, dried over sodium sulfate, filtered and evaporated. The reaction product is put on preparative TLC plates and eluted using 10% ether/hexane to yield the m-phenoxybenzyl ester of N-(2-chloro-4-trifluoromethyl phenyl)valine, MS m/e 477.1 (M+) .
Following the above procedure, there is prepared the m-phenoxy-a-cyanobenzyl ester of N-(2-chloro-4-trifluoromethylphenyl) valine, MS m/e 486.3 (M+), from the m-phenoxy-acyanobenzyl ester of N-(p-trifluoromethylphenyl)valine.
EXAMPLE 27 To N-phenylvaline hydrochloride (0.1 mole) in etherTHF at 5° is added dimethylformamide (0.06 mole) followed by dropwise addition of thionylchloride (0.15 mole). The reaction is stirred at 24° for 2.5 hours. The acid chloride hydrochloride is isolated and then in THF-ether, at 5°, is added a-cyano-3-phenoxybenzyl alcohol (0.09 mole) followed by slow addition of pyridine (0.3 mole). The reaction mixture is stirred at 24° for 17 hours and the product is worked up as in Example 6 to yield the 3-phenoxy-a-oyanobenzyl ester of N-phenylvaline.
EXAMPLE 28 Into a mixture of 1.0 g of the m-phenoxybenzyl ester of N-(p-methylphenyl)valine and 10 ml of ether, with stirring and cooled in an ice bath, is bubbled hydrogen chloride gas for about 15 minutes. The reaction product is filtered, washed With ether and recrystallized from hot ethanol to yield the hydrogen chloride salt of the m-phenoxybenzyl ester of N-(p30 methylphenyl)valine, m.p. 151-153°. -3646787 Following the procedure of Example 6, 2-fluoro-4trifluoromethylaniline is reacted with a-cyano-m-phenoxybenzyl α-bromosiovalerate to yield the α-cyano-m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine, MS m/e 502.1 (M+).
EXAMPLE 29 To a solution of 15.8 g (0.1 mole) ethyl 3,3-dimethyl-2-oxo-butyrate [Rabjohn et al., J. Org. Chem. 35, 3726 (1970)] is added 12.7 g (0.1 mole) p-chloroaniline and a catalytic amount (0.2 g) of p-toluenesulfonio acid. The solution is heated under reflux and water removed with a Dean-Stark trap. After 5 hours heating, the solution is poured into ether and this fraction is washed with saturated sodium bicarbonate and saturated brine solutions, and then dried over calcium sulfate. Removal of solvent by rotoevaporation yields the desired imine ester.
O To a solution of 13.4 g (0.05 mole) imine ester in 100 ml methanol at 10° is added excess (2 g, 0.032 mole) sodium cyanoborohydride in portions. The pH of the solution is maintained at about pH 6 during the course of the reduction by adding concentrated sulfuric acid. After several hours, the reaction is stopped, most of the alcohol is removed by rotoevaporation, and the residue is poured into ether and water. The organic fraction is washed with saturated brine solution and dried over calcium sulfate. Removal of solvent by rotoevaporation gives ethyl 2-(p-chlorophenylamino)-3,3-dimethylbutyrate. -37. A solution of 2.7 g (0.01 mole) of the above ethyl amino ester and 0.4 g (0.01 mole) of sidum hydroxide in 17 ml ethanol and 3 ml water is stirred at toom temperature for 2 days. The alcohol and water are removed by rotoevaporation under high vacuum to give the sodium salt of 2-(p-chlorophenylamino)-3r3-dimethylbutyric acid. To the sodium salt is added 50 ml HMPT and 2.63 g (0.01 mole) of m-phenoxybenzyl bromide. After overnight stirring, the reaction is poured into water and ether-hexane (1:1). The organic phase is washed several times with water and then dried over calcium sulfate. Removal of solvent by rotoevaporation gives the 3-phenoxybenzyl ester of 2-(p-chlorophenylamino)-3,3-dimethylbutyric acid, MS m/e 423 (M+).
The process of this example is repeated using 0.1 15 mole of ethyl 3,3,3-trifluoro-2-oxo-propionate in place of ethyl 3,3-dimethyl-2-oxo-butyrate to give as the final product the 3-phenoxybenzyl ester of 2-(p-chlorophenylamino)-3,3,3•trifluoropropionic acid.
EXAMPLE 30 N-(4-chlorophenyl)valine is reacted with m-phenoxya-methylbenzyl bromide in THF/HMPT and potassium carbonate to yield the m-phenoxy-a-methylbenzyl ester of H-(4-chlorophenyl) valine, MS m/e 423 (M+). The m-phenoxy-a-methylbenzyl bromide is prepared from m-phenoxybenzaldehyde by reaction with methyllithium to the secondary alcohol which is brominated . using phosphorous tribromide.
EXAMPLE 31 A mixture of 10 g of 4-fluoronitrobenzene, 5 g of -3846787 valine and 10 g of sodium bicarbonate is dissolved in 200 ml of ethanol and 100 ml of water. The reaction mixture is refluxed for 3 hours and cooled. Excess 4-fluoronitrobenzene is removed by ether extraction and the aqueous phase is brought to pH 3 to 4 with hydrochloric acid. The oily precipitate is extracted with methylene chloride. After drying and removal of solvent, the residue is treated with 3 equivalents of sodium carbonate and 1 equivalent of m-phenoxybenzyl bromide in dimethylformamide as solvent. After stirring 24 hours the mixture is diluted with water and extracted with ether. The organic phase is washed with water, dried and the solvent removed. The crude ester is purified by preparative TLC to give the m-phenoxybenzyl ester of N~(p-nitrophenyl)valine.
EXAMPLE 32 To a solution of 1.51 g of N-phenylglycine in 10 ml of dry dimethylformamide is added 2.76 g of dry potassium carbonate and 1.04 g of 3,3-dimethyl-2-propenyl chloride.
The mixture is stirred overnight at room temperature and then diluted with water and extracted with ether. The ether extracts are combined, and washed with water, dried over magnesium sulfate and ether evaporated to give the 3,3-dimethyl2-propenyl ester of N-phenylglycine.
To a solution of 2.19 g of the ester prepared above in 20 ml of THE and 5 ml of HMPT is added a solution of 1.03 g of lithium diisopropylamide in THF (prepared in situ from 1.01 g of diisopropylamine and 6.25 ml of 1.6M butyl lithium) while maintaining temperature of about -60°. The reaction is allowed to reach -30°, then 1.08 g of trimethylsilyl chloride in 5 ml of THF is added at -30° and then stirring for 20 -3946787 minutes. The reaction is then cooled to -78° and an additional 1.Q3 g of lithium diisopropylamide in THF added. The reaction is stirred at -60° for 30 min. and 1.08 g of trimethylsilyl chloride is added at -60®. After an hour at -60° the reaction is allowed to reach room temperature and 1 hour thereafter the reaction mixture is brought to reflux for 30 minutes. The reaction is cooled and poured into 10 ml of 2N sodium hydroxide The mixture is stirred for 20 minutes at room temperature and then extracted with ether. 'The aqueous phase is acidified to pH 3-4 and re-extracted with ether. The ether extracts are combined and washed with water, dried and evaporated to give 2-phenylamino-3,3-dimethyl-4-pentenoic acid which is esterified using m-phenoxybenzyl bromide by procedures hereinabove to yield m-phenoxybenzyl 2-phenylamino-3,3-dimethyl-4-pentenoate [m-phenoxyben2yl 2-phenylamino-2-(2-methyl-3-buten-2-yl)acetate].
EXAMPLE 33 A solution of 2 g of «-bromoisovaleric acid and 10 ml of methanol is titrated, at 0° to the phenolphthalein end point with sodium hydroxide/methanol solution. The solvent is then removed, 6 ml of dimethylformamide and 2.97 g of p-acetylaniline added. The resulting clear reaction mixture is heated at 100° for 3 hours and then stirred overnight at room temperature. The reaction is poured into 50 ml of 0.1N sodium hydroxide and washed with ether. The aqueous phase is acidified to pH 4 with concentrated hydrochloric acid and extracted 3X with chloroform. The chloroform extracts are dried and concentrated. The concentrate is taken up with 0.1N sodium hydroxide and washed with ether. The aqueous -4046787 phase is acidified and worked up as before to give 1.0 g of N-(p-acetylphenyl)valine which is reacted with 1.05 g of m-phenoxybenzyl bromide in dimethylformamide with potassium carbonate by procedures hereinabove to yield the m-phenoxybenzyl ester of N-(p-acetylphenyl)valine, MS m/e 417.1 (M+).
Following the above procedure, N-(p-cyanophenyl)valine is prepared from 0.011 mole of α-bromoisovaleric acid and 0.022 mole of p-cyanoaniline. Then 0.01 mole of N-(p-cyanophenyl)valine is esterified using 0.01 mole of m-phenoxybenzyl bromide and 0.020 mole of potassium carbonate in dimethylformamide to prepare the m-phenoxybenzyl ester of N-(p-cyanophenyl) valine, MS m/e 400.1 (M+).
EXAMPLE 34 The process of Example 29 is repeated using 0.1 mole of ethyl 3,3,3-trichloro-2-oxopropionate in place of ethyl 3,3-dimethyl-2-oxo-butyrate to give as the final product the 3-phenoxybenzyl ester of 2-(p-chlorophenylamino)-3,3,3-trichloropropionic acid.
EXAMPLE 35 A 100 ml flask is flushed with nitrogen and to it is added 25 ml of a 1M THF solution of lithium N-isopropylcyclohexylamide (0.025 mole) followed by HMPT (5 ml). The flask is cooled to -78° and 7.1 g (0.025 mole) of m-phenoxybenzyl 3methyl-2-butenoate in THF (25 ml) is added dropwise over 5 minutes. After the addition the mixture is stirred at -20° for 1 hour. This cold solution is then added dropwise to 1·1 equivalent of bromine in THF at -78°. After a further 1 hour at -78°, 5 ml of concentrated hydrochloric acid is added and the -4146787 mixture allowed to come to RT and poured into ether plus cold aqueous hydrochloric acid. The ether layer is washed with water and brine and dried over calcium sulfate. Removal of the solvent gives m-phenoxybenzyl 2-bromo-3-methyl-3-butenoate, which is reacted with p-methylaniline by the process of Example 5 to give m-phenoxybenzyl ester of 2-(p-methylphenylamino)-3methyl-3-butenoate.
EXAMPLE 36 Following the procedure of Example 1, the m-phenoxybenzyl ester of α-bromoisovaleric acid is reacted with 3,4methylenedioxyaniline (3 equivalents) at about 75° for about 14 hours to yield the m-phenoxybenzyl ester of N-(3,4-methylenedioxyphenyl) valine, MS m/e 419 (M+, 13.2), 192 (100).
Following the above procedure, the m-phenoxybenzyl ester of N-(3-methoxyphenyl)valine, MS m/e 405 (M+, 4.1), 178 (100), is prepared from m-anisidine.
EXAMPLE 37 A mixture of N-chlorosucoinimide (1.17 mmole),' m-phenoxybenzyl ester of N-(p-methoxyphenyl)valine (1.23 mmole) and benzene (20 ml) is refluxed under nitrogen for about 60 . hours.. The reaction is worked up in water/ether. The ether layer is washed with water and brine and dried over sodium sulfate. The crude product is purified by preparatory TLC eluting with 15% ether/hexane to give the m-phenoxybenzyl ester of N-(2-chloro-4-methoxyphenyl)valine, MS m/e 439 (M+, 7.4), 212 (100). -4246787 EXAMPLE 38 A solution of α-bromoisovaleric acid (8.17 mmole) in methanol is titrated to the phenophthalein end point using sodium methoxide. The solvent is removed by rotoevaporation and then there is added potassium carbonate (1.69 g), 2-fluoro4-methylaniline (16.38 mmole) and 3 ml HMPT. The reaction is heated at 60° for about 5 hours and then worked up with 5% sodium hydroxide/ether and washed with water (3X). The basic layer is acidified and extracted with ether, washed with water and brine, dried over sodium sulfate and rotoevaporated to yield a-(2-fluoro-4-methylphenylamino)isovaleric acid. (2-Fluoro-4-methylaniline is prepared from 3-fluoro-4-nitrotoluene in a Parr bottle using platinum oxide and hydrogen in ethanol.) To a mixture of 5.15 mmole of a-(2-fluoro-4-methylphenylamino)isovaleric acid, potassium carbonate (6.44 mmole), ml of HMPT and 3 ml of THF, stirred, is added 5.13 mmole of m-phenoxybenzyl bromide; The reaction is stirred overnight at RT. The reaction is poured into 5% sodium hydroxide/ether, extracted with water (2X) and then washed with water (2X), dried over sodium sulfate and rotoevaporated under vacuum.
The crude product is subjected to preparatory TLC eluting with 10% ether/hexane to give m-phenoxybenzyl ester of N-(2-fluoro4-methylphenyl)valine. nmr (CDC13) δ 0.98 [d, 3, J - 7 HZ, CH(CH3)2], 1.02 [d, 3, J = 7 Hz, CH(CH3)2), 2.22 (s, 3, FyryC^), and 5.13 ppm (s, 2, ArCH2O). IR (neat))1734 cm1 (C=0). -4346787 Following the above procedure, N-(4-tert-butylphenyl) valine is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N- (4-tert-butylpheny!) valine .5 nmr (CDC13) 5 centered at 0.99 [d, 6, J = 7 Hz, (CH3)2CH), 1.28 Is, 9, (CH3)3C-Ar], 3.93 (m, 2, NH and HN-CH-C-), and 5.11 ppm (s,.2, ArCHjO) . IR (film) 1743 cm-^ (C=O) .
The procedure of this example is used to prepare N-(3-chloro-4-fluorophenyl)valine and N-(3-fluoro-4-methyΙΙΟ phenyl)valine, each of which is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(3-chloro-4fluorophenyl)valine [MS m/e 427 (M+, 3.2), 200 (100)] and the m-phenoxybenzyl ester of N-(3-fluoro-4-methylphenyl)valinenmr (CDC13) 5 centered at 0.97 [d, 6, J = 7 Hz, CH(CH3)2J, 2.11 (d, 3, J = 2 Hz, xi-yCH-j) , and 5.10 ppm (s, 2, ArCH2O). IR (neat n; N'^'F- 1732 cm (C=O).
EXAMPLE 39 A mixture of 5 g of p-trifluoromethylaniline, 2.25 g of α-bromoisovaleric acid'and 2.0 g of potassium carbonate is heated at 10.0° for 1 hour. After 1.5 hour, 5 ml of HMPT is added and the mixture heated at 100° for 15 hr. The mixture is then poured into water and potassium carbonate added to about pH 11. The mixture is washed with ether, methylene chloride and the aqueous phase acidified to about pH 3 and washed with ether and concentrated. The residue is recrystallized from hexane/ether to yield N-(4-trifluoromethylpheny1)valine, which is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(4-triflurormethylpheny D'valine. MS m/e 443 (M+, 5.9). -4446787 The acid, N-(4-trifluoromethylphenyl)valine, is reacted, at RT in DMF/THF and potassium carbonate, with m-phenoxy-aethynylbenzyl bromide to yield the ra-phenoxy-a-ethynylbenzyl ester of N-(4-trifluoromethylphenyl)valine. MS m/e 467 (MT, 1.3), 216 (100).
The acid, N-(4-fluorophenyl)valine is prepared as above from 4-fluoroaniline and ct-bromoisovaleric acid and then reacted with m-phenoxybenzyl bromide, as above, to yield the m-phenoxybenzyl ester of N-(4-fluorophenyl)valine. nmr (CDCl-j) δ centered at 0.90 [m, 6, (CH^CH], 2.0 [m, 1, (CHjJjCH), 3.80 (m, 2, NH and'N-CH-C-), and 5.15 ppm (s, 2, ArCHjO). IR (film) 3400 an-1 (NH) .
N-(3-fluorophenyl)valine (prepared by reacting α-bromoisovaleric acid and 3-fluoroaniline at 140", under nitrogen, for 3.5 hr) is reacted with m-phenoxybenzyl bromide in HMPT/THF and potassium carbonate at RT to yield the m-phenoxybenzyl ester of N-(3-fluorophenyl)valine. MS m/e 393 (M+, 2), 166 (100).
N-(2-chloro-4-methylphenyl)valine is prepared as above from α-bromoisovaleric acid and 2-chloro~4-methylaniline and then reacted with m-phenoxybenzyl bromide, as above, to yield the m-phenoxybenzyl ester of N-(2-chloro-4-methylphenyl)valine. MS m/e 423 (M+, 4), 196 (100).
Similarly, there is prepared the m-phenoxybenzyl ester of N-(3-nitrophenyl)valine from N-(3-nitrophenyl)valine and m-phenoxybenzyl bromide. MS m/e 420 (M+, 4), 193 (100).
EXAMPLE 40 To 1.21 mmole of triethyl oxoniupi tetrafluoroborate 30 in about 5 ml methylene chloride under nitrogen is added 1.05 -45. mmole of the m-phenoxybenzyl ester of H-(4-chlorophenyl)valine.
The reaction is stirred at RT overnight and then poured into ether/water. The organic phase is washed with water and brine, dried over calcium.sulfate, and solvent removed. The crude product is applied to preparatory TIC eluting with 20% ether/hexane, to give the m-phenoxybenzyl ester N-ethyl,N-(4-chlorophenyl)valine. MS m/e 437 (M+, 3), 210 (100). t < EXAMPLE 41 N-(4-fluoro-2-methylphenyl)valine prepared from 4-fluoro-2-methylaniline and α-bromoisovaleric acid is reacted with m-phenoxybenzyl bromide-as in Example 38 to give the m-phenoxybenzyl ester of tT-(4-f luoro-2-methyIphenyl) valine.
MS m/e 407.2 (M+, 4.5), 180 (100).
EXAMPLE 42 To a mixture of 0.47 g of N-(4-methylphenyl)valine, 'ml of HMP.T, and 0.36 g of potassium carbonate, with stirring, is added 0.82 g of m-(3,4rdichlorophenoxy)benzyl bromide. The reaction mixture is stirred overnight at RT and then worked up by partition between water/ether. The aqueous phase is extracted with ether (2X) and then the combined ether phases are washed with, water and brine, dried over sodium sulfate, filtered and evaporated. The concentrate is subjected to preparatory TLC eluting with 10% ether/hexane to yield the m-(3,4-dichlorophenoxy)benzyl ester of N-(4-methylphenyl)valine. MS m/e 459.1 (M+, 2.4) , 162.1 (100) .
The m-phenoxybenzyl ester of N-(2-nitrophenyl)valine, MS m/e 420.1 (M+, 2.7), 193 (100), is prepared from the reaction -4646787 of m-phenoxybenzyl bromide and N-(2-nitrophenyl)valine as above. N-(4-methylphenyl)valine is reacted with m-phenoxya-ethynylbenzyl bromide in DMF/THF and potassium carbonate at RT, as above, to give the m-phenoxy-a-ethynylbenzyl aster of of N-(4-methylphenyl)valine. MS m/e 413.1 (M+, 3.8), 162.1 C=CH (100) .
CH N-(3,4,5-triohlorophenyl)valine, prepared from 3,4,5trichloroaniline and α-faromoisovaleric acid, is reacted with m-phenoxybenzyl bromide in HMPT/THF and potassium carbonate at ET to yield the m-phenoxybenzyl ester of N-(3,4,5-trichlorophenyl) valine . MS m/e 477.1 (M+, 9.8), 250 (100).
EXAMPLE 43 A mixture of 3,5-dimethoxyaniline (2.1 g), the mphenoxybenzyl ester of α-bromoisovaleric acid (1.0 g), potassium iodide (72.9 mg) and 5 ml of HMPT is heated overnight at 70-80®. The reaction is then worked up by partition between 100 ml of 2N sulfuric acid and 100 ml of ether. The aqueous phase is extracted with ether and then the combined ether phases are washed with 2N sulfuric acid, saturated sodium bicarbonate and brine, dried over potassium carbonate, filtered and evaporated.
The residue is subjected to prep. TLC eluting with ether/hexane to yield the m-phenoxybenzyl ester of N-(3,5-dimethoxyphenyl)valine. MS m/e 435.2 (M+, 11.7), 208.1 (100).
By the above procedure, 3,4,5-trimethoxyaniline is reacted with m-phenoxyben2yl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(3,4,5-trimethoxyphenyl)valine. -474 6 787 MS m/e 465.2 (M+, 39.0), 182.9 (100).
Following the procedures of Example 42 , tr- (4-chlorophenyl)valine is reacted with m-benzylbenzyl bromide to yield the m-benzylbenzyl ester of N-(4-chlorophenyl)valine. MS m/e 407.1 (M+, 6.2), 182 (100).
EXAMPLE 44 To m-phenoxyben2yl 3-methyl-2-butenoate (5.80 mmole) and carbon tetrachloride (30 ml), under nitrogen, is slowly added bromine (5.99 mmole) in carbon tetrachloride with the reaction flask in an ice-bath. After about 3 hr, the reaction is worked up by partition between water/ether. The aqueous phase is extracted with ether and then the combined ether phases are washed with water and brine, dried over potassium carbonate, filtered and evaporated to yield m-phenoxybenzyl 2,3-dibromo-3-methylbutanoate.
A mixture of the above dibromo ester (4.1 mmole), 4-methylaniline (12.6 mmole), triethylamine (8.6 mmole), THF (20 ml) and HMPT (2 ml) is heated at 50° under nitrogen. After 9 days, the reaction is worked up by partition between ether/2N HCl. The aqueous phase is extracted with ether and then the combined ether phases are washed with 2N HCl and brine, dried over potassium carbonate, filtered and evaporated. The residue is subjected to prep. TLC eluting with 10% ether/hexane to yield the m-phenoxybenzyl ester of a-(4-methylphenylamino) 3-methyl-3-butenoic acid. MS m/e 387.2 (M+, 2.7), 160 (100).
EXAMPLE 45 . . To ti-(4-chlorophenyl) isoleucine '(0.57 g) in about 5 ml of HMPT is added potassium carbonate (0.54 g) and then -4846787 m-phenoxybenzyl bromide (1.09 g). The reaction mixture is stirred overnight at BT. The reaction is worked up by partition between water/ether. The aqueous phase is extracted with ether and then the combined ether phases are washed with water and brine, dried over potassium carbonate, filtered and evaporated.
The residue is subjected to prep. TLC eluting with 10% ether/hexane to yield the m-phenoxybenzyl ester of N-(4-chlorophenyl)isoleucine. MS m/e 423 (M+, 3.7), 196 (100).
N- (4-chlorophenyl)isoleucine is prepared by the 10 reaction of 4-chloroaniline with the sodium salt of a-bromo-3methylpentanoic acid neat at 100°.
By the above procedure, m-phenoxybenzyl bromide is reacted with N-(4-methylphenyl)isoleucine to prepare the m-phenoxybenzyl ester of N-(4-methylphenyl)isoleucine. MS m/e 403.3 (M+, 3.3), 176.1 (100).
EXAMPLE 46 N-(4-methylphenyl)valine is reacted, with m-(4-methoxyphenoxy)benzyl bromide in THF/HMPT and potassium carbonate at BT overnight to yield the-m-(4-methoxyphenoxy) benzyl ester of N-(4-methylphenyl)valine. IR (film) 3380 cm~^ (NH) and 1735 cm (C-O).
EXAMPLE 47 To the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine (1.19 mmole) in ether (4.5 ml), under nitrogen, is added dimethylaminopyridine (4.25 mmole) which is cooled in an ice-bath and then trichloroacetyl chloride (3.58 mmole) in ether added slowly. The reaction mixture is heated at 40° for 3 days. The reaction is worked up with ether/water. The aqueous phase is extracted -49467 87 with ether and then the combined ether phases are washed with ‘ ' water and brine and dried over sodium sulfate. The residue is subjected to prep. TLC eluting with 10% ether/hexane to yield the m-phenoxybenzyl ester of N-trichloroacetyl,N-(4-chloro5 phenyl)valine. MS m/e 553 (M+, 1.8), 183 (100).
- EXAMPLE 48 Following the procedure of Example 47, the m-phenoxybenzyl ester of M-acetylformyI,M-(4-chlorophenyl)valine [MS m/e 479 (M+, 0.5), 183 (100)] is prepared by the reaction of the acid chloride of pyruvic acid with the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine· EXAMPLE 49 Following the procedure of Example 42, H-(4-chlorophenyl) valine is reacted with m-(3,4-dichlorophenoxy)benzyl bromide to yield the m-(3,4-dichlorophenoxy)benzyl ester of N-(4-chlorophenyl) valine. MS m/e 477 (M+, 2.1), 182 (100). .20 EXAMPLE 50 To the m-phenoxybenzyl ester of N-(4-methoxyphenyl)valine (0.89 mmol) in ether is added trifluoroacetic anhydride (4.46 mmol), under nitrogen. The reaction mixture is stirred for 2.5 hr and then worked up with ether/watar. The combined ether layers are washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated to yield the m-phenoxybenzyl ester of N-trifluoroacetyl,N-(4-methoxyphenyl)valine. MS m/e 501 (M+, 22.5), 183 (100). -5046787 EXAMPLE 51 A mixture of the m-phenoxybenzyl ester of N-(4chlorophenyl)valine (1.22 mmole), acetic formic anhydride in acetic acid (23.8 mmole, 2.1 g) and formic acid (1.5 ml) is stirred overnight at RT under nitrogen. The reaction product is concentrated and then subjected to prep. TLC eluting with 20% ethylacetate/hexane to yield the m-phenoxybenzyl ester of N-formyl,N-(4-chlorophenyl)valine, MS m/e 437 (M+, 8.1), 182 (100).
EXAMPLE 52 Following the procedure of Example 50, trifluoroacetic anhydride and the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine are reacted to yield the m-phenoxybenzyl ester of Ntrifluoroacetyl,N-(4-chlorophenyl)valine, MS m/e 505 (M+, 14.9), 278 (100).
I Following the procedure of, for example, Example 42, α-ethynyl-m-phenoxybenzyl bromide and N-(4-chlorophenyl)valine are reacted to yield the α-ethynyl-m-phenoxybenzyl ester of N-(4-chlorophenyl)valine, MS m/e 433 (M+, 2.2), 182 (100).
EXAMPLE 53 To the m-phenoxybenzyl ester of N-phenyl valine (1.2 mmole) is added 12.5% phosgene in benzene (2.3 mmole), cooled in an ice bath, and then dimethylaminopyridine (1.22 mmole). The reaction mixture is stirred at RT for 3 days. Then one ml of benzene, 0.15 g of dimethylaminopyridine and 2 ml of phosgene are added and the reaction stirred overnight at RT.
The reaction is worked up using chloroform/water. The chloroform layer is washed with dilute sulfuric acid, water and brine, -5146787 : . I dried over sodium sulfate and filtered. The solvent is removed by rotoevaporation to yield the m-phenoxybenzyl ester of N-chloroformyl,N-pheny1 valine.
A mixture of 0.89 mmole of the foregoing ester, one 5 ml of pyridine and methanol (0.91 mmole) is stirred at RT for days. The reaction is then worked up using dilute HCl/ether. The ether layer is washed with aqueous HCl, water and brine, dried over sodium sulfate and filtered. Solvent is removed and residue plated on prep. TLC plate eluting with 8%, 20% ether-hexane to yield the m-phenoxybenzyl ester of N-methoxycarbonyl,N-pheny1 valine, MS m/e 433 (M+, 6.7), 205 (100).
EXAMPLE 54 N-(2-chloro-4-cyanophenyl)valine and m-phenoxybenzyl 15 bromide in THF/HMPT with potassium carbonate are reacted using the procedure of Example 42 to prepare the m-phenoxybenzyl ester of N-(2-chloro-4-cyanophenyl)valine, MS m/e 434 (M+, 3.7), 207 (100). N-(2-chloro-4-cyanophenyl)valine is prepared by the reaction of 2-chloro-4-cyanoaniline with a-bromoiso20 valeric acid using the process of, for example, Example 18.
Similarly, there is prepared N-(2,4-difluorophenyl)valine from 2,4-difluoroaniline and α-bromoisovaleric acid.
The N—(2,4—difluorophenyl)valine is esterified using m-phenoxybenzyl bromide to prepare the m-phenoxybenzyl ester of N-(2,425 difluorophenyl)valine, MS m/e 411 (M+, 3.5), 184 (100).
EXAMPLE 55’ N-(2-fluoro-4-chlorophenyl)valine and m-phenoxybenzyl bromide are reacted using the process of Example 42 to yield the m-phenoxybenzyl ester of N-(2—fluoro-4-chlorophenyl)valine. -5246787 MS m/e 427.1 (M+, 4.1), 200 (100). N-(2-fluoro-4-chlorophenyl)valine is prepared by heating the potassium salt of a-bromoisovaleric acid and 2-fluoro-4-chloroaniline neat at 130° for about 2 hours.
Similarly, there is prepared N-(3-methyl-4-fluorophenyl)valine which is esterified using m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(3-methyl-4-fluorophenyl)valine, MS m/e 407.3 (M+, 0.3), 180 (100).
In the same way, there is prepared N-(3-methyl-6fluorophenyl)valine and N-(3-fluoro-6-methyIphenyl)valine, each of which is esterified using m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(3-methyl-6-fluorophenyl)valine [MS m/e 407.3 (M+, 4.3), 180 (100)] and the m-phenoxybenzyl ester of N-(3-fluoro-6-methyIphenyl)valine [MS m/e 407.3 (M+, 3.9), 180 (100)].
EXAMPLE 56 To a mixture of the a-cyano-m-phenoxybenzyl ester of N-(4-chlorophenyl)valine (0.79 g) and about 20 ml of dry DMP is added about one ml of triethanolamine at RT. Into the mixture is slowly bubbled HjS gas for about 3 hours. The reaction is then stirred overnight. The reaction is worked up by partition with ether/water. The organic phase is washed with brine (3X), dried over sodium sulfate, filtered and evaporated. The residue is plated on a prep. TLC plate eluting with 20% ethyl acetate/hexane to yield the desired thioamide, MS m/e -5346787 . EXAMPLE 57 N-(2-cyano-4-chlorophenyl)valine is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(2-cyano-4-chlorophenyl)valine using the procedure of Example 42. MS m/e 434.1 (M+, 3.5).
Similarly, there is prepared the a-cyano-m-phenoxybenzyl ester of N-(2-methylphenyl)valine, MS m/e 414.1 (M+, .8), from α-cyano-m-phenoxybenzyl bromide and N-(2-methylphenyl ) valine .
Likewise, there is prepared the m-phenoxybenzyl ester of N-(2-methyl-4-chlorophenyl)valine, MS m/e 423.1 (M+, 16.9), from m-phenoxybenzyl bromide and N-(2-methyl-4-chlorophenyl)valine.
In the same way, N-(pentafluorophenyl)valine is reacted With m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(pentafluorophenyl)valine, MS m/e 465 (M+, 4.2).
EXAMPLE 58 m-PhenOxybenzyl bromide is reacted with each of N—(2,4-dimethoxyphenyl)valine and N-(2-methyl-6-chlorophenyl)valine following the procedure of Example 42 to yield the m-phenoxybenzyl ester of N-(2,4-dimethoxyphenyl)valine, MS m/e 435.2 (M+, 12.4), and the m-phenoxybenzyl ester of N-(2-methyl6-chlorophenyl)valine, MS m/e 423.1 (M+, 3.7).
EXAMPLE 59 A mixture -of 0.5 g of the m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine, 0.21 g of N-chlorosuccinimide and 3 ml of benzene is heated at reflux for 2 hours. The reaction is diluted with hexane, washed with water (2X) and -5446787 solvent stripped to give the crude product. To the crude product is added 0.1 g of N-chlorosuccinimide and 3 ml benzene. The mixture is heated at reflux for 30 min and then allowed to stand overnight at RT. The reaction is worked up by diluting with hexane, washing with water and stripping off solvent to yield the m-phenoxybenzyl ester of N-(2,6-dimethyl-4-chlorophenyl)valine, MS m/e 437.1 (M+, 15.3).
EXAMPLE 60 N-(4-bromopheny1)valine, prepared from 4-bromoaniline and α-bromoisovaleric acid, is esterified using m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(4-bromophenyl)valine, MS m/e 454 (M+).
The sodium salt of α-bromoisovaleric acid is reacted with p-ethylaminobenzoate, neat, at 140° for 3 hr to yield N-(4-ethoxycarbonylphenyl)valine, which is reacted with mphenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(4-ethoxycarbonylphenyl)valine, MS m/e 447 (M+).
The m-phenoxybenzyl ester of N-(3-trifluoromethyl20 phenyl)valine, MS m/e 443 (M+), is prepared from N-(3-trifluoromethy lpheny1)valine and m-phenoxybenzyl bromide. The reaction of 3-trifluoromethylaniline with the sodium salt of a-bromoisovaleric acid provides the starting material.
Each of N-{3,4-dimethylphenyl)valine, N-(3-methyl25 phenyl)valine, N-(2,4,6-trimethylphenyl)valine, N-(2-chloro5-trifluoromethylphenyl)valine and N-(2,6-difluoro-4-chlorophenyl)valine is esterified using m-phenoxybenzyl bromide with potassium carbonate in THE/HMPT at RT to yield the respective ester below. -5546787 The m-phenoxybenzyl ester of . N-(3,4-dimethylphenyl)valine, MS m/e 403.2 (M+) , N-(3-methylphenyl)valine, MS m/e 389.2 (M+), N-(2,4,6-trimethylphenyl)valine, MS m/e 417.1 (M+), N-(2-chloro-5-trifluoromethylphenyl)valine, MS m/e 477 (M+), and 4.
N—(2,6—difluoro—4—chlorophenyl)valine, MS m/e 445.1 (M ) The starting material is prepared by the reaction of the sodium salt of α-bromoisovaleric acid with each of f 3,4-dimethylaniline, 3-methylaniline, 2,4,6-trimethylaniline, 3-chloro-5-trifluoromethylaniline and 2,6-difluoro-4-chloroaniline according to the procedure of Example 18.
Following the procedure of Example 1, each of 4-nbutylaniline and 4-cyclopropylaniline is reacted with m-phenoxy15 benzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(4-n-butylphenyl)valine, MS m/e 431.2 (M+), and the m-phenoxybenzyl ester of N-(4-cyclopropylphenyl)valine, MS m/e 415.1 (M+) .
Each of the m-phenoxybenzyl ester of N-(4-chloro20 phenyl)valine and N-(4-methylphenyl)valine is methylated using the procedure of Example 2 to yield the m-phenoxybenzyl ester of N-methyl,N-(4-chlorophenyl)valine, MS m/e 423 (M+), and the m-phenoxybenzyl ester of N-methyl,N-(4-methylphenyl)valine, MS m/e 403.2 . (M+).
EXAMPLE 61 To a mixture of 10 g of ethyl crotonate, 40 ml of dioxane and 60 ml of water, at 0°, is sl.owly added 15 g of N-bromosuccinimide. After addition is complete, the reaction 3.0 is allowed to stand at RT for 17 hr with stirring. The -5646787 reaction Is taken up in ether, washed with water and saturated sodium sulfite, dried over magnesium sulfate and evaporated under reduced pressure to yield ethyl 2-bromo-3-hydroxybutanoate.
To a mixture of ethyl 2-bromo-3-hydroxybutanoate (10 g) and 15 ml of HMPT is added 13.2 g of aniline. The reaction is stirred at RT for 3 days and then taken up in ether followed by washing with dilute sulfuric acid, pH 3, and water. The ether phase is dried over magnesium sulfate and evaporated to yield ethyl 2-phenylamino-3-hydroxybutanoate, which is saponified using 1.6 g of sodium hydroxide, 40 ml of methanol and 20 ml of water with stirring overnight at RT. The acid 2- phenylamino-3-hydroxybutanoic acid (3.0 g) is reacted with m-phenoxybenzyl bromide (3.4 g) in HMPT (20 ml) and potassium carbonate (2.12 g) at 35° for a few hours and worked up using ether/water to yield the m-phenoxybenzyl ester of 2-phenylamino3- hydroxybutanoic acid.
To a solution of N-chlorosuccinimide (1.24 g) and dry THF (60 ml), stirring at RT, is slowly added triphenylphosphine (2.43 g) in 50 ml of THF. Then the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoate (3.5 g) in 30 ml of THF is added slowly. The reaction mixture is stirred overnight. The reaction is then concentrated under reduced pressure. The residue (oil) is taken up in ether, washed with water, dried over magnesium sulfate and evaporated to yield the m-phenoxybenzyl ester of 2-phenylamino-3-chloro-butanoic acid, MS m/e 395 (M+).
The above prepared ester is methylated using the procedure of Example 2 to yield m-phenoxybenzyl 2-(methy1,phenylamino) -3-chlorobutanoate, MS m/e 409 (M+). -5746 7 87 EXAMPLE 62 I A mixture of 0.5 g of m-phenoxybenzyl 2-ΟΧΟ-3methylbutanoate, 0.39 g of 2,4,6-trichloroaniline, 0.02 g of p-toluenesulfonylacetate and 10 ml of benzene is heated to reflux for about 5.5 hr. A Dean-Stark trap is used to remove water. The reaction is worked by pouring into ether/sodium bicarbonate solution. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated. To the reaction product (0.79 g) is added 3 ml of methanol, 1 ml of thf and 0.19 g of NaCHBH^. The reaction mixture is stirred at RT and then adjusted to pH 3 to 4 with concentrated sulfuric acid. Stirring at RT is continued overnight. The reaction is worked up as before using ether/sodium bicarbonate solution and subjected to prep. TLC eluting with 20% ether/hexane to yield the m-phenoxybenzyl ester of N-(2,4,6-trichlorophenyl)valine, MS m/e 477 (M+).
N-(2,4-dichlorophenyl)valine, prepared from 2,4-dichloroaniline and sodium salt of α-bromoisovaleric acid, is - reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(2,4-dichlorophenyl)valine, MS m/e 443 (M+). i Following the procedure of Example 6, a-cyano-mphenoxybenzyl α-bromoisovalerate is reacted with each of 4-chloro aniline, 4-methoxyaniline and 4-methylaniline to prepare the α-cyano-m-phenoxybenzyl ester of N-(4-chlorophenyl)valine, MS m/e 434.1 (M+), N-(4-methoxyphenyl)valine, MS m/e 430.1 (M+), and N-(4-methylphenyl)valine, MS m/e 414.2 (M+).
The α-cyano-m-phenoxybenzyl ester of N- (4-chlorophenyl)valine is reacted with methyl iodide using the procedure of Example 2 to yield the α-cyano-m-phenoxybenzyl ester of -5846787 N-methyl,N-(4-chlorophenyl)valine, MS m/e 448.1 (M+).
N-(2,3-dichlorophenyl)valine, prepared from 2,3-dichloroaniline and sodium salt of α-bromoisovaleric acid, is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(2,3-dichlorophenyl)valine, MS m/e 443 (M+).
EXAMPLE 63 Following the procedure of Example 1, m-phenoxybenzyl α-bromoisovalerate is reacted with each of 4-ethylaniline and 4-isopropylaniline to yield the m-phenoxybenzyl ester of N-(4ethylphenyl)valine, MS m/e 403.2 (M+), and N-(4-isopropylphenyl)valine, MS m/e 417.2 (M+).
Following the procedure of Example 18, m-phenoxybenzyl bromide is reacted with each of N-(4-nitrophenyl)valine and N-(2,6-dichlorophenyl)valine to yield the respective m-phenoxybenzyl ester of N-(4-nitrophenyl)valine, MS m/e 420.1 (M+), and * + N-(2,6-dichlorophenyl)valine, MS m/e 443 (M ).
EXAMPLE 64 Following the procedure of Example 1, m-phenoxybenzyl α-bromoisovalexate is reacted with 3-chloroaniline to yield the m-phenoxybenzyl ester of N-(3-chlorophenyl)valine, MS m/e 409.2 (M+).
Following the procedure of Example 18, m-phenoxybenzyl bromide is reacted with each of N-(3-trifluoromethyl-4-chlorophenyl)valine, N-(2-chlorophenyl)valine, and N-(2,6-difluorophenyl) valine to yield the respective ester - the m-phenoxybenzyl ester of N-(3-trifluoromethyl~4-chlorophenyl)valine, MS m/e 477.1 (M+), -5946787 -. N-(2-chlorophenyl)valine, MS m/e 409 (M+) , and N-(2,6-difluorophenyl)valine, MS m/e 411.1 (M+) , N-(4-t-butylphenyl)valine is reacted with benzyl bromide using the procedure of Example 18 to yield the benzyl 5 ester of N-(4-t-butylphenyl)valine, MS m/e 431 (M+).
Following the procedure of Example 24, N-(4-chlorophenyl) valine is esterified using each of 4-allylbenzyl bromide m- (3-trifluoromethylphenoxy)benzyl bromide, m-(4-chlorophenoxy) benzyl bromide, m-(4-methylphenoxy)benzyl bromide, m-(4-methoxy phenoxy)benzyl bromide, and m-(4-t-butylphenoxy)benzyl bromide to yield the respective esters — the 4-allylbenzyl ester of N-(4-chlorophenyl)valine, MS m/e 357.1 (M+); the m-(3-trifluoro methylphenoxy)benzyl ester of K-(4-chlorophenyl)valine, MS m/e 477 (M+); the m-(4-chlorOphenoxy)benzyl ester of N-(4-chloro15 phenyl)valine, MS m/e 443 (M+); the m-(4-methylphenoxy)benzyl ester of N-(4-chlorophenyl)valine, MS m/e 423 (M+); the m-(4methoxyphenoxy)benzyl ester of N-(*)-chlorophenyl) valine, MS m/e 439 (M+); and the m-(4-t-butylphenoxy)benzyl ester of N-(4-chlorophenyl)valine, MS m/e 465.2 (M+).
Following the procedure of Example 42, N-(4-methy1phenyl)valine is reacted with each of 4-allylbenzyl bromide, m-(3-trifluoromethylphenoxy)benzyl bromide, m-(4-methylphenoxy) benzyl bromide, m-(4-chlorophenoxy)benzyl bromide and m-(4-tbuty lphenoxy) benzyl bromide to yield the respective esters — the 4-allylbenzyl ester of N-(4-methylphenyl)valine, MS m/e 337.1 (M+); the m-(3-trifluoromethylphenoxy)benzyl ester of N-(4-methylphenyl)valine, MS m/e 457.1 (M+); the m-(4-methy1phenoxy)benzyl ester of N-(4-methylphenyl)valine, MS m/e 403.2 (M+); the m-(4-chlorophenoxy)benzyl ester of N-(4-methy130 phenyl)valine, MS m/e 423 (M+); and the m-(4-t-butylphenoxy) benzyl ester of N-(4-methylphenyl)valine, MS m/e 445.2 (M+). -6046787 EXAMPLE 65 To a mixture of N-(4-methylphenyl)valine (2.77 mmol), potassium carbonate (3.25 mmol) and HMPT (3 ml), with stirring and under nitrogen, at RT, is added. 5-benzyl-3-furylmethyl bromide (2.77 mmol) in THF. The reaction is stirred at RT for about 48 hr and then worked up by partition between water/ether. The organic phase is washed with water and brine, dried over potassium carbonate, filtered and evaporated. The residue is plated on prep. TLC plate eluting with 10% ether/hexane to yield the 5-benzyl-3-furylmethyl ester of N-{4-methylphenyl)valine,' MS m/e 377.1 (M+) .
Following the procedure of Example 17, N-(2-trifluoromethyIphenyl)valine, prepared from 2-trifluoromethylaniline and sodium salt of α-bromoisovaleric acid by the procedure of Example 18, is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(2-trifluoromethyIphenyl)valine, MS m/e 443 (M+).
Hsing the procedure of Example 1, each of 2-methoxyaniline and 4-ethoxyaniline is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(2methoxyphenyl)valine, MS m/e 405.2 (M+), and the m-phenoxybenzyl ester of N-(4-ethoxyphenyl)valine, MS m/e 419.1 (M+).
Following the procedure of Example 42, N-(3,4-dichlorophenyl) valine is reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(3,4-dichlorophenyl)valine, MS m/e 443 (M+).
Each of N-(3-cyanophenyl)valine and H-(3,4-dimethoxyphenyl) valine is reacted with m-phenoxybenzyl bromide using the procedure of Example 17 to yield the m-phenoxybenzyl ester of N-(3-cyanophenyl)valine, MS m/e 400.1 (M+), and the m-phenoxybenzyl -6146787 + ester of N-(3,4-dimethoxyphenyl)valine, MS m/e 435 (M ).
Following the procedure of Example 6, 4-trifluoromethylaniline is reacted with α-cyano-m-phenoxybenzyl ct-bromoisovalerate to yield the α-cyano-m-phenoxybenzyl ester of . N-(4-trifluoromethylphenyl)valine, MS m/e 468.2 (M+) .
EXAMPLE 66 To p-nitrothiophenol (14.1 g) suspended in water (100 ml) at RT is added 2N sodium hydroxide (52 ml). The mixture is stirred for 15 min and methyl iodide (9.4 ml) added slowly at 10°. The reaction mixture is warmed to. RT and stirred for 2 hr. The reaction is worked up by extracting into ether (3X 80 ml), washing with water and brine, drying over calcium sulfate and evaporating to give p-nitrophenyl methylsulfide (12.2 g).
To p-nitrophenyl methylsulfide (10.5 g) in chloroform (120 ml), cooled to 10-17°, under nitrogen, is bubbled chlorine while illuminating with a lamp (150 watt). A trace of 2,2'azobis-(2-methylpropionitrile) is added. After about 3 hr of passing chlorine through the solution, the reaction is terminated 2o and nitrogen passed'through for 0.5 hr. The solution is concentrated and the product, p-nitrophenyl trichloromethyl sulfi'de recrystallized out of hot. acetone, m.p. 94-96°. p-Nitrophenyl trichloromethylsulfide (l.S g) and purified SbF^ (1.96 g) is stirred under nitrogen in a Claisen flask and heated to 110-120°. After about 0.5 hr, the product is distilled off at 85-90° (5 mm). The distillate is taken up in ether (50 ml) and the ether layer washed with 10% HCl until cloudiness no longer occurs on addition of water. The ether layer is washed with water until neutral and with brine, dried over calcium sulfate and evaporated to yield p-nitrophenyl trifluoromethyl sulfide. -6246787 To p-nitrophenyl trifluoromethyl sulfide (3.0 g) in absolute ethanol (30 ml) is added Adams catalyst (Pt2O, 0.026 g) . The mixture is hydrogenated in a Parr vessel at 50 lbs/sq. in. for about 15 min. The reaction is worked up by filtering through Celite and evaporating to yield p-aminophenyl trifluoromethyl sulfide.
Following the procedure of Example 43, p-aminophenyl trifluoromethyl sulfide is reacted with m-phenoxybenzyl ci-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylthiophenyl) valine, MS m/e 475 (M+).
Alternatively, using the procedure of Example 38, p-aminophenyl trifluoromethyl sulfide is reacted with the sodium salt of α-bromoisovaleric acid to yield N-(4-trifluoromethylthiophenyl) valine, which is esterified to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylthiophenyl)valine.
EXAMPLE 67 To a 100 ml, 3-necked flask equipped with addition funnel and reflux condensor to which is attached a water-gas trap, are placed 10.08 g (65 mmole) of 2-fluoro,4-nitrotoluene.
The addition funnel is charged with 7.0 ml (22.3 g; 138 mmole) of bromine and the flask is heated. When the temperature (oil bath) is approximately 100°, the bromine is introduced slowly while illuminating the flask with a 150 watt light bulb. The bromination starts readily as the temperature is increased to approx. 160-170° and HBr is smoothly evolved. After 4 hr, heating is discontinued. The cooled mixture is worked up by pouring into iee and saturated sodium bisulfite and extracting with ether (3X). The combined organic layers are washed once more with saturated NaHSOj, brine (IX), and dried over sodium sulfate. -6346787 Filtration and evaporation of the solvent yields 17.0 g of a mixture of the benzal bromide and benzyl bromide (1.7:1 by nmr analysis). The crude material is suspended in a hypobromite solution prepared by combining 60 g of sodium hydroxide and ml of bromine in 600 ml of water. This mixture is stirred for 6 days at RT and then filtered to yield 2-fluoro,4-nitroα,α,α-tribromotoluene, which may be recrystallized from methanol.
A mixture of 8.5 g of 2-fluoro,4-nitro-a,a,a-tribromo10 toluene (22 mmole) and 4.7 g (26 mmole) of antimony trifluoride are placed in a small flask equipped with a condensor set for distillation. The flask is heated slowly and the mixture distilled both at atmospheric pressure and then under reduced pressure until no further material distills. The distillate is partitioned between 6N hydrochloric acid and ether. The organic layer is then washed with 6H sodium hydroxide (IX) and brine (IX) and dried over sodium sulfate. Filtration and evaporation of the solvent yielded 2-fluoro,4-nitrobenzotrifluoride. * 20 V To a solution of 20 ml of concentrated hydrochloric acid and 15 ml of 95% ethanol is added 5.0 g (24 mmole) of 2-fluoro,4-nitrobenzotrifluoride. The mixture is stirred and g (88 mmole) of stannous chloride dihydrate is added in portions over a 30 min period. The reaction is exothermic and j25 during the addition the temperature is maintained at 60°. When the addition is complete, the mixture is stirred at 60° for an additional 30 min. The reaction is cooled and poured onto a mixture of ice and 36% sodium hydroxide, which is extracted with ether (3X). The combined ether layers are washed once with brine and dried over sodium sulfate. Filtration and evaporation -6446787 of the solvent gave 4-amino,2-fluorobenzotrifluoride (3-fluoro4-trifluoromethylaniline).
Following the procedure of Example 38, 3-fluoro-4trifluoromethylaniline is reacted with the sodium salt of α-bromoisovaleric acid to yield N-(3-fluoro-4-trifluoromethylphenyl)valine, which is esterifed to yield the m-phenoxybenzyl ester of N-(3-fluoro-4-trifluoromethylphenyl)valine.
N-(2,4-dinitrophenyl)valine is reacted with m-phenoxybenzyl bromide using the procedure of Example 38 to yield the m-phenoxybenzyl ester of N-(2,4-dinitrophenyl)valine.
This procedure is repeated using 3-fluoro-4-nitrotoluene in place of 2-fluoro-4-nitrotoluene to prepare 2-fluoro4-trifluoromethylaniline, which is converted into N-(2-fluoro4-trifluoromethylphenyl)valine and then esterified to yield the m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl) valine, MS m/e 461.1 (M+) .
EXAMPLE 68 A mixture of 2-fluoro-4-chlorotoluene (25.05 g), KMnO^ (55.04 g) and water (400 ml) is heated to reflux for about 5 hr. The reaction is then worked up by filtering while hot through *Celite and the filtrate is acidified with 2N HCI. White crystals are filtered off, dissolved in ether and washed with water and brine, dried over sodium sulfate, filtered and evaporated to yield 2-fluoro-4-chlorobenzoic acid.
A mixture of 2-fluoro-4-chlorobenzoic acid (6.05 g), polyphosphoric acid (62.51 g) and CH^NC^ (5.1 g) is heated at 130°. After about 2.5 hr, the reaction mixture is poured onto ice and made basic by addition of dilute sodium hydroxide. The reaction is then worked up by extracting with ether. The *Celite is a trade mark -654 6 7 8 7 combined ether extracts are washed with water and brine, dried over sodium, sulfate, filtered and evaporated to yield 2-fluoro4-chloroaniline.
EXAMPLE 69 A mixture of N-(4-chlorophenyl)valine (0.6 g) , m-phenoxybenzyl sulfide (0.57 g) and tetra(t-butoxy)titanate (0.9 g), in a flask fitted with a short path distillation head under nitrogen, is heated to about 150°, with stirring for about 7 hr, under vacuum (about 50 mm). The reaction mixture is allowed to cool and let stand for several hours. The reaction is worked up by adding ether and 2N sulfuric acid, which is extracted with ether. The combined ether layers are washed with water, 10% sodium bicarbonate, water, brine, dried over calcium sulfate and rotoevaporated. The concentrate is placed on prep. TLC, eluting with 10% ether/hexane, and the main band collected to yield the m-phenoxybenzyl thiolester of N-(4-chlorophenyl)valine, m.p. 103.5-105°.
The above process is repeated using N-(4-methylphenyl)20 valine to yield the m-phenoxybenzyl thiolester of N-(4-methylphenyl) valine, MS m/e 405 (M+).
EXAMPLE 70 To a solution of o-fluoroaniline (3.9 g) in methylene 25 chloride (50 ml), cooled to -20° under nitrogen, is added a solution of 2,4,4,6-tetrabromocyclohexadienone (35 mmol) in methylene chloride. After several hours, reaction is poured into 15% NaOH solution. The layers are separated and thejOrganic fraction shaken against 15% NaOH solution. The methylene chloride fraction is washed with saturated NaCl solution, dried -664 6 787 over calcium sulfate and evaporated to yield 4-bromo-2-fluoroaniline.
To the potassium salt of α-bromoisovaleric acid (1.42 gj is added 4-bromo-2-fluoroaniline (1.9 g). The mixture is heated at 125" under nitrogen for 3.5 hr and then cooled to RT. The reaction product is poured into 2M NaOH and ether/ chloroform. The basic phase is separated and acidified with cone. HCl and then extracted into ether, washed with saturated NaCl solution, dried over calcium sulfate and evaporated to yield N-(4-bromo-2-fluorophenyl)valine.
A mixture of N-(4-bromo-2-fluorophenyl)valine (0.45 g), potassium carbonate (0.25 g), THF (4 ml), DMF (4 ml) and mphenoxy-a-cyanobenzyl mesylate (0.43 g) is stirred for about 60 hr and then poured into water and hexane/ether (9:1). The organic phase is washed with water and saturated sodium chloride solution, dried over calcium sulfate and evaporated. The residue is placed on prep. TLC eluting with 25% methylene chloride/hexane once and then 30% methylene chloride/hexane and the major band collected to yield the m-phenoxy-a-cyanobenzyl ester of N-(4-bromo-2-fluorophenyl)valine, MS m/e 496 (M+) .
EXAMPLE 71 To 4.9 g of N-(4-chlorophenyl)valine (0.0215 mole) in 50 ml of 1,4-dioxane is slowly passed a stream of phosgene gas as the solution is stirred. Cooling is applied to keep the solution at RT. When the solution is saturated with phosgene, the phosgene is shut off and the mixture is allowed to stir under nitrogen at RT. After 45 hr, about twe-thirds of the dioxane is removed by distilling at aspirator pressure. -67f 46787 residue is diluted with hexane, then allowed to crystallize ‘ 'overnight at RT. The solid is collected by filtration and washed with hexane, with care being taken to minimize exposure to air. The solid is dried’ in vacuo to yield 3-(4-chlorophenyl) 4-isopropyloxazolidine-2,5-dione, m.p. 137-138°.
To a mixture of m-naphthoxybenzaldehyde (0.43 g), 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (0.5 g), and potassium cyanide (0.23 g) in benzene (about 10 ml), with stirring, is added benzyl triethyl ammonium chloride (about 0.1 g). The reaction mixture is stirred for about 50 hr. The reaction is then worked up by taking up in ether, washing with water and brine, drying over sodium sulfate and evaporating.
The concentrate is plated, prep. TLC, eluting with 20% ether/ hexane to yield the m-naphthoxy-a-cyanobenzyl ester of N-(415 chlorophenyl) valine. MS m/e 484 (M+). nmr (CDClg) δ centered at 1.0 [m, 6, (CH3)2CH], 2.10 [m, 1, (CH3)2CH], and 4.0 ppm (m, 2, NH and^N-CH).
EXAMPLE 72 The process of Example 69 is repeated using each of N-(2-chloro-4-trifluoromethylphenyl)valine, N-(4-chloro-2fluorophenyl)valine, N-(2-fluoro-4-trifluoromethylphenyl)valine and N-(4-bromo-2-fluorophenyl)valine as the starting material to yield the m-phenoxybenzyl thiolester of N-(2-chloro-4-trifluoromethylphenyl)valine, N-(4-chloro-2-fluorophenyl)valine, N—(2-fluoro—4—trifluoromethylphenyl)valine, and N-(4-bromo-2-fluorophenyl)valine. -6846787 EXAMPLE 73 N-(2-fluorophenyl)valine, prepared by the reaction of 2-fluoroaniline and α-bromoisovaleric acid, is reacted with m-phenoxybenzyl bromide, as in Example 17, to yield the m-phenoxybenzyl ester of N-(2-fluorophenyl)valine, MS m/e 493.2 (M+).
Following the procedure of Example 28, there is prepared the hydrogen chloride salt of the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine, m.p. 126-130°.
EXAMPLE 74 Following the procedure of Example 6, 2-fluoro-4-chloroaniline is reacted with m-phenoxy-a-cyanobenzyl a-bromoisovalerate to give the m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro-4chlorophenyl)valine, MS m/e 452 (M+). Alternatively 2-fluoro4-chloroaniline is reacted with the sodium salt of a-bromoisovaleric acid to give N~(2-fluoro-4-chlorophenyl)valine, which is then esterified using m-phenoxy-a-cyanobenzyl bromide or mesylate. 14-chlorophenyl)valine is reacted with m-phenylcarbonylbenzyl bromide or the mesylate following the procedure of Example 24 to yield the m-phenylcarbonylbenzyl ester of N-(4chlorophenyl)valine, MS m/e 421 (M+).
EXAMPLE 75 Each of N-(2-chloro-4-fluorophenyl)valine, N-(4-methylthiophenyl)valine, N-(4-chloro-3-fluorophenyl)valine, N-(4cyano-2-fluorophenyl)valine, N-(4-bromo-2-fluorophenyl)valine and N-(4-trifluoromethoxyphenyl)valine is reacted with m-phenoxybenzyl bromide using the procedure of Example 24 to yield -69m-phenoxybenzyl ester of N-(2-chloro-4-fluorophenyl)valine, MS m/e 427 (M+); N-(4-methylthiophenyl)valine, MS m/e 421 (M+); N-(4-chloro-3-fluorophenyl)valine, MS m/e 427 (M+, 200); N-(4-cyano-2-fluorophenyl)valine, MS m/e 418 (M+); N-(4-brqmo-2-fluorophenyl)valine, MS m/e 471 (M+); and N-(4-trifluoromethoxyphenyl)valine, MS m/e 459 (M ).
Following the procedure of Example 70, each of m-phenoxy-a-cyanobeiizyl ester of N-(4-chloro-3-fluorophenyl)valine, MS m/e 452 (M+), and the m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro-4-methyIphenyl)valine, MS m/e 432 (M+), is prepared from N-(4-chloro-3-fluorophenyl)valine and N-(2-fluoro-4-methylphenyl)valine and m-phenoxy-a-cyanobenzyl mesylate or bromide.
The starting materials are prepared by the reaction of 4-chloro3-fluoroaniline and 2-fluoro-4-methylaniline, respectively, with the potassium salt of α-bromoisovaleric acid. 3-(Trifluoroacetyl)diphenyl ether (0.984 g) is dissolved in 5 ml methanol and reduced with 0.25 g sodium borohydride to give the corresponding alcohol. To 0.27 g of this alcohol (1.0 mole) is added 2 ml of pyridine and 0.5 g of 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione (1.97 mole) The solution is heated at 80° for 15 hr under nitrogen. The reaction mixture is diluted with ether-hexane and washed with dilute hydrochloric acid followed by aqueous sodium bicarbonate. The organic phase is stripped and chromatographed on a 1 m silica plate eluted with 10% ether-hexane to give the 3-phenoxy-a-trifluoromethylbenzyl ester of N-(4-chlorophenyl)valine, MS m/e 477.1 (M+), 182 (100). -704 6 787 EXAMPLE 76 Following the procedure of Example 65, N-(4-chlorophenyl)valine is reacted with each of 5-benzyl-3-furylmethyl bromide, m-allyloxybenzyl bromide and m-propargyloxybenzyl bromide to yield the 5-benzyl-3-furylmethyl ester of N-(4chlorophenyl)valine, MS m/e 397 (M+), the m-allyloxybenzyl ester of N-(4-chlorophenyl)valine, MS m/e 373 (M+), and the m-propargyloxybenzyl ester of N-(4-chlorophenyl)valine, MS m/e 371 (M+) . 4-Chloroaniline is reacted with m-phenoxybenzyl 2-bromobutanoate using the process of Example 4 to yield m-phenoxybenzyl 2-(4-chlorophenylamino)butanoate, MS m/e 395 (M+).
Following the procedure of Example 6, 4-chloroaniline is reacted with each of p-benzylbenzyl α-bromoisovalerate and m-benzyl-a-cyanobenzyl α-bromoisovalerate to yield the p-benzylbenzyl ester of N-(4-chlorophenyl)valine, MS m/e 407 (M ), and the m-benzyl-a-cyanobenzyl ester of N-(4-chlorophenyl)valine, MS m/e 432 (M+).
Following the procedure of Example 60, N-(4-isopropoxycarbonylphenyl)valine is prepared and reacted with m-phenoxybenzyl bromide to yield the m-phenoxybenzyl ester of N-(4-isopropoxycarbonylphenyl)valine, MS m/e 461 (M+).
EXAMPLE 77 To a slurry of 0.50 g of sodium hydride in 25 ml of dioxane under argon is added 2.80 g of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid in small portions.
When hydrogen evolution is ceased, the mixture is cooled in an ice bath and phosgene is passed over the surface of the -7146787 stirring mixture. A reaction ensues, with dissolution of the sodium salt and evolution of more hydrogen. When the hydrogen evolution appears to have ceased, the ice bath is removed and the addition of phosgene is continued until the solution appears nearly saturated. The reaction mixture is then filtered through a glass frit to remove insoluble salts and the filtrate is distilled at 15-20 mm pressure to remove phosgene and about 15 ml of the dioxane solvent. The residue is then diluted with hexane and allowed to stand at RT until crystallization is complete. The anhydride is collected by filtration, washed with hexane and dried under vacuum, with care being taken to minimize exposure to moisture, to yield 3- (2-fluoro-4-trifluoromethylphenyl)-4-isopropyloxazolidine2,5-dione. 3-(2-Fluoro-4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with phenol using the procedure of Example 75 to give the phenyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine, which is reacted with NaHS using the method of Hirakayaski et al., Bull. Chem. Soc. Japan 38, 320 (1965) to give the sodium salt of the thioacid.
The thioacid is reacted with m-phenoxy-a-cyanobenzyl bromide or mesylate using the procedure of Example 70 to yield the m-phenoxy-a-cyanobenzyl thiolester of N-(2-fluoro-4-trifluoromethylphenyl)valine. -7246787 EXAMPLE 78 Following the procedure of Example 38, N-(4-trifluoromethylphenyl) valine is reacted with p-benzoylbenzyl bromide to yield the p-benzoylbenzyl ester of N-(4-trifluoromethylphenyl)valine.
Each of 3-(2-fluoro-4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione and 3-(4-trifluoromethylphenyl)-4isopropyloxazolidine-2,5-dione, prepared by the procedure of Example 77, is reacted with m-benzoylbenzaldehyde and potassium cyanide using the procedure of Example 71 to yield the m-benzoylα-cyanobenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine and the m-benzoyl-a-cyanobenzyl ester of N-(4-trifluoromethylphenyl) valine.
EXAMPLE 79 Each of N-(2-fluoro-4-trifluoromethylphenyl)valine, N-(2-chloro-4-trifluoromethylphenyl)valine, N-(4-chloro-2fluorophenyl)valine and N-(4-bromo-2-fluorophenyl)valine is esterified using m-(o-fluorophenoxy)benzyl bromide according to the procedure of Example 42 to yield the m-(o-fluorophenoxy)benzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine, N-(2-chloro-4-trifluoromethylphenyl)valine, N-(4-chloro-2-fluorophenyl)valine, and N-(4-bromo-2-fluorophenyl) valine.
By repeating the above procedure using m-(p-fluorophenoxy) benzyl bromide as the esterification reagent, the respective m-(p-£luorophenoxy)benzyl ester of the listed amino acids are prepared.
EXAMPLE 80 Following the procedure of Example 38, N-(2-fluoro4-methoxyphenyl)valine is prepared and reacted with each of m-phenoxybenzyl bromide and m-phenoxy-a-cyanobenzyl bromide to yield the m-phenoxybenzyl ester of N-(2-fluoro-4-methoxyphenyl)valine and the m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro-4methoxypheny1) valine.
Using the process of Example 42, each of N-(2-fluoro4-methoxyphenyl)valine and N-(2-fluoro-4-trifluoromethylphenyl)10 valine is reacted with m-(p-fluorophenoxy)benzyl bromide to yield the m-(p-fluorophenoxy)benzyl ester of N-(2—fluoro-4methoxyphenyl)valine and the m-(p-fluorophenoxy)benzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine.
EXAMPLE 81 Following the procedure of Example 17 or 42, N-(2fluoro-4-trifluoromethylphenyl)valine is esterified using each of 2,6-dimethyl-4-allylbenzyl bromide, 2,6-dimethyl-4-propargylbenzyl bromide, 4-propargylbenzyl bromide, 4-phenyl-3-chloro20 2-butene-l-yl bromide, 3,4-dichloro-a-ethvnylbenzyl bromide, 3-trifluoromethoxybenzyl bromide, 3-trifluoromethy1-a-ethynylbenzyl bromide, 4-(p-fluorophenyl)-3-chloro-2-butene-l-yl chloride, 4-(o-fluorophenyl)-3-chloro-2-butene-l-yl chloride and 3-(2,2-dichlorovinyloxy)benzyl bromide to yield 2,6-dimethyl-4-allylbenzyl ester of N-(2-fluoro-4trifluoromethylphenyl)valine, 2,6-dimethyl-4-propargylbenzyl ester of N-(2-fluoro4-trifluoromethylphenyl)valine, 4-propargylbenzyl ester of N-(2-fluoro-4-trifluoro30 methylphenyl)valine 4-phenyl-3-chloro-2-butene~l~yl ester of N-(2-fluoro4-trifluoromethylphenyl)valine, 3,4-dichloro-a-ethynylbenzyl ester of N-(2-fluoro-4trifluoromethylphenyl)valine, 3-trifluoromethoxybenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine, 3- trifluoromethyl-a-ethynylbenzyl ester of N-(2-fluoro4-trifluoromethylphenyl)valine, 4- (p-fluorophenyl)-3-chloro-2-butene-l-yl ester of N- (2-fluoro-4-trifluoromethylphenyl)valine, 4-(o-fluorophenyl)-3-chloro-2-butene-l-yl ester of H-(2-fluoro-4-trifluoromethylphenyl)valine, and 3-(2,2-diohlorovinyloxy)benzyl ester of N-(2-fluoro4-trifluoromethylphenyl)valine. Using the procedure of U.S. Patent '3,979,519, the 3-trifluoromethoxy-a-cyanobenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine is prepared by the reaction of the acid chloride of N-(2-fluoro-4-trifluoromethylphenyl)valine and 3-trifluoromethoxybenzaldehyde cyanohydrin. Alternatively, 3- trifluoromethoxybenzaldehyde is reacted with 3-(2-fluoro-4trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione and potassium cyanide using the procedure of Example 71 herein to yield the 3-tri£luoromethoxy-a-cyanobenzyl ester of N-(2-fluoro4- trifluoromethylphenyl)valine.
Young lima bean leaves (in water) infested with approximately 50 adult Tetranychus urticae are sprayed to runoff with m-phenoxy-a-cyanobenzyl ester of N-phenylvaline diluted to three different concentrations in -7546787 aqueous carrier containing 0.025% *Tween 20 and 0.1% wetting agent. The treated leaves are maintained at 24° and 16 hr photoperiod for 2 days. Live adult mites are then counted and substracted from the original total to obtain the number affected, which is stated as a percentage of the total. Correction is made for any control mortality using Abbott's formula. The compound had an LC^q of less than 0.1%.
Individual fava bean leaves are dipped in m-phenoxybenzyl ester of N-phenyl-N-methylvaline diluted to three different' concentrations in acetone with 0.025% Tween 20 and 0.1% wetting agent. The leaves are allowed to dry for 2 hr, then infested with 10 adult Aphis fabae caged on the upper surface of the leaves. The treated leaves are maintained for hours at 24° and 16 hr photoperiod. The effect is stated as the number dead calculated as a percentage of the total aphids. This is corrected for control mortality, if any, using Abbott's formula. The compound had an LC^q of less than 0.05%.
Fifteen 72-hr-old adult female Musca domestica L. are anesthetized with ether vapor. These are then treated with 1 uT of the m-phenoxybenzyl ester of N-(p-methylphenyl)valine diluted to three different concentrations in acetone applied to the dorsal surface of the prothorax. They are held in an assay container with milk-saturated cotton at 25°, 16 hr ,photoperiod for 24 hours. The effect is stated as the number dead calculated as a percentage of the total, corrected for any control mortality using Abbott's formula. The compound gave an LC50 of less than 0.01%.
Into a mixture of 45 mg of wettable powder [Attaclay (60%), Marosperse N-22 (26.7%) and Igepon T-77 (13.3%)1 and 0.5 ml of water containing the m-phenoxybenzyl ester *Tween is a trade mark -7646787 of N-(p-chlorophenyl)valine] at three different concentrations is dipped fifteen fed tick nymphs (Omithodoros nymph I). The treated nymphs are maintained on filter paper for 7 days at 28°, 64% humidity, 16 hr photoperiod and then observed. Correction is made for any mortality in the control using Abbott's formula. The LC^q of the compound was less than 0.01%.
Two groups of 10 each of 0-24 hr III instar Heliothis virescens larvae were treated with 1 ul of the m-phenoxybenzyl ester of N-(p-methoxyphenyl)valine in acetone at three different concentrations by application to the dorsum of the thorax. Two groups of 10 each are treated identically with 1 ul acetone as controls. Larvae are held individually in 30 ml plastic cups provided with artificial medium for 72 hours at 25° and 16 hr photoperiod. After 72 hr the number of dead is calculated as a percentage of the total number originally treated and then corrected for any mortality in the control groups using Abbott's formula. The LC^q of the compound was less than 0.5%.
Each of the compounds listed below were used to treat aphids (adult Aphis fabae) using the method described above.
Each of the compounds gave an LC^q of less than fifteen parts per million (ppm). m-phenoxy-a-cyanobenzyl ester of N-(2-chloro-4-trifluoromethylphenyl)valine m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl) valine m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine -7746787 A 4E emulsive concentrate was prepared using the m-phenoxybenzyl ester of N-(4-trifluoromethylphenyl)valine (51.3%),tAtlox 3404F (3%),*Atlox 3403F (3%) and Tenneco 500-100 (42.7%), was diluted with water and applied to Tet'ranychus urticae as described above. The LC^g value was less than 10 ppm.
The compounds listed below were used to treat tick nymphs (Ornithodoros nymph I) using the method described above and exhibited an LC^g of less than 15 ppm. m-phenoxy-a-cyanobenzyl ester of N-(2-chloro-4-trifluoromethylphenyl)valine m-phenoxy-a-cyanobenZyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine m-phenoxy-a-methylbenzyl ester of N-(4-chlorophenyl)valine m-phenoxy-a-ethynylbenzyl ester of N-(4-chloro-2fluorophenyl)valine m-phenoxy-a-ethynylbenzyl ester of N-(3-fluoro-4methylphenyl)valine m-phenoxy-a-ethynylbenzyl ester of N-(2-fluoro-4methylphenyl)valine m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro -4-methylphenyl) valine m-phenoxy-a-cyanobenzyl ester of N-(4-chloro-2-fluorophenyl) valine Each of the compounds listed below was applied to Heliothis virescens larvae using the method described above and gave an LCj-g value of less than 0.1%. m-phenoxybenzyl ester of II-(4-chloro-2-fluorophenyl)valine *Atlox is a trade mark -7846787 m-phenoxy-a-cyanobenzyl ester of N-(4-chloro-2fluorophenyl)valine m-phenoxybenzyl ester of N-(2-fluoro-4-trifluoromethyIphenyl)valine m-phenoxy-a-cyanobenzyl ester of N-(4-bromo-2-fluorophenyl)valine m-phenoxybenzyl ester of N-(2-chloro-4-trifluoromethyIphenyl)valine m-phenoxy-a-cyanobenzyl ester of N-(2-fluoro-4-trifluoromethyIphenyl)valine m-phenoxy-a-cyanobenzyl ester of N-(2-chloro-4-trifluoromethyIphenyl)valine m-phenoxybenzyl ester of N-(2-fluoro-4-methyIphenyl)valine
Claims (42)
1. A compound of the formula (A): I II ς N - C - C - WR (A) wherein with halo or lower alkyl, or the group Y in which t is zero, one, two, three or four; Y is independently selected from hydrogen, lower alkyl, lower haloalkyl, lower 10 alkoxy, lower alkylthio, lower alkylcarbonyl, lower alkoxycarbonyl, lower acyloxy, halogen, cyano, nitro, and lower haloalkylthio; and Z is independently selected from the values of Y, cycloalkyl, and lower haloalkoxy; or Y and Z form a methylenedioxy group; or formyl; 3’ R is alkyl of 2 to 5 carbon atoms alkenyl of 2 to 5 carbon atoms, haloalkyl of 1 to 4 carbon atoms, haloalkenyl of 2 to 4 carbon atoms, or cycloalkyl of 20 3 or 4 carbon atoms; 4 . R is hydrogen or fluoro; and R 5 is;— 4678 wherein, p is zero, one, two or three; R 6 is hydrogen, cyano, methyl, trifluoromethyl, ethynyl, or -C=S I ' NH 2 R is halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower alkylthio, lower alkenyl, or lower haloalkenyl; 8 7 R is hydrogen or together with R forms a lower alkylenedioxy bridge across adjacent ring carbon atoms; g R is hydrogen, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower haloalkynyl, lower alkylcarbonyl, arylcarbonyl, substituted arylcarbonyl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, aralkyl, substituted aralkyl, cycloalkyl, cycloalkalkyl, lower acyloxy, aryloxycarbonyl, lower alkoxycarbonyl, or lower haloalkenyloxy; R^O is hydrogen or lower alkyl; R 11 is hydrogen, lower alkenyl, lower alkynyl or aralkyl; R 12 and R 13 taken together form an alkylene bridge having •1 to 4 carbon atoms or a lower alkenylene bridge having 2 to 4 carbon atoms R·'· 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or aralkyl; £ s hydrogen or lower alkyl; R is hydrogen, chloro, fluoro, or methyl; 5 bD is hydrogen, chloro, fluoro, methyl, or taken together with R^ forms a carbon-carbon bond; R is phenyl or phenyloxy; R is hydrogen, halogen, methyl, or ethyl; R is allyl, propargyl, 3-butenyl, 3-butynyl, 10 phenyl, or benzyl; and the salts thereof of strong inorganic acids or organic acids.
2. A compound according to Claim 1 of the formula
3.., wherein R is isopropyl, isopropenyl, or tnfluoromethy1. 15 3. A compound according to Claim 1 of the formula wherein, 2 is hydrogen, trifluoromethyl, fluoro, chloro, bromo, cyclopropyl or lower alkyl of 1 to 4 carbon atoms; 2 R is hydrogen, methyl or ethyl; 6 ? R° is hydrogen, cyano, ethynvl or -C-HHj,· and g . R is phenoxy or p-fluorophenoxy.
4. A compound according to Claim 3 wherein each 2 6 9 of R and R is hydrogen and R is phenoxy.
5. A compound according to Claim 1 of the formula: g wherein, R is hydrogen, methyl or ethyl; g R 6 is hydrogen, cyano, ethynyl or -C-NH 2 ; q R is phenoxy or p-fluorophenoxy; Y is hydrogen, trifluoromethyl, fluoro, chloro, bromo, •jQ lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms or lower alkylthio of 1 to 3 carbon atoms; Z is independently selected from the values of Y, and cyclopropyl; and t is zero, one or two. 15
6. , A compound according to Claim 5 wherein t is one or two.
7. A compound according to Claim 5 wherein t is zero.
8. A compound according to Claim 5 wherein t is 20 zero and Z is in the meta position.
9. A compound according to Claim 5 wherein t is zero and Z is in the ortho position.
10. A compound according to Claim 5 wherein t is one, Y is in the ortho position and Z is in the para position.
11. A compound according to Claim 5 wherein t is one, Y is in the meta position and Z is in the para position
12. A compound according to Claim 11 wherein Y is fluoro.
13. A compound according to Claim 10 wherein Y is fluoro.
14. A compound according to Claim 5 wherein Z is lower alkyl of 1 to 4 carbon atoms, chloro, fluoro, bromo, trifluoromethyl or cyclopropyl;- Z is in the para position; 10 Y is in the ortho position; and t is one.
15. A compound according to Claim 14 wherein Y is fluoro.
16. A compound according to Claim 15 wherein each 2 6 of R and R is hydrogen. 15
17. A compound according to Claim 16 wherein R 9 is phenoxy.
18. A compound according to Claim 15 wherein Z is lower alkyl of 1 to 4 carbon atoms.
19. A compound according to Claim 18 wherein each 2 6· 20. Of R and R is hydrogen. g
20. A compound according to Claim 19 wherein R is phenoxy.
21. A compound according to Claim 1 of the formula: wherein R is isopropyl, isopropenyl or trifluoromethyl.
22. A compound according to Claim 21 wherein R is 5 hydrogen, R 3 is isopropyl, R 6 is hydrogen or cyano, R 9 is phenoxy, W is oxygen, and Y is bromo, chloro or fluoro.
23. , A compound according to Claim 1 of the formula: wherein R 6 is hydrogen or cyano. 10
24. A compound according to Claim 23 wherein Y is fluoro and Z is chloro, bromo, fluoro, trifluoromethyl, or alkyl of one to four carbon atoms.
25. A compound according to Claim 23 wherein Y is fluoro and Z is trifluoromethyl. 15
26. The m - phenoxy - a - cyanobenzyl ester of N - ( 2 - fluoro - 4 - trifluoromethylphenyl)valine.
27. A compound according to Claim 23 wherein Y is fluoro and Z is chloro.
28. A compound according to Claim 23 wherein Y is chloro and 20 Z is trifluoromethyl.
29. The m - phenoxy - a - cyanobenzyl ester of N - (2 - chloro - 4 - trifluoromethylphenyl)valine.
30. A salt of any of the foregoing compounds and a strong inorganic or organic acid.
31. A salt of any of the foregoing compounds formed from an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, p-benzenesulfonic acid, and methanesulfonic acid. 5
32. The salt of any of the foregoing compounds formed from hydrochloric acid.
33. a process for the manufacture of the compounds of formula A as defined herein and the salts thereof formed from a strong inorganic or organic acid according to the processes 10 described herein.
34. A method for the control of pests such as insects and acarids which comprises treating said pests with a pesticidally effective amount of a compound .of formula A, or the salt thereof, as defined herein. .15
35. The method according to Claim 34 wherein the pest is an insect of the order Lepidoptera, Orthoptera, Heteroptera, Homoptera, Diptera, Coleoptera, or Hymenoptera.
36. The method according to Claim 34 wherein the pest is a mite or a tick of the order Acarina. 20
37. The method according to Claim 35 wherein the mite is of the family Tetranychidae or Tarsonemidae.
38. A composition for the control of pests such as insects and acarids which comprises a suitable liquid or solid carrier and a pesticidally effective amount of a compound of 25 .formula A or the salt thereof as defined herein. s s
39. Each compound of the formula (A) given and defined in Claim 1 which is specifically disclosed herein.
40. Pest control methods substantially as herein described and exemplified.
41. Pest control compositions substantially as herein described and exemplified.
42. A compound of the formula (A) given and defined in Claim 1 whenever produced by a process according to Claim 33.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US77988677A | 1977-03-21 | 1977-03-21 | |
US82494777A | 1977-08-15 | 1977-08-15 | |
US05/878,091 US4243819A (en) | 1978-02-16 | 1978-02-16 | Substituted amino acids |
Publications (2)
Publication Number | Publication Date |
---|---|
IE780552L IE780552L (en) | 1978-09-21 |
IE46787B1 true IE46787B1 (en) | 1983-09-21 |
Family
ID=27419755
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE552/78A IE46787B1 (en) | 1977-03-21 | 1978-03-20 | Esters and thiolesters of amino acids,processes for their production, and compositions including them |
Country Status (14)
Country | Link |
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JP (1) | JPS53121731A (en) |
AR (1) | AR221332A1 (en) |
BG (1) | BG60495B2 (en) |
CA (1) | CA1147745A (en) |
CH (1) | CH632232A5 (en) |
DE (1) | DE2812169A1 (en) |
DK (1) | DK154642C (en) |
FR (2) | FR2405922A1 (en) |
GB (1) | GB1588111A (en) |
IE (1) | IE46787B1 (en) |
IL (1) | IL54293A (en) |
KE (1) | KE3413A (en) |
NL (1) | NL193021C (en) |
NZ (1) | NZ186688A (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3005201A1 (en) * | 1979-03-02 | 1980-09-11 | Zoecon Corp | NEW ESTERS AND THIOLESTERS OF N-PHENYL-SUBSTITUTED VALINE DERIVATIVES |
DE2915026A1 (en) * | 1979-04-12 | 1980-10-30 | Bayer Ag | N, N-DISUBSTITUTED ETHYLGLYCIN (THIOL) ESTERS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS FUNGICIDES |
US4224330A (en) * | 1979-09-13 | 1980-09-23 | Zoecon Corporation | Esters and thiolesters of benzothienyl acids |
US4260633A (en) * | 1980-04-21 | 1981-04-07 | Zoecon Corporation | Pesticidal esters of amino acids |
US4259348A (en) | 1980-05-02 | 1981-03-31 | Zoecon Corporation | Pesticidal esters of amino acids |
US4267356A (en) * | 1980-06-09 | 1981-05-12 | Ciba-Geigy Corporation | Process for the preparation of N-(1'-alkoxycarbonylethyl)-2,6-dialkylanilines |
US4260782A (en) * | 1980-06-09 | 1981-04-07 | Ciba-Geigy Corporation | Process for the preparation of N-(1'-alkoxycarbonylethyl)-2,6-dialkylanilines |
JPS59110604A (en) * | 1981-01-26 | 1984-06-26 | ザンドツ・アクチェンゲゼルシャフト | Novel agricultural drug composition |
DE3575918D1 (en) * | 1984-11-05 | 1990-03-15 | Sandoz Ag | AMINO ACID ESTER. |
JPS62111903A (en) * | 1985-11-11 | 1987-05-22 | Nippon Kayaku Co Ltd | Insecticidal composition |
DE3737986A1 (en) * | 1987-11-09 | 1989-05-18 | Bayer Ag | TRIFLUORMETHYLAMINOBENZOLS CONTAINING FLUOR AND / OR CHLORINE AND THEIR PRODUCTION |
WO2023203038A1 (en) | 2022-04-19 | 2023-10-26 | Syngenta Crop Protection Ag | Insect, acarina and nematode pest control |
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IT1065062B (en) * | 1975-08-08 | 1985-02-25 | Hoffmann La Roche | REPLACED BOSSILIC ALFA ARILOSSICAR ACID ESTERS |
DE2647368A1 (en) * | 1975-10-23 | 1977-05-05 | Ciba Geigy Ag | Phenoxybenzyl pyrrole-(1)-acetate derivs. - with insecticidal and acaricidal activity |
JPS5852987B2 (en) * | 1976-02-17 | 1983-11-26 | 大日本除虫菊株式会社 | Anilinoacetate derivative |
DE2753605A1 (en) * | 1976-12-01 | 1978-06-08 | Dainippon Jochugiku Kk | 3-Phenoxy:benzyl alpha-substd. isovalerate ester cpds. - useful as insecticides |
JP3108953B2 (en) * | 1992-04-01 | 2000-11-13 | セイコーエプソン株式会社 | Magneto-optical signal detector and recording / reproducing device |
JPH05291833A (en) * | 1992-04-08 | 1993-11-05 | Yokogawa Electric Corp | Peak value measurement circuit |
-
1978
- 1978-03-07 GB GB9026/78A patent/GB1588111A/en not_active Expired
- 1978-03-08 CA CA000298515A patent/CA1147745A/en not_active Expired
- 1978-03-14 NZ NZ186688A patent/NZ186688A/en unknown
- 1978-03-15 IL IL54293A patent/IL54293A/en unknown
- 1978-03-16 AR AR271452A patent/AR221332A1/en active
- 1978-03-20 DE DE19782812169 patent/DE2812169A1/en active Granted
- 1978-03-20 CH CH302178A patent/CH632232A5/en not_active IP Right Cessation
- 1978-03-20 FR FR7808047A patent/FR2405922A1/en active Granted
- 1978-03-20 IE IE552/78A patent/IE46787B1/en not_active IP Right Cessation
- 1978-03-20 JP JP3226378A patent/JPS53121731A/en active Granted
- 1978-03-21 DK DK127278A patent/DK154642C/en active Protection Beyond IP Right Term
- 1978-03-21 NL NL7803030A patent/NL193021C/en not_active IP Right Cessation
- 1978-08-24 FR FR7824616A patent/FR2392959A1/en not_active Withdrawn
-
1984
- 1984-06-12 KE KE3413A patent/KE3413A/en unknown
-
1994
- 1994-02-14 BG BG98476A patent/BG60495B2/en unknown
Also Published As
Publication number | Publication date |
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NL193021B (en) | 1998-04-01 |
DK154642C (en) | 1989-06-19 |
AR221332A1 (en) | 1981-01-30 |
JPS53121731A (en) | 1978-10-24 |
JPS623146B2 (en) | 1987-01-23 |
KE3413A (en) | 1984-07-13 |
NL7803030A (en) | 1978-09-25 |
IE780552L (en) | 1978-09-21 |
IL54293A (en) | 1982-08-31 |
NZ186688A (en) | 1980-11-14 |
BG60495B2 (en) | 1995-05-31 |
IL54293A0 (en) | 1978-06-15 |
DE2812169C2 (en) | 1991-10-17 |
NL193021C (en) | 1998-08-04 |
DK154642B (en) | 1988-12-05 |
FR2405922B1 (en) | 1984-03-30 |
DK127278A (en) | 1978-09-22 |
DE2812169A1 (en) | 1978-10-05 |
CH632232A5 (en) | 1982-09-30 |
FR2392959A1 (en) | 1978-12-29 |
FR2405922A1 (en) | 1979-05-11 |
CA1147745A (en) | 1983-06-07 |
GB1588111A (en) | 1981-04-15 |
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