WO2002053518A2 - HALOGENATED-α,β-UNSATURATED-β-(SUBSTITUTED-AMINO) CARBOXYLATE ESTERS - Google Patents
HALOGENATED-α,β-UNSATURATED-β-(SUBSTITUTED-AMINO) CARBOXYLATE ESTERS Download PDFInfo
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- WO2002053518A2 WO2002053518A2 PCT/US2001/049924 US0149924W WO02053518A2 WO 2002053518 A2 WO2002053518 A2 WO 2002053518A2 US 0149924 W US0149924 W US 0149924W WO 02053518 A2 WO02053518 A2 WO 02053518A2
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- straight chain
- alkyl
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- -1 CARBOXYLATE ESTERS Chemical class 0.000 title claims abstract description 112
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 238000000034 method Methods 0.000 claims abstract description 62
- 150000002148 esters Chemical class 0.000 claims abstract description 23
- 239000012038 nucleophile Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 45
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 125000003368 amide group Chemical group 0.000 claims description 35
- 229910052757 nitrogen Chemical group 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 150000001299 aldehydes Chemical class 0.000 claims description 17
- 125000004122 cyclic group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 230000003647 oxidation Effects 0.000 claims description 9
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 7
- 101150065749 Churc1 gene Proteins 0.000 claims description 7
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 7
- 102100038239 Protein Churchill Human genes 0.000 claims description 7
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 claims description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 6
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 150000003573 thiols Chemical class 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 150000001735 carboxylic acids Chemical class 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052723 transition metal Inorganic materials 0.000 claims description 5
- 150000003624 transition metals Chemical class 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 4
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 claims description 4
- 125000005005 perfluorohexyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 claims description 4
- 125000005008 perfluoropentyl group Chemical group FC(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)* 0.000 claims description 4
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000007824 aliphatic compounds Chemical class 0.000 claims description 3
- 150000001504 aryl thiols Chemical class 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 21
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims 3
- UFZTUXCMGJKESL-UHFFFAOYSA-N (cyanodiazenyl) cyanate Chemical compound C(#N)N=NOC#N UFZTUXCMGJKESL-UHFFFAOYSA-N 0.000 claims 1
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000002910 aryl thiol group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 238000006243 chemical reaction Methods 0.000 description 29
- 239000000543 intermediate Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 125000005843 halogen group Chemical group 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- CJLDUCGLKBVTIB-ARJAWSKDSA-N ethyl (z)-3-chloro-4,4,4-trifluorobut-2-enoate Chemical compound CCOC(=O)\C=C(/Cl)C(F)(F)F CJLDUCGLKBVTIB-ARJAWSKDSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 7
- NXVKRKUGIINGHD-ARJAWSKDSA-N ethyl (z)-3-amino-4,4,4-trifluorobut-2-enoate Chemical compound CCOC(=O)\C=C(/N)C(F)(F)F NXVKRKUGIINGHD-ARJAWSKDSA-N 0.000 description 7
- 150000007857 hydrazones Chemical class 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- WGWSPBHICNLGTE-IWQZZHSRSA-N (z)-3-chloro-4,4,4-trifluorobut-2-enal Chemical compound FC(F)(F)C(\Cl)=C\C=O WGWSPBHICNLGTE-IWQZZHSRSA-N 0.000 description 6
- MREXEYNYMOHMMS-UPHRSURJSA-N (z)-3-chloro-4,4,4-trifluorobut-2-enoic acid Chemical compound OC(=O)\C=C(/Cl)C(F)(F)F MREXEYNYMOHMMS-UPHRSURJSA-N 0.000 description 6
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical compound FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 229910052727 yttrium Inorganic materials 0.000 description 6
- FMCXFUVJJVOBLO-UHFFFAOYSA-N 3,3-dichloro-4,4,4-trifluorobutanal Chemical compound FC(F)(F)C(Cl)(Cl)CC=O FMCXFUVJJVOBLO-UHFFFAOYSA-N 0.000 description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- FUPGKCRMPLEPFF-UHFFFAOYSA-M sodium;3,3-dichloro-4,4,4-trifluoro-1-hydroxybutane-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(O)CC(Cl)(Cl)C(F)(F)F FUPGKCRMPLEPFF-UHFFFAOYSA-M 0.000 description 5
- BOSAWIQFTJIYIS-UHFFFAOYSA-N 1,1,1-trichloro-2,2,2-trifluoroethane Chemical compound FC(F)(F)C(Cl)(Cl)Cl BOSAWIQFTJIYIS-UHFFFAOYSA-N 0.000 description 4
- CQHZNVRUFLMHHS-UHFFFAOYSA-N 3,3-dichloro-4,4,4-trifluorobutanoic acid Chemical compound OC(=O)CC(Cl)(Cl)C(F)(F)F CQHZNVRUFLMHHS-UHFFFAOYSA-N 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 150000003979 beta-halocarboxylic acids Chemical class 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- NDCZMOSQVJGZCK-PLNGDYQASA-N ethyl (z)-4,4,4-trifluoro-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(/NC)C(F)(F)F NDCZMOSQVJGZCK-PLNGDYQASA-N 0.000 description 4
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 4
- 150000002923 oximes Chemical class 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- NHNMTHQWZKGCQJ-UHFFFAOYSA-N 4-butoxy-2,2,4-trichloro-1,1,1-trifluorobutane Chemical compound CCCCOC(Cl)CC(Cl)(Cl)C(F)(F)F NHNMTHQWZKGCQJ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 150000000180 1,2-diols Chemical class 0.000 description 2
- 150000000185 1,3-diols Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- YFTNILABSPAIQT-HWKANZROSA-N ethyl (e)-3-cyano-4,4,4-trifluorobut-2-enoate Chemical compound CCOC(=O)\C=C(/C#N)C(F)(F)F YFTNILABSPAIQT-HWKANZROSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical class FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- BEZRLSGYEXBECF-UHFFFAOYSA-M sodium;3-chloro-4,4,4-trifluoro-1-hydroxybut-2-ene-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(O)C=C(Cl)C(F)(F)F BEZRLSGYEXBECF-UHFFFAOYSA-M 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 0 *C1=CC=N*1 Chemical compound *C1=CC=N*1 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- MWHZNXQKTCECGM-UHFFFAOYSA-N 4-butoxy-2,2-dichloro-4-ethoxy-1,1,1-trifluorobutane Chemical compound CCCCOC(OCC)CC(Cl)(Cl)C(F)(F)F MWHZNXQKTCECGM-UHFFFAOYSA-N 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical group F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 101100537948 Mus musculus Trir gene Proteins 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical class C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- 125000005365 aminothiol group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 1
- 238000007033 dehydrochlorination reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 150000004662 dithiols Chemical class 0.000 description 1
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 238000005007 materials handling Methods 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 150000007934 α,β-unsaturated carboxylic acids Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/07—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton
- C07C309/08—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
- C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/02—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen
- C07C47/14—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/24—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
Definitions
- the present invention is directed to the synthesis of esters of halogenated- ⁇ , ⁇ - unsaturated- ⁇ -aminoalkanoic acids, and in particular to the synthesis of 3-(substituted- amino)-4,4,4-trifluorocrotonate esters.
- the present invention is directed to the synthesis of alkyl halogenated- ⁇ , ⁇ -unsaturated- ⁇ - (substituted-amino) carboxylate esters, such as alkyl 3-methylamino-4,4,4-trifluorocrotonate, prepared by the reaction of methylamine with alkyl esters of halogenated- ⁇ , ⁇ -unsaturated- ⁇ - haloalkanoic acids in a sequence of steps using a halofluorocarbon as a starting material.
- alkyl halogenated- ⁇ , ⁇ -unsaturated- ⁇ - (substituted-amino) carboxylate esters such as alkyl 3-methylamino-4,4,4-trifluorocrotonate
- (disubstituted-amino)-4,4,4-trifluorocrotonates are commercially useful intermediate compounds used in pharmaceutical and agricultural applications to manufacture, among other things, heterocycles, including substituted-methyl nitrogen-heterocycles.
- an alkyl 3-methylamino-4,4,4- trifluorocrotonate undergoes cyclization to a trifluoromethylated-N-methylated heterocycle such as 6-trif uoromethyl-l-methyluracil.
- US 6,207,830 discloses the conversion of ethyl 3-methylamino- 4,4,4-trifluorocrotonate to a l-methyl-6-trifluoromethyluracil derivative.
- alkyl 3-methylamino-4,4,4-trifluorocrotonates and related species A major shortcoming of all currently used processes for the production of alkyl 3-methylamino-4,4,4-trifluorocrotonates and related species is that the starting material, alkyl trifluoroacetoacetate, is expensive and of limited commercial availability. For this reason, it is desirable to have an alternate process for the synthesis of an alkyl 3-(substituted-amino)-4,4,4-trifluorocrotonate that does not use an alkyl trifluoroacetoacetate as starting material.
- a process for preparing a halogenated aliphatic- , ⁇ -unsaturated- ⁇ -nucleophile-functionalized carboxylate ester having the formula:
- R -C(-Nu) CH-COOR°
- the process includes the step of reacting a nucleophile with a halogenated aliphatic- , ⁇ -unsaturated- ⁇ -halocarboxylate ester having the formula:
- R 1 is selected from straight chain and branched halogenated C r C 12 aliphatic groups
- Nu is a nucleophile moiety
- X 1 is F, CI or Br
- R is selected from straight chain and branched C C 6 alkyl groups.
- R 1 is preferably polyhalogenated, more preferably polyfluorinated and most preferably perfluorinated.
- nucleophiles include, but are not limited to, anionic species such as the halide ions F “ , CI “ , Br “ and I “ , alkoxide ions, phenoxide ions, substituted phen- oxide ions, alkylamide ions, thiolate ions, acyloxy ions, cyanide, azide, cyanate ions, thiocyanate ions, and the like, and neutral species, such as straight chain, branched or cyclic C C 6 alkyl alcohols and thiols, arylthiols, and the like.
- a particularly preferred group of nucleophilic species are amine compounds having the formula:
- NR 9 R 10 H wherein R 9 and R 10 are independently selected from hydrogen and straight chain or branched C*-C 6 alkyl. These produce halogenated aliphatic- , ⁇ -unsaturated- ⁇ - nucleophile-functionalized carboxylate esters in which Nu is a -NR 9 R 10 group.
- the halogenated aliphatic- ⁇ , ⁇ -unsaturated- ⁇ -halocarboxylate ester may be part of an admixture that also includes the corresponding dihalogenated aliphatic ⁇ , ⁇ -dihalocarboxylate ester that is not unsaturated at the , ⁇ -position.
- a compound has the structure: R 1 -CX 1 X 2 CH 2 COOR 8
- R 1 , X 1 and R 8 are the same as described above with respect to the halogenated aliphatic- ⁇ , ⁇ -unsaturated- ⁇ -halocarboxylate ester.
- X 2 is, independently of X 1 , F, CI or Br.
- the ⁇ , ⁇ -saturated dihalocarboxylate ester dehydrohalogenates in situ to the halogenated aliphatic- ⁇ , ⁇ -unsaturated- ⁇ -halocarboxylate ester, which then reacts with the nucleophilic species to form the halogenated aliphatic- , ⁇ -unsaturated- ⁇ - nucleophile-functionalized carboxylate ester.
- the halogenated aliphatic- ⁇ , ⁇ -unsaturated- ⁇ -halocarboxylate esters are prepared by esterification of the corresponding carboxylic acids.
- the ⁇ - halocarboxylate esters that are saturated at the , ⁇ -position are likewise prepared by esterification of the corresponding carboxylic acids, and may then dehydrohalogenate in situ to the ⁇ , ⁇ -unsaturated- ⁇ -halocarboxylate esters.
- the halogenated aliphatic- , ⁇ -unsaturated- ⁇ -halocarboxylic acids are formed by oxidation of aldehydes having the formula:
- R 1 and X 1 are the same as described above for the halogenated aliphatic-c., ⁇ -unsatura- ted- ⁇ -halocarboxylate esters.
- halogenated aliphatic- ⁇ , ⁇ -dihalocarboxylic acids that are saturated at the , ⁇ -position are formed by oxidation of aldehydes having the formula:
- R 1 CX 1 X 2 -CH 2 CH 0
- R 1 and X 1 are the same as described above for the ⁇ , ⁇ -unsaturated aldehydes and X 2 , independently of X 1 , is F, CI or Br.
- the resulting ⁇ , ⁇ -saturated ⁇ , ⁇ -dihalocarboxylic acids may then dehydrohalogenate to the corresponding ⁇ , ⁇ -unsaturated- ⁇ -halo- carboxylic acids.
- the , ⁇ -saturated and , ⁇ -unsaturated aldehydes are together obtained by hydrolysis of a compound having the structure of Formula I:
- R 1 , X 1 and X 2 are the same as described above for the aldehydes.
- X 3 independent of X 1 and X 2 , is CI, Br or I.
- R b is a straight chain or branched C C 6 alkyl.
- the process includes the step of reacting a 1,1,1-trihalogenated aliphatic compound having the formula:
- R a is hydrogen, a straight chain or branched C*-C 6 alkyl, a straight chain or branched C*-C 6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido or nitrogen heterocycle containing five, six or seven ring members, a phenyl or a phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C C 6 alkyl or C C 6 alkoxy.
- X 1 , X 2 , X 3 , R 1 and R b are the same as described above with respect to Formula I.
- the compounds of Formula I may also be hydrolyzed in the presence of a bisulfite salt to form useful intermediate, water-soluble compounds that may then be oxidized to the ⁇ -halocarboxylic acids of the present invention. Therefore, according to another aspect of the present invention, a process is provided including the step of hydrolyzing the compound of Formula I with a bisulfite salt having the formula so that a mixture is obtained of a compound having the structure of Formula II:
- R 1 , X 1 and X 2 are the same as described above with respect to Formula I, Y is OH and Z is M'SO ⁇ wherein M 1 is a cation selected from alkali metal cations, alkaline earth metal cations, NH 4 + , NR 2 H 3 + and NR 2 R 3 H 2 + , wherein R 2 and R 3 are independently straight chain or branched - alkyl, phenyl or phen C C 6 alkyl.
- Oxidation of the bisulfite compounds of Formula II and Formula III to the corresponding carboxylic acids will include some dehydrohalogenation of the Formula II compounds to form the , ⁇ -unsaturated- ⁇ -halocarboxylic acids.
- a process including the step of reacting the compounds of Formula I with alcohols having the formula R 4 OH, so that a mixture is obtained of compounds having the structures of Formula II and Formula III, wherein R 1 , X 1 and X 2 are the same as described above with respect to Formula I, Y is OR b or OR 4 , and Z is OR 4 , wherein R 4 is a straight chain or branched C C 6 alkyl, a straight chain or branched C C 6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido or nitrogen heterocycle containing 5, 6 or 7 ring members, a phenyl, or a phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido,
- Oxidation of the acetal compounds of Formula II and Formula III to the corresponding carboxylic acid derivatives will also include some dehydrohalogenation of the Formula II compounds to form the , ⁇ -unsaturated - ⁇ -halocarboxylic acid derivatives.
- the compounds of Formula I may also be reacted with diols, dithiols, diamines, aminoalcohols, aminothiols or thioalcohols to form useful cyclic intermediate compounds that may then be oxidized to the ⁇ -halocarboxylic acids of the present invention. Therefore, according to another aspect of the present invention, a process is provided including the step of reacting the compound of Formula I with a compound having the Formula:
- Formula III wherein R , 1 , X vl and X are the same as described above with respect to Formula I, and Y and Z together form a ring structure with the carbon to which they are attached having as members -W a -R 5 -W b -, wherein W a and W b are independently selected from O, N and S, and R 5 is a C 2 -C 3 alkylene optionally substituted with straight chain, branched or cyclic C C 6 alkyl, or optionally forming part of 1,2- phenylene, which, in turn, is optionally ring-substituted with one or more groups selected from halo, cyano, nitro, amido, C*-C 6 alkyl or C C 6 alkoxy.
- Oxidation of the cyclic intermediate compounds of Formula II and Formula III to the corresponding carboxylic acid derivatives will include dehydrohalogenation of the Formula II compounds to form the ⁇ , ⁇ -unsaturated carboxylic acid derivatives.
- the compounds of Formula I may also be reacted with a hydroxylamine to form useful oxime intermediate compounds. Therefore, according to another aspect of the present invention, a process is provided including the step of reacting the compounds of Formula I with a hydroxylamine having the formula NH 2 OR 7 , so that a mixture is obtained of compounds having the structures of Formula II and Formula III,
- the oxime and hydrazone compounds of Formula II and Formula III may be further reacted by heating with or without acid or base catalysis to form useful heterocyclic compounds. Therefore, according to another embodiment of this aspect of the invention the methods of forming the hydrazone and oxime compounds of the present invention further include the steps of further heating the hydrazone and oxime compounds so that heterocyclic compounds are obtained having the structures of Formula IVa and Formula INb:
- G is O or ⁇ R 6
- R 1 is the same as described above with respect to Formula I
- R 6 is the same as described above with respect to the hydrazone compounds of Formula II and Formula III.
- R 1 is selected from straight chain and branched halogenated C r C 12 aliphatic groups
- Nu is a nucleophile moiety
- R 8 is selected from hydrogen, straight chain and branched C*-C 6 alkyl groups, NH 4 + , R 2 NH 3 + , alkali metal ions, alkaline earth metal ions, CI, NH 2 , NHR 2 , NHNHR 2 , CN, SH and SR 2 , wherein R 2 is selected from straight chain or branched C C 6 alkyl, phenyl or phen C C 6 alkyl.
- aldehyde compounds having the formulae:
- R 1 , X 1 and X 2 are as described above for the aldehydes.
- compounds are provided having the structures of Formula I and Formula la, wherein R 1 , X 1 , X 2 , X 3 , R a and R b are as described above for these compounds.
- heterocyclic ring compounds having the structures of Formula INa and Formula INb, wherein G, R 1 and R 6 are the same as described above for Formula INa and Formula INb.
- Step 1 of the five step inventive process a halofluorocarbon is catalytically added to a substituted vinyl ether to obtain the compound of Formula la:
- R a is hydrogen, or straight chain or branched C r C 6 alkyl, or straight chain or branched C ⁇ -C 6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, or nitrogen heterocycle containing five, six or seven ring members; or phenyl, or phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C C 6 alkyl, or C C 6 alkoxy; R b is straight chain or branched C*- C 6 alkyl; X and X 2 are independently selected from F, CI and Br; X 3 , independently of X 1 and X 2 is Br, CI or I; and R 1 is a straight chain or branched halogenated C C 12 aliphatic group.
- R a is preferably hydrogen, in which case the compounds of Formula la are the compounds of Formula I.
- R 1 is preferably polyhalogen
- R'-CX'X ⁇ 3 + CH 2 CR a -OR b -(Catalyst) ⁇ R r CX'X 2 -CH 2 CR a X 3 -OR b
- the inventive process generates useful intermediate compounds.
- Fluoroalkyl intermediate compounds are provided that are precursors to bioactive compounds, and others that are (or of themselves may be) bioactive, and thus are of commercial value in pharmaceutical and agricultural applications.
- Step 2 of the inventive process C-l of Formula I, the carbon bearing the halogen X and the -OR group, is modified by one of two general methods of broad utility:
- R 1 , X 1 and X 2 are the same as described above with respect to Formula I.
- R'CX 1 CHCHYZ (III) wherein R 1 , X 1 and X 2 are the same as described above with respect to Formula I, Y is -OH and Z is -S0 3 M'.
- novel intermediate compounds can be used in organic or in water solution, they can be isolated as stable solids, and they can be converted to the corresponding aldehydes in aqueous acid or base. Furthermore, these sulfonic acid salts chemically behave in a manner similar to the aldehydes without the need to isolate the aldehyde, and offer certain process advantages such as enhanced water solubility, improved stability and materials handling.
- the ion M 1 includes ammonium ion, NH 4 + , alkylammonium ions, NR 2 H 3 + , and NR 2 R 3 H 2 + , (where R 2 and R 3 are independently a straight chain or branched C r C 6 alkyl, phenyl or phen C C 6 alkyl), alkali metal ions, e.g., Na + , and K + , and alkaline earth metal ions e.g., Ca +2 , and Ba +2 .
- R 4 is straight chain or branched C r C 6 alkyl, or straight chain or branched C C 6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, or nitrogen heterocycle containing five, six or seven ring members; or phenyl, or phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C]-C 6 alkyl, or C r C 6 alkoxy.
- H-W a -R 5 -W b -H there are produced the novel cyclic intermediate compounds having the structures of Formula II or Formula III wherein Y and Z together with the carbon to which they are attached form a ring having as members - W a -R 5 -W b -, wherein W a , and W b are independently selected from O, N or S.
- R 5 is a C 2 -C 3 alkylene optionally substituted with straight chain, branched or cyclic C r C 6 alkyl, or a C 2 -C 3 alkylene that is part of a 1,2-phenylene, or a C 2 -C 3 alkylene that is part of a 1,2-phenylene substituted with one or more groups selected from halo, cyano, nitro, amido, C C 6 alkyl or C ⁇ -C 6 alkoxy.
- These novel intermediates can be used in solution, they can be isolated, and they can be converted to the corresponding aldehyde in aqueous acid or with an aqueous Lewis acid, e.g., BF 3 .
- R 1 , X 1 and X 2 are the same as described above with respect to Formula I, the reagent is an alcohol, 1,2-diol, 1,3-diol, 1,2-thiol, 1,3-thiol, 1,2-diamine, 1,3-diamine, ⁇ - aminoalcohol, ⁇ -aminoalcohol, ⁇ -aminothiol, ⁇ -aminothiol, hydrazine, hydroxylamine, and the like, and Y and Z correspond to the groups above-described as being obtained when these reagents are used.
- the oxime and hydrazone derivatives can be further heated to produce the heterocyclic derivatives of Formula IN, wherein G is O or ⁇ R wherein R is defined as before, and R 1 is the same as described above with respect to Formula I
- Step 3a and Step 3b the aldehydes from Step 2a or the related derivatives from Step 2b respectively are oxidized to the intermediates R 1 -CX I X 2 CH 2 COOH and R ⁇ CX ⁇ CH-COOH using e.g., chromic acid, potassium permanganate, or other oxidizing agents known to those skilled in the art.
- R , X and X are the same as described above with respect to Formula I. Step 3a.
- ion M 2 includes ammonium ion, NH 4 + , alkylammonium ion, R 2 NH 3 + , alkali metal ions, e.g., Na + , and K + , and alkaline earth metal ions e.g., Ca +2 , and Ba +2 .
- carboxylic acid - COOH
- Step 4 involves the esterification of the carboxylic acid derivatives from Step 3a and 3b with a compound capable of transferring the alkyl group, R 8 , to obtain the alkyl ester thereof.
- the reaction can be carried out in the presence of a base, e.g., potassium carbonate, with an alkylating agent, e.g., an alkyl halide such as ethyl bromide.
- the reaction can be carried out in the presence of an acid, e.g., methanesulfonic acid, and excess alcohol, e.g., n-butanol.
- R is a straight chain or branched C r C 6 alkyl.
- Step 5a is obtained in Step 5a, by reaction of R'-C X ⁇ CHaCOOR 8 and R ⁇ CX ⁇ CH-COOR 8 with a reagent capable of transferring a substituted-amino group.
- Step 5a R ⁇ CX ⁇ O COOR 8 + R'-CX ⁇ CH-COOR 8 +
- R 9 and R 10 are independently selected from hydrogen, and straight chain or branched C*-C 6 alkyl.
- Step 5b in a similar manner, other nucleophilic species, Nu, react with the esters from Step 4 to produce a halogenated- ⁇ , ⁇ -unsaturated- ⁇ -(Nu-functionalized) carboxylate ester of Formula VI:
- Nu is selected from anionic species, for example halide ion, I “ , Br “ , F, or alkoxide ion, phenoxide ion, or substituted-phenoxide ion, alkylamide ion, thiolate ion, acyloxy anion, cyanide ion, azide ion, cyanate ion, thiocyanate ion, or neutral species, for example straight chain or branched or cyclic C C alkyl alcohols, or alkyl or aryl thiols.
- anionic species for example halide ion, I “ , Br “ , F, or alkoxide ion, phenoxide ion, or substituted-phenoxide ion, alkylamide ion, thiolate ion, acyloxy anion, cyanide ion, azide ion, cyanate ion, thiocyanate ion, or neutral species, for
- Steps 1-5 occur at or near atmospheric pressure.
- the temperature of reaction ranges from 0°C to 100 °C.
- the method of separating the intermediates and the final products from the reaction mixtures are selected from standard manipulative techniques, including distillation, or crystallization.
- ketones have been used as intermediates in heterocyclic synthesis and have also been viewed as synthetic targets because of their possible pharmacological interest.
- Trifluoromethyl ketones are a particularly well-documented class of serine protease inhibitors, which have proven attractive against elastase, chymotrypsin, and CMV protease.
- R 1 as a halogenated aliphatic radical is preferably a substituted or unsubstituted C*-C 12 halogenated aliphatic radical, and is more preferably fluorinated. Even more preferably, R 1 is a perfluorinated aliphatic radical, and more preferably perfluorinated.
- substitution groups include C C 6 alphatics such as alkyls, alkyl ethers, alkyl esters and alkenyls containing nitro, aminos (primary and secondary), cyano, hydroxyl, thiol and alkylthio groups. The substitution groups are preferably attached to non-fluorinated carbon atoms of R 1 .
- R 1 as a C*-C 12 halogenated alkyl radical may be straight-chained or branched, for example, halogenated methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl or 2-ethylhexyl. Any of these groups may be substituted with essentially any conventional organic moiety, for example, methoxy, ethoxy, n- or iso- propoxy, n-butoxy, methane sulphonyl or cyano.
- C C 6 fluorinated alkyl radicals are even more preferred.
- Examples include fluoromethyl, difluoromethyl, trifluoromethyl, fluorethyl, difluoroeythl, trifluoroethyl, pentafluoroethyl, perfluoropropyl, perfluorobutyl, perfluoropentyl or perfluorohexyl.
- R 1 is a trifluoromethyl radical.
- Two preferred halofluorocarbon starting materials are the isomeric pair CFC- 113 (l,2,2-trichloro-l,l,2-trifluoroethane) and CFC 113a ( 1,1,1 -trichloro-2,2,2- trifluoroethane). More preferably, the starting material is l,l,l-trichloro-2,2,2- trir uoroethane, CFC-113a, which has the structure of CF 3 CC1 3 . It has been discovered that CFC-113a reacts with specificity in a way that allows incorporation of the CF 3 - functional group into the target molecules.
- Step 1 of the present invention the halofluorocarbon is photocatalytically added to an alkyl vinyl ether, preferably at a temperature between 25-40 °C.
- Suitable reagents, solvents and process conditions may be determined by reference to Bosone et.al., Pesticide Sci.. 17(6), 621-630 (1986) and also to EP 31,041, both incorporated herein by reference.
- Conditions suitable for transition metal catalyzed addition of halofluorocarbons to trialkylsilyl vinyl ethers may be determined by reference to
- Step 2a The hydrolysis of Step 2a is carried out over a period of 2-12 hours at approximately 20 °C, preferably with aqueous tetrahydrofuran, followed by isolation of the aldehyde, or by further reaction with one of the reagents of Step 2b.
- the oxidation of Step 3 is performed in aqueous chromic acid for 15-25 hours at approximately 20 °C in the presence of an organic solvent, for example diethyl ether, or dibutyl ether, or more preferably tetrahydrofuran, followed by phase separation, washing with brine and vacuum distillation.
- an organic solvent for example diethyl ether, or dibutyl ether, or more preferably tetrahydrofuran, followed by phase separation, washing with brine and vacuum distillation.
- the oxidation of Step 3 may also be performed using hypochlorous acid in alcohol solvent to allow direct formation of the corresponding carboxylate ester.
- the esterification of Step 4 is best performed in the presence of excess alcohol, for example methanol, ethanol or n-butanol, and an acid catalyst, for example methanesulfonic acid with sufficient heat to cause reaction.
- the water produced is distilled off as an azeotrope with the alcohol, or is removed by trapping with the appropriate drying agent, e.g., 3A molecular sieve.
- the ester is then isolated by direct distillation from the reactor.
- the reaction of the ester with the substituted amine in Step 5 preferably involves stirring the haloester with an excess of the substituted-amine in water solvent or in an organic solvent, or more preferably neat, at approximately 0-75 °C, at a pressure of approximately 0-200 psig for 1-20 hours.
- Ethyl 3-chloro-4,4,4-trifluorocrotonate (2.01 g, 9.93 mmol) was placed in a 90 cc glass pressure reactor containing a magnetic stir bar. The system was freeze-thaw degassed and then anhydrous methylamine (5 g) was condensed into the reactor at -70 °C. The mixture was warmed to 15-20 °C with stirring for 90 minutes. Excess methylamine was vented; the methylamine hydrochloride solid was filtered off, and rinsed with 1 mL of CH 2 C1 2 . The filtrate was distilled to yield 1.5 g of ethyl 3- methylamino-4,4,4-trifluorocrotonate, bp 70 °C at ca. 20 mm Hg.
- the insoluble organic layer was phase separated, dried over MgS0 4 , and distilled to provide 58.1 g of 3-chloro-4,4,4-trifluorocrotonaldehyde (32% yield), ca. 88 % pure by GC and NMR analyses, bp 74-78 °C, as a bright yellow lachrymatory oil, and 4 g of 3,3-dichloro-4,4,4-trifluorobutyraldehyde, (3% yield), bp ca 85-95 °C.
- Example 5 3,3-Dichloro-l-hydroxy-4,4,4-trifluorobutanesulfonic Acid Sodium Salt, and 3-Chloro-l-hydroxy-4,4,4-trifluoro-2-butenesulfonic Acid Sodium Salt
- Step 2b n-Butyl 1,3,3 trichloro-4,4,4-trir uorobutyl ether (29.57g, 0.10 mol) was added dropwise to a mixture of tetrahydrofuran (100 mL) and saturated aqueous brine (29 mL) maintained at 25 °C. After 30 minutes the organic layer is separated and washed with brine.
- the organic layer is then added to 48.9 g of 40 % (wt) sodium bisulfite solution at 25 °C with stirring for an additional 20 hours.
- the organic layer (upper) is phase separated and stripped to dryness in vacuo to yield 26.46 g of stable white solid crystals.
- n-butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether (4.32 g, 15 mmol)
- acetic acid (10.4 g, 0.17 mol)
- water (3.25 g)
- p-toluenesulfonic acid monohydrate (0.58 g) was added at once hydrazine monohydrate (6.03 g, 0.12 mol) with vigorous stirring under nitrogen, and with external cooling to maintain the temperature below 60 °C.
- reaction mixture was analyzed by GC, GC/MS, and l9 F and 1HNMR and found to contain a trace of unreacted starting material, and 3-(trifluoromethyl) pyrazole (17%), plus a component identified as the hydrazone of 3-chloro-4,4,4-trifluorocrotonaldehyde (69%).
- Example 7 3-Chloro-(l,l-ethylenedioxy)-4,4,4-trifluoro-2-butene (Step 2b) n-Butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether (286.4 g, 1.0 mol) was slowly added to stirred ethylene glycol (389 g, 6.3 mol) at 105 °C (Note exotherm) with additional stirring for 2-3 hours at 105 °C until HC1 gas evolution ceased.
- Dilute aqueous chromic acid (540 g, ca. 0.9 mol) was added over 1 hour to a stirred solution of 3-chloro-4,4,4-trifluorocrotonaldehyde and 3,3-dichloro-4,4,4- trifluorobutyraldehyde (71.3 g total, ca 0.4 mol) in diethyl ether (700 ml) at 20 °C. After stirring 18 hours at 20 °C the mixture was phase separated and the organic phase was washed with brine.
- a suspension (hydrazine hydrochloride salt) formed. Stirring continued at 85-100 °C for another 75 mins. Butyl acetate and acetic acid were distilled off, at 60°C and 70-15 mm Hg to constant weight, ca. 470 g. The semi-solid was cooled to 20 °C, followed by the addition of 500 mL hexane. After cooling to 10 °C 720 mL of 10 % (wt) aqueous sodium carbonate was added over one hour with vigorous stirring under nitrogen. Solid sodium bicarbonate (175 g) was then added incrementally over 2 hours at 10 °C; stirring continued for an additional hour until there was no further C02 gas evolution.
- Ethyl 3-chloro-4,4,4-trifluorocrotonate (2.01 g, 9.93 mmol) was placed in a 90 cc glass pressure reactor containing a magnetic stir bar. The system was freeze-thaw degassed and then anhydrous ammonia (5.03 g, 295 mmol) was condensed into the reactor at -70°C. The mixture was warmed to 15-20°C with stirring for 90 minutes (Pmax ca. 102 psig.). Excess ammonia was vented, the NH 4 C1 solid was filtered off, and rinsed with ImL of CH 2 C1 2 to give 0.45 g white solid NH 4 C1 (92 %).
- Ethyl 3-chloro-4,4,4-trif_uorocrotonate (ca. 50 mg, mmol) was stirred with 0.5 mL of 29 % (wt) aqueous ammonia at 25 °C for 2 hours. The clear colorless solution was extracted with 0.2 mL methylene chloride. GC analysis indicated > 99 % conversion with 100 % selectivity for ethyl 3-amino-4,4,4-trifluorocrotonate.
Abstract
A process for preparing a halogenated aliphatic-α,β-unsaturated-β-nucleophile-functionalized carboxylate ester having the formula: R1-C(-Nu)=CH-COOR8 by reacting a nucleophile with a halogenated aliphatic-α,β-unsaturated-β halocarboxylate ester having the formula: R1-CX1=CH-COOR8, wherein R1 is selected from the group consisting of straight chain and branched halogenated C¿1?-C12 aliphatic groups; Nu is a nucleophile moiety different from X?1; X1¿ is F, Cl or Br; and R8 is selected from the group consisting of straight chain and branched C¿1?-C6 alkyl groups. Halogenated aliphatic-α,β-unsaturated-β-nucleophile-functionalized carboxylate esters, halogenated aliphatic-α,β-unsaturated-β-halocarboxylate esters, and intermediate compounds and processes in the preparation thereof are also disclosed.
Description
HALOGENATED-α,β-UNSATURATED-β- (SUBSTITUTED-AMINO)
CARBOXYLATE ESTERS
FIELD OF THE INVENTION The present invention is directed to the synthesis of esters of halogenated-α,β- unsaturated-β-aminoalkanoic acids, and in particular to the synthesis of 3-(substituted- amino)-4,4,4-trifluorocrotonate esters. More specifically, the present invention is directed to the synthesis of alkyl halogenated-α,β-unsaturated-β- (substituted-amino) carboxylate esters, such as alkyl 3-methylamino-4,4,4-trifluorocrotonate, prepared by the reaction of methylamine with alkyl esters of halogenated-α,β-unsaturated-β- haloalkanoic acids in a sequence of steps using a halofluorocarbon as a starting material.
DESCRIPTION OF THE PRIOR ART Alkyl 3-(monosubstituted-amino)-4,4,4-trifluorocrotonates, and alkyl 3-
(disubstituted-amino)-4,4,4-trifluorocrotonates are commercially useful intermediate compounds used in pharmaceutical and agricultural applications to manufacture, among other things, heterocycles, including substituted-methyl nitrogen-heterocycles. In a reaction typical of commercial applications, an alkyl 3-methylamino-4,4,4- trifluorocrotonate undergoes cyclization to a trifluoromethylated-N-methylated heterocycle such as 6-trif uoromethyl-l-methyluracil.
The presently known commercial processes for the synthesis of alkyl 3- (substituted-amino)-4,4,4-trifluorocrotonates use alkyl trifluoroacetoacetates as starting materials. EP 808,826 discloses a method for preparing 3-amino-4,4,4- trihalocrotonates and their derivatives from a trihaloacetoacetate, or its analogs, in a
two step method consisting of: i) converting ethyl trifluoroacetoacetate to the ammonium salt [CF3-C (0")=COO-C2H5j [NH4 +] and ii) thermolyzing the ammonium salt to ethyl 3-amino-4,4,4-trifluorocrotonate in a subsequent step. WO 99/24,390 discloses a similar preparation of [CF3-C (0")=COO-C2H5] [CH3NH3 +] and thermo- lyzing this methylammonium salt to ethyl 3-methylamino-4,4,4-trifluorocrotonate in a subsequent step. US 6,207,830, discloses the conversion of ethyl 3-methylamino- 4,4,4-trifluorocrotonate to a l-methyl-6-trifluoromethyluracil derivative.
A major shortcoming of all currently used processes for the production of alkyl 3-methylamino-4,4,4-trifluorocrotonates and related species is that the starting material, alkyl trifluoroacetoacetate, is expensive and of limited commercial availability. For this reason, it is desirable to have an alternate process for the synthesis of an alkyl 3-(substituted-amino)-4,4,4-trifluorocrotonate that does not use an alkyl trifluoroacetoacetate as starting material.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
This need is met by the present invention. The present invention provides a novel approach for the synthesis of an alkyl halogenated-α,β-unsaturated-β- (substituted-amino) carboxylate esters of formula R^C (-NR9R10)=CH-COOR8 based upon the use of halofluorocarbons as starting material. This is particularly advantageous for the economical production of alkyl 3-methylamino-4,4,4- trifluorocrotonates.
According to one aspect of the present invention, a process is provided for preparing a halogenated aliphatic- ,β-unsaturated-β-nucleophile-functionalized carboxylate ester having the formula:
R -C(-Nu)=CH-COOR°
wherein the process includes the step of reacting a nucleophile with a halogenated aliphatic- ,β-unsaturated-β-halocarboxylate ester having the formula:
R^CX^CH-COOR8
wherein R1 is selected from straight chain and branched halogenated CrC12 aliphatic groups;
Nu is a nucleophile moiety;
X1 is F, CI or Br; and
R is selected from straight chain and branched C C6 alkyl groups.
R1 is preferably polyhalogenated, more preferably polyfluorinated and most preferably perfluorinated.
Examples of nucleophiles include, but are not limited to, anionic species such as the halide ions F", CI", Br" and I", alkoxide ions, phenoxide ions, substituted phen- oxide ions, alkylamide ions, thiolate ions, acyloxy ions, cyanide, azide, cyanate ions, thiocyanate ions, and the like, and neutral species, such as straight chain, branched or cyclic C C6 alkyl alcohols and thiols, arylthiols, and the like. A particularly preferred group of nucleophilic species are amine compounds having the formula:
NR9R10H wherein R9 and R10 are independently selected from hydrogen and straight chain or branched C*-C6 alkyl. These produce halogenated aliphatic- ,β-unsaturated-β- nucleophile-functionalized carboxylate esters in which Nu is a -NR9R10 group.
According to one embodiment of this aspect of the invention, the halogenated aliphatic-α,β-unsaturated-β-halocarboxylate ester may be part of an admixture that also includes the corresponding dihalogenated aliphatic β,β-dihalocarboxylate ester that is not unsaturated at the ,β-position. Such a compound has the structure:
R1-CX1X2CH2COOR8
R1, X1 and R8 are the same as described above with respect to the halogenated aliphatic-α,β-unsaturated-β-halocarboxylate ester. X2 is, independently of X1, F, CI or Br. The α,β-saturated dihalocarboxylate ester dehydrohalogenates in situ to the halogenated aliphatic-α,β-unsaturated-β-halocarboxylate ester, which then reacts with the nucleophilic species to form the halogenated aliphatic- ,β-unsaturated-β- nucleophile-functionalized carboxylate ester.
The halogenated aliphatic-α,β-unsaturated-β-halocarboxylate esters are prepared by esterification of the corresponding carboxylic acids. The β- halocarboxylate esters that are saturated at the ,β-position are likewise prepared by esterification of the corresponding carboxylic acids, and may then dehydrohalogenate in situ to the α,β-unsaturated-β-halocarboxylate esters.
According to one embodiment of this aspect of the invention, the halogenated aliphatic- ,β-unsaturated-β-halocarboxylic acids are formed by oxidation of aldehydes having the formula:
R1-CX1=CHCH=0
R1 and X1 are the same as described above for the halogenated aliphatic-c.,β-unsatura- ted-β-halocarboxylate esters.
In a related embodiment, the halogenated aliphatic-β,β-dihalocarboxylic acids that are saturated at the ,β-position are formed by oxidation of aldehydes having the formula:
R1CX1X2-CH2CH=0 R1 and X1 are the same as described above for the α,β-unsaturated aldehydes and X2, independently of X1, is F, CI or Br. The resulting α,β-saturated β,β-dihalocarboxylic
acids may then dehydrohalogenate to the corresponding α,β-unsaturated-β-halo- carboxylic acids.
According to another embodiment of this aspect of the present invention, the ,β-saturated and ,β-unsaturated aldehydes are together obtained by hydrolysis of a compound having the structure of Formula I:
R1-CX1X2-CH2-CHX3-ORb (I)
R1, X1 and X2 are the same as described above for the aldehydes. X3, independent of X1 and X2, is CI, Br or I. Rb is a straight chain or branched C C6 alkyl.
According to another aspect of the present invention, a process is provided for the preparation of the compounds of Formula la (which include the compounds of Formula I):
R1-CX1X2-CH2-CRaX3-ORb (la)
The process includes the step of reacting a 1,1,1-trihalogenated aliphatic compound having the formula:
R^CX^X3
with an unsaturated compound having the formula:
CH2=CRa-ORb using UN light or transition metal catalysis. Ra is hydrogen, a straight chain or branched C*-C6 alkyl, a straight chain or branched C*-C6 alkyl substituted with one or
more groups independently selected from halo, cyano, nitro, amido or nitrogen heterocycle containing five, six or seven ring members, a phenyl or a phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C C6 alkyl or C C6 alkoxy. X1, X2, X3, R1 and Rb are the same as described above with respect to Formula I.
The compounds of Formula I may also be hydrolyzed in the presence of a bisulfite salt to form useful intermediate, water-soluble compounds that may then be oxidized to the β-halocarboxylic acids of the present invention. Therefore, according to another aspect of the present invention, a process is provided including the step of hydrolyzing the compound of Formula I with a bisulfite salt having the formula
so that a mixture is obtained of a compound having the structure of Formula II:
R1CX1X2CH2CHYZ (II)
and a compound having the structure of Formula III:
wherein R1, X1 and X2 are the same as described above with respect to Formula I, Y is OH and Z is M'SO^ wherein M1 is a cation selected from alkali metal cations, alkaline earth metal cations, NH4 +, NR2H3 + and NR2R3H2 +, wherein R2 and R3 are independently straight chain or branched - alkyl, phenyl or phen C C6 alkyl. Oxidation of the bisulfite compounds of Formula II and Formula III to the corresponding carboxylic acids will include some dehydrohalogenation of the Formula II compounds to form the ,β-unsaturated-β-halocarboxylic acids.
The compounds of Formula I may also be reacted with alcohols to form useful acetal intermediate compounds that may be then oxidized to the β-halocarboxylic acids of the present invention. Therefore, according to another aspect of the present invention, a process is provided including the step of reacting the compounds of Formula I with alcohols having the formula R4OH, so that a mixture is obtained of compounds having the structures of Formula II and Formula III, wherein R1, X1 and X2 are the same as described above with respect to Formula I, Y is ORb or OR4, and Z is OR4, wherein R4 is a straight chain or branched C C6 alkyl, a straight chain or branched C C6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido or nitrogen heterocycle containing 5, 6 or 7 ring members, a phenyl, or a phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido,
alkyl or C*-C6 alkoxy. Oxidation of the acetal compounds of Formula II and Formula III to the corresponding carboxylic acid derivatives will also include some dehydrohalogenation of the Formula II compounds to form the ,β-unsaturated -β-halocarboxylic acid derivatives.
The compounds of Formula I may also be reacted with diols, dithiols, diamines, aminoalcohols, aminothiols or thioalcohols to form useful cyclic intermediate compounds that may then be oxidized to the β-halocarboxylic acids of the present invention. Therefore, according to another aspect of the present invention, a process is provided including the step of reacting the compound of Formula I with a compound having the Formula:
H-Wa-R5-W -H
so that a mixture is obtained of compounds having the structures of Formula II and
Formula III , wherein R , 1 , X vl and X are the same as described above with respect to
Formula I, and Y and Z together form a ring structure with the carbon to which they are attached having as members -Wa-R5-Wb-, wherein Wa and Wb are independently selected from O, N and S, and R5 is a C2-C3 alkylene optionally substituted with straight chain, branched or cyclic C C6 alkyl, or optionally forming part of 1,2- phenylene, which, in turn, is optionally ring-substituted with one or more groups selected from halo, cyano, nitro, amido, C*-C6 alkyl or C C6 alkoxy. Oxidation of the cyclic intermediate compounds of Formula II and Formula III to the corresponding carboxylic acid derivatives will include dehydrohalogenation of the Formula II compounds to form the α,β-unsaturated carboxylic acid derivatives.
The compounds of Formula I may also be reacted with a hydrazine to form useful hydrazone intermediate compounds that may then be oxidized to the β-halocarboxylic acids of the present invention. Therefore, according to another aspect of the present invention, a process is provided including the step of reacting the compounds of Formula I with a hydrazine having the formula NH2NHR6, so that a mixture is obtained of compounds having the structures of Formula II and Formula III, wherein R , X and X are the same as described above with respect to Formula I and Y and Z together form =NNHR6 group, wherein R6 is hydrogen, a straight chain or branched C*-C6 alkyl, a straight chain or branched -C6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido or nitrogen heterocycle containing 5, 6 or 7 ring members, a phenyl, or a phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C C6 alkyl or C C6 alkoxy.
The compounds of Formula I may also be reacted with a hydroxylamine to form useful oxime intermediate compounds. Therefore, according to another aspect of the present invention, a process is provided including the step of reacting the compounds of Formula I with a hydroxylamine having the formula NH2OR7, so that a
mixture is obtained of compounds having the structures of Formula II and Formula III,
1 1 wherein R , X and X are the same as described above with respect to Formula I and Y and Z together form =NOR7 group, wherein R7 is hydrogen, or a straight chain or branched C C6 alkyl.
The oxime and hydrazone compounds of Formula II and Formula III may be further reacted by heating with or without acid or base catalysis to form useful heterocyclic compounds. Therefore, according to another embodiment of this aspect of the invention the methods of forming the hydrazone and oxime compounds of the present invention further include the steps of further heating the hydrazone and oxime compounds so that heterocyclic compounds are obtained having the structures of Formula IVa and Formula INb:
IV /vt>
wherein G is O or ΝR6, R1 is the same as described above with respect to Formula I, and R6 is the same as described above with respect to the hydrazone compounds of Formula II and Formula III.
The processes of the present invention prepare useful compounds having biological and pharmaceutical activity, and intermediate compounds useful in the preparation of compounds having biological and pharmaceutical activity. Therefore, according to another aspect of the present invention, halogenated aliphatic-α,β- unsaturated-β-nucleophile-functionalized carbocylic acids and derivatives thereof are provided having the formula:
R'-C(-Nu)=CH-COOR8
wherein R1 is selected from straight chain and branched halogenated CrC12 aliphatic groups;
Nu is a nucleophile moiety; and
R8 is selected from hydrogen, straight chain and branched C*-C6 alkyl groups, NH4 +, R2NH3 +, alkali metal ions, alkaline earth metal ions, CI, NH2, NHR2, NHNHR2, CN, SH and SR2, wherein R2 is selected from straight chain or branched C C6 alkyl, phenyl or phen C C6 alkyl.
According to another embodiment of this aspect of the invention, aldehyde compounds are provided having the formulae:
R1-CX1=CHCH=0
and:
-lv2
RiCX1X -CH7CH=0
wherein R1, X1 and X2 are as described above for the aldehydes. According to another embodiment of this aspect of the invention, compounds are provided having the structures of Formula I and Formula la, wherein R1, X1, X2, X3, Ra and Rb are as described above for these compounds.
According to yet another embodiment of this aspect of the invention, compounds are provided having the structures of Formula II and Formula III, wherein R1, X1 and X2 are the same as described above for these compounds, and Y and Z are selected so that Y is OH when Z is M'S03, Y is OR1 when Z is OR4, or Y and Z together form a =NNHR group, a =NHOR group or, a ring structure with the carbon
to which they are attached having as members -Wa-R5-Wb-, wherein M1, R1, R4, R5, R6, R7, Wa, and Wb are the same as described above for Formula II and Formula III.
According to still yet another embodiment of this aspect of the invention, heterocyclic ring compounds are provided having the structures of Formula INa and Formula INb, wherein G, R1 and R6 are the same as described above for Formula INa and Formula INb.
As is more specifically shown in Step 1 of the five step inventive process, a halofluorocarbon is catalytically added to a substituted vinyl ether to obtain the compound of Formula la:
R1-CX1X2-CH2-CRaX3-ORb (la)
using UN light catalysis or transition metal catalysis, wherein Ra is hydrogen, or straight chain or branched CrC6 alkyl, or straight chain or branched Cι-C6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, or nitrogen heterocycle containing five, six or seven ring members; or phenyl, or phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C C6 alkyl, or C C6 alkoxy; Rb is straight chain or branched C*- C6 alkyl; X and X2 are independently selected from F, CI and Br; X3, independently of X1 and X2 is Br, CI or I; and R1 is a straight chain or branched halogenated C C12 aliphatic group. Ra is preferably hydrogen, in which case the compounds of Formula la are the compounds of Formula I. R1 is preferably polyhalogenated, and is most preferably polyfluorinated or perfluorinated.
Step 1.
R'-CX'X^3 + CH2=CRa-ORb -(Catalyst)→ RrCX'X2-CH2CRaX3-ORb
The inventive process generates useful intermediate compounds. Fluoroalkyl intermediate compounds are provided that are precursors to bioactive compounds, and others that are (or of themselves may be) bioactive, and thus are of commercial value in pharmaceutical and agricultural applications.
In Step 2 of the inventive process, C-l of Formula I, the carbon bearing the halogen X and the -OR group, is modified by one of two general methods of broad utility:
The hydrolysis of compounds of Formula I is accomplished as outlined in Step 2a to form the intermediate aldehydes R1-CX1X2CH2CH=0 and R1-CX1=CHCH=0 in water, or more preferably in a mixture of water and an organic solvent, e.g., acetone, tetrahydrofuran, or 1 ,2-dimethoxyethane. R1, X1 and X2 are the same as described above with respect to Formula I.
Step 2a.
Formula I + H20 -»
Novel variations of the hydrolysis induce derivitization of C-l of Formula I, as indicated in Step 2b. When a compound of Formula I is hydrolyzed in the presence of an organic solvent and a bisulfite salt, MΗS03, there is produced the novel intermediate compounds of Formula II and Formula III:
R'CX'X2CH2CHYZ (II)
R'CX1 =CHCHYZ (III)
wherein R1, X1 and X2 are the same as described above with respect to Formula I, Y is -OH and Z is -S03M'.
These novel intermediate compounds can be used in organic or in water solution, they can be isolated as stable solids, and they can be converted to the corresponding aldehydes in aqueous acid or base. Furthermore, these sulfonic acid salts chemically behave in a manner similar to the aldehydes without the need to isolate the aldehyde, and offer certain process advantages such as enhanced water solubility, improved stability and materials handling. The ion M1 includes ammonium ion, NH4 +, alkylammonium ions, NR2H3 +, and NR2R3H2 +, (where R2 and R3 are independently a straight chain or branched CrC6 alkyl, phenyl or phen C C6 alkyl), alkali metal ions, e.g., Na+, and K+, and alkaline earth metal ions e.g., Ca+2, and Ba+2.
When the compounds of Formula I are reacted with an alcohol, R4OH, there are produced acetal intermediate compounds having the structures of Formula II or Formula III wherein Y is 0Rb or OR4 and Z is OR4. R4 is straight chain or branched CrC6 alkyl, or straight chain or branched C C6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, or nitrogen heterocycle containing five, six or seven ring members; or phenyl, or phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C]-C6 alkyl, or CrC6 alkoxy. When the structures of Formula I are reacted with a 1,2-diol, a 1,3-diol, a 1,2- diothiol, a 1,3-diothiol, a 1,2-diamine, a 1,3-diamine, a β-aminoalcohol, a γ- aminoalcohol, a β-aminothiol, or a γ-aminothiol, i.e. compounds having the structure:
H-Wa-R5-Wb-H there are produced the novel cyclic intermediate compounds having the structures of Formula II or Formula III wherein Y and Z together with the carbon to which they are
attached form a ring having as members - Wa-R5-Wb-, wherein Wa, and Wb are independently selected from O, N or S. R5 is a C2-C3 alkylene optionally substituted with straight chain, branched or cyclic CrC6 alkyl, or a C2-C3 alkylene that is part of a 1,2-phenylene, or a C2-C3 alkylene that is part of a 1,2-phenylene substituted with one or more groups selected from halo, cyano, nitro, amido, C C6 alkyl or Cι-C6 alkoxy. These novel intermediates can be used in solution, they can be isolated, and they can be converted to the corresponding aldehyde in aqueous acid or with an aqueous Lewis acid, e.g., BF3.
When the compounds of Formula I are reacted in an organic solvent, e.g., acetic acid, with a hydrazine, NH2NHR6 there is produced the novel hydrazone intermediate compounds having the structures of Formula II or Formula III wherein Y and Z together form an =NNHR6 group, wherein R6 is hydrogen, or straight chain, branched or cyclic C C6 alkyl, or straight chain, branched or cyclic CrC6 alkyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, or nitrogen heterocycle containing five, six or seven ring members; or phenyl, or phenyl substituted with one or more groups independently selected from halo, cyano, nitro, amido, C*-C6alkyl, or C C6 alkoxy; or CrC6 alkanesulfonyl, or phenylsulfonyl, or phenylsulfonyl substituted with C Cό alkyl.
When the compounds of Formula I are reacted in an organic solvent, e.g., methanol, with a hydroxylamine, NH2OR , there is produced the novel oxime intermediate compounds having the structures of Formula II or Formula III, wherein Y and Z together form a =NOR7 group, wherein R7 is hydrogen, or C C6 alkyl. These novel intermediate compounds can be used in solution, they can be isolated, and they can be converted to the corresponding aldehyde in aqueous acid.
Step 2b.
Formula I + Reagent -> R1-CX1X2CH2CHYZ (Formula II) +
R^CX^CH-CHYZ (Formula III)
R1, X1 and X2 are the same as described above with respect to Formula I, the reagent is an alcohol, 1,2-diol, 1,3-diol, 1,2-thiol, 1,3-thiol, 1,2-diamine, 1,3-diamine, β- aminoalcohol, γ-aminoalcohol, β-aminothiol, γ-aminothiol, hydrazine, hydroxylamine, and the like, and Y and Z correspond to the groups above-described as being obtained when these reagents are used.
The oxime and hydrazone derivatives can be further heated to produce the heterocyclic derivatives of Formula IN, wherein G is O or ΝR wherein R is defined as before, and R1 is the same as described above with respect to Formula I
It is understood that dehydrohalogenation to halogenated-α,β-unsaturated-β- halocarboxaldehydes, R'-CX'=CH-CH=0, and to the various halogenated-α,β- unsaturated-β-haloalkane structures of Formula III, R'-CX^CH-CHYZ, can occur to varying amounts depending on the specific reaction and process conditions in Steps 2a, and 2b. In Step 3a and Step 3b the aldehydes from Step 2a or the related derivatives from Step 2b respectively are oxidized to the intermediates R1-CXIX2CH2COOH and
R^CX^CH-COOH using e.g., chromic acid, potassium permanganate, or other oxidizing agents known to those skilled in the art. R , X and X are the same as described above with respect to Formula I. Step 3a.
R^CX'X^HzCH^O + R1-CX1=CHCH=0
-> R'-CX'X^H^OOH + R'-CX^CH-COOH
Step 3b.
R'-CX^CHzCHYZ + R^CX^CH-CHYZ
-» R'-CX^CT^COOH + R'-CX^CH-COOH
It is understood that dehydrohalogenation to halogenated- α,β -unsaturated- β- halocarboxylic acids, R'-CX^CH-COOH, can occur to varying amounts depending on the specific oxidizing agent and reaction conditions in Step 3a and 3b. The carboxylic acids from Step 3a and 3b can be isolated as salts R!-C X1X2CH2COOM2 and R'-CX^CH-COOM2, where the ion M2 includes ammonium ion, NH4 +, alkylammonium ion, R2NH3 +, alkali metal ions, e.g., Na+, and K+, and alkaline earth metal ions e.g., Ca+2, and Ba+2. It is further recognized that the carboxylic acid, - COOH, can be reacted to form standard derivatives such as -CO-Cl, -CO-NH2, -CO- NHR, -CO-NHNHR, -CN, -CO-SH, and -CO-SR by standard methods known to those skilled in the art.
Step 4 involves the esterification of the carboxylic acid derivatives from Step 3a and 3b with a compound capable of transferring the alkyl group, R8, to obtain the alkyl ester thereof. The reaction can be carried out in the presence of a base, e.g., potassium carbonate, with an alkylating agent, e.g., an alkyl halide such as ethyl
bromide. The reaction can be carried out in the presence of an acid, e.g., methanesulfonic acid, and excess alcohol, e.g., n-butanol. R is a straight chain or branched CrC6 alkyl.
Step 4.
R'-CX^CHaCOOH + R1-CX=CH-COOH
-> R'-CX^CT COOR8 + R^CX^CH-COOR8
It is understood that dehydrohalogenation to halogenated- ,β -unsaturated- β- halocarboxylate esters, R^CX^CH-COOR8, can occur to varying amounts depending on the specific reaction conditions in Step 4.
The final product, having the structure of Formula N:
R -C (-ΝR9R10)=CH-COOR8 (V)
is obtained in Step 5a, by reaction of R'-C X^CHaCOOR8 and R^CX^CH-COOR8 with a reagent capable of transferring a substituted-amino group.
Step 5a. R^CX^O COOR8 + R'-CX^CH-COOR8 +
NR9R10H - RJ-C (-NR9R10)=CH-COOR8 (Formula V)
It is understood that structures R'-C X1X2CH2COOR8 undergo dehydrohalogenation in situ to halogenated-α,β-unsaturated -β-halocarboxylate esters, which then react further to form the desired R!-C (-NR9R10)=CH-COOR8. R9 and R10 are independently selected from hydrogen, and straight chain or branched C*-C6 alkyl.
In Step 5b, in a similar manner, other nucleophilic species, Nu, react with the esters from Step 4 to produce a halogenated-α,β-unsaturated-β-(Nu-functionalized) carboxylate ester of Formula VI:
Step 5b.
R'-C (-Nu)=CH-COOR8 (VI)
Nu is selected from anionic species, for example halide ion, I", Br", F, or alkoxide ion, phenoxide ion, or substituted-phenoxide ion, alkylamide ion, thiolate ion, acyloxy anion, cyanide ion, azide ion, cyanate ion, thiocyanate ion, or neutral species, for example straight chain or branched or cyclic C C alkyl alcohols, or alkyl or aryl thiols.
Steps 1-5 occur at or near atmospheric pressure. The temperature of reaction ranges from 0°C to 100 °C. The method of separating the intermediates and the final products from the reaction mixtures are selected from standard manipulative techniques, including distillation, or crystallization.
Another aspect of the present invention is that the compounds of Formula V and VI wherein R1 is CF3 are chemically equivalent and convertible to trifluoromethyl ketone derivatives, CF3-CO-.CH=CH-COOR8. Such ketones have been used as intermediates in heterocyclic synthesis and have also been viewed as synthetic targets because of their possible pharmacological interest. Trifluoromethyl ketones are a particularly well-documented class of serine protease inhibitors, which have proven attractive against elastase, chymotrypsin, and CMV protease.
By way of further description of the various substituents in the inventive process R1 as a halogenated aliphatic radical, is preferably a substituted or unsubstituted C*-C12 halogenated aliphatic radical, and is more preferably fluorinated. Even more preferably, R1 is a perfluorinated aliphatic radical, and more preferably
perfluorinated. Examples of substitution groups include C C6 alphatics such as alkyls, alkyl ethers, alkyl esters and alkenyls containing nitro, aminos (primary and secondary), cyano, hydroxyl, thiol and alkylthio groups. The substitution groups are preferably attached to non-fluorinated carbon atoms of R1. R1 as a C*-C12 halogenated alkyl radical may be straight-chained or branched, for example, halogenated methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl or 2-ethylhexyl. Any of these groups may be substituted with essentially any conventional organic moiety, for example, methoxy, ethoxy, n- or iso- propoxy, n-butoxy, methane sulphonyl or cyano.
C C6 fluorinated alkyl radicals are even more preferred. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, fluorethyl, difluoroeythl, trifluoroethyl, pentafluoroethyl, perfluoropropyl, perfluorobutyl, perfluoropentyl or perfluorohexyl. In the most preferred form, R1 is a trifluoromethyl radical.
Two preferred halofluorocarbon starting materials are the isomeric pair CFC- 113 (l,2,2-trichloro-l,l,2-trifluoroethane) and CFC 113a ( 1,1,1 -trichloro-2,2,2- trifluoroethane). More preferably, the starting material is l,l,l-trichloro-2,2,2- trir uoroethane, CFC-113a, which has the structure of CF3CC13. It has been discovered that CFC-113a reacts with specificity in a way that allows incorporation of the CF3- functional group into the target molecules. In Step 1 of the present invention the halofluorocarbon is photocatalytically added to an alkyl vinyl ether, preferably at a temperature between 25-40 °C. Suitable reagents, solvents and process conditions may be determined by reference to Bosone et.al., Pesticide Sci.. 17(6), 621-630 (1986) and also to EP 31,041, both incorporated herein by reference. Conditions suitable for transition metal catalyzed addition of halofluorocarbons to trialkylsilyl vinyl ethers may be determined by reference to
Eguchi et al., J. Org. Chem., 58, 5163-5166 (1993) incoφorated herein by reference.
The hydrolysis of Step 2a is carried out over a period of 2-12 hours at approximately 20 °C, preferably with aqueous tetrahydrofuran, followed by isolation of the aldehyde, or by further reaction with one of the reagents of Step 2b. In a preferred example of derivatization in Step 2b, structures of Formula I are stirred with a solution of NaHS03 in aqueous tetrahydrofuran for 5-20 hours at 20 °C, and the majority of the water and tetrahydrofuran are removed in vacuo, and the solid halogenated hydroxyalkanesulfonic acid salt is isolated by filtration.
The oxidation of Step 3 is performed in aqueous chromic acid for 15-25 hours at approximately 20 °C in the presence of an organic solvent, for example diethyl ether, or dibutyl ether, or more preferably tetrahydrofuran, followed by phase separation, washing with brine and vacuum distillation. The oxidation of Step 3 may also be performed using hypochlorous acid in alcohol solvent to allow direct formation of the corresponding carboxylate ester.
The esterification of Step 4 is best performed in the presence of excess alcohol, for example methanol, ethanol or n-butanol, and an acid catalyst, for example methanesulfonic acid with sufficient heat to cause reaction. The water produced is distilled off as an azeotrope with the alcohol, or is removed by trapping with the appropriate drying agent, e.g., 3A molecular sieve. The ester is then isolated by direct distillation from the reactor. The reaction of the ester with the substituted amine in Step 5 preferably involves stirring the haloester with an excess of the substituted-amine in water solvent or in an organic solvent, or more preferably neat, at approximately 0-75 °C, at a pressure of approximately 0-200 psig for 1-20 hours. Following the reaction, the amine hydrochloride salt solid by-product is filtered off or is extracted from the mixture with water and the desired halogenated- β- (substituted-amino) crotonate ester is distilled or recrytallized.
Example 1. Ethyl 3-methylamino-4, 4,4-trifluorocrotonate (Step 5a)
Ethyl 3-chloro-4,4,4-trifluorocrotonate (2.01 g, 9.93 mmol) was placed in a 90 cc glass pressure reactor containing a magnetic stir bar. The system was freeze-thaw degassed and then anhydrous methylamine (5 g) was condensed into the reactor at -70 °C. The mixture was warmed to 15-20 °C with stirring for 90 minutes. Excess methylamine was vented; the methylamine hydrochloride solid was filtered off, and rinsed with 1 mL of CH2C12. The filtrate was distilled to yield 1.5 g of ethyl 3- methylamino-4,4,4-trifluorocrotonate, bp 70 °C at ca. 20 mm Hg.
Example 2. Ethyl 3-Cyano-4,4,4-trifluorocrotonate by Reaction of Ethyl 3- chloro-4,4,4-trifluorocrotonate with Potassium Cyanide (Step 5b)
A mixture of ethyl 3-chloro-4,4,4-trifluorocrotonate (4.0 g, 20 mmol) and potassium cyanide (1.4 g, 21 mmol) in 25 mL of ethanol was refluxed under nitrogen for 10 hours. The mixture was fractionally distilled to provide the ethyl 3-cyano-4,4,4- trifluorocrotonate in 85 % yield.
Example 3. 3,3-Dichloro-4,4,4-trifluorobutyraldehyde and 3-Chloro-4,4,4- trifluorocrotonaldehyde (Step 2a) n-Butyl 1,3,3 trichloro-4,4,4-trifluorobutyl ether was added to a stirred mixture of excess water and tetrahydrofuran at 25 °C, with additional stirring for 2 hours. GC and NMR analyses indicated > 99 % conversion with > 99 % selectivity for 3,3- dichloro-4,4,4-trifluorobutyraldehyde. The addition of aqueous potassium hydroxide to pH-adjust to pH +1.0 causes dehydrochlorination to 3-chloro-4,4,4-trifluorocroton- aldehyde in >95% conversion and >75% selectivity by gc and nmr analyses.
Comparative Example 1. Preparation of 3,3-Dichloro-4,4,4- trifluorobutyraldehyde in Aqueous Sodium Carbonate n-Butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether (287.8 g, 1.0 mol) was stirred with 1.12L of 10 % (wt) aqueous sodium carbonate for 24 hours under nitrogen. The insoluble organic layer was phase separated, dried over MgS04, and distilled to provide 58.1 g of 3-chloro-4,4,4-trifluorocrotonaldehyde (32% yield), ca. 88 % pure by GC and NMR analyses, bp 74-78 °C, as a bright yellow lachrymatory oil, and 4 g of 3,3-dichloro-4,4,4-trifluorobutyraldehyde, (3% yield), bp ca 85-95 °C.
Example 4. 3,3-Dichloro-l-hydroxy-4,4,4-trifluorobutanesulfonic Acid Sodium Salt (Step 2b) n-Butyl 1,3,3 trichloro-4,4,4-trifluorobutyl ether (28.74 g, 0.1 mol) was added to a stirred mixture of tetrahydrofuran (88.4 g) and 59.7 g of an aqueous solution of 40%(wt) sodium bisulfite, with additional stirring for 12 hours. NMR analyses indicated > 99 % conversion with >99 % selectivity for 3,3-dichloro-4,4,4-trifluoro-l- hydroxybutanesulfonic acid sodium salt. The volatiles were removed in vacuo to leave 38.6 g of solid containing of crude 3,3-dichloro-l-hydroxy-4,4,4- trifluorobutanesulfonic acid sodium salt as a stable white salt.
Example 5. 3,3-Dichloro-l-hydroxy-4,4,4-trifluorobutanesulfonic Acid Sodium Salt, and 3-Chloro-l-hydroxy-4,4,4-trifluoro-2-butenesulfonic Acid Sodium Salt (Step 2b) n-Butyl 1,3,3 trichloro-4,4,4-trir uorobutyl ether (29.57g, 0.10 mol) was added dropwise to a mixture of tetrahydrofuran (100 mL) and saturated aqueous brine (29 mL) maintained at 25 °C. After 30 minutes the organic layer is separated and washed with brine. The organic layer is then added to 48.9 g of 40 % (wt) sodium bisulfite
solution at 25 °C with stirring for an additional 20 hours. The organic layer (upper) is phase separated and stripped to dryness in vacuo to yield 26.46 g of stable white solid crystals. NMR analyses indicated > 99 % conversion to a mixture of 3,3-dichloro- 4,4,4-trifluoro-l-hydroxybutane-sulfonic acid sodium salt (92 %) and 3-chloro-4,4,4- trifluoro-l-hydroxy-2-butene-sulfonic acid sodium salt (8 %).
Example 6. Preparation of the Hydrazone of 3-Chloro-4,4,4- trifluorocrotonaldehyde (Step 2b)
To a solution of n-butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether (4.32 g, 15 mmol), acetic acid (10.4 g, 0.17 mol), water (3.25 g), and p-toluenesulfonic acid monohydrate (0.58 g) was added at once hydrazine monohydrate (6.03 g, 0.12 mol) with vigorous stirring under nitrogen, and with external cooling to maintain the temperature below 60 °C. After 1 hour the reaction mixture was analyzed by GC, GC/MS, and l9F and 1HNMR and found to contain a trace of unreacted starting material, and 3-(trifluoromethyl) pyrazole (17%), plus a component identified as the hydrazone of 3-chloro-4,4,4-trifluorocrotonaldehyde (69%).
Example 7. 3-Chloro-(l,l-ethylenedioxy)-4,4,4-trifluoro-2-butene (Step 2b) n-Butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether (286.4 g, 1.0 mol) was slowly added to stirred ethylene glycol (389 g, 6.3 mol) at 105 °C (Note exotherm) with additional stirring for 2-3 hours at 105 °C until HC1 gas evolution ceased. The reaction mixture was fractionally distilled to yield 97.3 g of 3-chloro-(l,l-ethylenedioxy)-4,4,4- trifluoro-2-butene, bp 71-85 °C at 30 mm Hg.
Example 8. 3-Chloro-((l,l),(3,3)-bis-ethylenedioxy))-4,4,4-trifluorobutane
Examination of the pot residue, 50.1 g of a mobile red oil from Example 7 indicated the major component to be 3-chloro-((l,l),(3,3)-bis-ethylenedioxy))-4,4,4- trifluorobutane, identified by NMR and GC/MS.
Example 9. 3-Chloro-4,4,4-trifluorocrotonic Acid, and 3,3-Dichloro-4,4,4- trifluorobutyric Acid (Step 3a)
Dilute aqueous chromic acid (540 g, ca. 0.9 mol) was added over 1 hour to a stirred solution of 3-chloro-4,4,4-trifluorocrotonaldehyde and 3,3-dichloro-4,4,4- trifluorobutyraldehyde (71.3 g total, ca 0.4 mol) in diethyl ether (700 ml) at 20 °C. After stirring 18 hours at 20 °C the mixture was phase separated and the organic phase was washed with brine. Distillation gave 69.2 g of a mixture of 3-chloro-4,4,4- trifluorocrotonic acid (major), and 3,3-dichloro-4,4,4-trifluorobutyric acid (minor), bp 65-75 °C at 4 mm Hg as oily colorless crystals, 95 % pure by GC and by NMR analyses.
Example 10. 3-Chloro-4,4,4-trifluorocrotonic Acid and 3,3-Dichloro-4,4,4- trifluorobutyric Acid (Step 3b)
Dilute aqueous chromic acid (18 g) was added over 1 hour to a stirred mixture of 1.04 g of the sulfonic acid salts from Example 5 in water (3.1 g) and ether (3.2 g) at 20 °C. After stirring 18 hours at 20 °C the mixture was phase separated and the organic phase was washed with brine. NMR and GC analyses indicated a mixture of 3,3-dichloro- 4,4,4-trifluorobutyric acid and 3-chloro-4,4,4-trifluorocrotonic acid in > 90% purity.
Example 11. Ethyl 3-chloro-4,4,4-trifluorocrotonate (Step 4)
A solution of 3-chloro-4,4,4-trifluorocrotonic acid (2.0 g) was stirred with a solution of methanesulfonic acid (0.05 g) in ethanol at reflux for 6 hours under nitrogen with slow removal of the distillate containing water of reaction. The reaction mixture was then fractionally distilled in vacuo to give 1.8 g of ethyl 3-chloro-4,4,4- trifluorocrotonate, bp 82-83 °C at 108 mm Hg, > 95 % pure by GC and NMR.
Example 12. Preparation of 3-(Trifluoromethyl)pyrazole (Step 2b)
To a solution of p-toluenesulfonic acid monohydrate (46 g, 0.24 mol) in anhydrous acetic acid (432 g, 7.2 mol) was added hydrazine monohydrate (185 g, 3.62 mol) with vigorous stirring over 10 mins under nitrogen and external cooling to maintain the temperature below 100 °C. Crude butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether ( 345 g, 1.2 mol) was added over 25 mins with vigorous stirring at 95 °C. An exotherm ensues within 3 mins of complete addition causing vigorous reflux at 107 °C, accompanied by rapid HC1 gas evolution (Caution, this is an extremely vigorous reaction!). A suspension (hydrazine hydrochloride salt) formed. Stirring continued at 85-100 °C for another 75 mins. Butyl acetate and acetic acid were distilled off, at 60°C and 70-15 mm Hg to constant weight, ca. 470 g. The semi-solid was cooled to 20 °C, followed by the addition of 500 mL hexane. After cooling to 10 °C 720 mL of 10 % (wt) aqueous sodium carbonate was added over one hour with vigorous stirring under nitrogen. Solid sodium bicarbonate (175 g) was then added incrementally over 2 hours at 10 °C; stirring continued for an additional hour until there was no further C02 gas evolution. The solids were filtered off, with the filter cake rinsed with hexane (two times with 150 mL). The combined organic layers were washed with 200 mL of saturated brine solution and then distilled through a 6" vigreux column to
provide 108.2 g (66% yield) 3-(trifluoromethyl) pyrazole as a white-cream colored solid, bp 63 °C at 2 mm Hg, mp 46-50 °C, > 97 % pure (GC, and Η and 19F NMR).
Comparative Example 2. Attempted Preparation of 3-(Trifluoromethyl) Pyrazole: Sodium Dithionite Procedure
The literature procedure was conducted without success (see C-M. Hu et al., J. Chem. Soc, Perkins Transactions I, 2161-2163 (1994)).
Comparative Example 3. Attempted Preparation of 3-(Trifluoromethyl) pyrazole: Reaction of Hydrazine Hydrate with n-Butyl l,3,3-Trichloro-4,4,4- trifluorobutyl Ether in Refluxing Ethanol; Preparation of 1-n-Butoxy -3,3- Dichloro-l-Ethoxy-4,4,4-trifluorobutane
A solution of n-butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether (1.47 g, 5.1 mmol), hydrazine monohydrate (1.99 g, 24.9 mmol) and ethanol (11 mL) was refluxed under nitrogen for four hours. GC indicated a single new component, and Η and 19F NMR were consistent with formation of the mixed acetal l-n-butoxy-3,3-dichloro-l-ethoxy- 4,4,4-trifluorobutane.
Comparative Example 4. Attempted Preparation of 3 -(Trifluoromethyl) pyrazole: Reaction of Hydrazine Hydrate with n-Butyl l,3,3-Trichloro-4,4,4- trifluorobutyl Ether at 85 °C in Ethanol Containing Aqueous Acetic Acid
A solution of butyl l,3,3-trichloro-4,4,4-trifluorobutyl ether (1.44 g, 5.0 mmol), hydrazine monohydrate (2.0 g, 25 mmol), acetic acid (1.5 g, 26 mmol), water (1.0 g, 58 mmol), p-toluenesulfonic acid monohydrate (0.05 g, 0.2 mmol) and ethanol (10 mL) was stirred at 85 °C under nitrogen for 2 hours. GC indicated a single
component, and Η and 19F NMR were consistent with formation of the mixed acetal l-n-butoxy-3,3-dichloro-l -ethoxy -4,4,4-trifιuorobutane.
Example 13. Ethyl 3-amino-4,4,4-trifluorocrotonate by Reaction of Ethyl 3- chloro-4,4,4-trifluorocrotonate with Anhydrous Ammonia (Step 5a)
Ethyl 3-chloro-4,4,4-trifluorocrotonate (2.01 g, 9.93 mmol) was placed in a 90 cc glass pressure reactor containing a magnetic stir bar. The system was freeze-thaw degassed and then anhydrous ammonia (5.03 g, 295 mmol) was condensed into the reactor at -70°C. The mixture was warmed to 15-20°C with stirring for 90 minutes (Pmax ca. 102 psig.). Excess ammonia was vented, the NH4C1 solid was filtered off, and rinsed with ImL of CH2C12 to give 0.45 g white solid NH4C1 (92 %). The filtrate was distilled to yield 1.76 g of ethyl 3-amino-4,4,4-trifluorocrotonate (97% yield), bp 71 °C at 27 mm Hg, colorless oily solid, mp ca. 20°C.
Example 14. Ethyl 3-amino-4,4,4-trifluorocrotonate by Reaction of Ethyl 3- chloro-4,4,4-trifluorocrotonate with Aqueous Ammonia (Step 5a)
Ethyl 3-chloro-4,4,4-trif_uorocrotonate (ca. 50 mg, mmol) was stirred with 0.5 mL of 29 % (wt) aqueous ammonia at 25 °C for 2 hours. The clear colorless solution was extracted with 0.2 mL methylene chloride. GC analysis indicated > 99 % conversion with 100 % selectivity for ethyl 3-amino-4,4,4-trifluorocrotonate.
Example 15. Ethyl 3-amino-4,4,4-trifluorocrotonate by Reaction of Ethyl 3- chloro-4,4,4-trifluorocrotonate with Ammonium Acetate (Step 5a)
A solution of ethyl 3-chloro-4,4,4-trifluorocrotonate (0.99 g. 4.89 mmol) and ammonium acetate (7.70 g, 100 mmol) in 12 mL of ethanol was refluxed under nitrogen with periodic GC analysis; see Table 1 for results.
Table 1. Formation of Ethyl 3-amino-4,4,4-trifluorocrotonate Using Ammonium Acetate in Refluxing Ethanol (Relative GC area %)
* Note: an additional 1.54 g (20 mmol) of ammonium acetate was added after 26 hours of reflux.
Example 16. n-Butyl l,3,3-Trichloro-4,4,4-trifluorobutyl Ether (Step 1)
A solution of CF3CC13 (1438 g, 7.67 mol) and n-butyl vinyl ether (254 g, 2.49 mol) was irradiated with a 450 watt medium pressure Hg UV lamp with quartz immersion well for 2.5 hours with stirring at 40°C. Conversion is 100% and the majority of the excess CF3CCI3 was distilled off in vacuo leaving a residual clear light yellow- colorless oil containing 88% (mol) n-butyl 1,3,3 trichloro-4,4,4-trifluorobutyl ether and 12% CF3CCI3. The yield of ether is 700g (98 % yield), > 98 % pure (excluding 113a, by 1H and 19 F NMR analysis.) The ether, stable when stored under nitrogen at 5°C, is used without further purification.
Example 17. Ethyl l,3,3-trichloro-4,4,4-trifluorobutyl Ether (Step 1)
A solution of CF3CC13 (850 g, 4.53 mol) and ethyl vinyl ether (218 g, 3.03 mol) was irradiated similarly to Example 16 above. After 12 hours the conversion and
selectivity is > 90%. The majority of the excess CF3CC13 was distilled of in vacuo leaving a clear light yellow - colorless oil in 70-90 % yield by nmr analysis. This ethyl ether derivative is unstable, and is used immediately without further purification.
Example 18. Ethyl 3-chloro-4,4,4-trifluorocrotonate (Step 4)
A solution of 3-chloro-4,4,4-trifluorocrotonic acid (15.6 g, 0.090 mol) was stirred with a mixture of anhydrous potassium carbonate (14.1 g, 0.102 mol), ethyl bromide (221 g, 2.03 mol), Aliquat 336™ (0.5 h, 1.3 mmol), and Adogen 464™ (0.57 g) at 25 °C for 93 hours under nitrogen. Then inorganic solids were filtered off through a thin pad of silica gel with rinsing by methylene chloride. Distillation gave 10.3 g (57 % yield) of ethyl 3-chloro-4,4,4-trifluorocrotonate, bp 82-83°C at 108 mm Hg, > 99 % pure by GC and NMR.
Claims
1. A process for preparing a halogenated aliphatic-α,β-unsaturated-β- nucleophile-functionalized carboxylate ester having the formula:
R'-C(-Nu)=CH-COOR8
comprising reacting a nucleophile with a halogenated aliphatic-α,β-unsaturated-β- halocarboxylate ester having the formula:
R'-CX^CH-COOR8
wherein R is selected from the group consisting of straight chain and branched halogenated C*-Cι2 aliphatic groups;
Nu is a nucleophile moiety different from X1; X1 is F, CI or Br; and
R8 is selected from the group consisting of straight chain and branched C C6 alkyl groups.
2. The process of claim 1, wherein said nucleophile is selected from the group consisting of F", CI", Br", I", alkoxide ions, phenoxide ions, substituted phenoxide ions, alkylamide ions, thiolate ions, acyloxy ions, cyanide ions, azide ions, cyanate ions, thiocyanate ions, straight chain, branched and cyclic C C6 alkyl alcohols, straight chain, branched and cyclic C C6 alkyl thiols and arylthiols.
3. The process of claim 1, wherein said nucleophile is an amine compound having the formula NR9R10H, wherein R9 and R10 are independently selected from the group consisting of hydrogen and straight chain and branched C C6 alkyl groups.
4. The process of claim 1, wherein said halogenated aliphatic-α,β- unsaturated-β-halocarboxylate ester is in admixture with a halogenated aliphatic- ,β- saturated-β,β-dihalocarboxylate ester having the formula:
R1-CX1X2CH2COOR8
wherein X2 is, independently of X1, F, CI or Br.
5. The process of claim 4, wherein said halogenated aliphatic-β- halocarboxylate esters and halogenated aliphatic- ,β-saturated-β,β-dihalocarboxylate esters are prepared by esterification of carboxylic acids.
6. The process of claim 5, wherein the halogenated aliphatic-β-halo- carboxylic acids and halogenated aliphatic- ,β-saturated-β,β-dihalocarboxylic acids are formed by oxidation of an admixture of aldehydes having the formulae:
R1-CX1=CHCH=0 and
R1CX,X2-CH9CH=0
9 I wherein X , independently of X , is F, CI or Br.
7. The process of claim 6, wherein said aldehydes are together obtained by hydrolysis of an ether compound having the formula:
R ' -CX ' X2-CH2-CHX3-ORb
wherein X3, independent of X1 and X2, is CI, Br or I, and Rb is a straight chain or branched C C6 alkyl group.
8. The process of claim 5, wherein the halogenated aliphatic-β-halo- carboxylic acids and halogenated aliphatic- ,β-saturated-β,β-dihalocarboxylic acids are formed by oxidation of an admixture of compounds having the formulae:
R^CX ^CHCHYZ and R1CX,X2-CH2CHYZ wherein X2, independently of X1, is F, CI or Br; and
Y is OH when Z is M^Os, or Y is ORb or OR4 when Z is OR4, or Y and Z together form a =NNHR6 group, a =NHOR7 group or, a ring structure with the carbon to which they are attached having as members -Wa-R5-Wb-; wherein M1 is a cation selected from the group consisting of alkali metal cations, alkaline earth metal cations, NH4 +, NR2H3 + and NR2R3H2 +; Rb is a straight chain or branched C C6 alkyl group.
R and R are independently selected from the group consisting of straight chain and branched C C6 alkyl, phenyl and phen C C6 alkyl groups; R4 is selected from the group consisting of straight chain and branched CrC6 alkyl groups, straight chain and branched C*-C6 alkyl groups substituted with one or
more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycles containing 5, 6 and 7 ring members, phenyl and phenyl substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, CrC6 alkyl groups and C*-C6 alkoxy groups;
R5 is selected from the group consisting of C2-C3 alkylene optionally substituted with straight chain, branched or cyclic Cι-C6 alkyl groups, or C2-C3 alkylene optionally forming part of a 1 ,2-phenylene ring optionally ring-substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C C6 alkyl groups or C C6 alkoxy groups;
R6 is selected from the group consisting of straight chain and branched C C6 alkyl groups, straight chain and branched C C6 alkyl groups substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycles containing 5, 6 and 7 ring members, phenyl and phenyl substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C C6 alkyl groups and C C6 alkoxy groups;
R is selected from the group consisting of hydrogen, and straight chain and branched C C6 alkyl groups; and
Wa and Wb are independently selected from the group consisting of O, N and S
9. The process of claim 8, wherein Y is OH and Z is M'S03, and said admixture of compounds is formed by reacting a bisulfite salt having the formula M1HS03 with an ether compound having the formula:
R l -CX ' X2-CH2-CHX3-ORb wherein X3, independent of X1 and X2, is CI, Br or I, and Rb is a straight chain or branched C C6 alkyl group.
10. The process of claim 8, wherein Y is ORb or OR4, and Z is OR4, and said admixture of compounds is formed by reacting an alcohol having the formula R4OH with an ether compound having the formula:
R1-CX1X2-CH2-CHX3-ORb
wherein X3, independent of X1 and X2, is CI, Br or I, and Rb is a straight chain or branched C C6 alkyl group.
11. The process of claim 8, wherein Y and Z together form a =NNHR6 group, and said admixture of compounds is formed by reacting a hydrazine compound having the formula NH2NHR6 with an ether compound having the formula:
R1-CX1X2-CH2-CHX3-OR
wherein X3, independent of X1 and X2, is CI, Br or I, and Rb is a straight chain or branched C C6 alkyl group.
12. The process of claim 8, wherein Y and Z together form a =NOR7 group, and said admixture of compounds is formed by reacting a hydroxylamine having the formula NH2OR7 with an ether compound having the formula:
R1-CX1X2-CH2-CHX3-ORb
wherein X3, independent of X1 and X2, is CI, Br or I, and Rb is a straight chain or branched C*-C alkyl group.
13. The process of claim 8, wherein Y and Z together form a ring structure with the carbon to which they are attached having as members -Wa-R5-Wb-; and said admixture of compounds is formed by reacting an compound having the formula HWa-R5-WbH with an ether compound having the formula:
R1 -CX ' X2-CH2-CHX3-ORb
1 9 h wherein X , independent of X and X , is CI, Br or I, and R is a straight chain or branched C*-C6 alkyl group.
14. The process of claim 7, 9, 10, 11, 12 or 13, wherein said ether compound is prepared by reacting a 1,1,1-trihalogenated aliphatic compound having the formula:
R'-CX'X^3
with an unsaturated compound having the formula:
CH2=CH-ORD
using UV light or transition metal catalysis.
15. A process for preparing an ether compound having the formula:
R1-CX1X2-CH2-CRaX3-ORb comprising reacting a 1,1,1-trihalogenated aliphatic compound having the formula:
R'-CX'X^3
with an unsaturated compound having the formula:
CH2=CRa-ORb
using UV light or transition metal catalysis, wherein R1 is selected from the group consisting of straight chain and branched halogenated C C12 aliphatic groups;
X and X are independently selected from the group consisting of F, CI and Br, and X3 is, independently of X1 and X2, CI, Br or I;
Ra is selected from the group consisting of hydrogen, straight chain and branched C*-C6 alkyls, straight chain and branched C C6 alkyls substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycle containing five, six and seven ring members, phenyl and phenyl substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C C6 alkyl and C C6 alkoxy; and
Rb is a straight chain or branched C C6 alkyl group.
16. The process of claim 15, wherein Ra is hydrogen, and said process further comprises the step of hydrolyzing said ether compound to form an admixture of aldehydes having the formulae:
R1-CX1=CHCH=0 and
R1CX1X2-CH2CH=0.
17. The process of claim 15, wherein Ra is hydrogen, and said process further comprises the step of reacting said ether compound with a bisulfite salt having the formula MΗS03 to form an admixture of compounds having the formulae:
R'-CX^CHCHYZ and R1CX1X2-CH2CHYZ
wherein Y is OH, Z is M'S03, M1 is a cation selected from the group consisting of alkali metal cations, alkaline earth metal cations, NH4 +, NR2H3 + and NR2R3H2 +, and R2 and R3 are independently selected from the group consisting of straight chain and branched Cι-C6 alkyl, phenyl and phen C C6 alkyl groups.
18. The process of claim 15, wherein Ra is hydrogen, and said process further comprises the step of reacting said ether compound with an alcohol having the formula R4OH to form an admixture of compounds having the formulae:
R^CX^CHCHYZ and R1CXIX2-CH2CHYZ
wherein Y is ORb or OR4, Z is OR4 and R4 is selected from the group consisting of straight chain and branched C C6 alkyl groups, straight chain and branched C*-C6 alkyl groups substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycles containing 5, 6 and 7 ring members, phenyl and phenyl substituted with one or more groups
independently selected from the group consisting of halo, cyano, nitro, amido, C C6 alkyl groups and C*-C6 alkoxy groups.
19. The process of claim 15, wherein Ra is hydrogen, and said process further comprises the step of reacting said ether compound with a compound having the formula HWa-R5-WbH to form an admixture of compounds having the formulae:
R^CX^CHCHYZ and R'CX'X^CHzCHYZ wherein Y and Z together form a ring structure with the carbon to which they are attached having as members -Wa-R5-Wb-; R5 is a C2-C3 alkylene optionally substituted with a straight chain, branched or cyclic CrC6 alkyl group, or a C2-C3 alkylene forming part of 1,2-phenylene ring optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C*-C6 alkyl groups and C C6 alkoxy groups; and Wa and Wb are independently selected from the group consisting of O, N and S.
20. The process of claim 15, wherein Ra is hydrogen, and said process further comprises the step of reacting said ether compound with a hydrazine compound having the formula NH2NHR6 to form an admixture of compounds having the formulae:
R'-CX^CHCHYZ and R1CX1X2-CH2CHYZ wherein Y and Z together form a =NNHR6 group, and R6 is selected from the group consisting of straight chain and branched C C6 alkyl groups, straight chain and
branched C C6 alkyl groups substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycles containing 5, 6 and 7 ring members, phenyl and phenyl substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C C6 alkyl groups and CrC6 alkoxy groups.
21. The process of claim 15, wherein Ra is hydrogen, and said process further comprises the step of reacting said ether compound with a hydroxylamine compound having the formula NH2OR7 to form an admixture of compounds having the formulae:
R^CX ^CHCHYZ and R1CXIX2-CH2CHYZ
7 7 wherein Y and Z together form a =NOR group, and R is selected from the group consisting of hydrogen, and straight chain and branched C*-C6 alkyl groups.
22. The process of claim 20 or claim 21, additionally comprising the step of further heating said admixture to produce either the heterocyclic compound of Formula IVa or the heterocyclic compound of Formula IVb
23. The process of claim 1 or claim 15, wherein R1 is a substituted or unsubstituted C Cι2 halogenated aliphatic radical.
24. The process of claim 23, wherein R1 is fluorinated.
25. The process of claim 24, wherein R1 is polyfluorinated.
26. The process of claim 25, wherein R1 is perfluorinated.
27. The process of claim 23, wherein R1 is substituted with one or more groups independently selected from the group consisting of C C6 alkyls, C C6 alkyl ethers, C*-C6 alkyl esters and CrC6 alkenyls, each optionally containing one or more nitro, primary amino, secondary amino, cyano, hydroxyl, thiol or C C6 alkylthiol groups.
28. The process of claim 23, wherein R is selected from the group consisting of halogenated methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl or 2-ethylhexyl optionally further substituted with one or more groups independently selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, methane sulphonyl and cyano.
29. The process of claim 28, wherein R1 is selected from the group consisting of C*-C6 fluorinated alkyl radicals.
30. The process of claim 29, wherein R1 is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, fluorethyl, difluoroeythl,
trifluoroethyl, pentafluoroethyl, perfluoropropyl, perfluorobutyl, perfluoropentyl and perfluorohexyl groups.
31. The process of claim 30, wherein R1 is a trifluoromethyl group.
32. A compound having the formula:
R1-C(-Nu)=CH-COOR8 wherein R1 is selected from the group consisting of straight chain and branched halogenated C C12 aliphatic groups; Nu is a nucleophile moiety; and
R8 is selected from the group consisting of hydrogen, straight chain and branched CrC6 alkyl groups, NH4 +, R2NH3 +, alkali metal ions, alkaline earth metal ions, CI, NH2, NHR2, NHNHR2, CN, SH and SR2, wherein R2 is selected from the group consisting of straight chain or branched C C alkyl groups, phenyl and phen C C6 alkyl groups.
33. The compound of claim 32, wherein Nu is selected from the group consisting of F, CI, Br, I, straight chain, branched and cyclic C C12 alkoxy groups, phenoxy, substituted phenoxy groups, straight chain, branched and cyclic C C12 alkylamido groups, thiol, straight chain, branched and cyclic C Cι2 alkylthiol groups, arylthiol groups, acyloxy, cyano, azo, cyanate and thiocyanate.
34. The compound of claim 32, wherein Nu is an amino group having the formula NR9R10, wherein R9 and R10 are independently selected from the group consisting of hydrogen and straight chain and branched C C6 alkyl groups.
35. A compound having the formula:
R ' -CX1 X2-CH2-CRaX3-ORb
wherein R1 is selected from the group consisting of straight chain and branched halogenated C C1 aliphatic groups;
X'and X2 are independently selected from the group consisting of F, CI and Br, and X3, independently of X1 and X2, is CI, Br or I;
Ra is selected from the group consisting of hydrogen, straight chain and branched CrC6 alkyls, straight chain and branched C C6 alkyls substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycle containing five, six and seven ring members, phenyl and phenyl substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C C6 alkyl and C C6 alkoxy; and Rb is a straight chain or branched C C6 alkyl group.
36. A compound selected from the group consisting of:
R'-CX1=CHCH=0 and
R'CX1X2-CH7CH=0
wherein R1 is selected from the group consisting of straight chain and branched halogenated C Cι2 aliphatic groups; and X1 and X2 are independently selected from the group consisting of F, CI and Br.
37. A compound selected from the group consisting of:
R'-CX'=CHCHYZ and
5. R'CX'X2-CH2CHYZ
wherein Y is OH, Z is M'S03, and M1 is a cation selected from the group consisting of alkali metal cations, alkaline earth metal cations, NH4 +, NR2H3 + and NR2R3H2 +;
R2 and R3 are independently selected from the group consisting of straight chain and branched C C6 alkyl, phenyl and phen C*-C6 alkyl groups;
R1 is selected from the group consisting of straight chain and branched halogenated Cι-C12 aliphatic groups; and
X1 and X2 are independently selected from the group consisting of F, CI and Br.
5 38. A compound selected from the group consisting of:
R^CX^CHCHYZ and R1CX1X2-CH2CHYZ 0 wherein Y is ORb or OR4, Z is OR4; Rb is a straight chain or branched C C6 alkyl group; and R4 is selected from the group consisting of straight chain and branched C C6 alkyl groups, straight chain and branched C C6 alkyl groups substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycles containing 5, 6 and 7 ring members, phenyl and 5 phenyl substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C*-C6 alkyl groups and CrC6 alkoxy groups;
R1 is selected from the group consisting of straight chain and branched halogenated C*-C*2 aliphatic groups; and
1 9
X and X are independently selected from the group consisting of F, CI and Br.
39. A compound selected from the group consisting of:
R'-CX^CHCHYZ and R1CX1X2-CH2CHYZ
wherein Y and Z together form a ring structure with the carbon to which they are attached having as members -Wa-R5-Wb-;
R5 is a C2-C3 alkylene optionally substituted with a straight chain, branched or cyclic C*-C6 alkyl group, or a C2-C3 alkylene forming part of 1,2-phenylene ring optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, Cι-C6 alkyl groups and C C6 alkoxy groups Wa and Wb are independently selected from the group consisting of O, N and S; R1 is selected from the group consisting of straight chain and branched halogenated C C12 aliphatic groups; and X1 and X2 are independently selected from the group consisting of F, CI and Br.
40. A compound selected from the group consisting of:
R'-CX'=CHCHYZ and
R1CX1X2-CH2CHYZ
wherein Y and Z together form a =NNHR6 group, and R6 is selected from the group consisting of straight chain and branched C*-C6 alkyl groups, straight chain and branched C C6 alkyl groups substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido and nitrogen heterocycles containing 5, 6 and 7 ring members, phenyl and phenyl substituted with one or more groups independently selected from the group consisting of halo, cyano, nitro, amido, C C6 alkyl groups and C*-C6 alkoxy groups;
R1 is selected from the group consisting of straight chain and branched halogenated -C-2 aliphatic groups; and
X and X are independently selected from the group consisting of F, CI and Br.
41. A compound selected from the group consisting of:
R^CX^CHCR^Z and
R1CX1X2-CH2CRaYZ
wherein Y and Z together form a =NOR7 group, and R7 is selected from the group consisting of hydrogen, and straight chain and branched C C6 alkyl groups; R1 is selected from the group consisting of straight chain and branched halogenated C C12 aliphatic groups; and
1 9
X and X are independently selected from the group consisting of F, CI and Br.
42. A compound selected from the group consisting of:
R1 is selected from the group consisting of straight chain and branched halogenated C C12 aliphatic groups.
43. The compound of claim 32, 35, 36, 37, 38, 39, 40 or 41 , wherein R1 is a substituted or unsubstituted Cι-C12 halogenated aliphatic radical.
44. The compound of claim 43, wherein R1 is fluorinated.
45. The compound of claim 44, wherein R1 is polyfluorinated.
46. The compound of claim 45, wherein R1 is perfluorinated.
47. The compound of claim 43, wherein R is substituted with one or more groups independently selected from the group consisting of CrC6 alkyls, CrC6 alkyl ethers, CrC6 alkyl esters and C C6 alkenyls, each optionally containing one or more nitro, primary amino, secondary amino, cyano, hydroxyl, thiol or C C6 alkylthiol groups.
48. The compound of claim 43, wherein R1 is selected from the group consisting of halogenated methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl or 2-ethylhexyl optionally further substituted with one or more groups independently selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, methane sulphonyl and cyano.
49. The compound of claim 48, wherein R1 is selected from the group consisting of C C6 fluorinated alkyl radicals.
50. The compound of claim 49, wherein R is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, fluorethyl, difluoroeythl, trifluoroethyl, pentafluoroethyl, perfluoropropyl, perfluorobutyl, perfluoropentyl and perfluorohexyl groups.
51. The compound of claim 50, wherein R1 is a trifluoromethyl group.
52. The compound of claim 42, wherein R1 is a substituted or unsubstituted
C Ci2 halogenated aliphatic radical.
53. The compound of claim 52, wherein R1 is fluorinated.
54. The compound of claim 53, wherein R 1 i •s polyfluorinated
55. The compound of claim 54, wherein R1 is perfluorinated.
56. The compound of claim 52, wherein R1 is substituted with one or more groups independently selected from the group consisting of CrC6 alkyls, C*-C6 alkyl ethers, C*-C6 alkyl esters and CrC6 alkenyls, each optionally containing one or more nitro, primary amino, secondary amino, cyano, hydroxyl, thiol or C C6 alkylthiol groups.
57. The compound of claim 52, wherein R1 is selected from the group consisting of halogenated methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl or 2-ethylhexyl optionally further substituted with one or more groups independently selected from the group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, methane sulphonyl and cyano.
58. The compound of claim 57, wherein R1 is selected from the group consisting of C C6 fluorinated alkyl radicals.
59. The compound of claim 58, wherein R1 is selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, fluorethyl, difluoroeythl, trifluoroethyl, pentafluoroethyl, perfluoropropyl, perfluorobutyl, perfluoropentyl and perfluorohexyl groups.
60. The compound of claim 59, wherein R1 is a trifluoromethyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002235247A AU2002235247A1 (en) | 2000-12-29 | 2001-12-31 | Halogenated-alpha,beta-unsaturated-beta-(substituted-amino) carboxylate esters |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25920400P | 2000-12-29 | 2000-12-29 | |
| US60/259,204 | 2000-12-29 |
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| Publication Number | Publication Date |
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| WO2002053518A2 true WO2002053518A2 (en) | 2002-07-11 |
| WO2002053518A3 WO2002053518A3 (en) | 2003-09-12 |
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|---|---|---|---|
| PCT/US2001/049924 WO2002053518A2 (en) | 2000-12-29 | 2001-12-31 | HALOGENATED-α,β-UNSATURATED-β-(SUBSTITUTED-AMINO) CARBOXYLATE ESTERS |
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| Country | Link |
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| AU (1) | AU2002235247A1 (en) |
| WO (1) | WO2002053518A2 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10237285A1 (en) * | 2002-08-14 | 2004-02-26 | Degussa Ag | Production of 3-amino-4,4,4-trifluorocrotonate ester for use in synthesis of plant protection agents involves reacting alkyl trifluoroacetate with alkyl acetate and metal alcoholate to form an enolate which is then reacted with amine |
| JP2008239572A (en) * | 2007-03-28 | 2008-10-09 | Sagami Chem Res Center | Perfluoroalkyl-group-containing heterocyclic compound and method for producing the same |
| US8431710B2 (en) | 2008-09-30 | 2013-04-30 | Solvay Sa | Process for the synthesis of halogenated cyclic compounds |
| CN106748882A (en) * | 2016-11-18 | 2017-05-31 | 成都新柯力化工科技有限公司 | A kind of lithium battery electrolytes high temperature flame-proof additive |
| CN106916107A (en) * | 2015-12-28 | 2017-07-04 | 联化科技(上海)有限公司 | A kind of preparation method of pyrazole compound |
| WO2020139740A1 (en) | 2018-12-27 | 2020-07-02 | Dow Agrosciences Llc | Preparation of sulfonamide herbicide process intermediates |
| WO2020139734A1 (en) | 2018-12-27 | 2020-07-02 | Dow Agrosciences Llc | Preparation of sulfonamide herbicide process intermediates |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4468247A (en) * | 1980-06-09 | 1984-08-28 | Chevron Research Company | Herbicidal 4-[3'-(4"-trifluoromethyl-phenoxy)-phenoxy]-4-methyl-crotonates |
-
2001
- 2001-12-31 WO PCT/US2001/049924 patent/WO2002053518A2/en not_active Application Discontinuation
- 2001-12-31 AU AU2002235247A patent/AU2002235247A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4468247A (en) * | 1980-06-09 | 1984-08-28 | Chevron Research Company | Herbicidal 4-[3'-(4"-trifluoromethyl-phenoxy)-phenoxy]-4-methyl-crotonates |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10237285A1 (en) * | 2002-08-14 | 2004-02-26 | Degussa Ag | Production of 3-amino-4,4,4-trifluorocrotonate ester for use in synthesis of plant protection agents involves reacting alkyl trifluoroacetate with alkyl acetate and metal alcoholate to form an enolate which is then reacted with amine |
| JP2008239572A (en) * | 2007-03-28 | 2008-10-09 | Sagami Chem Res Center | Perfluoroalkyl-group-containing heterocyclic compound and method for producing the same |
| US8431710B2 (en) | 2008-09-30 | 2013-04-30 | Solvay Sa | Process for the synthesis of halogenated cyclic compounds |
| US8981115B2 (en) | 2008-09-30 | 2015-03-17 | Solvay Sa | Process for the synthesis of halogenated cyclic compounds |
| CN106916107A (en) * | 2015-12-28 | 2017-07-04 | 联化科技(上海)有限公司 | A kind of preparation method of pyrazole compound |
| CN106748882A (en) * | 2016-11-18 | 2017-05-31 | 成都新柯力化工科技有限公司 | A kind of lithium battery electrolytes high temperature flame-proof additive |
| WO2020139740A1 (en) | 2018-12-27 | 2020-07-02 | Dow Agrosciences Llc | Preparation of sulfonamide herbicide process intermediates |
| WO2020139734A1 (en) | 2018-12-27 | 2020-07-02 | Dow Agrosciences Llc | Preparation of sulfonamide herbicide process intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2002235247A1 (en) | 2002-07-16 |
| WO2002053518A3 (en) | 2003-09-12 |
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