GB2452805A - Use of t-Bu QuinoxP - Google Patents
Use of t-Bu QuinoxP Download PDFInfo
- Publication number
- GB2452805A GB2452805A GB0813271A GB0813271A GB2452805A GB 2452805 A GB2452805 A GB 2452805A GB 0813271 A GB0813271 A GB 0813271A GB 0813271 A GB0813271 A GB 0813271A GB 2452805 A GB2452805 A GB 2452805A
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- United Kingdom
- Prior art keywords
- group
- formula
- compound
- substituted
- represented
- Prior art date
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- Granted
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title description 8
- -1 allyl compound Chemical class 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 12
- 238000005859 coupling reaction Methods 0.000 claims abstract description 11
- 150000003216 pyrazines Chemical class 0.000 claims abstract description 11
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 9
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 8
- 150000003624 transition metals Chemical group 0.000 claims abstract description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 7
- 230000008878 coupling Effects 0.000 claims abstract description 3
- 238000010168 coupling process Methods 0.000 claims abstract description 3
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 claims abstract 2
- 125000003277 amino group Chemical group 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000004185 ester group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 150000001733 carboxylic acid esters Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 150000002941 palladium compounds Chemical class 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 15
- 229910052763 palladium Inorganic materials 0.000 abstract description 9
- UVJZGFKZGQSKDV-OUKQBFOZSA-N [(e)-1,3-diphenylprop-2-enyl] acetate Chemical compound C=1C=CC=CC=1C(OC(=O)C)\C=C\C1=CC=CC=C1 UVJZGFKZGQSKDV-OUKQBFOZSA-N 0.000 abstract description 2
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract 1
- 239000012038 nucleophile Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 125000004437 phosphorous atom Chemical group 0.000 description 8
- 229910052698 phosphorus Inorganic materials 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000004296 chiral HPLC Methods 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
- 238000004821 distillation Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003252 quinoxalines Chemical class 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- KOUOYBLNBHOXFR-UHFFFAOYSA-N 2,5-dimethylphospholane Chemical group CC1CCC(C)P1 KOUOYBLNBHOXFR-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003890 2-phenylbutyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- 235000008100 Ginkgo biloba Nutrition 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100028920 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cfp gene Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 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 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- QLZHNIAADXEJJP-UHFFFAOYSA-L dioxido-oxo-phenyl-$l^{5}-phosphane Chemical compound [O-]P([O-])(=O)C1=CC=CC=C1 QLZHNIAADXEJJP-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229910021472 group 8 element Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 1
- ZIYVHBGGAOATLY-UHFFFAOYSA-L methylmalonate(2-) Chemical compound [O-]C(=O)C(C)C([O-])=O ZIYVHBGGAOATLY-UHFFFAOYSA-L 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-L methylphosphonate(2-) Chemical compound CP([O-])([O-])=O YACKEPLHDIMKIO-UHFFFAOYSA-L 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical group C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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Abstract
A process of preparing an optically active allyl compound comprising asymmetrically coupling an allyl compound with an organic nucleophilic compound in the presence of a catalyst. Preferably, the nucleophile is a malonate compound or an amine. The preferred allylic compound is 1,3-diphenyl-2-propenyl acetate. The catalyst is preferably a transition metal complex compound having a phosphine ligand. The transition metal is preferably palladium. The phosphine ligand is preferably a 2,3-bis(dialkylphosphino)pyrazine derivative. The pyrazine derivative is preferably a quinoxaline derivative, more preferably a compound of formula (V): <EMI ID=1.1 HE=40 WI=39 LX=847 LY=1226 TI=CF> <PC>wherein * is an asymmetric centre, R6 and R7 are each independently an optionally substituted alkyl group, R8 and R9 are each independently selected from hydrogen, an optionally substituted alkyl group and a ring system, or R8 and R9 are taken together to form a fused ring.
Description
PROCESS OF PREPARING OPTICALLY ACTIVE ALLYL COMPOUND
Technical Field
This invention relates to a process of preparing an optically active allyl compound that is important as an intermediate for pharmaceuticals, agricultural s chemicals, or physiologically active substances, for example, very useful as an intermediate for synthesizing antibiotics.
Background Art
Processes that are known or thought to be useful for the production of an optically active allyl compound include (1) once synthesizing a racemic form of a desired ally! compound, followed by optical resolution using an optically active resolving agent or an enzyme, (2) starting with an asymmetric compound, or (3) using an asymmetric catalyst.
The process (1) which uses an optically active resolving agent requires an equivalent or more amount of a resolving agent relative to an ally! compound.
Moreover, complicated procedures such as crystallization, separation, and purification, are involved before obtaining an optically active allyl compound. The process (1) which uses an enzyme, while capable of yielding an allyl compound with relatively high optical purity, limits the type of a reaction substrate and the absolute configuration of a resulting allyl compound.
The process (2) is conceivable but problematic in that an optically active starting compound is not only expensive but must be used in a stoichiometric excess.
As the process (3), detailed researches have recently been done into catalytic asymmetric synthesis of an optically active allyl compound that can achieve high efficiency and asymmetric yield, as reported in Trost, B.M. & Van Vranken, D.L. Chem. ----Rev., 96, 395-422 (1996) and Trost, B.M. & Crawley, M.L., Chein. Rev., 103, 2921-2944 (2003). The techniques in this line are still under suL ------
Summary of the Invention
In the light of the above circumstances, it is an object of the invention to provide a process of preparing an optically active allyl compound at high efficiency in high asymmetric yield.
s As a result of extensive studies on catalytic asymmetric synthesis of an optically active allyl compound, the present inventors have found that asymmetric coupling reaction of an allyl compound with an organic nucleophilic compound in the presence of a catalyst gives a desired optically active allyl compound with the reduced number of steps at high efficiency in good asymmetric yield. The present invention has been reached based on this finding.
The invention provides a process of preparing an optically active allyl compound represented by formula (IU): Nu (III) R2 wherein R1, R2, R3, R4, and R5 each represent a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an arailcyl group, a substituted arailcyl group, an aryl group, a substituted aryl group, an aliphatic heterocyclic group, a substituted aliphatic heterocyclic group, an aromatic heterocyclic group, or a substituted aromatic heterocyclic group; Nu represents a nucleophilic group selected from an a-ketocarbanion group, an amino group, and a substituted amino group; and the asterisk * indicates an asymmetric center.
or an optically active allyl compound represented by formula (IV): Nu R5 R17'R4 wherein R', R2, R3, R4, R5, Nu, and * are as defined above.
or a mixture of the compound of formula (HI) and the compound of formula (IV).
The process comprises asymmetrically coupling an allyl compound represented by formula (1): C') wherein R', R2, R3, R4, and R5 axe as defined above; and E represents a leaving group selected from a group comprising an oxygen atom and the group which is represented by R', R2, R3, R4, and R5 and is bonded to the oxygen atom; a halogeno group; a carbonic ester group; a sulfonic ester group; a phosphonic ester group; a phoshoric ester group; and a carboxylic ester group.
with an organic nucleophilic compound represented by formula (II): Nu-H (II) wherein Nu is as defined above.
in the presence of a catalyst.
Detailed Descnption of the Invention -he aiIyfco otiiidth in &üsedás a St teriatin-the-process-of-the-invention is represented by formula (I). The product obtained by the process of the invention is the optically active allyl compound represented by formula (III), the optically active allyl compound represented by formula (IV), or a mixture thereof. The groups represented by R1, R2, R3, R4, and R5 in formulae (I), (Ill), and (IV) will be described.
The term "ailcyl group" includes straight-chain or branched ailcyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, tert-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, tert-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 5-methylpentyl.
The term "substituted alkyl group" includes the above recited alkyl groups at least one hydrogen atom of which is displaced with a substituent, such as an ailcyl group, a cycloalkyl group, an ailcoxy group, a halogen atom, an amino group, or a protected amino group. Any protective group known for the protection of an amino group can be used. Examples of the amino protective group are described, e.g., in Protective Groups in Organic Synthesis, 2nd Ed., John Wiley & Sons, Inc. Examples of useful amino protective groups include an alkyl group, a cycloallcyl group, an aralkyl group, an acyl group, and an alkyloxycarbonyl group.
The term "cycloallcyl group" includes a cycloalkyl group having 3 to 16 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 3-methylcyclopentyl, cycloheptyl, 2-methylcyclohexyl, 3-methylcyclohexyl, and 4-methylcyclohexyl. The term "cycloalkyl group" also includes a polycyclic alkyl group, such as menthyl, bomyl, norbornyl, or adamantyl.
The substituted cycloalkyl group includes the above described cycloalicyl groups at least one hydrogen atom of which is displaced with a substituent such as an alkyl group, a cycloalkyl group, an alkoxy group, a halogen atom, an amino group or a protected amino group.
-The term "arailcyl group" includes aralkyl groups having 7 to 12 carbon atoms, such as benzyl, 2-phenylethyl, 1-phenyipropyl, 2-pheylrcy1, ènlpl, -- 1 -phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, I -phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, I -phenyihexyl, 2-phenyihexyl, 3-phenyihexyl, 4-phenylhexyl, 5-phenylhexyl, and 6-phenyihexyl.
The substituted aralkyl group includes the above described aralkyl groups at least one hydrogen atom of which is displaced with a substituent such as an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogen atom, an amino group, or an allcyl-substituted amino group.
The term "aryl group" includes aryl groups having 6 to 14 carbon atoms, such as phenyl, naphthyl, and anthryl.
The substituted aryl group includes the above described aryl groups at least one hydrogen atom of which is displaced with a substituent such as an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogen atom, an amino group, or an alkyl-substjtuted amino group and the above described aryl groups adjacent two hydrogen atoms of which are displaced with a substituent such as an alkylenedioxy group.
The "aliphatic heterocyclic group" is preferably 5-or 6-membered. The aliphatic heterocyclic group includes one containing 1 to 3 hetero atoms such as nitrogen, oxygen, and sulfur atoms. Examples of the aliphatic heterocyclic group include pyrrolidy-2-one, piperidino, piperazinyl, morpholino, tetrahydrofuryl, and tetrahydropyranyl.
The term "substituted aliphatic heterocyclic group" includes the above described aliphatic heterocyclic groups at least one hydrogen atom of which is displaced with a substituent such as an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, or a halogen atom.
The term "aromatic heterocyclic group" preferably includes 5-or 6-membered, monocyclic or polycyclic aromatic heterocyclic rings containing 1 to 3 hetero atoms such as nitrogen, oxygen, and sulfur atoms. Examples of the aromatic heterocyclic group include pyridyl, imidazolyl, thiazolyl, flirfuryl, pyranyl, fuzyl, benzofuryl, and thienyl. --_-The "substituted aromatic heterocyclic group" includes the above described aromatic heterocyclic groups at least one hydrogen atom of which* is displaced with a substituent such as an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, or a halogen atom.
In formulae (I), (Ill), and (LV), R', R2, R3, R4, and R5 may be the same or different. They may be independent of each other, or two or more of them may be crosslinked to each other.
In formula (I), E represents a leaving group. Specifically E represents a group comprising (a) a hydrogen atom or the group represented by R', R2, R3, R4, and R5, and (b) an oxygen atom. In this case E is bonded to the carbonyl group via the oxygen atom. E also represents a halogeno group, a carbonic ester group, a sulfonic ester group, a phosphonic ester group, a phoshoric ester group, and a carboxylic ester group.
Examples of the group comprsing the hydrogen atom or the group as represented by R', R2, R3, R4, or R5 and an oxygen atom include a hydroxyl group, a methoxy group, an ethoxy group, a phenyloxy group, a benzyloxy group, and a p-methoxybenzyloxy group. Examples of the halogeno group are fluoro, chioro, bromo, and iodo. Examples of the carbonic ester are methyl carbonate, ethyl carbonate, and tert-butyl carbonate. Examples of the sulfonic ester are a methanesulfonate a benzenesulfonate, a p-toluenesulfonate, and a trifluoromethanesulfonate Examples of the phosphonic ester are methyl phosphonate, ethyl phosphonate, and phenyl phosphonate. Examples of the phosphoric ester are methyl phosphate, ethyl phosphate, and phenyl phosphate. Examples of the carboxylic ester include an acetate, a propionate, an oxalate, and a benzoate.
The organic nucleophilic compound represented by formula (II) that is used in the coupling reaction of the allyl compound of formula (I) is described below. The group represented by Nu in formula (H) is a nucleophilic group selected from an a-ketocarbanjon group, an amino group, and a substituted amino group.
Examples of the a-ketocarbanjon include organic compounds having a structure of formula as described below. Examples of such organic compounds include acetone ci-dehydro anion, ethyl acetate a-dehydro anion, and diethyl malonate a-dehydro anion.
II -c-c
The term "substituted amino group" refers to an amino group at least one hydrogen of which is displaced with a substituent such as an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, or a halogen atom. The term "substituted amino group" includes a cyclic amino group, such as a morpholino group, a pyrrolidino group, and a 3-oxazolin-2-on-1-yl group.
The coupling reaction between the allyl compound of formula (1) and the organic nucleophilic compound of formula (U) is carried out in the presence of a catalyst. In the present invention, a transition metal complex compound having a phosphine ligand is preferably used as a catalyst.
It is particularly preferred to use, as a phosphine ligand, a 2,3-bis(dia1Iphosphno)pyrine derivative represented by formula (V): R6 R7 ::x:x' R7 R6 wherein * is as defined above; R6 and R7 each represent -----ancLR! --each have the same meaning as R', R2, R3, R4, and R5, or R8 and R9 are taken together to form a fused ring.
In formula (V), the alkyl group and the substituted alkyl group as R6 and R7 are exemplified by the same examples as recited for R', R2, R3, R4, and R5. R6 and R7 may be the same or different. Although R6 and R7 may be independent of each other or crosslinked to each other, it is essential to select R6 and R7 so as to result in asymmetry on the phosphorus atom or to make the phosphorus atom constitute a point of the symmetry plane of axial asymmetry.
In order to effectively induce asymmetry on the phosphorus atom, it is preferred that R6 and R7 are selected so as to make a large difference in three-dimensional bulkiness therebetween. Examples of a preferred combination of R6 and R7 are a combination of a methyl group and a tert-butyl group and a combination of a methyl group and an adamantyl group.
In order to make the phosphorus atom constitute a point of the symmetry plane of axial asymmetry, it is preferred that the moieties of R6 and R7 providing the asymmetry are as close as possible to the phosphorus atom so as to effectively induce the asymmetry. This is exemplified by a configuration in which R6 and R7 are crosslinked to each other, and an atomic group including the crosslinked moiety and the phosphorus atom is 2,5-dimethylphospholane.
The group represented by R8 and R9 in formula (V) is then described. As stated, R8 and K9 have the same meaning as R', R2, R3, R4, and R5. R8 and R9 may be the same or different. R8 and K9 may be taken together to form a fused ring.
Examples of the fused ring include a benzene ring, a naphthalene ring, a phenanthrene ring, a methylenedioxy ring, an ethylenedioxy ring, and a cyclohexane ring.
It is particularly preferred that R8 and R9 are taken together to form a benzene ring. In this case, the pyrazine derivative represented by formula (V) is a 2,3-bis(diaIlcylphosphjno)qoxalj derivative represented by formula (Vi): R6 R7 Rw-(t R7 R6 wherein R6, R7, and the asterisk * are as defined above; In formula (VI), the substituent represented by R'° is a monovalent substituent.
Examples of the monovalent substituent include an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogen atom, an amino group, a protected amino group, and a nitro group. The benzene ring may have one or more than one substituents R'°. When there are two or more substituents R'°, they may be either the same or different.
Examples of the pyrazine derivative of formula (V) having asymmetry introduced at the phosphorus atom are shown below.
t-Bu Me Ad Me 0(1; Me t-Bu Me Aci (a) (b) (a): (S,S)-2,3-Bis(tertbuty1methy1phosphjno)quoxa] or (b): or (R)-2Bis(adamanethy1phosphjflo)qujnoxaljne Examples of the pyrazine derivative of formula (V) in which the phosphorus atom constitutes a point of symmetry plane of axial asymmetry as shown below.
(c) (d) (c): 2,3-Bis[(R,R)-2,5-dimethylphospholano]quinoxaline (d): 2,3-Bis[(S,S)-2,5-dimethylphospholano]quinoxaline The pyrazine derivatives of formula (V) including the quinoxaline derivatives of formula (VI) can be prepared in accordance with the process disclosed in commonly assigned U.S. Patent Application 2007/0021610A1, the disclosure of which is incorporated herein by reference.
The pyrazine derivative of formula (V) including the quinoxaline derivative of formula (VI) reacts with a transition metal to form a complex compound, which can be used as a catalyst for asymmetric synthesis. Examples of the transition metal with which to form a complex include rhodium, ruthenium, iridium, palladium, nickel, and iron. Preferred of them are the group VIII elements, such as rhodium, ruthenium, iridium, palladium, and nickel. Palladium is particularly preferred. A palladium complex having the pyrazine derivative of formula (V) as a ligand can be prepared by, for example, mixing a pyrazine derivative of formula (V) and a palladium compound having an allyl compound coordinated to a palladium atom, e.g., [PdCI(Tf-C3H5)]2.
---The catalyst comprising the transition metal complex compound is preferably used in an amount of 0.0001 to 100 mol%, more preferably 0.001 to 10 rnol%, based on ---the reaction substrate. To promote the reaction moderately while suppressing the amount of the catalyst to be used, an even more preferred amount of the catalyst to be used is 0.02 to 5 mol%.
II
To accelerate smooth progress of the asymmetric coupling reaction, a base may be used. Examples of useful bases include, but are not limited to, N,O-bis(trimethylsjlyl)acetamjde (BSA), potassium acetate, and a mixture thereof.
The asymmetric coupling reaction is usually carried out in a solvent commonly employed in general organic chemical reactions, such as toluene, hexane, tetrahydrofliran (THF), diethyl ether, dioxane, acetone, ethyl acetate, chlorobenzene, dimethylformam.ide (DMF), acetic acid, and water. Preferred solvents are methanol, ethanol, and dichioromethane.
The amount of the solvent to be used is decided appropriately, taking into consideration the fluidity of the reaction mixture during the reaction and the effects the solvent exerts on the reaction. Where the reaction proceeds well without a solvent, for example, when the reactant mixture to be reacted is a low-viscosity, homogeneous fluid with no aid of a solvent, it is not necessary to use a solvent.
The asymmetric coupling reaction temperature is preferably -80°C to 150°C, more preferably 0°C to 120°C in which range the reaction is promoted while suppressing a side reaction and raceinization.
The asymmetric coupling reaction is preferably carried out for a period of from one minute to one month, more preferably a period of from 3 hours to 3 days, which period is adequate for completion of the reaction.
The asymmetric coupling reaction according to the present invention generally results in the formation of the optically active allyl compound of formula (III). When rearrangement of the leaving group occurs during the reaction, the optically active allyl compound of formula (IV) is obtained. When it is desired to selectively obtain either one of them, reaction conditions that will result in an increased selectivity to a desired -coipound are established through proper selection of the catalyst, the solvent, and the like. Otherwise, a mixture of the two compounds as obtained can be subjected to crystallization, distillation, column chromatography, preparative HPLC, and so forth to isolate a desired optically active allyl compound.
The optically active allyl compound synthesized by the process of the invention can be used in the form of a reaction mixture as obtained. If desired, the reaction mixture may be subjected to usual work-up and purification procedures such as solvent removal, liquid- liquid separation, crystallization, distillation, sublimation, and column s chromatography.
The preparation process of the invention may be performed either batchwise or continuously.
The optically active ally! compound obtained by the process of the invention is used as an intermediate for pharmaceuticals, agricultural chemicals, and physiologically active substances. For example, it is useful as an intermediate for synthesis of antibiotics.
Examples
The present invention will now be illustrated in greater detail with reference to Examples, but it should be understood that the invention is not construed as being limited thereto.
All the synthesis operations in Examples were carried out using thoroughly dried glassware. The reaction was performed in an argon or nitrogen atmosphere. A commercially available phosphine ligand, (R,R)-2,3-bis(tert-butylmethylphospjijno)..
quinoxaline ((R,R)tBuQuinoxp*), from Sigma-Aldrich Japan, was used as such.
The solvent and the metal compound such as [PdCl(13-C3H5)]2 were general reagents.
NMR spectrum measurement was performed using an NMR spectrometer from JEOL, Ltd. (H: 300 MHz; 3C: 75.4 MHz; 31P: 121.4 MHz). Tetramethylsilane (H) was used as an internal standard. GC analysis was performed using GC-l4B FID detector from Shimadzu Corp. Mass spectrometry was conducted using GC-MS from -Shimadzu Cor ------
Example I
Synthesis of dimethyl (S)-cc-( 1,3-diphenyl-2-propen-1 -yl)malonate In 0.5 ml of dichioromethane were suspended 0.9 mg (2.5 j.tmol) of [PdCI(i3-C3H5)}2 and 1.8 mg (5.5 iimol) of (R,R)tBu.Qujnoxp* (1), followed by stirring at room temperature for 10 to 30 minutes. To the resulting solution were added a solution of 126 mg (0.50 mmol) of l,3-diphenyl-2-propenyl acetate in 1.5 ml of dichloromethane, 171 il (1. 50 mmol) of dimethyl malonate, 367 j.tl (1.50 mmol) of N,O-bis(trimethylsj1yl)acenjde (BSA), and a trace amount of potassium acetate.
The reaction system was stirred at room temperature for 1 hour. The reaction mixture was diluted with diethyl ether, and a saturated aqueous solution of ammonium chloride was added to stop the reaction. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with a sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. Any volatile matter was evaporated off, and the residue was purified by silica gel column chromatography.
Examples 2 to 13
Various optically active allyl compounds were synthesized in the same manner as in Example 1, except for altering the nucleophilic compound (Nu-H), additive, and so forth as shown in Table 1 below. The results obtained are shown in Table I together with the results of Example 1. Unless otherwise specified, the allylalkylation reaction system was I,3-diphenyl-2-propenyj acetate (3)/malonic ester or acetylacetoncfBSAJtBuQujnoxp* (1)/[PdC1(3-C3H5)]2/CH2C12 = 0.50 mmol/ 1.5 minolll.5 mmo]J0.0055 mmolJO.0025 mmol/2.0 nil; 1 mol% Pd, and the allylamination reaction system was l,3-diphenyl-2-propenyl acetate (3)/ainine/BSA/ tBu.QuinoxP* (1)/[PdCI(13-C3fl5)]2/CR2CI2 = 0.50 mmolJl.5 mmolJl.5 mmoll 0.011 mmoIJO.0050 mmoJJ2.0 nil; 2 mol% Pd.
Table 1
Synthesis of Optically Active Allyl Compound t-Bu Me OAc [PdCI(113.C3H&]2 /1 Nu N fr + Nu-H Additive, CH2C1, PV-"Ph XNP temp. Me t-Bu * 1 1 Example Nu.H Additive Catalyst T(e;.
_________ H2C(COOMe)2 KOAc+BSA I r.t. 1 85 (4a) 92 (S) 2 HCCH3(COOMe)2 KOAc+BSA I r.t. 1 97 (4b) 95(R) 3 HC(n-Bu)(COOEt)2 KOAC-1-BSA I ri 1 87 (4c) 92 4 HC(C}1zPh)(COOEt) KOAc+BSA I r.t. 48 93 (4d) 90 HC(N}ICHO)(COOE*)2 KOAc+BSA 1 r.L 26 94 (4e) 91 6 HC(NHACXCOOEt)Z KOAc-I-BSA 1 r.t. 27 83 (41) 91 CR) 7 H2C(COMe)2 KOAc+BSA I r.t. 1 88 (4g) 95 (S) 8 HCCH3(COOMc)2 KOAc+BSA 3 -50°C 20 92 (4b) 98.7 (R) 9 morpholine -2 r.t. 13 69 (4h) 78 rnorpholine BSA 2 r.t. 13 94 (4h) 89 11 pro1idine BSA 2 r.t. 20 81 (4i) 90 (R) 12 butylamine BSA 2 r.L 63 >99 (4j) 73 _________ cyclohexylamine BSA 4 r.t. 48 96 (4k) 89 Note: *1: isolation yield *2: Determined by chiral HPLC *3: Determined by comparing the chiral HPLC results with literature data.
*4: Reaction system was 1,3-diphenyl-2-propenyl acetate (3)/methyl malonate/BSA/t-Bu-Qujnoxy * (1)/[PdCI(i3-C3H5)]z/CJ12C12 = 0. 50 tnmol/ 1.5 mmol/1.5 mmoIiO.016 mmolIO.0075 nunoll2.O ml; 3 mol% Pd *5: Reaction system was l,3-diphenyl-2-propenyl acetate (3)/cyclohexylamine/ -------BSAJtBuQuinox*(4)/[pdCl(fl3..C3fls)J2/CH2C12_0j0j,moJ/j5noJJ ---1. 5 mmoJJOO2l mmolJO.O10 mrnol/1.O ml; 4 mol% Pd According to the process of the present invention, an optically active ally! compound with high optical purity can be produced with the reduced number of steps using a small amount of a catalyst, and the catalyst used in the process achieves excellent catalytic activity and enantio-. and diastereoselectivity. The optically active allyl compound obtained by the process of the invention is important as an intermediate for pharmaceuticals, agricultural chemicals, and physiologically active substances.
For example, it is very useful as an intermediate for synthesizing antibiotics. Thus, the present invention is of very high industrial utility.
Claims (5)
- WHAT IS CLAIMED IS: 1. A process of preparing an optically active allyl compound represented by formula (III): R1 Nu R2R5 (III) wherein R', R2, R3, R4, and R5 each represent a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aralkyl group, a substituted aralkyl group, an aiyl group, a substituted aryl group, an aliphatic heterocyclic group, a substituted aliphatic heterocyclic group, an aromatic heterocyclic group, or a substituted aromatic heterocyclic group; Nu represents a nucleophilic group selected from an cz-ketocarbanion group, an amino group, and a substituted amino group; and the asterisk * indicates an asymmetric center, or an optically active allyl compound represented by formula (IV) : Nu R5 R1"f'R4 wherein R1, R2, R3, R4, R5, Nu, and * are as defined above, or a mixture of the compound of formula (Ill) and the compound of formula (IV), the process comprising asymmetrically coupling an allyl compound represented by formula (I): R2(''R5 (I) wherein R', R2, R3, R4, and R5 are as defined above; and E represents a leaving group selected from a group comprising an oxygen atom and the group which is represented by R', R2, R3, R4, and R5 and is bonded to the oxygen atom; a halogeno group; a carbonic ester group; a sulfonic ester group; a phosphonic ester group; a phoshoric ester group; and a carboxylic ester group, with an organic nucleophjljc compound represented by formula (Ii): Nu-H (II) wherein Nu is as defmed above, in the presence of a catalyst.
- 2. The process according to claim 1, wherein the catalyst is a transition metal complex compound having a phosphine ligand.
- 3. The process according to claim 2, wherein the transition metal complex compound is a palladium compound.
- 4. The process according to claim 2, wherein the phosphine ligand is a pyrazine derivative represented by formula (V): R6 R7 R8 N flrP* 9.A%R N R7 R6-Whreiii*1s as defined-above;-R and-R1eacb-represent ------------an alkyl group or a substituted alkyl group; R8 and R9 each have the same meaning as R', R2, R3, R4, and R5, or R8 and R9 are taken together to form a fused ring. I ?
- 5. The process according to claim 4, wherein the pyrazine derivative represented by formula (V) is a quinoxaline derivative represented by formula (Vi): R6 R7 R1O4JcEP. (VI) RT R6 wherein R6, R7, and * are as defined above;
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US20070066825A1 (en) * | 2003-05-22 | 2007-03-22 | Ulrich Scholz | Chiral ligands and their transition metal complexes |
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