CN1178517A - Process for reduction of carbonyl compounds - Google Patents
Process for reduction of carbonyl compounds Download PDFInfo
- Publication number
- CN1178517A CN1178517A CN 97190044 CN97190044A CN1178517A CN 1178517 A CN1178517 A CN 1178517A CN 97190044 CN97190044 CN 97190044 CN 97190044 A CN97190044 A CN 97190044A CN 1178517 A CN1178517 A CN 1178517A
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- China
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- substituted
- carbon atoms
- general formula
- unsubstituted
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- 150000001728 carbonyl compounds Chemical class 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 48
- -1 alcohol compound Chemical class 0.000 claims abstract description 115
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 122
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 41
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 38
- 238000006722 reduction reaction Methods 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 27
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 claims description 9
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 8
- 229910052782 aluminium Inorganic materials 0.000 claims description 7
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 5
- YFNGCPVGPCKWAL-UHFFFAOYSA-N bis(2-methylpropyl)-propan-2-yloxyalumane Chemical compound CC(C)[O-].CC(C)C[Al+]CC(C)C YFNGCPVGPCKWAL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- DUDSDLYLQRNMIY-UHFFFAOYSA-N bis(2-methylpropyl)alumanylium;diphenylmethanolate Chemical compound CC(C)C[Al+]CC(C)C.C=1C=CC=CC=1C([O-])C1=CC=CC=C1 DUDSDLYLQRNMIY-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- GHOXYLYITXKSDS-INIZCTEOSA-N benzyl n-[(2r)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound C([C@@H](C(=O)CCl)NC(=O)OCC=1C=CC=CC=1)SC1=CC=CC=C1 GHOXYLYITXKSDS-INIZCTEOSA-N 0.000 claims description 3
- GHOXYLYITXKSDS-MRXNPFEDSA-N benzyl n-[(2s)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound C([C@H](C(=O)CCl)NC(=O)OCC=1C=CC=CC=1)SC1=CC=CC=C1 GHOXYLYITXKSDS-MRXNPFEDSA-N 0.000 claims description 3
- KSRZEIAFVUNSKV-JTQLQIEISA-N methyl n-[(2r)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound COC(=O)N[C@H](C(=O)CCl)CSC1=CC=CC=C1 KSRZEIAFVUNSKV-JTQLQIEISA-N 0.000 claims description 3
- KSRZEIAFVUNSKV-SNVBAGLBSA-N methyl n-[(2s)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C(=O)CCl)CSC1=CC=CC=C1 KSRZEIAFVUNSKV-SNVBAGLBSA-N 0.000 claims description 3
- GLDHIVIONXFFQT-LBPRGKRZSA-N tert-butyl n-[(2r)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)CCl)CSC1=CC=CC=C1 GLDHIVIONXFFQT-LBPRGKRZSA-N 0.000 claims description 3
- GLDHIVIONXFFQT-GFCCVEGCSA-N tert-butyl n-[(2s)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C(=O)CCl)CSC1=CC=CC=C1 GLDHIVIONXFFQT-GFCCVEGCSA-N 0.000 claims description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 2
- OYHLRJGDELITAF-MRXNPFEDSA-N benzyl n-[(2r)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound C([C@H](C(=O)CCl)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 OYHLRJGDELITAF-MRXNPFEDSA-N 0.000 claims description 2
- OYHLRJGDELITAF-INIZCTEOSA-N benzyl n-[(2s)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound C([C@@H](C(=O)CCl)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 OYHLRJGDELITAF-INIZCTEOSA-N 0.000 claims description 2
- CQXLRNNWSQJZRZ-NSHDSACASA-N ethyl n-[(2r)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound CCOC(=O)N[C@H](C(=O)CCl)CSC1=CC=CC=C1 CQXLRNNWSQJZRZ-NSHDSACASA-N 0.000 claims description 2
- CQXLRNNWSQJZRZ-LLVKDONJSA-N ethyl n-[(2s)-4-chloro-3-oxo-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound CCOC(=O)N[C@@H](C(=O)CCl)CSC1=CC=CC=C1 CQXLRNNWSQJZRZ-LLVKDONJSA-N 0.000 claims description 2
- 230000000707 stereoselective effect Effects 0.000 claims 2
- FIEZLSTZTKVKAT-LLVKDONJSA-N ethyl n-[(2r)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound CCOC(=O)N[C@@H](C(=O)CCl)CC1=CC=CC=C1 FIEZLSTZTKVKAT-LLVKDONJSA-N 0.000 claims 1
- FIEZLSTZTKVKAT-NSHDSACASA-N ethyl n-[(2s)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound CCOC(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 FIEZLSTZTKVKAT-NSHDSACASA-N 0.000 claims 1
- VFHUZXQGMFOLRF-SNVBAGLBSA-N methyl n-[(2r)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C(=O)CCl)CC1=CC=CC=C1 VFHUZXQGMFOLRF-SNVBAGLBSA-N 0.000 claims 1
- VFHUZXQGMFOLRF-JTQLQIEISA-N methyl n-[(2s)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound COC(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 VFHUZXQGMFOLRF-JTQLQIEISA-N 0.000 claims 1
- JAKDNFBATYIEIE-GFCCVEGCSA-N tert-butyl n-[(2r)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C(=O)CCl)CC1=CC=CC=C1 JAKDNFBATYIEIE-GFCCVEGCSA-N 0.000 claims 1
- JAKDNFBATYIEIE-LBPRGKRZSA-N tert-butyl n-[(2s)-4-chloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 JAKDNFBATYIEIE-LBPRGKRZSA-N 0.000 claims 1
- 150000002440 hydroxy compounds Chemical class 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000002329 infrared spectrum Methods 0.000 description 15
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000013078 crystal Substances 0.000 description 12
- 230000007062 hydrolysis Effects 0.000 description 12
- 238000006460 hydrolysis reaction Methods 0.000 description 12
- GFGQSTIUFXHAJS-QWHCGFSZSA-N tert-butyl n-[(2s,3s)-4-chloro-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@H](O)CCl)CC1=CC=CC=C1 GFGQSTIUFXHAJS-QWHCGFSZSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 230000000694 effects Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- GFGQSTIUFXHAJS-STQMWFEESA-N tert-butyl n-[(2s,3r)-4-chloro-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)CCl)CC1=CC=CC=C1 GFGQSTIUFXHAJS-STQMWFEESA-N 0.000 description 5
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- NOUYQAAYWDNRNG-UEWDXFNNSA-N methyl (3S)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)C(=O)OC)CC1=CC=CC=C1 NOUYQAAYWDNRNG-UEWDXFNNSA-N 0.000 description 4
- BSVHDHJWGZVKHH-LBPRGKRZSA-N methyl (3s)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-2-oxo-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)C(=O)OC)CC1=CC=CC=C1 BSVHDHJWGZVKHH-LBPRGKRZSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- NOUYQAAYWDNRNG-STQMWFEESA-N methyl (2s,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@H](O)C(=O)OC)CC1=CC=CC=C1 NOUYQAAYWDNRNG-STQMWFEESA-N 0.000 description 3
- ZAZXPIZQYVPWAW-WDEREUQCSA-N methyl n-[(2s,3s)-4-chloro-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound COC(=O)N[C@H]([C@H](O)CCl)CC1=CC=CC=C1 ZAZXPIZQYVPWAW-WDEREUQCSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 125000004344 phenylpropyl group Chemical group 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XWCQSILTDPAWDP-UHFFFAOYSA-N 2-chloro-1-phenylethanol Chemical compound ClCC(O)C1=CC=CC=C1 XWCQSILTDPAWDP-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- YMCLVAZUQJPLTE-DLBZAZTESA-N benzyl n-[(2r,3s)-4-chloro-3-hydroxy-1-phenylsulfanylbutan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](CCl)O)NC(=O)OCC=1C=CC=CC=1)SC1=CC=CC=C1 YMCLVAZUQJPLTE-DLBZAZTESA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 2
- GCPCLEKQVMKXJM-UHFFFAOYSA-N ethoxy(diethyl)alumane Chemical compound CCO[Al](CC)CC GCPCLEKQVMKXJM-UHFFFAOYSA-N 0.000 description 2
- QMUUYKTXISVGTG-QWRGUYRKSA-N ethyl N-[(2S,3S)-4,4-dichloro-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound CCOC(=O)N[C@H]([C@H](O)C(Cl)Cl)CC1=CC=CC=C1 QMUUYKTXISVGTG-QWRGUYRKSA-N 0.000 description 2
- MFGNHTYSRALQHO-JTQLQIEISA-N ethyl n-[(2s)-4,4-dichloro-3-oxo-1-phenylbutan-2-yl]carbamate Chemical compound CCOC(=O)N[C@H](C(=O)C(Cl)Cl)CC1=CC=CC=C1 MFGNHTYSRALQHO-JTQLQIEISA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- NOUYQAAYWDNRNG-QWHCGFSZSA-N methyl (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(=O)OC)CC1=CC=CC=C1 NOUYQAAYWDNRNG-QWHCGFSZSA-N 0.000 description 2
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- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
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- 238000011916 stereoselective reduction Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- MCULRUJILOGHCJ-UHFFFAOYSA-N triisobutylaluminium Chemical compound CC(C)C[Al](CC(C)C)CC(C)C MCULRUJILOGHCJ-UHFFFAOYSA-N 0.000 description 2
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- BAYAKMPRFGNNFW-UHFFFAOYSA-N 2,4-dimethylpentan-3-ol Chemical compound CC(C)C(O)C(C)C BAYAKMPRFGNNFW-UHFFFAOYSA-N 0.000 description 1
- DCQQZLGQRIVCNH-UHFFFAOYSA-N 2-methoxycyclohexan-1-ol Chemical compound COC1CCCCC1O DCQQZLGQRIVCNH-UHFFFAOYSA-N 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
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention provides a process for reducing carbonyl compounds to hydroxy compounds, in particular stereoselectively reducing alpha -aminohaloketone derivatives in an easy and simple manner, which comprises reacting a carbonyl compound of the general formula (1) with an organoaluminum compound of the general formula (4) to provide the corresponding alcohol compound of the general formula (5).
Description
Technical Field
The present invention relates to a method for reducing carbonyl compounds.
Background
The reduction of carbonyl compounds constitutes a very important technology in various fields, for example in the preparation of intermediates for pharmaceuticals. As practical methods for reducing carbonyl compounds known so far, mention may be made of Meerwein-Ponndorf-Varley reduction (MPV reduction) and reduction using diisobutylaluminum hydride (DIBAH).
MPV reduction is carried out using an aluminum trialkoxy such as Al (O-iPr)3A method for reducing carbonyl compounds as a reducing agent or a reduction catalyst. Since the trialkoxyaluminum and the alcohol such as isopropanol used are inexpensive, this process is often used as an economical process for reducing various ketones and aldehydes [ Organic Reactions, volume 2, page 178 (1944)]。
However, this MPV reduction method using trialkoxyaluminum has a problem. At low reaction temperatures, the reaction tends to proceed very slowly, mainly because of the low activity of the above-mentioned reagents. In order to increase the reaction rate and yield, a higher reaction temperature, for example, not lower than 50 ℃ is required. Therefore, the above-mentioned reduction method is not suitable for reducing an unstable carbonyl compound, or in the case where a carbonyl compound shows low activity, the reduction reaction hardly proceeds even if the reaction temperature is raised.
Among other methods, the method of reducing carbonyl compounds using DIBAH is an industrially very useful method because it has excellent activity and is very economical. This method is used, for example, for the reduction of alpha-aminochloroketone derivatives obtained from leucine. When DIBAH is used to reduce the above-mentioned alpha-aminochloroketone derivative at-78 deg.C, an erythro-form product is preferentially obtained, whose diastereomeric excess (diastereomer processes) is about 75% [ Tetrahedron Letters, 36, 5453(1995) ].
The term "erythro" as used herein refers to an isomer in which adjacent amino and hydroxyl groups exhibit the following relative configurations:
however, this reduction method requires a very low temperature to control the activity. Furthermore, when this method is used for the reduction of the above-mentioned α -aminochloroketone derivatives, it is impossible to obtain stereoselectivities (expressed in diastereomeric excess) as high as 90% or more.
As regards the reduction of carbonyl compounds with diisobutylaluminum hydride, the literature indicates that diisobutylaluminum alkoxides (diisoisobutylaluminum alkoxides) may take part in the reduction reaction in the intermediate part of the reaction [ Journal of Organic Chemistry, 38, 4232(1973) ]. However, there has never been reported that dialkyl monoalkoxyaluminas such as diisobutyl isopropoxyaluminum may be effective for the reduction or stereoselective reduction of carbonyl compounds. Likewise, there has been no report that a reducing agent prepared from a dialkylaluminum hydride such as diisobutylaluminum hydride and an alcohol such as isopropanol may be effective for the reduction or stereoselective reduction of a carbonyl compound.
In view of the above, it is an object of the present invention to provide a simple and convenient method for reducing a carbonyl compound to the corresponding hydroxyl compound under relatively mild conditions. It is another object to provide a method for reducing certain carbonyl compounds which are hardly reducible by conventional trialkoxyaluminum, especially a method for stereoselectively reducing alpha-aminoketone derivatives.
Summary of the invention
The gist of the present invention is directed to the reduction of a carbonyl compound, which comprises reacting a carbonyl compound of general formula (1) with an organoaluminum compound of general formula (4) to give the corresponding alcohol compound of general formula (5).
Wherein, in the general formula (1), if R is1And R2Is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms or a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, then R1And R2Each represents a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, a cyano group, a hydrogen atom, a group of the general formula (2) or a group of the general formula (3);
CHnX3-n (2)
in the general formula (2), X represents a halogen atom, and n represents an integer of 0 to 2;
in the general formula (3), Y represents an alkoxy group, an aralkyloxy group, a substituted or unsubstituted amino group or an alkylthio group;
in the general formula (4), R3And R4Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, R5Represents a substituted or unsubstituted primary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted secondary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted primary aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted secondary aralkyl group having 7 to 30 carbon atoms;
in the general formula (5), R1And R2As defined above.
Brief description of the drawings
FIG. 1 is a nuclear magnetic resonance spectrum (NMR spectrum) of tert-butyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate, which is the product obtained in example 5.
FIG. 2 is an infrared spectrum (IR spectrum) of the product tert-butyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate obtained in example 5.
FIG. 3 is a nuclear magnetic resonance spectrum (NMR spectrum) of the product of methyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate obtained in example 8.
FIG. 4 is an infrared spectrum (IR spectrum) of the product methyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate obtained in example 8.
FIG. 5 is a nuclear magnetic resonance spectrum (NMR spectrum) of benzyl [1(R) -phenylthiomethyl-2 (S) -hydroxy-3-chloropropyl ] carbamate, which is the product obtained in example 9.
FIG. 6 is an infrared spectrum (IR spectrum) of benzyl [1(R) -phenylthiomethyl-2 (S) -hydroxy-3-chloropropyl ] carbamate, which is the product obtained in example 9.
FIG. 7 is a nuclear magnetic resonance spectrum (NMR spectrum) of methyl 2(R, S) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate obtained in example 14.
FIG. 8 is an infrared spectrum (IR spectrum) of methyl 2(R, S) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate obtained in example 14.
FIG. 9 is a nuclear magnetic resonance spectrum (NMR spectrum) of the product ethyl [1(S) -benzyl-2 (R, S) -hydroxy-3, 3-dichloropropyl ] carbamate obtained in example 15.
FIG. 10 is an infrared spectrum (IR spectrum) of the product ethyl [1(S) -benzyl-2 (R, S) -hydroxy-3, 3-dichloropropyl ] carbamate obtained in example 15.
Detailed description of the invention
With respect to the carbonyl compounds of the above general formula (1), provided that R1And R2Is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, then R is1And R2Each represents a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, a cyano group, a hydrogen atom, a group of the above general formula (2) or a group of the above general formula (3).
As the substituent, there may be mentioned a halogen atom, an alkoxycarbonyl group, an alkoxy group, a protected amino group, a cyano group, a nitro group, a sulfinyl group, a sulfonyl group, an alkylthio group and the like. R1Or R2Each of the groups represented may contain two or more such substituents.
The above-mentioned substituted or unsubstituted alkyl group having 1 to 30 carbon atoms is not limited to any particular species but includes, for example, methyl, ethyl, butyl, isopropyl, cyclohexyl and the like. Preferred are groups containing 1 to 20 carbon atoms.
The above-mentioned substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms is not limited to any particular species but includes, for example, benzyl, phenylpropyl, phenethyl, p-methoxybenzyl, 1- (N-t-butoxycarbonylamino) -2-phenylethyl, 1- (N-benzyloxycarbonylamino) -2-phenylethyl and the like. Preferred are groups containing 7 to 20 carbon atoms.
The above-mentioned substituted or unsubstituted aryl group having 6 to 30 carbon atoms is not limited to any particular species but includes, for example, phenyl, p-chlorophenyl, p-nitrophenyl, naphthyl and the like. Preferred are groups containing 6 to 20 carbon atoms.
With respect to the group represented by the above general formula (2), X represents a halogen atom, and n represents an integer of 0 to 2.
The above-mentioned halogen atom is not limited to any particular species, but includes a chlorine atom, a bromine atom, an iodine atom or a fluorine atom, and the most preferable is a chlorine atom.
The above-mentioned group of the general formula (2) is not limited to any particular species but includes: chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, iodomethyl, diiodomethyl, triiodomethyl and the like. Preference is given to chloromethyl, dichloromethyl and trichloromethyl.
With respect to the above-mentioned group of the general formula (3), Y represents an alkoxy group, an aralkyloxy group, a substituted or unsubstituted amino group or an alkylthio group.
The above alkoxy group is not limited to any particular species but includes, for example, methoxy, ethoxy, t-butoxy and the like. Preferred are groups containing 1 to 10 carbon atoms.
The above-mentioned aralkyloxy group is not limited to any particular species, but includes: benzyloxy, and the like. Preferred are groups containing 6 to 20 carbon atoms.
The substituted or unsubstituted amino group mentioned above is not limited to any particular species but includes, for example, amino group, dimethylamino group and the like.
The above-mentioned alkylthio group is not limited to any particular species, but includes: methylthio, phenylthio, and the like.
The above-mentioned group of the general formula (3) is not limited to any particular species but includes: methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, and the like. However, preferred are methoxycarbonyl and ethoxycarbonyl.
As the above-mentioned carbonyl compound of the general formula (1), there may be mentioned, for example: aldehydes such as benzaldehyde, isobutyraldehyde, etc.; and ketones such as acetophenone, phenylethyl ketone, cyclohexanone, ethyl acetoacetate, methyl benzoylformate, phenacyl chloride, α -dichloroacetophenone, α -trichloroacetophenone, ethyl 4-chloroacetoacetate, benzoyl cyanide, tert-butyl 1(S) -benzyl-2-oxo-3, 3-dichloropropylcarbamate, tert-butyl 1(S) -benzyl-2-oxo-3, 3, 3-trichloropropylcarbamate, methyl 3(S) - (N-benzyloxycarbonylamino) -2-oxo-4-phenylacetate and the like.
With respect to the above-defined symbol R3And R4The substituted or unsubstituted alkyl group having 1 to 10 carbon atoms is not limited to any particular species but includes, for example, methyl, ethyl, n-butyl, isobutyl, isopropyl, cyclohexyl, methoxymethyl and the like. The above group preferably contains 1 to 6 carbon atoms, more preferably isobutyl.
Or about the symbol R3And R4The aralkyl group having 7 to 20 carbon atoms is not limited to any particular species but includes, for example, benzyl, 3-phenyl-1-propyl, α -phenylethyl, p-methoxybenzyl and the like. Preferred are groups containing 7 to 15 carbon atoms.
With reference again to the symbol R3And R4The aryl group having 6 to 20 carbon atoms is not limited to any particular species but includes, for example, phenyl, p-hydroxyphenyl, p-chlorophenyl, p-nitrophenyl, naphthyl and the like. Preferred are groups containing 6 to 15 carbon atoms.
With respect to the above-defined symbol R5The substituted or unsubstituted primary alkyl group having 1 to 20 carbon atoms or the substituted or unsubstituted secondary alkyl group having 1 to 20 carbon atoms is, for example, methyl, ethyl, isopropyl, cyclohexyl, 2, 4-dimethyl-3-pentyl, etc. Preferred are groups having 1 to 10 carbon atoms. More preferred are isopropyl group, cyclohexyl group and 2, 4-dimethyl-3-pentyl group.
With respect to the symbol R5The substituted or unsubstituted primary aralkyl group having 7 to 30 carbon atoms or the substituted or unsubstituted secondary aralkyl group having 7 to 30 carbon atoms is, for example, benzhydryl, benzyl, phenylpropyl, α -phenylethyl, p-methoxybenzyl, or the like. Preferred are groups having 7 to 15 carbon atoms, and more preferred is a benzhydryl group.
As the organoaluminum compound represented by the above general formula (4), there can be mentioned: diisobutyl isopropoxyaluminum, diisobutyl benzhydryloxyaluminum, diisobutyl ethoxyaluminum, diisobutyl cyclohexyloxyaluminum, diisobutyl 2, 4-dimethyl-3-pentyloxyaluminum, diethylethoxyaluminum, and the like. Among them, diisobutyl isopropoxyaluminum and diisobutyl benzhydryloxyaluminum are preferable.
The organoaluminum compound of the above general formula (4) can be prepared, for example, by reacting (1) dialkylaluminum hydride with an alcohol, (2) trialkylaluminum with an alcohol (German patent specification No.2507532), (3) a reaction mixture obtained by reduction reaction of, for example, a carbonyl compound such as acetone with DIBAH, (4) trialkylaluminum with trialkoxyaluminum (German patent specification No.2304617), or (5) trialkylaluminum with trialkylborate (German patent specification No. 2151176).
The method of reducing a carbonyl compound of the present invention can be used for reducing an α -aminoketone derivative of the general formula (6) shown below and for reducing an α -aminohaloketone derivative of the general formula (7) shown below. The process for reducing a carbonyl compound of the present invention makes it possible to prepare an α -aminoalcohol derivative of the general formula (8) shown below from an α -aminoketone derivative of the general formula (6) or an α -aminohalohydrin derivative of the general formula (9) shown below from an α -aminohaloketone derivative of the general formula (7). Alpha-aminoalcohol derivatives and alpha-aminohalohydrin derivatives are useful compounds as intermediates for pharmaceutical compounds.
The process for the preparation of the above-mentioned alpha-aminoalcohol derivatives comprises reacting an alpha-aminoketone derivative of the general formula (6), in particular an alpha-aminohaloketone derivative of the general formula (7), with an organoaluminum compound of the above general formula (4) to give the corresponding alpha-aminoalcohol derivative of the general formula (8), in particular the corresponding alpha-aminohalohydrin derivative of the general formula (9). Wherein,
in the general formula (6), R6Represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms or a hydrogen atom, R7Represents a group of the above general formula (2) or a group of the above general formula (3), P1And P2Each represents a hydrogen atom or an amino-protecting group, or P1And P2Taken together to represent a phthaloyl group, but excluding P1And P2Both are the case of hydrogen atoms;
in the general formula (7), X represents a halogen atom, R6As defined above;
in the general formula (8), R6、R7、P1And P2As defined above;
in the general formula (9), X, R6、P1And P2As defined above.
As to the above-mentioned alpha-aminoketone derivatives of the general formula (6) and alpha-aminohaloketone derivatives of the general formula (7), R6Is a side chain of a common α -amino acid or a side chain of an α -amino acid derivative obtained by treating such a common α -amino acid, which represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or a hydrogen atom.
The above-mentioned substituted or unsubstituted alkyl group having 1 to 20 carbon atoms is not limited to any particular species but includes, for example, methyl, ethyl, isopropyl, isobutyl, tert-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, methylthiomethyl and the like. Preferred are groups containing 1 to 10 carbon atoms.
The above-mentioned substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms is not limited to any particular species but includes, for example, benzyl, p-hydroxybenzyl, p-methoxybenzyl, phenylthiomethyl, α -phenylethyl and the like. Preferred are groups containing 7 to 15 carbon atoms.
The above-mentioned substituted or unsubstituted aryl group having 6 to 20 carbon atoms is not limited to any particular species but includes, for example, phenyl, p-hydroxyphenyl, p-methoxyphenyl and the like. Preferred are groups containing 6 to 15 carbon atoms.
With respect to the above-mentioned alpha-aminoketone derivative of the general formula (6) and the above-mentioned alpha-aminohaloketone derivative of the general formula (7), P1And P2Each represents a hydrogen atom or an amino-protected group, or P1And P2Taken together to represent a phthaloyl group, but excluding P1And P2Both in the case of hydrogen atoms.
The above-mentioned amino-protecting group is not limited to any particular species as long as it can effectively protect an amino group in the reduction reaction in question. It therefore includes Protective group in Organic Synthesis second edition, by Theodora w.green, those described in John Wiley & Sons, 1990, pages 309 to 384, for example: ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, dibenzyl, tosyl, benzoyl, phthaloyl and the like. The amino protecting group is preferably selected in view of the stereoselectivity of the reduction reaction. The reduction reaction can be carried out by using, for example: alkoxycarbonyl such as methoxycarbonyl, tert-butoxycarbonyl or ethoxycarbonyl, or aralkyloxycarbonyl such as benzyloxycarbonyl, with high erythro-selectivity.
As to the above-mentioned alpha-aminoketone derivative of the general formula (6), R7Represents a group of the above general formula (2) or a group of the above general formula (3).
With regard to the above-mentioned α -aminohaloketone derivative of the general formula (7), X represents a halogen atom.
The above-mentioned halogen atom is not limited to any particular species, but may be a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. However, a chlorine atom is preferred. The above-mentioned α -aminoketone derivatives of the general formula (6) include, but are not limited to, optically active tert-butyl (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate, (R) - (1-benzyl-3-chloro-2-oxopropyl) carbamate, (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate methyl ester, (R) - (1-benzyl-3-chloro-2-oxopropyl) carbamate methyl ester, (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate ethyl ester, (R) - (1-benzyl-3-chloro-2-oxopropyl) carbamate ethyl ester, (S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester, (R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester, (S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester, (R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester, (S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid methyl ester, (R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid methyl ester, (S) - (tert-Butoxycarbonylamino) -2-oxo-4-phenylbutyric acid methyl ester, (R) - (tert-Butoxycarbonylamino) -2-oxo-4-phenylbutyric acid methyl ester, (S) - (methoxycarbonylamino) -2-oxo-4-phenylbutyric acid methyl ester, (R) - (methoxycarbonylamino) -2-oxo-4-phenylbutyric acid methyl ester, [1(S) -benzyl-2-oxo-3, 3, 3-trichloropropyl ] carbamic acid benzyl ester, [1(R) -benzyl-2-oxo-3, 3, 3-trichloropropyl ] carbamic acid benzyl ester, [1(S) -benzyl-3, 3-dichloro-2-oxopropyl ] carbamic acid ethyl ester, [1(R) -benzyl-3, 3-dichloro-2-oxopropyl ] carbamic acid ethyl ester, and the like. The above-mentioned α -aminohaloketone derivatives include, but are not limited to, optically active tert-butyl (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate, (R) - (1-benzyl-3-chloro-2-oxopropyl) carbamate, (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate methyl ester, (R) - (1-benzyl-3-chloro-2-oxopropyl) carbamate ethyl ester, (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate ethyl ester, (R) - (1-benzyl-3-chloro-2-oxopropyl) carbamate ethyl ester, (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester, (R) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester, (S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester, (R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester,
(S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester,
(R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester,
(S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid methyl ester,
(R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid methyl ester,
(S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid ethyl ester,
(R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid ethyl ester, and the like. Of these, preferred are tert-butyl (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate and benzyl (S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamate.
Referring now to the process for reducing carbonyl compounds of the present invention, the reduction of carbonyl compounds of general formula (1) is carried out by: the carbonyl compound of the general formula (1) is added to the reaction system or the reducing agent is added to the carbonyl compound of the general formula (1), followed by stirring. The reduction reaction is preferably carried out at-10 ℃ to 60 ℃, more preferably at-10 ℃ to 30 ℃.
The organoaluminum compound of the general formula (4) is used in an amount of preferably 1 to 5 molar equivalents, more preferably 1.5 to 3 molar equivalents, based on the carbonyl compound of the general formula (1).
Solvents used in the practice of the present invention are not limited to any particular species, but include: the molecular formula is R5Alcohol compounds of OH, wherein R5And R in the general formula (4) shown above5Similarly, toluene, hexane, cyclohexane, heptane, tetrahydrofuran, t-butyl methyl ether, 1, 2-dimethoxyethane, dichloromethane, N-dimethylformamide and the like can be used. Among these solvents (in addition to the above-mentioned alcohols), preferred are toluene, tetrahydrofuran and hexane.
Although the method of the subsequent treatment is not limited to any particular method, the alcohol compound product of the general formula (5) may be recovered after the completion of the reaction by usual post-treatment and separation methods, for example, by hydrolyzing the reaction mixture with an aqueous acid solution, extracting the reaction mixture, concentrating the extract, and then subjecting the concentrate to separation treatment by a separation column (column), crystallization, distillation and/or the like.
The above-mentioned compounds of the general formula (4) can also be prepared by the following reaction, and the reaction mixture thus prepared can be used as such to reduce the carbonyl compounds of the general formula (1), (6) or (7).
Therefore, the product prepared by reacting the organoaluminum compound of general formula (10) with the alcohol compound of general formula (11) can be used for reducing the above-mentioned carbonyl compound.
R5-OH (11)
Wherein, in the general formula (10), R3And R4Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms; in the general formula (11), R5Is a substituted or unsubstituted primary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted secondary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted primary aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted secondary aralkyl group having 7 to 30 carbon atoms.
The organoaluminum compound of the above general formula (10) is, for example, diethylaluminum hydride, diisobutylaluminum hydride or the like. Among them, diisobutylaluminum hydride is preferred.
The alcohol compound of the above general formula (11) is not limited to any particular species in the case where it has a strong ability to donate hydrogen ions. For example, there may be mentioned isopropanol, diphenylmethanol, 2, 4-dimethyl-3-pentanol, cyclohexanol, 2-methoxycyclohexanol and the like. Preferred are alcohol compounds of the general formula (12)
(wherein, R8And R9Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or R8And R9Taken together to represent a cycloalkyl group). More preferred are isopropanol and benzhydrol.
The above-mentioned substituted or unsubstituted alkyl group having 1 to 10 carbon atoms is, for example: methyl, ethyl, isopropyl, and the like. However, methyl is preferred.
The above-mentioned substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms is, for example: benzyl, phenylpropyl, alpha-phenylethyl, p-methoxybenzyl, and the like.
The above-mentioned substituted or unsubstituted aryl group having 6 to 20 carbon atoms is, for example: phenyl, p-hydroxyphenyl, p-chlorophenyl, p-nitrophenyl, naphthyl, and the like.
The above cycloalkyl groups are, for example: cyclohexyl, cyclopentyl, and the like.
The method for reducing a carbonyl compound of the present invention can be carried out by the following method:
first, the reducing agent is prepared by the reaction of the organoaluminum compound of general formula (10) with the alcohol compound of general formula (11).
The organoaluminum compound of the above general formula (10) is used in an amount of 3 molar equivalents or less, preferably 1 to 5 molar equivalents, more preferably 1.5 to 3 molar equivalents, based on the carbonyl compound of the general formula (1).
The alcohol of the above general formula (11) is used in an amount of 3 molar equivalents or less, preferably 1 to 2 molar equivalents, based on the organoaluminum compound of the general formula (10).
The process for preparing the reducing agent by reacting the organoaluminum compound of the above general formula (10) with the alcohol compound of the above general formula (11) can be carried out as follows: for example, the alcohol compound of the general formula (11) is added to a solution of the organoaluminum compound of the general formula (10) in toluene, tetrahydrofuran, hexane or the like, and then the mixture is stirred. The conditions for adding the alcohol compound are not critical, but the alcohol compound is preferably added at a temperature of-10 ℃ to 60 ℃, more preferably at a temperature of 0 ℃ to 40 ℃. The stirring conditions are not critical, but stirring at 0 to 30 ℃ for 1 to 10 hours is preferred. The organoaluminum compound of the general formula (10) may also be added to the alcohol compound of the general formula (11).
Then, the carbonyl compound of the general formula (1) is added to the reaction system, or a reducing agent is added to the carbonyl compound of the general formula (1), and the mixture is stirred to effect reduction of the carbonyl compound of the general formula (1). The reduction temperature is preferably in the range of-10 to 60 ℃ and more preferably in the range of-10 to 30 ℃.
According to the invention, the carbonyl compound is reduced with an aluminum alkyl alkoxide (aluminum alkyl alkoxide) which is different from the aluminum alkyl alkoxide produced from the reactant carbonyl compound. In this case, by appropriately selecting the alkoxide group of the above aluminum alkyl alkoxide in accordance with the alkoxide group as an intermediate produced from the carbonyl compound, it is possible to accelerate the formation rate of the intermediate, to carry out the reaction at a low temperature, and to control the configuration of the alcohol as a reduction product. It is possible to reduce the carbonyl compounds of the formula (1), (6) or (7) under mild conditions, and furthermore, it is possible to stereoselectively reduce certain carbonyl compounds, such as α -ketoester derivatives, which are hardly reduced by the usual trialkoxyaluminum.
For example, by appropriately selecting the above-mentioned amino-protecting group, it is possible to produce an α -aminoalcohol derivative of the formula (8) or an α -aminohalohydrin derivative of the formula (9) having a high stereoselectivity in the erythro form. Thus, for example, by reducing optically active tert-butyl (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate, which is a derivative of phenylalanine, the corresponding optically active aminohalohydrin can be obtained in a diastereomeric excess (d.e.) of not less than 94%. For example, using benzhydrol as the alcohol compound, the corresponding optically active amino halohydrins can be obtained with a diastereomeric excess surprisingly up to 98%. Also, in the case of reducing (S) - (tert-butoxycarbonylamino) -2-oxo-4-phenylbutyric acid methyl ester, the corresponding optically active α -hydroxy ester can be obtained, which has a high erythro selectivity. The α -aminoketone derivative of the general formula (7) as a raw material can be generally produced by reacting a corresponding α -amino acid derivative (e.g., α -amino acid ester) with magnesium enolate of α -chloroacetic acid (e.g., Japanese patent application laid-open No. 07-273547). HIV protease inhibitors are readily available from the above optically active amino halohydrins (Japanese laid-open publication Hei 08-99959).
The following examples are further illustrative of the present invention and are not intended to limit the scope of the present invention.Example 1Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid tert-butyl ester (I)
0.76ml (10mmol) of 2-propanol was added to a 1.0M ice-cooled hexane solution of triisobutylaluminum (10.5ml, 10.5mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with 10ml of toluene, then 0.759g (2.5mmol) of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate was added, and the resulting mixture was stirred at room temperature for 2 hours. Hydrolysis with 1N hydrochloric acid, extraction with ethyl acetate and concentration gave 0.840g of pale yellow crystals. The resulting crystals were quantitatively analyzed by HPLC, and the yield and selectivity were determined.
Yield: 97.4% of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester; [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester 2.6%. The selection rate is as follows: the (1S, 2S)/(1S, 2R) form is 97.4/2.6.
Example 2Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid tert-butyl ester (I)
0.47g (2.5mmol) of triisopropoxyborane was added to a 1.0M hexane solution of triisobutylaluminum (10.5ml, 10.5mmol), and the mixture was heated at 170 ℃ for 2 hours. After cooling to 80 ℃, the pressure was reduced to 10mmHg to distill off the excess triisobutylborane. After cooling to room temperature, it was diluted with 20ml of toluene, 0.744g (2.5mmol) of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate was then added and the resulting mixture was stirred at room temperature for 3 hours. Hydrolysis with 1N hydrochloric acid, extraction with ethyl acetate and concentration gave 0.995g of pale yellow crystals. The resulting crystals were quantitatively analyzed by HPLC, and the yield and selectivity were determined.
Yield: tert-butyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate 80.1%; 3.4% of [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester. The selection rate is as follows: the (1S, 2S)/(1S, 2R) form is 95.9/4.1.
Example 3Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid tert-butyl ester (I)
A hexane solution of diethylaluminum ethoxide (ca. 1M, 10.4ml, 10.4mmol) was diluted with 18ml of toluene, then 1.489g (5mmol) of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate was added, and the mixture was stirred at room temperature for 24 hours. After quenching with 1N hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was concentrated to give 2.560g of pale yellow crystals. The resulting crystals were quantitatively analyzed by HPLC, and the yield and selectivity were determined.
Yield: tert-butyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate 55.7%; tert-butyl [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamate 8.3%. The selection rate is as follows: type (1S, 2S/(1S, 2R) ═ 87/13.
Example 4Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid tert-butyl ester (I)
Acetone (581mg, 10mmol) was added to 9.9ml (10mmol) of DIBAH in toluene (1.02M) at room temperature and the mixture was stirred at room temperature for 1 hour. Then, 1.489g (5mmol) of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate was added, and the resulting mixture was stirred at room temperature for 2 hours. After hydrolysis with 1N hydrochloric acid, the reaction mixture was extracted with ethyl acetate. The extract was concentrated to give 1.635g of pale yellow crystals. The resulting crystals were quantitatively analyzed by HPLC, and the yield and selectivity were determined.
Yield: 82.6% of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester; [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester 4.1%. The selection rate is as follows: the (1S, 2S)/(1S, 2R) form is 95.2/4.8.
Example 5Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid tert-butyl ester (I)
2-propanol (1.53ml, 20mmol) was added to 9.8ml (10mmol) of DIBAH in toluene (1.02M) at room temperature and the mixture was stirred at room temperature for 1 hour. 1.489g (5.0mmol) of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate was further added thereto, and the resulting mixture was stirred at room temperature for 2 hours, followed by hydrolysis with 1N hydrochloric acid under ice-cooling. Extraction with ethyl acetate and concentration gave 1.61g of pale yellow crystals. Purification by silica gel column chromatography (hexane/ethyl acetate) gave 1.386g of tert-butyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate (yield: 92.5%) and 33mg of tert-butyl [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamate (yield: 2.2%). The (1S, 2S)/(1S, 2R) form is 97.7/2.3.
The NMR spectrum of the product, [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester, thus obtained is shown in FIG. 1, and the IR spectrum thereof is shown in FIG. 2.
[αD 25]＝-3.44(c＝1.05，MeOH)
Melting point: 168.5 to 169.5 ℃.
Example 6Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid tert-butyl ester (I)
Diphenylmethanol (3.68g, 20mmol) was added to 9.9ml (10mmol) of DIBAH in toluene (1.02M) at room temperature, followed by 20ml of toluene. After the mixture was stirred at room temperature for 1 hour, 1.489g (5mmol) of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate was added, and the resulting mixture was stirred at room temperature for 2 hours. After hydrolysis with 1N hydrochloric acid, the reaction mixture was extracted with ethyl acetate, and the resulting organic layer was quantitatively analyzed by HPLC to determine the yield and selectivity.
Yield: 99.1% of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester; 0.9% of [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester. The selection rate is as follows: the (1S, 2S)/(1S, 2R) form is 99.1/0.9.
Example 7Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid tert-butyl ester (I)
Cyclohexanol (2.0g, 20mmol) and 10ml toluene were added to a solution of 9.8ml (10mmol) DIBAH in toluene (1.02M) at room temperature, and the mixture was stirred at room temperature for 1 hour. 1.489g (5.0mmol) of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate was further added thereto, and the resulting mixture was stirred at room temperature for 2 hours, followed by hydrolysis with 1N hydrochloric acid under ice-cooling. Extraction with ethyl acetate and concentration gave 1.53g of pale yellow crystals. The resulting crystals were quantitatively analyzed by HPLC, and the yield and selectivity were determined.
Yield: 93.4% of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester; [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamic acid tert-butyl ester 2.9%. The selection rate is as follows: the (1S, 2S)/(1S, 2R) form is 97.0/3.0.
Example 8Preparation of [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid methyl ester (II)
Proceeding following the procedure of example 1, 1.28g (5mmol) of methyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate were used instead of tert-butyl [1(S) -benzyl-2-oxo-3-chloropropyl ] carbamate, giving 1.314g of pale yellow crystals. Recrystallization from hexane/ethyl acetate/ethanol gave 1.063g of methyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate (yield: 78.0%). The mother liquor was analyzed by HPLC, and found to be present in 60.0mg of methyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate (yield: 4.5%) and 36.1mg of methyl [1(S) -benzyl-2 (R) -hydroxy-3-chloropropyl ] carbamate (yield: 2.8%). Selectivity of total reaction products: the (1S, 2S)/(1S, 2R) form is 96.7/3.3.
The NMR spectrum of the product [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamic acid methyl ester thus obtained is shown in fig. 3, and the IR spectrum thereof is shown in fig. 4.
Example 9Preparation of [1(R) -phenylthiomethyl-2 (S) -hydroxy-3-chloropropyl]Carbamic acid benzyl ester (III)
2-propanol (26.44g, 440mmol) was added to 216ml (220mmol) of DIBAH in toluene (1.02M) at room temperature and the mixture was stirred at room temperature for 1 hour. 39.6g (108.9mmol) of benzyl [1(R) -phenylthiomethyl-2-oxo-3-chloropropyl ] carbamate were further added thereto, and the resulting mixture was stirred at room temperature for 3 hours, followed by hydrolysis with 500ml of 1N hydrochloric acid under ice-cooling. After extraction with 300ml of ethyl acetate, the extract was washed successively with 500ml of a 2% aqueous solution of sodium hydrogencarbonate and 200ml of a 2% aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give 75.6g of a pale yellow solid. The resulting solid was crystallized from toluene/hexane to give 32.9g of benzyl [1(R) -phenylthiomethyl-2 (S) -hydroxy-3-chloropropyl ] carbamate (yield: 82.7%). The mother liquor was analyzed by HPLC, and found to be present in 2.03g of benzyl [1(R) -phenylthiomethyl-2 (S) -hydroxy-3-chloropropyl ] carbamate (yield: 5.1%) and 1.753g of benzyl [1(R) -phenylthiomethyl-2 (R) -hydroxy-3-chloropropyl ] carbamate (yield: 4.4%). Selectivity of total reaction products: type (1R, 2S/(1R, 2R) ═ 95.2/4.8. The NMR spectrum of the product benzyl [1(R) -phenylthiomethyl-2 (R) -hydroxy-3-chloropropyl ] carbamate thus obtained is shown in FIG. 5, and the IR spectrum thereof is shown in FIG. 6.
Example 10Preparation of benzyl alcohol
2-propanol (1.53ml, 20mmol) was added to 9.8ml (10mmol) of DIBAH in toluene (1.02M) at room temperature and the mixture was stirred at room temperature for 1 hour. 0.531g of benzaldehyde was further added thereto, and the resulting mixture was stirred at room temperature for 2 hours and then hydrolyzed with 1N hydrochloric acid under ice-cooling. Extraction with ethyl acetate and concentration gave 615mg of benzyl alcohol as an oil. The resulting oil was analyzed by HPLC and found to have a conversion of 99.9% and a yield of 78.0%.
Example 11Preparation of 1-phenyl-2-chloroethanol
Following the procedure of example 10, substituting benzaldehyde with 0.773g (5mmol) of phenacyl chloride, 809mg of 1-phenyl-2-chloroethanol was obtained in the form of an oil. Conversion rate: 97.5 percent; yield: 80.4 percent.
Example 12Preparation of alpha-phenylethyl alcohol
2-propanol (1.53ml, 20mmol) was added to 9.9ml (10mmol) of DIBAH in toluene (1.02M) at room temperature and the mixture was stirred at room temperature for 1 hour. 0.601g of acetophenone was further added thereto, and the resulting mixture was stirred at room temperature for 6 hours, followed by hydrolysis with 1N hydrochloric acid under ice-cooling. Extraction with ethyl acetate and concentration gave 1.001g of α -phenylethyl alcohol as an oil. The conversion was 55% and the yield was 47.7%.
Example 13Preparation of alpha-phenylethyl alcohol
Diphenylmethanol (3.68g, 20mmol) was added to 9.9ml (10mmol) of DIBAH in toluene (1.02M) at room temperature, and the mixture was stirred at room temperature for 1 hour. 0.601g (5mmol) of acetophenone was further added thereto, and the resulting mixture was stirred at room temperature for 2 hours, followed by hydrolysis with 1N hydrochloric acid under ice-cooling. Extraction with ethyl acetate and concentration gave an oil which was quantitatively analyzed by HPLC. Thus, it was confirmed that α -phenylethyl alcohol was formed in a yield of 42.3% (conversion: 53.3%).
Example 14Preparation of methyl 2(S) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate (IV)
Diphenylmethanol (0.737g, 4mmol) was added to 2ml (2.04mmol) of DIBAH in toluene (1.02M) at room temperature, and the mixture was stirred at room temperature for 1 hour. 0.307g (1mmol) of methyl 3(S) - (tert-butoxycarbonylamino) -2-oxo-4-phenylbutyrate was further added thereto, and the resulting mixture was stirred at room temperature for 2 hours, followed by hydrolysis with 1N hydrochloric acid under ice-cooling. Extraction with ethyl acetate, concentration of the extract and purification of the resulting oil by preparative thin layer chromatography gave 217mg of a mixture of methyl 2(S) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate and methyl 2(R) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate. Analysis by HPLC revealed a diastereomer selectivity of (2S, 3S)/(2R, 3S) ═ 94/6.
Yield: 2(S) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyric acid methyl ester 65.9%; 4.2% of methyl 2(R) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate.
The NMR spectrum of the product, methyl 2(R, S) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate, thus obtained is shown in FIG. 7, and the IR spectrum thereof is shown in FIG. 8.
Example 15Preparation of [1(S) -benzyl-3, 3-dichloro-2 (S) -hydroxypropyl]Carbamic acid ethyl ester (V)
2-propanol (920mg, 1.5mmol) was added to 0.73ml (0.74mmol) of DIBAH in toluene (1.01M) at room temperature, and the mixture was stirred at room temperature for 1 hour. 100mg (0.33mmol) of [1(S) -benzyl-3, 3-dichloro-2-oxopropyl ] carbamic acid ethyl ester was added thereto, and the resulting mixture was stirred at room temperature for 3.5 hours, then at 40 ℃ for 2 hours, and then at room temperature for 15 hours, followed by hydrolysis with 1N hydrochloric acid under ice-cooling. Extraction with ethyl acetate and concentration of the extract gave an oil which was purified by preparative thin layer chromatography to give 66.7mg (0.22mmol) of a mixture of ethyl [1(S) -benzyl-3, 3-dichloro-2 (S) -hydroxypropyl ] carbamate and ethyl [1(S) -benzyl-3, 3-dichloro-2 (R) -hydroxypropyl ] carbamate. The diastereomer selectivity by HPLC was (1S, 2S)/(1S, 2R) ═ 95/5.
Yield: 62.7% of [1(S) -benzyl-2 (S) -hydroxy-3, 3-dichloropropyl ] carbamic acid ethyl ester; [1(S) -benzyl-2 (R) -hydroxy-3, 3-dichloropropyl ] carbamic acid ethyl ester 33%.
The NMR spectrum of the product [1(S) -benzyl-3, 3-dichloro-2 (R, S) -hydroxypropyl ] ethyl carbamate thus obtained is shown in fig. 9, and the IR spectrum thereof is shown in fig. 10.
Comparative example 1Preparation of [1(S) -benzyl-2 (S), 3-epoxypropyl]Carbamic acid tert-butyl ester
A portion of 0.976g of the product tert-butyl [1(S) -benzyl-2 (S) -hydroxy-3-chloropropyl ] carbamate obtained in example 1 was suspended in 8ml of acetone, 2ml of 10% sodium hydroxide were then added, and the mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and the organic layer was concentrated to dryness to give [1(S) -benzyl-2 (S), 3-epoxypropyl ] carbamic acid tert-butyl ester. After purification by preparative thin layer chromatography, the optical purity (optical purity) was confirmed to be 99.8% ee with a chiral column (chiralcolumn).
Comparative example 2Preparation of alpha-phenylethyl alcohol
Acetophenone (0.601g) was dissolved in 15ml of 2-propanol, 2.04g of triisopropoxyaluminum was added, and the resulting mixture was stirred at 25 ℃ for 4 hours. After hydrolysis with 1N hydrochloric acid, the mixture was extracted with ethyl acetate. Concentration gave 0.564g of oil, which was analyzed by HPLC and had a conversion of 0.6% and a yield of 0.4%.
Comparative example 3With Al (O-iPr)3Reduction of 3(S) - (tert-Butoxycarbonylamino) -2-oxo-4-phenylbutyric acid methyl ester
Methyl 3(S) - (tert-Butoxycarbonylamino) -2-oxo-4-phenylbutyrate (307mg) was dissolved in 6ml of 2-propanol, and 204mg (2mmol) of Al (O-iPr)3The mixture was stirred at room temperature for 1 hour and then at 50 ℃ for another 15 hours. However, the reduction product methyl 2(R, S) -hydroxy-3 (S) - (tert-butoxycarbonylamino) -4-phenylbutyrate was hardly found to be formed.
INDUSTRIAL APPLICABILITY
The present invention is constituted as described above, and it makes it possible to reduce carbonyl compounds to the corresponding hydroxyl compounds simply and conveniently at a relatively low temperature with high stereoselectivity. The present invention thus makes it possible, for example, to prepare derivatives of amino halohydrins, which are intermediates for preparing useful pharmaceutical compounds, from derivatives of amino haloketones (from phenylalanine and the like) under mild conditions with very high stereoselectivity.
Claims (23)
1. A process for reducing a carbonyl compound, which comprises reacting a carbonyl compound of the general formula (1) with an organoaluminum compound of the general formula (4) to give a corresponding alcohol compound of the general formula (5),
wherein, in the general formula (1), if R is1And R2Is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, then R is1And R2Each represents a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, a cyano group, a hydrogen atom, a group of the general formula (2) or a group of the general formula (3);
CHnX3-n (2)
in the general formula (2), X represents a halogen atom, and n represents an integer of 0 to 2;
in the general formula (3), Y represents an alkoxy group, an aralkyloxy group, a substituted or unsubstituted amino group or an alkylthio group;
in the general formula (4), R3And R4Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, R5Represents a substituted or unsubstituted primary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted secondary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted primary aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted secondary aralkyl group having 7 to 30 carbon atoms;
in the general formula (5), R1And R2As defined above.
2. A process for reducing a carbonyl compound as claimed in claim 1, characterized in that, the organic aluminum compound of the general formula (4) is diisobutyl isopropoxyaluminum or diisobutyl benzhydryloxyaluminum.
3. A process for reducing a carbonyl compound, which comprises reacting a carbonyl compound of the general formula (1) with a compound previously prepared from an organoaluminum compound of the general formula (10) and an alcohol compound of the general formula (11) to give a corresponding alcohol compound of the general formula (5),
R5-OH (11)
wherein, in the general formula (1), if R is1And R2Is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, then R is1And R2Each represents a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, a substituted or unsubstituted aryl group having 6 to 30 carbon atoms, a cyano group, a hydrogen atom, a group of the general formula (2) or a group of the general formula (3);
CHnX3-n (2)
in the general formula (2), X represents a halogen atom, and n represents an integer of 0 to 2;
in the general formula (3), Y represents an alkoxy group, an aralkyloxy group, a substituted or unsubstituted amino group or an alkylthio group;
in the general formula (10), R3And R4Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms;
in the general formula (11), R5Represents a substituted or unsubstituted primary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted secondary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted primary aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted secondary aralkyl group having 7 to 30 carbon atoms;
in the general formula (5), R1And R2As defined above.
4. A process for reducing a carbonyl compound as claimed in claim 3, characterized in that, the organic aluminum compound of the general formula (10) is diisobutylaluminum hydride.
5. Reduced carbonyl compounds as claimed in claim 3 or 4Characterized in that the alcohol compound of the general formula (11) is an alcohol compound of the general formula (12),
wherein R is8And R9Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or R8And R9Taken together, represent a cycloalkyl group.
6. A process for reducing a carbonyl compound as claimed in claim 5, characterized in that, the alcohol compound of the general formula (12) is isopropanol.
7. A process for reducing a carbonyl compound as claimed in claim 5, characterized in that, the alcohol compound of the general formula (12) is benzhydrol.
8. A process for the reduction of a carbonyl compound as claimed in claim 1, 2, 3, 4, 5, 6 or 7, characterized in that, the reduction reaction is carried out at a temperature of-10 ℃ to 30 ℃.
9. A process for the reduction of a carbonyl compound as claimed in claim 1, 2, 3, 4, 5, 6, 7 or 8, characterized in that:
in the carbonyl compound of the general formula (1), R1Is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 30 carbon atoms; r2Is a group of the general formula (2) or a group of the general formula (3);
CHnX3-n (2)
wherein, in the general formula (2), X represents a halogen atom, and n represents an integer of 0 to 2;
in the general formula (3), Y represents an alkoxy group, an aralkyloxy group, a substituted or unsubstituted amino group or an alkylthio group.
10. A process for preparing an alpha-aminoalcohol derivative, which comprises reacting an alpha-aminoketone derivative of the general formula (6) with an organoaluminum compound of the general formula (4) to obtain a corresponding compound of the general formula (8),
wherein, in the general formula (6), R6Represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms or a hydrogen atom, R7Represents a group of the formula (2) or a group of the formula (3), P1And P2Each represents a hydrogen atom or an amino-protecting group, or P1And P2Taken together to represent a phthaloyl group, but excluding P1And P2Both are the case of hydrogen atoms;
CHnX3-n (2)
wherein, in the general formula (2), X represents a halogen atom, and n represents an integer of 0 to 2;
in the general formula (3), Y represents an alkoxy group, an aralkyloxy group, a substituted or unsubstituted amino group or an alkylthio group;
in the general formula (4), R3And R4Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, R5Represents a substituted or unsubstituted primary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted secondary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted primary aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted secondary aralkyl group having 7 to 30 carbon atoms;
in the general formula (8), R6、R7、P1And P2As defined above.
11. The process for producing an α -aminoalcohol derivative according to claim 10, wherein the organoaluminum compound of the formula (4) is diisobutyl isopropoxyaluminum or diisobutyl diphenylmethoxy aluminum.
12. A process for producing an alpha-aminoalcohol derivative, which comprises reacting an alpha-aminoketone derivative of the general formula (6) with a compound previously prepared from an organoaluminum compound of the general formula (10) and an alcohol compound of the general formula (11) to obtain a corresponding compound of the general formula (8),
R5-OH (11)
wherein, in the general formula (6), R6Represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms or a hydrogen atom, R7Represents a group of the formula (2) or a group of the formula (3), P1And P2Each represents a hydrogen atom or an amino-protecting group, or P1And P2Taken together to represent a phthaloyl group, but excluding P1And P2Both are the case of hydrogen atoms;
CHnX3-n (2)
wherein, in the general formula (2), X represents a halogen atom, and n represents an integer of 0 to 2;
in the general formula (3), Y represents an alkoxy group, an aralkyloxy group, a substituted or unsubstituted amino group or an alkylthio group;
in the general formula (10), R3And R4Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms;
in the general formula (11), R5Represents a substituted or unsubstituted primary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted secondary alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted primary aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted secondary aralkyl group having 7 to 30 carbon atoms;
in the general formula (8), R6、R7、P1And P2As defined above.
13. The process for producing an α -aminoalcohol derivative according to claim 12, characterized in that the organoaluminum compound of the general formula (10) is diisobutylaluminum hydride.
14. The process for producing an α -aminoalcohol derivative according to claim 12 or 13, characterized in that the alcohol compound of the general formula (11) is an alcohol compound of the general formula (12),
wherein R is8And R9Each represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, or R8And R9Taken together, represent a cycloalkyl group.
15. The process for producing an α -aminoalcohol derivative according to claim 14, characterized in that the alcohol compound of the general formula (12) is isopropanol.
16. The process for producing an α -aminoalcohol derivative according to claim 14, characterized in that the alcohol compound of the general formula (12) is diphenylmethanol.
17. A process for the preparation of α -aminoalcohol derivatives as claimed in claim 10, 11, 12, 13, 14, 15 or 16, characterized in that the reduction is carried out at a temperature of-10 ℃ to 30 ℃.
18. The process for producing an α -aminoalcohol derivative according to claim 10, 11, 12, 13, 14, 15, 16 or 17, wherein in the α -aminoketone derivative of the formula (6), P is1And P2One of which is a hydrogen atom and the other is an alkoxycarbonyl group or an aralkyloxycarbonyl group protecting an amino group.
19. A process for the preparation of α -aminoalcohol derivatives as claimed in claims 10, 11, 12, 13, 14, 15, 16, 17 or 18, characterized in that the α -aminoalcohol derivatives of formula (11) obtained are stereoselective and in erythro form.
20. The process for preparing an α -aminoalcohol derivative according to claim 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, characterized in that the α -aminoketone derivative of the formula (6) is an α -aminohaloketone derivative of the formula (7),
wherein X represents a halogen atom, R6Represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, a substituted or unsubstituted aryl group having 6 to 20 carbon atoms or a hydrogen atom, P1And P2Each represents a hydrogen atom or an amino-protecting group, or P1And P2Taken together to represent a phthaloyl group, but excluding P1And P2Both are the case of hydrogen atoms;
the alpha-aminoalcohol derivative of the formula (8) is an alpha-aminohalohydrin derivative of the formula (9),
wherein, X, R6、P1And P2As defined above.
21. The process for preparing α -aminoalcohol derivatives as claimed in claim 20, characterized in that the α -aminohaloketone derivative of the formula (7) is optically active
(S) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester,
(R) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester,
(S) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid methyl ester,
(R) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid methyl ester,
(S) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid ethyl ester,
(R) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid ethyl ester,
(S) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester,
(R) - (1-benzyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester,
(S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester,
(R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid benzyl ester,
(S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester,
(R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid tert-butyl ester,
(S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid methyl ester,
(R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid methyl ester,
(S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid ethyl ester or
(R) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamic acid ethyl ester.
22. The process for preparing α -aminoalcohol derivatives according to claim 20, wherein the α -aminohaloketone derivative of the formula (7) is tert-butyl (S) - (1-benzyl-3-chloro-2-oxopropyl) carbamate or benzyl (S) - (1-phenylthiomethyl-3-chloro-2-oxopropyl) carbamate, the organoaluminum compound of the formula (4) is diisobutylaluminum hydride, and the alcohol compound of the formula (5) is isopropanol or benzhydrol.
23. A process for the preparation of α -aminoalcohol derivatives as claimed in claims 20, 21 or 22, characterized in that the α -aminohalohydrin derivatives of formula (9) obtained are stereoselective and in erythro form.
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|---|---|---|---|
| CN 97190044 CN1178517A (en) | 1996-01-29 | 1997-01-29 | Process for reduction of carbonyl compounds |
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| Application Number | Priority Date | Filing Date | Title |
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| JP35632/96 | 1996-01-29 | ||
| JP37256/96 | 1996-01-30 | ||
| JP110317/96 | 1996-04-04 | ||
| CN 97190044 CN1178517A (en) | 1996-01-29 | 1997-01-29 | Process for reduction of carbonyl compounds |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766074A (en) * | 2012-08-07 | 2012-11-07 | 江西东邦药业有限公司 | Preparation method of anti-AIDs drug intermediates |
| CN110878003A (en) * | 2019-09-11 | 2020-03-13 | 安徽圣诺贝化学科技有限公司 | Isofol and new method for coproducing isophorol and carvone |
-
1997
- 1997-01-29 CN CN 97190044 patent/CN1178517A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766074A (en) * | 2012-08-07 | 2012-11-07 | 江西东邦药业有限公司 | Preparation method of anti-AIDs drug intermediates |
| CN102766074B (en) * | 2012-08-07 | 2014-05-07 | 江西东邦药业有限公司 | Preparation method of anti-AIDs drug intermediates |
| CN110878003A (en) * | 2019-09-11 | 2020-03-13 | 安徽圣诺贝化学科技有限公司 | Isofol and new method for coproducing isophorol and carvone |
| CN110878003B (en) * | 2019-09-11 | 2023-03-28 | 安徽圣诺贝化学科技有限公司 | Isofol and new method for coproducing isophorol and carvone |
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