WO2000049028A1 - Procede de preparation de diphosphines chirales - Google Patents
Procede de preparation de diphosphines chirales Download PDFInfo
- Publication number
- WO2000049028A1 WO2000049028A1 PCT/FR2000/000083 FR0000083W WO0049028A1 WO 2000049028 A1 WO2000049028 A1 WO 2000049028A1 FR 0000083 W FR0000083 W FR 0000083W WO 0049028 A1 WO0049028 A1 WO 0049028A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- phenyl
- group
- nitrile
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 32
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 16
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 11
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 7
- -1 dibromo compound Chemical class 0.000 claims description 66
- 239000003446 ligand Substances 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 31
- 239000003054 catalyst Substances 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- 230000008569 process Effects 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 150000002825 nitriles Chemical class 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 15
- 229910052786 argon Inorganic materials 0.000 claims description 15
- 238000006555 catalytic reaction Methods 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 229910052707 ruthenium Inorganic materials 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 150000002009 diols Chemical class 0.000 claims description 14
- 239000010948 rhodium Substances 0.000 claims description 13
- 230000009471 action Effects 0.000 claims description 12
- 150000002576 ketones Chemical class 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052703 rhodium Inorganic materials 0.000 claims description 10
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 238000005893 bromination reaction Methods 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910052723 transition metal Inorganic materials 0.000 claims description 9
- 150000003624 transition metals Chemical class 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 230000031709 bromination Effects 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 150000004696 coordination complex Chemical class 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 229910052741 iridium Inorganic materials 0.000 claims description 6
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 5
- 230000000269 nucleophilic effect Effects 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052759 nickel Inorganic materials 0.000 claims description 4
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- WDQZIRSDNFWMAE-UHFFFAOYSA-L dichloronickel;1-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 WDQZIRSDNFWMAE-UHFFFAOYSA-L 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 description 29
- 125000004432 carbon atom Chemical group C* 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 239000000758 substrate Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 239000012429 reaction media Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 239000012041 precatalyst Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000004215 Carbon black (E152) Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 150000003303 ruthenium Chemical class 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 4
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 0 C*c(c(-c1c(*)ccc(C#N)c1S)c1S)ccc1C#N Chemical compound C*c(c(-c1c(*)ccc(C#N)c1S)c1S)ccc1C#N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 239000012327 Ruthenium complex Substances 0.000 description 3
- 229910018286 SbF 6 Inorganic materials 0.000 description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000006880 cross-coupling reaction Methods 0.000 description 3
- 150000004292 cyclic ethers Chemical class 0.000 description 3
- 239000012973 diazabicyclooctane Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 150000002503 iridium Chemical class 0.000 description 3
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000005394 methallyl group Chemical group 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 150000003460 sulfonic acids Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 150000007934 α,β-unsaturated carboxylic acids Chemical class 0.000 description 3
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- HVHZEKKZMFRULH-UHFFFAOYSA-N 2,6-ditert-butyl-4-methylpyridine Chemical compound CC1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1 HVHZEKKZMFRULH-UHFFFAOYSA-N 0.000 description 2
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001253 acrylic acids Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- 238000007350 electrophilic reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000006459 hydrosilylation reaction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 2
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000005561 phenanthryl group Chemical group 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000003283 rhodium Chemical class 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 150000007970 thio esters Chemical class 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- OJZVBUYHVVFBBP-UHFFFAOYSA-N (1-naphthalen-1-ylnaphthalen-2-yl) trifluoromethanesulfonate Chemical group C1=CC=C2C(C3=C4C=CC=CC4=CC=C3OS(=O)(=O)C(F)(F)F)=CC=CC2=C1 OJZVBUYHVVFBBP-UHFFFAOYSA-N 0.000 description 1
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 1
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- IALJQRICMSDTDV-UHFFFAOYSA-N 2-(5-methoxynaphthalen-1-yl)propanoic acid Chemical compound C1=CC=C2C(OC)=CC=CC2=C1C(C)C(O)=O IALJQRICMSDTDV-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-ARJAWSKDSA-M 2-Methyl-2-butenoic acid Natural products C\C=C(\C)C([O-])=O UIERETOOQGIECD-ARJAWSKDSA-M 0.000 description 1
- TYEYBOSBBBHJIV-UHFFFAOYSA-N 2-Oxobutanoic acid Natural products CCC(=O)C(O)=O TYEYBOSBBBHJIV-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- JQPFYXFVUKHERX-UHFFFAOYSA-N 2-hydroxy-2-cyclohexen-1-one Natural products OC1=CCCCC1=O JQPFYXFVUKHERX-UHFFFAOYSA-N 0.000 description 1
- 239000001903 2-oxo-3-phenylpropanoic acid Substances 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KVFQMAZOBTXCAZ-UHFFFAOYSA-N 3,4-dioxohexane Natural products CCC(=O)C(=O)CC KVFQMAZOBTXCAZ-UHFFFAOYSA-N 0.000 description 1
- QHKABHOOEWYVLI-UHFFFAOYSA-N 3-Methyl-2-oxobutanoic acid Natural products CC(C)C(=O)C(O)=O QHKABHOOEWYVLI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GQVKRDRDFJTFEZ-UHFFFAOYSA-N 3-bromo-4,6-dimethyl-[1,2]thiazolo[5,4-b]pyridine Chemical compound CC1=CC(C)=C2C(Br)=NSC2=N1 GQVKRDRDFJTFEZ-UHFFFAOYSA-N 0.000 description 1
- 239000001388 3-methyl-2-oxobutanoic acid Substances 0.000 description 1
- PESKGJQREUXSRR-ZTPZMMAUSA-N 3-oxocholestane Chemical compound C1CC2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 PESKGJQREUXSRR-ZTPZMMAUSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical class O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical class O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 1
- PESKGJQREUXSRR-UHFFFAOYSA-N 5beta-cholestanone Natural products C1CC2CC(=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 PESKGJQREUXSRR-UHFFFAOYSA-N 0.000 description 1
- OORIFUHRGQKYEV-UHFFFAOYSA-N 6-bromo-1-(6-bromo-2-hydroxynaphthalen-1-yl)naphthalen-2-ol Chemical group BrC1=CC=C2C(C3=C4C=CC(Br)=CC4=CC=C3O)=C(O)C=CC2=C1 OORIFUHRGQKYEV-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- XYZAPOXYXNIBEU-UHFFFAOYSA-N Dipropylglyoxal Natural products CCCC(=O)C(=O)CCC XYZAPOXYXNIBEU-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- LDLDJEAVRNAEBW-UHFFFAOYSA-N Methyl 3-hydroxybutyrate Chemical compound COC(=O)CC(C)O LDLDJEAVRNAEBW-UHFFFAOYSA-N 0.000 description 1
- YARAXWGKSJCKNA-UHFFFAOYSA-N NCC=1C(=C(C2=CC=CC=C2C=1)C1=C(C=CC2=CC=CC=C12)P(C1=CC=CC=C1)C1=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 Chemical group NCC=1C(=C(C2=CC=CC=C2C=1)C1=C(C=CC2=CC=CC=C12)P(C1=CC=CC=C1)C1=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 YARAXWGKSJCKNA-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-N PYRUVIC-ACID Natural products CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 1
- BTNMPGBKDVTSJY-UHFFFAOYSA-N Phenyl pyruvic acid Natural products OC(=O)C(=O)CC1=CC=CC=C1 BTNMPGBKDVTSJY-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Natural products CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000005599 alkyl carboxylate group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000004808 allyl alcohols Chemical class 0.000 description 1
- UMLWXYJZDNNBTD-UHFFFAOYSA-N alpha-dimethylaminoacetophenone Natural products CN(C)CC(=O)C1=CC=CC=C1 UMLWXYJZDNNBTD-UHFFFAOYSA-N 0.000 description 1
- XLSMFKSTNGKWQX-UHFFFAOYSA-N alpha-hydroxyacetone Natural products CC(=O)CO XLSMFKSTNGKWQX-UHFFFAOYSA-N 0.000 description 1
- DEDGUGJNLNLJSR-UHFFFAOYSA-N alpha-hydroxycinnamic acid Natural products OC(=O)C(O)=CC1=CC=CC=C1 DEDGUGJNLNLJSR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- YGXMUPKIEHNBNQ-UHFFFAOYSA-J benzene;ruthenium(2+);tetrachloride Chemical group Cl[Ru]Cl.Cl[Ru]Cl.C1=CC=CC=C1.C1=CC=CC=C1 YGXMUPKIEHNBNQ-UHFFFAOYSA-J 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- WXMZPPIDLJRXNK-UHFFFAOYSA-N butyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CCCC)C1=CC=CC=C1 WXMZPPIDLJRXNK-UHFFFAOYSA-N 0.000 description 1
- SLFKPACCQUVAPG-UHFFFAOYSA-N carbon monoxide;nickel;triphenylphosphane Chemical compound O=C=[Ni]=C=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 SLFKPACCQUVAPG-UHFFFAOYSA-N 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- GGCLNOIGPMGLDB-GYKMGIIDSA-N cholest-5-en-3-one Chemical compound C1C=C2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 GGCLNOIGPMGLDB-GYKMGIIDSA-N 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000005888 cyclopropanation reaction Methods 0.000 description 1
- 125000002704 decyl 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])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- ZWWQRMFIZFPUAA-UHFFFAOYSA-N dimethyl 2-methylidenebutanedioate Chemical compound COC(=O)CC(=C)C(=O)OC ZWWQRMFIZFPUAA-UHFFFAOYSA-N 0.000 description 1
- AAXGWYDSLJUQLN-UHFFFAOYSA-N diphenyl(propyl)phosphane Chemical compound C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 AAXGWYDSLJUQLN-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 239000012374 esterification agent Substances 0.000 description 1
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004721 gamma keto acids Chemical class 0.000 description 1
- SPUWOYCLMKSXKU-UHFFFAOYSA-N gamma-Keto-decansaeure Natural products CCCCCCC(=O)CCC(O)=O SPUWOYCLMKSXKU-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- YUWFEBAXEOLKSG-UHFFFAOYSA-N hexamethylbenzene Chemical compound CC1=C(C)C(C)=C(C)C(C)=C1C YUWFEBAXEOLKSG-UHFFFAOYSA-N 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 238000007037 hydroformylation reaction Methods 0.000 description 1
- 238000006267 hydrovinylation reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- GFAZHVHNLUBROE-UHFFFAOYSA-N hydroxymethyl propionaldehyde Natural products CCC(=O)CO GFAZHVHNLUBROE-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- JOOXCMJARBKPKM-UHFFFAOYSA-N laevulinic acid Natural products CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- LDLDJEAVRNAEBW-SCSAIBSYSA-N methyl (3r)-3-hydroxybutanoate Chemical group COC(=O)C[C@@H](C)O LDLDJEAVRNAEBW-SCSAIBSYSA-N 0.000 description 1
- XJMIXEAZMCTAGH-UHFFFAOYSA-N methyl 3-oxopentanoate Chemical compound CCC(=O)CC(=O)OC XJMIXEAZMCTAGH-UHFFFAOYSA-N 0.000 description 1
- YLHXLHGIAMFFBU-UHFFFAOYSA-N methyl phenylglyoxalate Chemical compound COC(=O)C(=O)C1=CC=CC=C1 YLHXLHGIAMFFBU-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N p-methylisopropylbenzene Natural products CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- GNKZMNRKLCTJAY-UHFFFAOYSA-N p-methylphenyl methyl ketone Natural products CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- BVQVLAIMHVDZEL-UHFFFAOYSA-N phenyl-methyl-diketone Natural products CC(=O)C(=O)C1=CC=CC=C1 BVQVLAIMHVDZEL-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
- C07F9/5068—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure >P-Hal
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- 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
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5027—Polyphosphines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5063—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds
- C07F9/5072—Preparation; Separation; Purification; Stabilisation from compounds having the structure P-H or P-Heteroatom, in which one or more of such bonds are converted into P-C bonds from starting materials having the structure P-H
Definitions
- the invention relates to a process for the preparation of chiral disphosphines useful as bidentate ligands in the synthesis of transition metal catalysts intended for asymmetric catalysis.
- Asymmetric catalysis has experienced considerable growth in recent years. It has the advantage of leading directly to the preparation of optically pure isomers by asymmetric induction without it being necessary to carry out the resolution of racemic mixtures.
- BINAP 2,2'-bis (diphenylphosphino) -1 J '-binaphtyl
- BINAP 2,2'-bis (diphenylphosphino) -1 J '-binaphtyl
- the development of new chiral ligands is desirable so as to improve the enantioselectivity of the reactions and more generally, the general conditions for carrying out these reactions.
- the present invention more specifically provides a process for the preparation of biphosphorus bidentate chiral ligands of the 2,2'-bis-diarylphosphino) -1, 1 '-binaphtyl and 2,2'-bis (diarylphosphino) -1, 1' - type. biphenyl functionalized at the binaphthyl group, respectively biphenyl.
- transition metals such as ruthenium or rhodium form complexes useful in the asymmetric catalysis of various reactions and more particularly of asymmetric hydrogenation reactions.
- ligands prepared according to the process of the invention are in particular dicyano derivatives, of formula I:
- A represents phenyl or naphthyl; and Ar-i and Ar 2 independently represent a saturated or aromatic carbocyclic radical.
- phenyl and naphthyl radicals are optionally substituted.
- cabocyclic radical is meant according to the invention a monocyclic or polycyclic radical optionally substituted, preferably C 3 -Cso. Preferably, it is a C 3 -C- ⁇ 8 radical, preferably mono-, bi- or tricyclic.
- the carbocyclic radical can comprise a saturated part and / or an aromatic part.
- the carbocyclic radical comprises more than one cyclic nucleus (in the case of polycyclic carbocycles)
- the cyclic nuclei can be condensed two by two or attached two by two by ⁇ bonds.
- saturated carbocyclic radicals are cycloalkyl groups.
- the cycloalkyl groups are saturated cyclic hydrocarbon radicals, preferably C 3 -Ci 8 , better still C 3 - C-to, and in particular the cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or norbomyl radicals.
- aromatic carbocyclic radicals are the (C 6 -C ⁇ 8 ) aryl groups and in particular phenyl, naphthyl, anthryl and phenanthryl.
- the substituents of the phenyl, naphthyl and carbocyclic radicals are such that they do not interfere with the reactions involved in the process of the invention. These substituents are inert under the conditions involved in bromination (step i), esterification (step ii), nucleophilic substitution (step iii) and coupling reactions.
- the substituents are alkyl or alkoxy groups.
- alkyl is meant a saturated, linear or branched hydrocarbon radical, comprising in particular up to 25 carbon atoms, and, for example from 1 to 12 carbon atoms, better still from 1 to 6 carbon atoms.
- alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1 -methylpentyle, 3- methylpentyle, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-1- ethylpropyl, heptyle, 1-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyle, octyl, 1-methylheptyle, 2- ethyihexyl, 5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and 7,7-
- dicyano derivatives of formula I are such that:
- A represents naphthyl or phenyl, optionally substituted by one or more radicals chosen from (CrC 6 ) alkyl and (C ⁇ -C 6 ) alkoxy;
- Ar-i, Ar 2 independently represent a phenyl group optionally substituted by one or more (C ⁇ -C 6 ) alkyl or (CrC- 6 ) alkoxy; or a (C 4 - C 8 ) cycloalkyl group optionally substituted by one or more (CC 6 ) alkyl groups.
- alkyl groups examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1 -methylpentyle, 3- methylpentyle, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl and 1-methyl-
- the alkyl radical comprises from 1 to 4 carbon atoms.
- alkoxy designates the radical -O-alkyl where alkyl is as defined above.
- the cycloalkyl groups are chosen from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. It should be understood that, according to the invention, each of the naphthyl and phenyl groups representing A can be substituted.
- ligands of formula I are those for which Ar- and Ar 2 are independently phenyl optionally substituted by methyl or tert-butyl; or (C 5 -C 6 ) cycloalkyl optionally substituted by methyl or tert-butyl.
- a clearly preferred meaning of A and Ar 2 is optionally substituted phenyl.
- A represents naphthyl optionally substituted by one to five, preferably one to two, groups chosen from (C 1 -C 6 ) alkyl and (C 1 -C 6 ) alkoxy. More preferably, A represents unsubstituted naphthyl.
- A represents optionally substituted phenyl
- a more particularly preferred group of compounds consists of the compounds of formula I having an axis of symmetry C 2 to the exclusion of any other element of symmetry.
- the concept of axis of symmetry C 2 is described in "Elements of
- a and Ar 2 are as defined above and S represents a substituent compatible with the reactions involved, and in particular alkyl or alkoxy, preferably Ci-C ⁇ , wherein Ar- t and Ar 2 are as defined above.
- the process of the invention more precisely comprises the steps consisting in: i) carrying out the bromination of a diol of formula II:
- A is as defined above; ii) esterifying the compound of formula III obtained in the preceding step by the action of a sulfonic acid or of an activated form thereof so as to obtain the corresponding disulfonate; iii) substituting the two bromine atoms for cyano groups by reacting the disulfonate obtained in the previous step with an appropriate nucleophilic agent so as to obtain the corresponding nitrile; iv) coupling of a phosphine of formula VI: XPAr 1 Ar 2 VI in which X represents a hydrogen atom of a halogen atom and An and Ar 2 are as defined above, with the nitrile obtained in the preceding step in the presence of a catalyst based of a transition metal, so as to obtain the expected compound of formula I.
- step (i) the phenyl nucleus, respectively naphthyl, of the diol of formula
- A is a phenyl ring which is unsubstituted or bearing in the meta position relative to the OH group a substituent, such as (C ⁇ -C ⁇ ) alkyl or (dC 6 ) alkoxy, the corresponding diol of formula Ma:
- Si and S 2 are as defined for S above or independently represent a hydrogen atom, an alkyl or alkoxy group, preferably C- ⁇ -C- 6 , leads to the corresponding bromine compound of formula IIIa:
- the hydroxyl groups present on the naphthyl and phenyl nuclei direct the electrophilic reaction so that the position of the bromine atoms on these nuclei is well determined.
- the bromination reaction of phenyl or naphthyl rings is an electrophilic reaction which is easily carried out by the action of Br 2 on the corresponding diol.
- This reaction can be carried out in the presence of a catalyst such as a Lewis acid and in particular iron chloride.
- a catalyst such as a Lewis acid and in particular iron chloride.
- the diols of formula II are so reactive that it is desirable to carry out the bromination at low temperature, for example between -78 ° and -30 ° C, preferably between -78 ° C and -50 ° C.
- the bromination takes place in an inert aprotic solvent such as a halogenated aromatic hydrocarbon (for example chlorobenzene and dichlorobenzene); a nitrated aromatic hydrocarbon such as nitrobenzene; an optionally halogenated aliphatic hydrocarbon such as hexane, heptane, methylene chloride, carbon tetrachloride or dichioroethane; or an alicyclic hydrocarbon.
- a halogenated aromatic hydrocarbon for example chlorobenzene and dichlorobenzene
- a nitrated aromatic hydrocarbon such as nitrobenzene
- an optionally halogenated aliphatic hydrocarbon such as hexane, heptane, methylene chloride, carbon tetrachloride or dichioroethane
- an alicyclic hydrocarbon such as a halogenated aromatic hydrocarbon (for example chlorobenzene and dichlorobenzene); a nitrated
- halogenated aliphatic hydrocarbons and in particular methylene chloride.
- the molar ratio of the brominating agent to the diol II varies between 2 and 5, better still between 2 and 3.
- the concentration of reagents can vary widely between 0.01 and 10 mol / l, for example between 0.05 and 1 mol / l.
- step (ii) the hydroxyl functions of the diol III are esterified by the action of a sulfonic acid or of an activated form thereof, so as to obtain the corresponding disulfonate.
- the nature of the sulfonic acid used is not decisive in itself.
- the sulfonic acid has the formula:
- P-S0 2 -OH where P represents an aliphatic hydrocarbon group; an aromatic carbocyclic group; or an aliphatic group substituted by an aromatic carbocyclic group.
- aliphatic hydrocarbon group is understood to mean in particular an alkyl group as defined above, optionally substituted.
- the nature of the substituent is such that it does not react under the conditions of the esterification reaction.
- a preferred example of an alkyl group substituent is a halogen atom such as fluorine, chlorine, bromine or iodine.
- aromatic carbocyclic group is meant the mono- or polycyclic aromatic groups and in particular the mono-, bi- or tricyclic defined above and for example, phenyl, naphthyl, anthryl or phenanthryl.
- the aromatic carbocyclic group is optionally substituted.
- the nature of the substituent is not critical since it does not react under the conditions of esterification.
- the substituent is optionally halogenated alkyl, alkyl being as defined above and halogen representing chlorine, fluorine, bromine or iodine and, preferably chlorine.
- optionally halogenated alkyl denotes perfluorinated alkyl such as trifluoromethyl or pentafluoroethyl.
- the sulfonic acid has the formula:
- P-S0 2 -OH where P represents (C- 6 -C- ⁇ o) aryl optionally substituted by one or more (C- ⁇ -C 6 ) optionally halogenated alkyl; (C- ⁇ -C 6 ) optionally halogenated alkyl; or (C 6 -C ⁇ 0 ) aryl- (C ⁇ -C 6 ) alkyl in which the aryl group is optionally substituted by one or more (C ⁇ -Ce) optionally halogenated alkyl and the alkyl group is optionally halogenated.
- Suitable examples of such sulfonic acids are paratoluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, the latter being more particularly preferred.
- an activated derivative of sulfonic acid is used.
- activated derivative is meant a sulfonic acid in which the acid function -S0 3 H is activated, for example by formation of an anhydride bond or of the group -S0 3 CI.
- a particularly advantageous sulfonic acid derivative is the symmetrical anhydride of trifluoromethanesulfonic acid, of formula (CF 3 -SO 2 ) 2 ⁇ .
- a and P are as defined above.
- the conditions for the esterification reaction will be easily developed by a person skilled in the art. These depend in particular on the nature of the esterification agent.
- the esterifying agent is a sulfonic acid
- a higher reaction temperature between 20 and 100 ° C
- an activated form of this acid such as an anhydride or sulfonyl chloride
- a lower temperature may be suitable.
- the esterification is preferably carried out in a solvent.
- Suitable solvents are in particular aliphatic, aromatic or cyclic optionally halogenated hydrocarbons, such as those defined above. Mention may be made of carbon tetrachloride and dichloromethane. Dichloromethane is particularly preferred.
- the ethers can also be used as a solvent. Examples include dialkyl ethers C- ⁇ -C- 6 (diethyl ether and diisopropyl ether), cyclic ethers (tetrahydrofuran and dioxane), dimethoxyethane and dimethyl ether of diethylene glycol.
- the esterifying agent is an activated form of a sulfonic acid
- Basic examples are N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-dimethylpyridine, 4- (1 -pyrrolidinyl) pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butyl-4-methylpyridine, quinoline, N, N-dimethylaniline and N, N-diethylaniline.
- pyridine and 4-dimethylaminopyridine will be used.
- the reaction can also be carried out in a two-phase mixture of water and an organic solvent such as a halogenated aliphatic hydrocarbon (for example carbon tetrachloride).
- an esterifying agent in the form of anhydride and to operate in the presence of a water-soluble base such as KOH, NaOH or K 2 C0 3 , preferably KOH.
- the concentration of the reactants which is not a critical parameter according to the invention, may vary between 0.1 and 10 mol / l, advantageously between 1 and 5 mol / l.
- the next step (iii) is a nucleophilic substitution.
- the two bromine atoms carried by the A nuclei are displaced by cyano groups by the action of an appropriate nucleophilic agent.
- an appropriate nucleophilic agent In order to carry out this substitution, a person skilled in the art can use any of the methods known in the art.
- the nucleophilic agent used is copper cyanide.
- the molar ratio of copper cyanide to disulfonate is preferably greater than 2, it can advantageously vary between 2 and 4, preferably between 2 and 3.
- the reaction is preferably carried out in a solvent.
- solvents that may be mentioned are amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone and hexamethylphosphorylamide. Dimethylformamide is much preferred.
- Pyridine is also a suitable solvent.
- the reaction temperature is advantageously maintained between 50 and 200 ° C, for example between 70 and 190 ° C, better still between 80 and 180 ° C. A more particularly suitable temperature is between 100 and 190 ° C.
- the concentration of reagents in the reaction medium generally varies between 0.1 and 10 mol / l, for example between 2 and 7 mol / l.
- the isolation of the nitrile involves the decomposition of the intermediate complex formed and the trapping of the excess cyanide.
- the hydrolysis of the intermediate complex can be carried out either by the action of hydrated iron chloride, or by the action of aqueous ethylenediamine.
- reaction medium is poured into an aqueous solution of iron chloride at 50-80% (g / ml) containing concentrated hydrochloric acid.
- the resulting solution is heated to 40-80 ° C until complete decomposition of the complex.
- the medium is decanted and extracted in a conventional manner.
- reaction medium is poured into an aqueous solution of ethylenediamine (ethylenediamine / water: 1/5 - 1/1 (v / v), for example 1/3) then the whole is vigorously stirred. The medium is then decanted and extracted in a manner known per se.
- ethylenediamine ethylenediamine / water: 1/5 - 1/1 (v / v), for example 1/3
- step (iv) cross-coupling of a phosphine of formula VI is carried out: XPAr ⁇ Ar 2 VI in which X is a halogen or hydrogen atom and Ar-i, Ar 2 are as defined above with the nitrile obtained in the preceding step, in the presence of a catalyst based on a transition metal.
- This coupling leads directly to the expected compound of formula I.
- Suitable catalysts are catalysts based on nickel, palladium, rhodium, ruthenium, platinum or a mixture of these metals.
- the preferred catalysts are nickel-based catalysts such as those selected from NiCI 2 ; NiBr 2 ; NiCI (dppp); NiCI 2 (dppb); NiCI 2 (dppf); NiCI 2 (dppe); NiCI 2 (PPh 3 ) 2 ; Ni (CO) 2 (PPh 3 ) 2 ; Ni (PPh 3 ) and Ni [P (PhO) 3 ] 4 where dppe means (diphenylphosphino) ethane, dppp means (diphenylphosphino) propane, dppb means (diphenylphosphino) butane, and dppf means
- the reaction is generally carried out at a temperature of 50 to 200 ° C, preferably from 80 to 130 ° C.
- the molar ratio of compound VI to nitrile is at least 2. It generally varies between 2 and 4, for example between 2 and 3.
- the amount of catalyst is preferably such that the molar ratio of nitrile to catalyst varies between 5 and 100, especially between 5 and 80.
- the reaction is preferably carried out in a polar aprotic solvent and in particular an amide such as those mentioned above.
- a polar aprotic solvent and in particular an amide such as those mentioned above.
- N, N-dimethylformamide is preferred.
- Other types of polar solvents can nevertheless be used such as (CrC 6 ) alkanols (ethanol), aromatic hydrocarbons (toluene, xylene and benzene), ethers (dioxane) and acetonitrile.
- reaction conditions depend on the nature of the compound of formula VI involved in the reaction.
- Particularly suitable bases are pyridine, 4-dimethylaminopyridine, 2,6-di-tertbutylpyridine, 1,8-diazabicyclo [5.4.0] - undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1, 4- diazabicyclo [2.2.2] octane (DABCO or triethylenediamine).
- DABCO will be used as a base.
- the molar ratio of the nitrile to the catalyst is between 5 and 20, for example between 7 and
- the amount of zinc is preferably such that the molar ratio of zinc to halPAr-
- reaction takes place by heating to an appropriate temperature of between 50 and
- the molar ratio of the nitrile to the catalyst is between 40 and 80, for example between 50 and 70.
- step (iv) When A represents phenyl optionally substituted preferably by (CrCe) alkyl or (CC 6 ) alkoxy, the compound obtained at the end of step (iv) has the formula:
- step (iv) When A represents naphthyl, the compound obtained at the end of step (iv) has the formula Ib: in which An and Ar 2 are as defined above.
- the compounds of formula I are ligands capable of coordinating with transition metals of the ruthenium and rhodium type. Associated with these metals, the ligands form complexes useful in the asymmetric catalysis of enantioselective hydrogenation reactions from various substrates such as ⁇ -ketoesters, ⁇ -ketoesters and dehydroamino acids.
- the present invention further provides a process for transforming the compounds of formula I (which have two cyano functions) into corresponding diaminomethylated compounds.
- the invention relates to a process comprising in addition to steps (i) to (iv) defined above, the step consisting in reducing the nitrile function of the compound of formula I by the action of a reducing agent so as to obtain a compound of formula VII:
- a suitable reducing agent is lithium aluminum hydride
- the invention is not intended to be limited to the use of this particular reducing agent.
- the reaction is preferably carried out in a solvent or a mixture of solvents.
- the solvent advantageously comprises one or more aromatic hydrocarbons (such as benzene, toluene and xylene) in admixture with one or more ethers.
- aromatic hydrocarbons such as benzene, toluene and xylene
- ether of CrC 6 alkyl ethers (diethyl and diisopropyl ether), cyclic ethers (dioxane, tetrahydrofuran), dimethoxyethane and diethylene glycol dimethyl ether.
- Cyclic ethers of the tetrahydrofuran type are preferred.
- the reduction can be carried out at a temperature between 20 ° C and 100 ° C, preferably between 40 ° C and 80 ° C.
- the molar ratio of the reducing agent to the compound of formula I generally varies between 1 and 30, for example between 2 and 20, in particular between 5 and 18.
- the concentration of reagents in the medium is variable; it can be maintained between 0.005 and 1 mol / l.
- a preferred group of these diamines consists of the compounds of formula VIIa in which An and Ar 2 are independently chosen from phenyl optionally substituted by methyl or tert-butyl; and (C 5 -C 6 ) cycloalkyl optionally substituted by methyl or tert-butyl. More preferably, the compounds in which An and Ar 2 are identical and represent optionally substituted phenyl are preferred.
- the invention provides a process comprising, in addition to steps (i) to (iv) defined above, the step consisting in treating in an acidic or basic medium, the compound of formula I, so as to obtain the corresponding carboxylic acid of formula VIII:
- aqueous sodium hydroxide as the hydrolysis agent.
- the process of the invention can be carried out starting from an optically active compound II with conservation of the chirality from one end to the other of the synthesis.
- the compound of formula III will be esterified under anhydrous conditions in the presence of appropriate bases chosen from N-methylmorpholine, triethylamine, tributylamine, diisopropylethamine, dicyclohexylamine, N-methylpiperidine , pyridine, 2,6-dimethylpyridine, 4- (1-pyrrolidinyl) pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butyl-4-methylpyridine , quinoline, N, N-dimethylaniline and N, N-diethyaniline.
- bases chosen from N-methylmorpholine, triethylamine, tributylamine, diisopropylethamine, dicyclohexylamine, N-methylpiperidine , pyridine, 2,6-dimethylpyridine, 4- (1-pyrrolidinyl) pyridine, picoline, 4- (N, N-dimethylamin
- optically active isomers of the compounds of formula II are isolated in a conventional manner from the corresponding racemic mixtures. Usually, an optically active resolving agent is used for this.
- the resolution of the enantiomers can be carried out by formation of an inclusion complex with the (R, R) -1, 2-cyclohexanediamine, the (R, R ) or (S, S) -2,3 - (+) - dimethoxy-N, N, N ', N'- tetramethylsuccinamide, or else (R, R) or (S, S) - (+) - N , N, N ', N'-tetramethyl-2,2'-dimethyl-1, 3-dioxolane-trans-dicarboxamide.
- step a) it is possible, with a view to preparing an optically active compound of formula I, to carry out step a) starting from a diol of racemic formula II , to carry out the splitting of the bromine derivative obtained of formula III, then continue the synthesis starting from the appropriate optically active brane III compound.
- the bifunctional ligands obtained according to the methods of the invention can be used in the preparation of metal complexes intended for the asymmetric catalysis of hydrogenation, hydrosilylation, hydroboration of unsaturated compounds, epoxidation of allyl alcohols, d vicinal hydroxylation, hydrovinylation, hydroformylation, cyclopropanation, isomerization of olefins, polymerization of propylene, addition of organometallic compounds to aldehydes, allyl alkylation, aldol-type reactions, reactions of Diels-Alder and, in general, reactions of formation of bonds CC (such as the allylic substitutions or the cross couplings of Grignard).
- the complexes which can be used in this type of reaction are complexes of rhodium, ruthenium, palladium, platinum, iridium, cobalt, nickel or rhenium, preferably complexes of rhodium, ruthenium, iridium, palladium and platinum. Even more advantageously, rhodium, ruthenium or iridium complexes are used. Specific examples of said complexes of the present invention are given below, without limitation.
- P represents a ligand according to the invention.
- a preferred group of rhodium and iridium complexes is defined by the formula: [MeLig 2 P] Y ⁇ IX in which:
- P represents a ligand according to the invention
- Y ⁇ represents an coordinating anionic ligand
- Me represents iridium or rhodium
- Lig represents a neutral ligand.
- - Lig represents an olefin having from 2 to 12 carbon atoms
- - Y represents an anion PF 6 " , PCI 6 " , BF 4 “ , BCI 4 " , SbF 6 “ , SbCI 6 “ , BPh “ , CI0 4 “ , CN “ , CF 3 S0 3 “ , preferably halogen CI “ or Br " , an anion 1, 3-diketonate, alkylcarboxylate, haloalkylcarboxylate with a lower alkyl radical (preferably in C- ⁇ -C 6 ), a phenylcarboxylate or phenolate anion whose benzene ring can be substituted by alkyl radicals lower (preferably C C ⁇ ) and / or halogen atoms, are particularly preferred.
- Lig 2 can represent two ligands Lig as defined above or a bidental ligand such as bidental ligand, linear or cyclic, polyunsaturated and comprising at least two unsaturations.
- Lig 2 represents 1,5-cyclooctadiene, norbornadiene or that Lig represents ethylene.
- lower alkyl radicals is generally meant a linear or branched alkyl radical having from 1 to 4 carbon atoms.
- Other iridium complexes are those of formula:
- a preferred group of ruthenium complexes consists of the compounds of formula: [RuY ⁇ 1 Y, 2 P] XI in which:
- - P represents a ligand according to the invention
- 2 identical or different, represent an anion PF 6 " , PCl6 “ , BF “ , BCI 4 “ , SbF 6 “ , SbCI 6 “ , BPh 4 “ , CIO 4 “ , CF 3 S0 3 " , a halogen atom , more particularly chlorine or bromine or a carboxylate anion, preferably acetate, trifluoroacetate.
- ruthenium complexes are those corresponding to the following formula XIV:
- - P represents a ligand according to the invention
- - Ar represents benzene, p-methylisopropylbenzene or hexamethylbenzene
- Y ⁇ 3 represents a halogen atom, preferably chlorine or bromine
- Y ⁇ 4 represents an anion, preferably an anion PF 6 " , PCI 6 " , BF 4 “ , BCI 4 “ , SbF 6 “ , SbCI 6 “ , BPh 4 “ , CIO 4 “ , CF 3 SO 3 " .
- Pd (hal) 2 P and Pt (hal) 2 P where P represents a ligand according to the invention and hal represents halogen such as, for example, chlorine.
- the complexes comprising a ligand according to the invention and the transition metal can be prepared according to the known methods described in the literature.
- the complexes are generally prepared from a precatalyst, the nature of which varies according to the transition metal selected.
- the precatalyst is for example one of the following compounds: [Rh '(CO) 2 CI] 2; [Rh '(COD) CI] 2 where COD denotes cyclooctadiene; or Rh '(acac) (CO) 2 where acac denotes acetylacetonate.
- ruthenium complexes particularly suitable precatalysts are bis- (2-methylallyl) -cycloocta-1, 5-diene ruthenium and [RuCI 2 (benzene)] 2 .
- RuCI 2 benzene
- COD Ru (COD) ( ⁇ 3 - (CH 2 ) 2 CHCH 3 ) 2 .
- a solution or suspension is prepared containing the metal precatalyst, a ligand and a perfectly degassed solvent such as acetone (the ligand concentration of the solution or suspension varying between 0.001 and 1 mol / l), to which a methanolic solution of hydrobromic acid is added.
- the ratio of ruthenium to bromine advantageously varies between 1: 1 and 1: 4, preferably between 1: 2 and 1: 3.
- the molar ratio of the ligand to the transition metal is about 1. It can be between 0.8 and 1.2.
- the complex is prepared by mixing the precatalyst, the ligand and an organic solvent and optionally maintaining at a temperature between 15 and 150 ° C for
- aromatic hydrocarbons As solvent, mention may be made of aromatic hydrocarbons
- amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphorylamide
- alcohols such as ethanol, methanol, n-propanol and isopropanol
- the solvent is an amide, in particular dimethylformamide
- the mixture of the ligand, the precatalyst and the solvent is heated to between 80 and 120 ° C.
- the reaction medium is heated to a temperature between 30 and 70 ° C.
- the catalyst is then recovered according to conventional techniques
- reaction to be catalyzed by the complex thus prepared can be carried out without intermediate isolation of the catalyst complex.
- the hydrogenation is for example carried out at a pressure varying between 1, 5 and 100 bar, and at a temperature between 20 ° C and 100 ° C.
- the reaction medium can consist of the reaction medium in which the catalyst was obtained.
- the hydrogenation reaction then takes place in situ.
- the catalyst is isolated from the reaction medium in which it was obtained.
- the reaction medium for the hydrogenation reaction consists of one or more solvents, in particular chosen from C 1 -C 5 aliphatic alcohols such as methanol or propanol and an amide as defined above. above, for example dimethylformamide, optionally in admixture with benzene.
- perfectly degassed methanol and the substrate are added to the reaction medium containing the complex.
- the amount of methanol, or more generally of solvent, which can be added is such that the concentration of the substrate in the hydrogenation reaction medium is between 1 J 0 "3 and 10 mol / l, preferably between 0.01 and 1 mol / l.
- the molar ratio of the substrate to the catalyst generally varies from 1/100 to 1/100,000, preferably from 1/20 to 1/2000. This ratio is for example of 1/1000.
- the rhodium complexes prepared from the ligands of the invention are more particularly suitable for the asymmetric catalysis of isomerization reactions of olefins.
- the suitable substrates are of the ⁇ , ⁇ -unsaturated carboxylic acid type and / or derivatives of ⁇ , ⁇ -unsaturated carboxylic acid. These substrates are described in EP 95943260.0.
- the ⁇ , ⁇ -unsaturated carboxylic acid and / or its derivative more particularly corresponds to formula A:
- R2 R3 and R4 represent a hydrogen atom or any hydrocarbon group, insofar as:
- R3 can be any hydrocarbon or functional group designated by R,
- where R2 represents a hydrogen atom and if R-
- Rj is identical to R2 and represents any hydrocarbon or functional group designated by R, then R3 is different from -CH- (R) 2 and different from -COOR4, - one of the groups R-
- where R2 represents a hydrogen atom and if R-
- R3 is different from a hydrogen atom and different from -COOR4, .
- Rj is identical to R2 and represents any hydrocarbon or functional group designated by R, then R3 is different from -CH- (R) 2 and different from -COOR4, - one of the groups R-
- a first group of preferred substrates is formed by substituted acrylic acids which are precursors of amino acids and / or derivatives.
- substituted acrylic acids all of the compounds whose formula derives from that of acrylic acid by substitution of at most two of the hydrogen atoms carried by the ethylenic carbon atoms by a hydrocarbon group or by a functional group. They can be symbolized by the following chemical formula:
- Rg, R'g, identical or different represent a hydrogen atom, an alkyl group, linear or branched having from 1 to 12 carbon atoms, a phenyl group or an acyl group preferably having from 2 to 12 carbon atoms , an acetyl or benzoyl group
- - R ⁇ represents a hydrogen atom, an alkyl group having from 1 to 12 carbon atoms, a cycloalkyl radical having from 3 to 8 carbon atoms, an arylalkyl radical having from 6 to 12 carbon atoms carbon, an aryl radical having from 6 to 12 carbon atoms, a heterocyclic radical having from 4 to 7 carbon atoms
- o represents a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 carbon atoms.
- a second preferred group of substrates consists of itaconic acid and its derivatives of formula:
- 2 > identical or different represent a hydrogen atom, a linear or branched alkyl group having from 1 to 12 carbon atoms, a cycloalkyl radical having from 3 to 8 carbon atoms, a arylalkyl radical having from 6 to 12 carbon atoms, an aryl radical having from 6 to 12 carbon atoms, a heterocyclic radical having from 4 to 7 carbon atoms.
- o > R'10 > identical or different represent a hydrogen atom or a linear or branched alkyl group, having from 1 to 4 carbon atoms.
- a third preferred group of substrates is defined by the formula A3:
- Q represents a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms.
- 3 represents a phenyl or naphthyl group, optionally carrying one or more substituents.
- the appropriate ketone type substrates more preferably correspond to formula B:
- R5 and R ⁇ represent a hydrocarbon radical having from 1 to 30 carbon atoms optionally comprising one or more functional groups
- - R5 and R ⁇ can form a cycle optionally comprising another heteroatom, - Z is or comprises a heteroatom, oxygen or nitrogen or a functional group comprising at least one of these heteroatoms.
- a first preferred group of such ketone substrates has the formula
- R5 is different from R ⁇ , the radicals R5 and R ⁇ represent a hydrocarbon radical having from 1 to 30 carbon atoms optionally comprising another ketone and / or acid function, ester, thioacid, thioester;
- R5 and R ⁇ can form a carbocyclic or heterocyclic ring, substituted or not, having 5 to 6 atoms.
- ketones chosen from:
- Aldehyde / ketone type substrates having a second carbonyl group in position ⁇ , ⁇ , ⁇ or ⁇ relative to the first carbonyl group are also particularly suitable in the context of the invention.
- diketonic compounds are:
- keto acids or their derivatives and ketothio acids or their derivatives with a functional group (acid, ester, thioacid or thioester) in the ⁇ , ⁇ , ⁇ or ⁇ position relative to the carbonyl group.
- a functional group ascid, ester, thioacid or thioester
- Examples are: - 2-acetylbenzoic acid,
- the product obtained is generally a derivative of ⁇ -butyrolactone and in the case of a ⁇ -keto acid, it s' is a derivative of valerolactone.
- ketones there may be mentioned, among others, the following cyclic, saturated or unsaturated, monocyclic or polycyclic ketone compounds:
- R represents a phenyl substituted or not by alkyl radicals, alkoxy or a halogen atom; or R represents an alkyl group or cycloalkyl substituted or not by alkyl radicals, alkoxy, or a halogen atom, a hydroxyl group, ether, amino; or R represents a halogen atom, a hydroxyl, alkoxy or amino group.
- ketones of steroid type for example 3-cholestanone, 5-cholesten-3-one.
- R 14 a group of formula - N. ⁇
- R14, R-15, Ri ⁇ and R-17 which represent a hydrogen atom or a hydrocarbon group having from 1 to 30 carbon atoms.
- R14, R-15, Ri ⁇ and R-17 which represent a hydrogen atom or a hydrocarbon group having from 1 to 30 carbon atoms.
- Examples of compounds of formula B2 are: ⁇ N-alkylketoimine, such as: - N-isobutyl-2-iminopropane
- N-arylalkyl ketoimine such as:
- the substrate is a ⁇ -ketoester (such as methyl acetoacetate or methyl 3-oxovalerate), an ⁇ -ketoester (such as methyl benzoylformate or pyruvate methyl), a ketone (such as acetophenone), an olefin, an unsaturated amino acid or one of its derivatives (and in particular one of its esters).
- a ⁇ -ketoester such as methyl acetoacetate or methyl 3-oxovalerate
- an ⁇ -ketoester such as methyl benzoylformate or pyruvate methyl
- a ketone such as acetophenone
- an olefin an unsaturated amino acid or one of its derivatives (and in particular one of its esters).
- the invention relates to the use of a compound of formula I or of formula VII or of formula VIII for the preparation of a metal complex intended for asymmetric catalysis, and more particularly of a ruthenium, iridium or rhodium complex.
- a ligand of formula VII for the preparation of a metal complex and more specifically of a ruthenium complex, intended for the asymmetric catalysis of ketone hydrogenation reactions forms a preferred object of the invention.
- the following examples illustrate the invention more precisely.
- the solid obtained is recrystallized from a mixture of tuuene / cyclohexane) at 80 ° C to give 9.8 g (22 mmol, 82% yield) of the expected product.
- the title compound can be prepared from (R) -6,6'-dibromo-2,2'-dihydroxy-1, 1 '-binaphtyle by following the procedure described below. 10.0 g (22.52 mmol) of (R) -6,6'-dibromo-2,2'-dihydroxy-1, 1 '-binaphtyle are dissolved in a solution of 6.3 g (0.1 1 mol of KOH in 300 ml of degassed water The mixture is cooled to 0 ° C.
- the catalyst is prepared in situ. All the solvents used have been carefully degassed and are anhydrous. The reaction medium is maintained under an argon atmosphere. The ligand and the metal precatalyst, bis- (2-methylallyl) cycloocta-1,5,5-diene ruthenium, are directly weighed in a 5 ml conical bottom glass reactor removed from the oven and equipped with a stirrer. in a ligand / metal molar ratio of 1: 1. The reactor is closed by a septum and the air is expelled by an inlet of argon. Acetone is then added (1 ml) to give a white suspension.
- Diam-BINAP starting from (S) -6,6'-diaminomethyl-2,2'- bis (diphenylphosphino) -1, 1 '-binaphtyle (obtained in Example 2).
- This example illustrates the hydrogenation of a ⁇ -ketoester in the presence of the ruthenium complexes prepared in Example 3.
- the hydrogenation protocol is described below: The methanol which has been previously dried over magnesium, is added (2.5 ml) under argon in the conical reactor where the catalyst has just been prepared, the substrate is then added ( in a defined catalyst / substrate ratio). The operation of vacuuming and filling the argon reactor is repeated three times. The septum is then replaced by a pierced plug and the reactor is placed in an autoclave. The autoclave is purged three times under argon then three times under hydrogen before receiving 40 bar of hydrogen pressure. The autoclave is placed on a hot plate (50 ° C) and stirring is continued overnight.
- the conical reactor is finally recovered, the plug is replaced by a septum, and the argon is reinjected into this reactor.
- the reactor is placed in a centrifuge, then the solution is extracted using a syringe. It is placed in a 50 ml flask and diluted in 20 ml of methanol, ready then to be injected into a chromatography column for gas chromatography for analysis of the conversion rate and the enantioselectivity of the reaction.
- the determination of enantiomeric excesses is carried out by chiral gas chromatography on a column of Macheray-Nagel type (Lipodex A 25 m ⁇ 0.25 mm).
- the substrate tested is a ⁇ -ketoester, namely methyl acetoacetate. It leads, after hydrogenation, to methyl 3-hydroxybutanoate.
- the compound obtained is the S enantiomer, the catalysts being prepared from the compounds of Examples 1 and 2.
- the complexes prepared from the compounds of Examples 1 and 2 above lead to excellent enantiomeric excesses.
- the catalysts of the invention therefore allow the implementation of a highly enantioselective hydrogenation reaction.
- EXAMPLE 5 This example illustrates the hydrogenation of an aromatic ketone in the presence of the ruthenium complexes prepared in Example 3.
- the hydrogenation protocol followed is as described in Example 4, except that the substrate used is acetophenone. It leads to phenylethanol.
- the hydrogenation reaction conditions are as described above.
- the results obtained are a conversion rate of less than 1% (traces) and an enantiomeric excess of 0%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000599766A JP2002537305A (ja) | 1999-02-19 | 2000-01-14 | キラルジホスフィンの製造方法 |
AU30551/00A AU3055100A (en) | 1999-02-19 | 2000-01-14 | Method for preparing chiral diphosphines |
US09/913,831 US6610875B1 (en) | 1999-02-19 | 2000-01-14 | Method for preparing chiral diphosphines |
EP00900591A EP1153031A1 (fr) | 1999-02-19 | 2000-01-14 | Procede de preparation de diphosphines chirales |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9902119A FR2789992B1 (fr) | 1999-02-19 | 1999-02-19 | Procede de preparation de diphosphines chirales utiles comme ligands dans la synthese de complexes destines a la catalyse asymetrique |
FR99/02119 | 1999-02-19 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/913,831 A-371-Of-International US6610875B1 (en) | 1999-02-19 | 2000-01-14 | Method for preparing chiral diphosphines |
US10/454,510 Division US20030225297A1 (en) | 1999-02-19 | 2003-06-05 | Process for preparing chiral diphosphines |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000049028A1 true WO2000049028A1 (fr) | 2000-08-24 |
Family
ID=9542315
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2000/000083 WO2000049028A1 (fr) | 1999-02-19 | 2000-01-14 | Procede de preparation de diphosphines chirales |
Country Status (6)
Country | Link |
---|---|
US (2) | US6610875B1 (fr) |
EP (1) | EP1153031A1 (fr) |
JP (1) | JP2002537305A (fr) |
AU (1) | AU3055100A (fr) |
FR (1) | FR2789992B1 (fr) |
WO (1) | WO2000049028A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2807042A1 (fr) * | 2000-04-03 | 2001-10-05 | Rhodia Chimie Sa | Diphosphines chirales hydrosolubles utiles comme ligands dans la synthese de complexes hydrosolubles destines a la catalyse asymetrique |
FR2849036A1 (fr) * | 2002-12-18 | 2004-06-25 | Rhodia Chimie Sa | Diphosphines chirales, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique |
WO2004056483A1 (fr) * | 2002-12-18 | 2004-07-08 | Rhodia Chimie | Diphosphines, leur preparation et leurs utilisations |
FR2853652A1 (fr) * | 2003-04-09 | 2004-10-15 | Rhodia Chimie Sa | Diphosphines chirales, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2801886B1 (fr) * | 1999-12-02 | 2002-10-11 | Fournier Ind & Sante | Ligands et catalyseurs chiraux notamment utiles pour hydrogenation asymetrique |
US7124110B1 (en) * | 2002-07-15 | 2006-10-17 | Trading Technologies International Inc. | Method and apparatus for message flow and transaction queue management |
FR2849037A1 (fr) * | 2002-12-18 | 2004-06-25 | Rhodia Chimie Sa | Diphosphines chirales, leur preparation et leurs utilisations coome ligands dans la synthese de complexes destines a la catalyse asymetrique |
JP5124210B2 (ja) * | 2007-08-24 | 2013-01-23 | 日本化学工業株式会社 | ビアリールホスフィン化合物の製造方法 |
WO2009054240A1 (fr) * | 2007-10-24 | 2009-04-30 | National University Corporation Nagoya University | PROCÉDÉ DE FABRICATION D'UN COMPOSÉ D'ACIDE DISULFONIQUE, CATALYSEUR DE MANNICH ASYMÉTRIQUE, PROCÉDÉ DE FABRICATION D'UN DÉRIVÉ β-AMINOCARBONYLE ET NOUVEAU SEL DE DISULFONATE |
CN106458897A (zh) * | 2014-03-14 | 2017-02-22 | 武田药品工业株式会社 | 制备杂环化合物的方法 |
US11427543B2 (en) | 2016-07-19 | 2022-08-30 | The General Hospital Corporation | Compounds for targeting cancer stem cells |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08311090A (ja) * | 1995-05-18 | 1996-11-26 | Merck & Co Inc | ビナフチル誘導体合成方法 |
WO1998012202A1 (fr) * | 1996-09-20 | 1998-03-26 | Oxford Asymmetry International Plc. | Ligands phosphiniques |
WO1998042716A1 (fr) * | 1997-03-26 | 1998-10-01 | Nsc Technologies Llc | Preparation de phosphines tertiaires par couplage croise catalisee par du nickel |
WO1999036397A1 (fr) * | 1998-01-15 | 1999-07-22 | Merck Patent Gmbh | Derives d'acide perfluoro-n-alcanesulfonique |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62178594A (ja) * | 1986-02-01 | 1987-08-05 | Takasago Corp | 新規ホスフイン化合物 |
JPH0474192A (ja) * | 1990-07-12 | 1992-03-09 | Takasago Internatl Corp | 2,2′―ビス(ジシクロペンチルホスフィノ)―1,1′―ビナフチル及びこれれを配位子とする遷移金属錯体 |
DE4422672A1 (de) * | 1994-06-30 | 1996-01-04 | Hoechst Ag | Halogenierte Biphenyl-2,2'-diyl-bis-diphenylphosphine, ihre Herstellung und ihre Verwendung |
JP3770639B2 (ja) * | 1995-10-31 | 2006-04-26 | 高砂香料工業株式会社 | 光学活性ジホスフィンの製造方法 |
US6162951A (en) * | 1996-09-20 | 2000-12-19 | Oxford Asymmetry International Plc | Phosphine ligands |
JP3445451B2 (ja) * | 1996-10-24 | 2003-09-08 | 高砂香料工業株式会社 | 光学活性ジホスフィン配位子の製造方法 |
JP3892118B2 (ja) * | 1997-07-31 | 2007-03-14 | 高砂香料工業株式会社 | 2,2’−ビス(ジアリールホスフィノ)−6,6’−ビス(トリフルオロメチル)−1,1’−ビフェニル、これを配位子とする遷移金属錯体および光学活性な3−ヒドロキシ酪酸エステル誘導体あるいはβ−ブチロラクトンの製造方法 |
US5990318A (en) * | 1998-03-06 | 1999-11-23 | The Hong Kong Polytechnic University | Soluble polyester-supported chiral phosphines |
US6395916B1 (en) * | 1998-07-10 | 2002-05-28 | Massachusetts Institute Of Technology | Ligands for metals and improved metal-catalyzed processes based thereon |
FR2790477B1 (fr) * | 1999-03-01 | 2001-05-25 | Rhodia Chimie Sa | Polymere lineaire optiquement actif utilisable comme ligand dans la preparation de complexes metalliques destines a la catalyse asymetrique |
-
1999
- 1999-02-19 FR FR9902119A patent/FR2789992B1/fr not_active Expired - Fee Related
-
2000
- 2000-01-14 US US09/913,831 patent/US6610875B1/en not_active Expired - Fee Related
- 2000-01-14 WO PCT/FR2000/000083 patent/WO2000049028A1/fr not_active Application Discontinuation
- 2000-01-14 AU AU30551/00A patent/AU3055100A/en not_active Abandoned
- 2000-01-14 EP EP00900591A patent/EP1153031A1/fr not_active Withdrawn
- 2000-01-14 JP JP2000599766A patent/JP2002537305A/ja not_active Withdrawn
-
2003
- 2003-06-05 US US10/454,510 patent/US20030225297A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08311090A (ja) * | 1995-05-18 | 1996-11-26 | Merck & Co Inc | ビナフチル誘導体合成方法 |
WO1998012202A1 (fr) * | 1996-09-20 | 1998-03-26 | Oxford Asymmetry International Plc. | Ligands phosphiniques |
WO1998042716A1 (fr) * | 1997-03-26 | 1998-10-01 | Nsc Technologies Llc | Preparation de phosphines tertiaires par couplage croise catalisee par du nickel |
WO1999036397A1 (fr) * | 1998-01-15 | 1999-07-22 | Merck Patent Gmbh | Derives d'acide perfluoro-n-alcanesulfonique |
Non-Patent Citations (2)
Title |
---|
CHEMICAL ABSTRACTS, vol. 126, no. 7, 17 February 1997, Columbus, Ohio, US; abstract no. 089568, KAI D W ET AL: "Method for producing 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) derivatives" XP002047609 * |
VONDENHOF M.: "Sulfonic acid esters derived from 1,1'-binaphtalene as new axially chiral photosensitizers", TETRAHEDRON LETTERS., vol. 31, no. 7, 1990, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, pages 985 - 988, XP002135636, ISSN: 0040-4039 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2807042A1 (fr) * | 2000-04-03 | 2001-10-05 | Rhodia Chimie Sa | Diphosphines chirales hydrosolubles utiles comme ligands dans la synthese de complexes hydrosolubles destines a la catalyse asymetrique |
WO2001074828A1 (fr) * | 2000-04-03 | 2001-10-11 | Rhodia Chimie | Diphosphines chirales hydrosolubles |
FR2849036A1 (fr) * | 2002-12-18 | 2004-06-25 | Rhodia Chimie Sa | Diphosphines chirales, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique |
WO2004056483A1 (fr) * | 2002-12-18 | 2004-07-08 | Rhodia Chimie | Diphosphines, leur preparation et leurs utilisations |
FR2853652A1 (fr) * | 2003-04-09 | 2004-10-15 | Rhodia Chimie Sa | Diphosphines chirales, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique |
Also Published As
Publication number | Publication date |
---|---|
US20030225297A1 (en) | 2003-12-04 |
EP1153031A1 (fr) | 2001-11-14 |
AU3055100A (en) | 2000-09-04 |
US6610875B1 (en) | 2003-08-26 |
JP2002537305A (ja) | 2002-11-05 |
FR2789992B1 (fr) | 2001-05-25 |
FR2789992A1 (fr) | 2000-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0297752B1 (fr) | Procédé de préparation d'un alcool optiquement actif | |
EP1153031A1 (fr) | Procede de preparation de diphosphines chirales | |
US6380412B1 (en) | Optically active diphosphines, preparation thereof according to a process for the resolution of the racemic mixture and use thereof | |
FR2830254A1 (fr) | Nouvelles diphosphines, leurs complexes avec des metaux de transition et leur utilisation en synthese asymetrique | |
WO2008029754A1 (fr) | Procédé de fabrication d'un acide aminophosphinylbutanoïque optiquement actif | |
US6166257A (en) | Asymmetric hydrogenation method of a ketonic compound and derivative | |
EP1161481B1 (fr) | Polymere lineaire optiquement actif utilisable comme ligand dans la preparation de complexes metalliques destines a la catalyse asymetrique | |
US20020035271A1 (en) | Process for preparing oprtically active trimethyllactic acid and its ester | |
WO2001074828A1 (fr) | Diphosphines chirales hydrosolubles | |
EP0580336A1 (fr) | Procédé de préparation de 4-méthyl-2-oxétanones optiquement actives | |
US7534920B2 (en) | Optically-active bis(alkynylphosphino) ethane-borane derivative and process for producing the same | |
EP0592881B1 (fr) | Procédé pour la fabrication des gamma-hydroxycétones optiquement actives | |
EP0968220A1 (fr) | Diphosphines de 6,6'-bis-(1-phosphanorbornadiene) | |
JPH092995A (ja) | キラルα−ハロゲンカルボン酸の製造方法 | |
FR2849036A1 (fr) | Diphosphines chirales, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique | |
CA2509911A1 (fr) | Diphosphines, leur preparation et leurs utilisations | |
FR2810666A1 (fr) | Ligands chiraux de type (beta-aminoalkyl)-phosphine, -phosphite, -phosphonite et -phosphinite, complexes metalliques correspondants et leur utilisation dans la catalyse asymetrique | |
FR2853652A1 (fr) | Diphosphines chirales, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique | |
FR2849037A1 (fr) | Diphosphines chirales, leur preparation et leurs utilisations coome ligands dans la synthese de complexes destines a la catalyse asymetrique | |
WO2000027854A1 (fr) | Derives de type phosphine-phosphite | |
FR2854405A1 (fr) | Diphosphines chirales sous forme insoluble; leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique. | |
FR2854401A1 (fr) | Diphosphines chirales sous forme insoluble, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique. | |
FR2734823A1 (fr) | Nouveaux complexes metalliques optiquement actifs et leur utilisation en catalyse asymetrique | |
FR2853653A1 (fr) | Diphosphines chirales, leur preparation et leurs utilisations comme ligands dans la synthese de complexes destines a la catalyse asymetrique | |
JPH07179483A (ja) | 光学活性ホスホネートの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2000900591 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2000 599766 Kind code of ref document: A Format of ref document f/p: F |
|
WWP | Wipo information: published in national office |
Ref document number: 2000900591 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09913831 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000900591 Country of ref document: EP |