WO2002012185A1 - Process for preparing 2,3-diaminopropanols and synthesis of other compounds using 2,3-diaminopropanols - Google Patents
Process for preparing 2,3-diaminopropanols and synthesis of other compounds using 2,3-diaminopropanols Download PDFInfo
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- WO2002012185A1 WO2002012185A1 PCT/KR2001/001362 KR0101362W WO0212185A1 WO 2002012185 A1 WO2002012185 A1 WO 2002012185A1 KR 0101362 W KR0101362 W KR 0101362W WO 0212185 A1 WO0212185 A1 WO 0212185A1
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- compound
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- aziridine
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- QHBWSLQUJMHGDB-UHFFFAOYSA-N 2,3-diaminopropan-1-ol Chemical class NCC(N)CO QHBWSLQUJMHGDB-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 title claims description 47
- 230000015572 biosynthetic process Effects 0.000 title description 21
- 238000003786 synthesis reaction Methods 0.000 title description 21
- 238000004519 manufacturing process Methods 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 48
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 15
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 12
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 4
- 125000001118 alkylidene group Chemical group 0.000 claims abstract description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 2
- -1 3- triazinyl Chemical group 0.000 claims description 36
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 238000007142 ring opening reaction Methods 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical group N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 claims description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004678 hydrides Chemical class 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 230000001012 protector Effects 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical group C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 2
- ZZOKVYOCRSMTSS-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl carbamate Chemical compound C1=CC=C2C(COC(=O)N)C3=CC=CC=C3C2=C1 ZZOKVYOCRSMTSS-UHFFFAOYSA-N 0.000 claims description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 2
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 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 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229940015043 glyoxal Drugs 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- VCARPLHUPPGQJK-UHFFFAOYSA-N n-azidohydroxylamine Chemical compound ONN=[N+]=[N-] VCARPLHUPPGQJK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims 2
- UCKORWKZRPKRQE-UHFFFAOYSA-N bromo(triethyl)silane Chemical compound CC[Si](Br)(CC)CC UCKORWKZRPKRQE-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 238000006722 reduction reaction Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- 229960005335 propanol Drugs 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000004430 oxygen atom Chemical group O* 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 125000004434 sulfur atom Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000010531 catalytic reduction reaction Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 229910017052 cobalt Inorganic materials 0.000 description 3
- 239000010941 cobalt Substances 0.000 description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229950009195 phenylpropanol Drugs 0.000 description 3
- HZLFQUWNZMMHQM-UHFFFAOYSA-N piperazin-1-ylmethanol Chemical compound OCN1CCNCC1 HZLFQUWNZMMHQM-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- 0 *C(C1N(*)C1)O Chemical compound *C(C1N(*)C1)O 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004069 aziridinyl group Chemical group 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 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
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- BMEHDCBKAUDFBH-WKAHHKJFSA-N [(2r)-1-[(1s)-1-phenylethyl]aziridin-2-yl]methanol Chemical compound N1([C@@H](C)C=2C=CC=CC=2)C[C@@H]1CO BMEHDCBKAUDFBH-WKAHHKJFSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- MEGROZMJHSAQKL-UHFFFAOYSA-N azido(triethyl)silane Chemical compound CC[Si](CC)(CC)N=[N+]=[N-] MEGROZMJHSAQKL-UHFFFAOYSA-N 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- PPLMQFARLJLZAO-UHFFFAOYSA-N triethyl(iodo)silane Chemical compound CC[Si](I)(CC)CC PPLMQFARLJLZAO-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
Definitions
- the obtained optically pure 2,3-diaminopropanol is used to produce, for example, hydroxymethylpiperazine which is useful as an intermediate of medicament.
- the processes for producing an optically active piperazine was proposed via a catalytic hydrogenation (U.S. Patent No. 5,977,364), or resolution of racemic mixture (U.S. Patent No. 5,945,534) were known.
- the present invention is characterized by a process for preparing 2,3- diaminopropanol from a chiral diamine.
- morpholine is used as amine in the present process, D-threo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol etc. can be produced, which is biologically active. Disclosure of the Invention
- the present invention provides a process for producing 2,3-diaminopropanol in high yields of more than 90% by ring opening an inactivated optically pure aziridine and reacting it with various amines.
- the obtained 2,3-diaminopropanol is used in the synthesis of high value-added compounds, such as hydroxymethylpiperazine, D-threo-l-phenyl-2- decanoylamino-3 -morpholino- 1 -propanol, etc.
- the object of the present invention is to provide a process for producing 2,3- diaminopropanol derivatives of formula (2) which act as intermediates in the synthesis of medicaments from aziridine alcohol of formula (1) and a process for producing the other useful compounds therefrom. Accordingly, the processes of the present invention can have four preparations as follows.
- a compound of formula (1) was reacted with halotrialkylsilane [Si(R) 3 X] to carry out a regiospecific ring opening reaction of the aziridine, and then the resulting intermediate was reacted with an amine (NHR 3 R 4 ) to produce a compound of formula (2).
- This can be schematically illustrated in the following Scheme 1
- R 1 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; 3- triazinyl or pyrimidyl acyl; aryl; hydrocarbon residues; aralkyl; and those substituted with suitable substituent(s), and includes 4-chlorophenyl, 4-methoxyphenyl, benzyl, 2,4- dimethoxyphenyl, (lR)-phenylethyl and (lS)-phenylethyl, preferences are given to (1R)- phenylethyl and (lS)-phenylethyl;
- R 2 is selected from the group consisting of hydrogen; alkyl including, but not limiting to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-
- Preparation 2 may be applied.
- aryl includes, but is not limited to, C 5 -C 14 aromatic hydrocarbon group such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl etc.
- heteroaryl includes, but is not limited to, 1 to 4 unsaturated 3- to 8- membered heterocyclic moieties containing 1 to 4 nitrogen atoms (e.g., pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 to 4 nitrogen atom(s) (e.g., pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl etc.); unsaturated condensed heterocyclic moieties containing 1 to 4 nitrogen atom(s) (e.g., indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl,
- pyrrolyl pyrazolyl
- imidazolyl oxazolyl
- isoxazolyl isoxazolyl
- thiazolyl isothiazolyl
- 1,2,3 -oxadiazolyl triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl.
- suitable substituent(s) includes, but is not limited to, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1-, 2- or 3-butenyI, 1-, 2-, 3- or 4-pentenyl etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargon
- haIotrialkylsilane[Si(R) 3 X] includes, but is not limited to, chlorotrimethylsilane, bromotrimethylsilane, iodotriethylsilane.
- lower means that the number of carbon is 1 to 6.
- lower alkyl indicates, but not limited to C,-C 6 linear or branched moiety(ies) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, and the term "alkyl” includes, but is not limited to, linear or branched C,-C 20 alkyl such as methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl, and octadecyl.
- all the preparation processes of the present invention are usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or other solvents which do not adversely influence the reaction.
- a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or other solvents which do not adversely influence the reaction.
- a conventional organic solvent can be used. More preferably halogenated organic solvent, and most preferably methylene chloride can be used.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
- An azidoaminoalcohol of formula (3) was produced by reacting a compound of formula (1), the same starting material as in Preparation 1 by a known process (Y. Lim, Tetrahedron Letters, 1995, 36, 8431, and B. C. Kim, Tetrahedron, 1996, 52, 12117), reacting the compound with azidotrialkylsilane[Si(R') 3 N 3 ] to carry out a regiospecific ring opening reaction of the aziridine.
- 2,3-diaminopropanol of formula (4) was produced by reducing the obtained compound of formula (3) using a conventional azido reduction process. According to this procedure, a product wherein R 3 and R 4 are both hydrogen [i.e., a compound of formula (4)] can be produced.
- Aldotrialkylsilane[Si(R') 3 N 3 ] M as used herein includes, but is not limited to, azidotrimethylsilane or azidotriethylsilane. Preference is given to azidotrimethylsilane.
- the "reduction” according to this invention can be commonly carried out by the conventional procedures in the art such as chemical reduction and catalytic reduction. The following is a brief introduction of the reduction procedure, which can be used in the present invention.
- Suitable reducing agents to be used in the chemical reduction are hydride (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride etc.); mixture of borane and tetrahydrofuran or di(lower)alkyl sulfide (e.g., dimethyl sulfide etc.); or mixture of metal (e.g., tin, zinc, iron etc.) or acid compound (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid etc.).
- hydride e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride etc.
- borane and tetrahydrofuran or di(lower)alkyl sulfide e.g., dimethyl sulfide etc.
- metal e.g., tin,
- Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire etc.), palladium catalyst (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalyst (e.g., reduced cobalt, Raney cobalt etc.), iron catalyst (e.g., reduced iron, Raney iron, Ullmann iron etc.) and the like.
- platinum catalyst e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire etc.
- palladium catalyst e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palla
- the known reduction procedures can be utilized in reducing an azido group to an amino group in Preparation 2, and the typical examples are reduction by LiAlH 4 , reduction by Ph 3 P and catalytic reduction (catalytic hydrogenation), etc.
- the reduction is usually carried out in a solvent such as water, alcohol, tetrahydrofuran, dioxane, N,N-dimethylformamide, or a mixture thereof; or other solvents which do not adversely influence the reaction.
- a solvent such as water, alcohol, tetrahydrofuran, dioxane, N,N-dimethylformamide, or a mixture thereof; or other solvents which do not adversely influence the reaction.
- the acid used in chemical reduction is liquid, it can also act as a solvent.
- the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
- a compound of formula (6) can be produced by subjecting 2,3-diaminopropanol of formula (5) (i.e., the compound of formula (2) obtained from Preparation 1, wherein R 3 is hydrogen) to reduction as shown in Scheme 3, preferably reduction using a compound having a dialdehyde group and a hydride reducing agent.
- the compound of formula (6) was subjected to a conventional reduction in the presence of a compound capable of producing an amino protecting group (i.e., amino protector), preferably reduction by catalytic hydrogenation (catalytic reduction) as described above to produce a compound of formula (7).
- Typical compound of formula (7) includes l,4-di-t-Boc-2(R)-hydroxymethylpiperazine (wherein "Boc” stands for tert-butyloxycarbonyl).
- R 1 , R 2 and R 4 are as defined hereinbefore, and R 5 is an amino protecting group, which is suitable for protecting (or blocking) an amino group from chemical reaction, and is easily removable after completing the desired reaction on the other site.
- Typical examples of this type include substituted or unsubstituted acyl, aryl, aralkoxymethyl or aralkyl group etc.
- the name or size of amino protecting groups is not critical because they are removed after completing the desired reaction. However, those having 1 to 20 carbon atom(s), particularly 1 to 8 carbon atom(s) can be preferably used.
- acyl group as used herein can have the broadest meaning in regard to this process. It includes an acyl group derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acid or sulfonic acid as well as alkoxycarbonyl, aryloxycarbonyl, particularly aralkoxycarbonyl group.
- acyl group include, but are not limited to, alkanoyl such as acetyl, propionyl, butyryl, decanoyl etc.; aralkanoyl such as phenylacetyl etc.; aroyl such as benzoyl or toluyl etc.; aryloxyalkanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl etc.; aralkylcarbonyl such as Cbz(carbobenzoxy), 4-methoxybenzyloxycarbonyl, Fmoc (9- fluorenylmethoxycarbonyl) etc.; arylsulfonyl.
- alkanoyl such as acetyl, propionyl, butyryl, decanoyl etc.
- aralkanoyl such as phenylacety
- amino protecting group the preference is given to Boc, and also to Cbz, Fmoc, benzyl or acetyl.
- amino protector t-butyl carbonate, methylcarbamate, ethylcarbamate or 9- fluorenylmethylcarbamate can be preferably used.
- the “hydride” includes, but is not limited to, lithium aluminum hydride, sodium borohydride or sodium cyanoborohydride.
- a compound having a dialdehyde group is well known in the art, and preferably glyoxal can be used.
- the compound of formula (8) can be prepared by subjecting R 1 group of the compound of formula (2) to a conventional reduction procedure, preferably to a reduction using catalytic hydrogenation as described hereinbefore, and then reacting it with alkanoyl halide (R 6 X).
- alkanoyl halide R 6 X
- Typical examples of the compound of formula (8) include D-threo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol.
- R 1 , R 2 , R 3 and R 4 and the redction are as defined hereinbefore,
- R 6 includes, but is not limited to, alkanoyl group such as acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, isobutyryl, 2-ethylbutyryl, 3,3-dimethylbutyryl, decanoyl, preference is given to decanoyl, and X is fluoro, chloro, bromo or iodo.
- alkanoyl group such as acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, isobutyryl, 2-ethylbutyryl, 3,3-dimethylbutyryl, decanoyl, preference is given to decanoyl
- X is fluoro, chloro, bromo or iodo.
- N-[(S)-l-phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol (201 mg) was dissolved in methylene chloride, to which azidotrimethylsilane (0.25 ml) was added.
- the reaction mixture was stirred at ambient temperature for 12 hours, was treated with IN of aqueous hydrochloric acid solution and then was stirred for 1 more hour.
- the solution was neutralized with sodium hydrogen carbonate, and the reaction product was extracted twice each with 5.0 mi of methylene chloride.
- the combined organic extracts were dried under anhydrous magnesium sulfate, and the solution was filtered, concentrated in vacuo and purified to give 154 mg of product as an oil.
- N-[(S)-l-phenylethyl]aziridine-2(R)-methanol 60 mg was dissolved in 1.0 ml of acetonitrile, and then 107 mg of sodium iodide and 86 mg of chlorotnmethylsilane were added to this solution. After stirring the reaction mixture at ambient temperature for 1 hour and 50 minutes, 16.8 mg of pyrrolidine was added, and then the reaction mixture was heated for 2 hours with stirring. After the reaction was completed, the reaction mixture was treated with 1.2N aqueous hydrochloric acid solution, neutralized with sodium hydrogen carbonate and extracted twice each with 5 mi of methylene chloride. The combined organic extracts were rinsed with brine, and dried under anhydrous magnesium sulfate. The solution was filtered, concentrated in vacuo, and purified to give 73 mg of titled product as an oil.
- the present invention produces the known 2,3-diaminopropanol in high yields of more than 90% by ring opening an inactivated optically pure aziridine and reacting with various amines.
- the obtained 2,3-diaminopropanol can be used in synthesis of high value-added fine chemical compounds, such as hydroxymethylpiperazine, D-threo-l-phenyl-2-decanoylamino- 3 -morpholino-1 -propanol etc.
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Abstract
The invention relates to a process for producing 2,3-diaminopropanol of formula (II) from aziridine of formula (I) wherein, R1 is selected from a group consisting of hydrogen, alkyl, cycloalkyl, acyl, aryl, hydrocarbon residues, aralkyl, and those groups substituted with suitable substituent(s); R2 is selected from a group consisting of hydrogen, alkyl, cycloalkyl, C¿2?-C5-alkenyl, aralkyl which may be optionally substituted with suitable substituent(s), aryl which may be optionally substituted with suitable substituent(s), and heteroaryl which may be optionally substituted with suitable substituent(s); each of R?3 and R4¿ is independently selected from a group consisting of hydrogen, C¿1?-C12 alkyl, C1-C12 alkylcarbonyl, C1-C12 alkyloxycarbonyl, aryl, mono- or di(C1-C12)alkylamino, mono- or di(C1-C12)amino carbonyl, wherein C1-C12 may be optionally substituted, or R?3 and R4¿, together with nitrogen atom which they are attached to, may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C¿1?-C12)alkylamino C1-C4 alkylidene.
Description
PROCESS FOR PREPARING 2,3-DIAMINOPROPANOLS AND SYNTHESIS OF OTHER COMPOUNDS USING 2,3-DIAMINOPROPANOLS
Technical Field 2,3-diaminopropanol is an important material used in production of fine chemicals, particularly medicaments or their intermediates or other catalyst and high value-added compounds (D. Lucet, Angew. Chem. Int. Ed. Engl. 1998, 37, 2580-2627). Background Art
Heretofore, the processes for preparing 2,3-diaminopropanol by directly incorporating two amines into alkene, or oxidizing the alkene, and subsequently subjecting to animation (A. Chong, J Am. Chem. Soc. 1977, 99, 3420, and H. C. Kolb, Chem. Rev. 1994, 94, 2483-2547) were known. However, the present invention relates to a process for preparing 2,3-diaminopropanol by regiospecifϊc ring opening of an optically pure aziridine ring using nitrogen nucleophile. Of course, researches have been made as to the method of preparing azide by ring opening an aziridine having no protecting groups on the nitrogen atom, or an activated aziridine ring having a strong electron-withdrawing group such as tosyl on the nitrogen atom (G. Swift, J. Org. Chem. 1967, 32, 511-517 and T. Turoki, Chem. Lett. 1995, 337-338). But, these processes have limitations that the reaction yield is very low, e.g., not more than 40% and only an activated aziridine should be used. Also, these processes have low regioselectivity. Thus, the present inventors propose a process for producing 2,3- diaminopropanol, by ring opening an optically pure aziridine, and reacting it with an amine.
The obtained optically pure 2,3-diaminopropanol is used to produce, for example, hydroxymethylpiperazine which is useful as an intermediate of medicament. The processes for producing an optically active piperazine was proposed via a catalytic hydrogenation (U.S. Patent No. 5,977,364), or resolution of racemic mixture (U.S. Patent No. 5,945,534) were known. The present invention is characterized by a process for preparing 2,3- diaminopropanol from a chiral diamine. In addition, when morpholine is used as amine in the present process, D-threo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol etc. can be produced, which is biologically active.
Disclosure of the Invention
The present invention provides a process for producing 2,3-diaminopropanol in high yields of more than 90% by ring opening an inactivated optically pure aziridine and reacting it with various amines. The obtained 2,3-diaminopropanol is used in the synthesis of high value-added compounds, such as hydroxymethylpiperazine, D-threo-l-phenyl-2- decanoylamino-3 -morpholino- 1 -propanol, etc.
The object of the present invention is to provide a process for producing 2,3- diaminopropanol derivatives of formula (2) which act as intermediates in the synthesis of medicaments from aziridine alcohol of formula (1) and a process for producing the other useful compounds therefrom. Accordingly, the processes of the present invention can have four preparations as follows.
Preparation 1
A compound of formula (1) was reacted with halotrialkylsilane [Si(R)3X] to carry out a regiospecific ring opening reaction of the aziridine, and then the resulting intermediate was reacted with an amine (NHR3R4) to produce a compound of formula (2). This can be schematically illustrated in the following Scheme 1
Scheme 1
(1 ) (2) wherein R1 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; 3- triazinyl or pyrimidyl acyl; aryl; hydrocarbon residues; aralkyl; and those substituted with suitable substituent(s), and includes 4-chlorophenyl, 4-methoxyphenyl, benzyl, 2,4- dimethoxyphenyl, (lR)-phenylethyl and (lS)-phenylethyl, preferences are given to (1R)- phenylethyl and (lS)-phenylethyl; R2 is selected from the group consisting of hydrogen; alkyl including, but not limiting
to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, dodecyl; cycloalkyl including, but not limiting to cyclohexyl, cyclopentyl; C2-C5 alkenyl including, but not limiting to ethenyl, propenyl, butenyl, pentenyl; aralkyl; heteroaryl; and those which can be substituted with suitable substituent(s), preferences are given to hydrogen, lower alkyl, C2-C6 alkenyl, thiazolyl, phenyl, lower alkyl, lower alkoxy, or phenyl substituted halogen atom(s); and each R3 and R4 is independently selected from the group consisting of hydrogen, Cr C12 alkyl, C Cu alkylcarbonyl, CrC12 alkyloxycarbonyl, aryl, amino, mono- or di(C1-C12)alkyl amino, mono- or di(Cι-C12)aminocarbonyl, wherein CrCn may be optionally substituted with the suitable substituent(s), or R3 and R4, together with nitrogen atom which they are attached to, can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C,- C12)alkylamino(C1-C4)alkylidene; with the proviso that Preparation 1 is excluded when R3 and R4 are both equal to hydrogen. Where R3 and R4 are both hydrogen, Preparation 2 may be applied. In this specification, the term "aryl" includes, but is not limited to, C5-C14 aromatic hydrocarbon group such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl etc.
The term "heteroaryl" includes, but is not limited to, 1 to 4 unsaturated 3- to 8- membered heterocyclic moieties containing 1 to 4 nitrogen atoms (e.g., pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 to 4 nitrogen atom(s) (e.g., pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl etc.); unsaturated condensed heterocyclic moieties containing 1 to 4 nitrogen atom(s) (e.g., indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., oxazolyl, isoxazolyl, oxadiazolyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., morpholinyl etc.); unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., benzoxazolyl, benzoxadiazolyl); unsaturated 3- to 8-membered heterocyclic moieties containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g.,
thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g., thiazolinyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 or 2 sulfur atom(s) (e.g., thienyl, dihydrodithiinyl, dihydrodithionyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 or 2 oxygen atom(s) (e.g., tetrahydrofuryl, tetrahydropyranyl etc.); unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g., benzothiazolyl, benzothiadiazolyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 oxygen atom (e.g., furyl etc.); spiro heterocyclic moieties containing 1 or 2 oxygen atom(s) (e.g., dioxaspiroundecanyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 oxygen atom and 1 or 2 sulfur atom(s) (e.g., dihydrooxathiinyl etc.); unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atom(s) (e.g., benzothienyl, benzodithiinyl etc.); unsaturated condensed heterocyclic groups containing 1 oxygen atom and 1 or 2 sulfur atom(s) (e.g., benzoxathiinyl etc.). Preferences are given to pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3 -oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl.
The term "suitable substituent(s)" includes, but is not limited to, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1-, 2- or 3-butenyI, 1-, 2-, 3- or 4-pentenyl etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1-butynyl, 5-hexynyl etc.), mono- (or di- or tri-)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dibromomethyl, 2,2-difluoroethyl etc.), halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl etc.), ar(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, nitro, amino, protected imino, di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino etc.), hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, acyl, cyano, mercapto, lower alkylthio, imino.
The term "aralkyl" includes, but is not limited to, phenyl(lower)alkyl such as benzyl, phenethyl, phenylpropyl.
The term "haIotrialkylsilane[Si(R)3X]" includes, but is not limited to, chlorotrimethylsilane, bromotrimethylsilane, iodotriethylsilane. The term "lower" means that the number of carbon is 1 to 6. The term "lower alkyl" indicates, but not limited to C,-C6 linear or branched moiety(ies) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, and the term "alkyl" includes, but is not limited to, linear or branched C,-C20 alkyl such as methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl, and octadecyl. Also, all the preparation processes of the present invention are usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or other solvents which do not adversely influence the reaction. Preferably, a conventional organic solvent can be used. More preferably halogenated organic solvent, and most preferably methylene chloride can be used. The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
Preparation 2
An azidoaminoalcohol of formula (3) was produced by reacting a compound of formula (1), the same starting material as in Preparation 1 by a known process (Y. Lim, Tetrahedron Letters, 1995, 36, 8431, and B. C. Kim, Tetrahedron, 1996, 52, 12117), reacting the compound with azidotrialkylsilane[Si(R')3N3] to carry out a regiospecific ring opening reaction of the aziridine. 2,3-diaminopropanol of formula (4) was produced by reducing the obtained compound of formula (3) using a conventional azido reduction process. According to this procedure, a product wherein R3 and R4 are both hydrogen [i.e., a compound of formula (4)] can be produced.
Scheme 2
Si(R')3N3 reduction
(3) (4)
(1 )
"Azidotrialkylsilane[Si(R')3N3]M as used herein includes, but is not limited to, azidotrimethylsilane or azidotriethylsilane. Preference is given to azidotrimethylsilane. The "reduction" according to this invention can be commonly carried out by the conventional procedures in the art such as chemical reduction and catalytic reduction. The following is a brief introduction of the reduction procedure, which can be used in the present invention.
Suitable reducing agents to be used in the chemical reduction are hydride (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride etc.); mixture of borane and tetrahydrofuran or di(lower)alkyl sulfide (e.g., dimethyl sulfide etc.); or mixture of metal (e.g., tin, zinc, iron etc.) or acid compound (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire etc.), palladium catalyst (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalyst (e.g., reduced cobalt, Raney cobalt etc.), iron catalyst (e.g., reduced iron, Raney iron, Ullmann iron etc.) and the like.
The known reduction procedures can be utilized in reducing an azido group to an amino group in Preparation 2, and the typical examples are reduction by LiAlH4, reduction by Ph3P and catalytic reduction (catalytic hydrogenation), etc.
The reduction is usually carried out in a solvent such as water, alcohol, tetrahydrofuran, dioxane, N,N-dimethylformamide, or a mixture thereof; or other solvents which do not adversely influence the reaction. When the acid used in chemical reduction is
liquid, it can also act as a solvent.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Preparation 3
A compound of formula (6) can be produced by subjecting 2,3-diaminopropanol of formula (5) (i.e., the compound of formula (2) obtained from Preparation 1, wherein R3 is hydrogen) to reduction as shown in Scheme 3, preferably reduction using a compound having a dialdehyde group and a hydride reducing agent. The compound of formula (6) was subjected to a conventional reduction in the presence of a compound capable of producing an amino protecting group (i.e., amino protector), preferably reduction by catalytic hydrogenation (catalytic reduction) as described above to produce a compound of formula (7). Typical compound of formula (7) includes l,4-di-t-Boc-2(R)-hydroxymethylpiperazine (wherein "Boc" stands for tert-butyloxycarbonyl).
Scheme 3
(5) (6) {')
wherein R1, R2 and R4 are as defined hereinbefore, and R5 is an amino protecting group, which is suitable for protecting (or blocking) an amino group from chemical reaction, and is easily removable after completing the desired reaction on the other site.
Typical examples of this type include substituted or unsubstituted acyl, aryl, aralkoxymethyl or aralkyl group etc. The name or size of amino protecting groups is not critical because they are removed after completing the desired reaction. However, those having 1 to 20 carbon atom(s), particularly 1 to 8 carbon atom(s) can be preferably used.
The term "acyl group" as used herein can have the broadest meaning in regard to this process.
It includes an acyl group derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acid or sulfonic acid as well as alkoxycarbonyl, aryloxycarbonyl, particularly aralkoxycarbonyl group. The examples of acyl group include, but are not limited to, alkanoyl such as acetyl, propionyl, butyryl, decanoyl etc.; aralkanoyl such as phenylacetyl etc.; aroyl such as benzoyl or toluyl etc.; aryloxyalkanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl etc.; aralkylcarbonyl such as Cbz(carbobenzoxy), 4-methoxybenzyloxycarbonyl, Fmoc (9- fluorenylmethoxycarbonyl) etc.; arylsulfonyl. As the amino protecting group, the preference is given to Boc, and also to Cbz, Fmoc, benzyl or acetyl. Thus, as the "amino protector" in the present invention, t-butyl carbonate, methylcarbamate, ethylcarbamate or 9- fluorenylmethylcarbamate can be preferably used.
The "hydride" includes, but is not limited to, lithium aluminum hydride, sodium borohydride or sodium cyanoborohydride.
The "a compound having a dialdehyde group" is well known in the art, and preferably glyoxal can be used.
Preparation 4
As can be seen in Scheme 4, the compound of formula (8) can be prepared by subjecting R1 group of the compound of formula (2) to a conventional reduction procedure, preferably to a reduction using catalytic hydrogenation as described hereinbefore, and then reacting it with alkanoyl halide (R6X). Typical examples of the compound of formula (8) include D-threo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol.
Scheme 4
(2) (8)
Unless otherwise indicated, R1, R2, R3 and R4 and the redction are as defined
hereinbefore,
R6 includes, but is not limited to, alkanoyl group such as acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, isobutyryl, 2-ethylbutyryl, 3,3-dimethylbutyryl, decanoyl, preference is given to decanoyl, and X is fluoro, chloro, bromo or iodo.
The following examples are given for the purpose of illustrating the present invention in more detail.
Example
Example 1
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-methylpropanol
N-[(S)-l-phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol (201 mg) was dissolved in methylene chloride, to which azidotrimethylsilane (0.25 ml) was added. The reaction mixture was stirred at ambient temperature for 12 hours, was treated with IN of aqueous hydrochloric acid solution and then was stirred for 1 more hour. The solution was neutralized with sodium hydrogen carbonate, and the reaction product was extracted twice each with 5.0 mi of methylene chloride. The combined organic extracts were dried under anhydrous magnesium sulfate, and the solution was filtered, concentrated in vacuo and purified to give 154 mg of product as an oil. Rf 0.21 (EtOAc/hexane 20:80). [α ]D 26= -146.3 (c 2.00, CHC13). Η NMR (200 MHz, CDC13) δ 7.38-7.25 (m, 5H), 3.96 (q, J= 6.5 Hz, 1H), 3.64 (m, 2H), 3.35 (dd, J= 12.8, 3.0 Hz, 1H), 2.25 (m, 1H), 1.40 (d, J= 6.4 Hz, 3H), 1.09 (d, J= 6.2 Hz, 3H).
Example 2
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-n-butylpropanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)-n-butyl]methanol, the titled compound was produced.
Rf 0.24 (EtOAc/hexane 20:80). [α ]D 27 = -98.6 (c 1.00, CHC13). Η NMR (200 MHz, CDC13) δ 7.33-7.24 (m, 5H), 3.95 (q, J- 6.5 Hz, IH), 3.63 (dd, J= 12.6, 4.6 Hz, IH), 3.39 (m, 2H), 2.33 (m, 2H), 1.38 (d, J= 6.5 Hz, 3H), 1.23 (m, 5H), 0.86 (m, 3H).
Example 3
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-t-butylpropanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)-t-butyl]methanol, the titled compound was produced.
Rf 0.46 (EtOAc/hexane 20:80). [α ]D 26= -99.2 (c 1.00, CHC13). Η NMR (200 MHz, CDC13) δ 7.33-7.24 (m, 5H), 3.97 (q, J= 6.6 Hz, IH), 3.64 (dd, J= 12.6, 4.6 Hz, IH), 3.32 (dd, J = 12.6, 4.8 Hz, IH), 2.98 (d, J- 4.9 Hz, IH), 2.77 (m, 2H), 2.62 (q, J = 4.8 Hz, IH), 1.42 (d, J= 6.5 Hz, 3H), 0.70 (s, 9H).
Example 4
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-phenylpropanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [1 (R)-phenyl]methanol, the titled compound was produced.
Rf 0.24 (EtOAc/hexane 20:80). [α ]D 2S= -134.2 (c 0.50, CHC13). Η NMR (200 MHz, CDC13) δ 7.38-7.17 (m, 10H), 4.43 (d, J= 8.5 Hz, IH), 3.52 (dd, J= 12.8, 4.0 Hz, IH), 3.02 (dd, J= 12.8, 2.9 Hz, IH), 2.56 (m, IH), 1.41 (d, J= 6.5 Hz, 3H).
Example 5
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(2-methoxy phenyl)propanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)-
phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)-(2-methoxyphenyl)]methanol, the titled compound was produced.
Rf 0.12 (EtOAc/hexane 20:80). [α ]D 26= -141.0 (c 1.00, CHC13). Η NMR (200 MHz, CDC13) δ 7.30-7.17 (m, 7H), 6.94-6.78 (m, 2H), 4.83 (d, J= 7.4 Hz, IH), 3.83 (q, J = 7.4 Hz, IH), 3.83 (q, J= 6.4 Hz, IH), 3.69 (s, 3H), 3.51 (dd, J- 12.6, 4.6 Hz, IH), 3.07 (dd, J = 12.8, 3.5 Hz, IH), 2.72 (m, IH), 1.37 (d, J= 6.6 Hz, 3H).
Example 6 Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(4-chlorophenyl) propanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)(4-chlorophenyl)]methanol, the titled compound was produced.
Rf 0.26 (EtOAc/hexane 20:80). [α ]D 26= -114.6 (c 1.00, CHC13). 'H NMR (200 MHz, CDC13) δ 7.38-7.11 (m, 9H), 4.42 (d, J = 8.3 Hz, IH), 3.92 (q, J = 6.5 Hz, IH), 3.57 (dd, J- 12.9, 4.1 Hz, IH), 3.04 (dd, J- 12.8, 2.8 Hz, IH), 1.42 (d, J- 6.5 Hz, 3H).
Example 7
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(l-hexynyl) propanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(lS)-phenylethyl]aziridine-2(R)- [l(R)-(l-hexynyl)]methanol, the titled compound was produced.
Rf 0.28 (EtOAc/hexane 20:80). [α ]D 2 - -88.0 (c 1.00, CHC13). Η NMR (200
MHz, CDC13) δ 7.35-7.23 (m, 5H), 4.22 (m, IH), 3.96 (q, = 6.4 Hz, IH), 3.65 (dd, J= 12.6,
4.4 Hz, IH), 3.52 (dd, J= 12.5, 3.5 Hz, IH), 2.60 (m, IH), 2.18 (m, 2H), 1.39 (m, 7H), 0.88 (t,
J- 7.0 Hz, 3H).
Example 8
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(4-fluorophenyl) propanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(lS)-phenylethyl]aziridine-2(R)- [l(R)-(4-fluorophenyl)]methanol, the titled compound was produced.
Rf 0.22 (EtOAc/hexane 20:80). [α ]D 28= -136.0 (c 0.50, CHC13). Η NMR (200 MHz, CDC13) δ 7.38-6.92 (m, 9H), 4.42 (d, J = 8.4 Hz, IH), 3.93 (q, J = 6.3 Hz, IH), 3.57 (dd, J= 13.0, 3.8 Hz, IH), 3.01 (dd, J- 12.8, 2.4 Hz, IH), 2.48 (m, IH), 1.42 (d, J- 6.2 Hz, 3H).
Example 9
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(3-methylphenyl) propanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl] aziridine-2(R)- [ 1 (R)-methyl]methanol with N- [( 1 S)-phenylethyl]aziridine-2(R)- [l(R)-(3-methylphenyl)]methanol, the titled compound was produced.
Rf 0.29 (EtOAc/hexane 20:80). [α ]D 27= -128.0 (c 1.00, CHC13). !H NMR (200
MHz, CDC13) δ 7.37-6.99 (m, 9H), 4.40 (d, J - 8.4 Hz, IH), 3.91 (q, J = 6.5 Hz, IH), 3.54 (dd, J- 12.8, 4.0 Hz, IH), 3.03 (dd, J= 12.8, 2.7 Hz, IH), 2.54 (m, IH), 2.28 (s, 3H), 1.40 (d, J= 6.5 Hz, 3H).
Example 10
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(2-thiazolyl) propanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)-
[l(R)-(2-thiazolyl)]methanol, the titled compound was produced.
mp 68-70 °C . Rf 0.27 (EtOAc/hexane 30:70). [α ]D 26= -81.2 (c 0.50, CHC13). Η NMR (200 MHz, CDC13) δ 7.68 (d, J= 3.3 Hz, IH), 7.32-7.16 (m, 6H), 4.79 (d, J= 6.4 Hz, IH), 3.83 (q, J= 6.6 Hz, IH), 3.68 (dd, J= 12.6, 4.7 Hz, IH), 3.59 (dd, J= 12.6, 4.3 Hz, IH), 2.85 (m, IH), 1.38 (d, J= 6.5 Hz, 3H).
Example 11
Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(2-propenyl) propanol
Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(lS)-phenylethyl]aziridine-2(R)- [l(R)-(2-propenyl)]methanol, the titled compound was produced.
Rf 0.38 (EtOAc/hexane 30:70). [α ]D 26= -158.2 (c 1.00, CHC13). Η NMR (200 MHz, CDC13) δ 7.38-7.25 (m, 5H), 4.96 (d, J - 13.9 Hz, 2H), 3.92 (m, 2H), 3.60 (dd, J = 12.5, 4.5 Hz, IH), 3.30 (dd, J= 12.5, 3.2 Hz, IH), 1.45 (s, 3H), 1.40 (d, J= 6.5 Hz, 3H).
Example 12
Synthesis of 2(R)-N-[(S)-l-phenylethyl]amino-3-pyrrolidinopropanol
N-[(S)-l-phenylethyl]aziridine-2(R)-methanol (60 mg) was dissolved in 1.0 ml of acetonitrile, and then 107 mg of sodium iodide and 86 mg of chlorotnmethylsilane were added to this solution. After stirring the reaction mixture at ambient temperature for 1 hour and 50 minutes, 16.8 mg of pyrrolidine was added, and then the reaction mixture was heated for 2 hours with stirring. After the reaction was completed, the reaction mixture was treated with 1.2N aqueous hydrochloric acid solution, neutralized with sodium hydrogen carbonate and extracted twice each with 5 mi of methylene chloride. The combined organic extracts were rinsed with brine, and dried under anhydrous magnesium sulfate. The solution was filtered, concentrated in vacuo, and purified to give 73 mg of titled product as an oil.
Rf 0.26 (MeOH/EtOAc 30:70). [α ]D 26= -19.4 (c 1.00, CHC13). Η NMR (500
MHz, CDC13) δ 7.10-7.36 (m, 10H), 4.80 (d, J = 3.9 Hz, IH), 3.76-3.80 (q, IH), 2.87 (m, IH), 2.61-2.72 (m, 6H), 1.79-1.81 (m, 4H), 1.24-1.25 (d, J= 6.35 Hz, 3H).
Example 13 Synthesis of 2(R)-N-[(S)-l-phenylethyl]amino-3-piperidinopropanol
Using the analogous procedure described in Example 12, and replacing pyrrolidine with piperidine, the titled compound was produced.
Rf 0.21 (MeOH/EtOAc 10:90). [α ]D 26= -35.5 (c 1.00, CHC13). Η NMR (200 MHz, CDC13) δ 7.14-7.33 (m, 10H), 4.74-1.80 (d, J= 4.0 Hz, IH), 3.71-3.81 (q, IH), 2.92- 3.00 (m, IH), 2.39-2.47 (m, IH), 1.44-1.80 (m, 6H), 1.21-1.24 (d, J= 6.6 Hz).
Example 14
Synthesis of 2(R)-N-[(S)-l-phenylethyl]amino-3-hexamethyleneimino propanol Using the analogous procedure described in Example 12, and replacing pyrrolidine with hexamethyleneimine, the titled compound was produced.
Rf 0.67 (MeOH/EtOAc 10:90). [α ]D 26= -33.7 (c 1.00, CHC13). Η NMR (200 MHz, CDC13) δ 7.17-7.33 (m, 10H), 4.70 (d, IH), 2.83-3.00 (m, IH), 2.55-2.83 (m, 7H), 1.55-1.94 (b, 8H), 1.21-1.24 (d, J= 6.6 Hz, 3H).
Example 15
Synthesis of 2(R)-N-[(S)-l-phenylethyI]amino-3-morpholino-l(R)-phenyl propanol Using the analogous procedure described in Example 12, and replacing pyrrolidine with morpholine, the titled compound was produced.
Rf 0.33 (EtOAc). [α ]D 26=-32.2 (c 1.00, CHC13). Η NMR (300 MHz, CDC13) δ 7.08-7.33 (m, 10H), 4.66 (d, J= 4.1 Hz, IH), 3.68-3.73 (m, 5H), 2.40-2.59 (m, 6H), 1.20 (d,
J- 6.9 Hz, 3H).
Example 16
Synthesis of D-threo-l-phenyI-2-decanoylamino-3-morpholino-l-propanol 230 mg of 2(R)-N-[(S)-l-phenylethyl]amino-3-morpholino-l(R)-phenylpropanol obtained from Example 14 was dissolved in 3.4 mi of methanol, and 0.8 mi of acetic acid and 69 mg of Pd(OH)2 (25 wt%) were added to this solution. After thoroughly stirring the mixture, it was allowed to react under the atmospheric pressure and at 40 °C for 4 hours. The catalyst was filtered off, the reaction solution was concentrated in vacuo, and the residue was dissolved in 3 mi of tetrahydrofuran. 0.8 mi of 10% NaOH solution, followed by 0.13 mi of decanoyl chloride were added to this solution. After the completion of the reaction was confirmed by TLC, water was added to the reaction container. The solution was separated into an organic phase and an aqueous phase. The organic phase was dried under anhydrous magnesium sulfate. The solution was filtered, concentrated in vacuo and purified to give 212 mg of product as an oil.
Rf 0.40 (EtOAc). [α ]D 25 = +8.02 (c 0.30, CHC13). Η NMR (500 MHz, CDC13) δ 7.31 (m, 5H), 5.84 (d, J= 6.83 HZ, IH), 4.96 (d, J- 3.90 Hz, IH), 4.28 (m, IH), 3.72 (t, J = 4.88, 4.39 Hz, 4H), 2.47-2.62 (m, 6H), 2.10 (t, J= 7.32, 7.81 Hz, 2H), 1.50 (m, 2H), 1.23- 1.31 (m, 12H), 0.88 (t, J- 6.83 Hz, 3H).
The present invention produces the known 2,3-diaminopropanol in high yields of more than 90% by ring opening an inactivated optically pure aziridine and reacting with various amines. The obtained 2,3-diaminopropanol can be used in synthesis of high value-added fine chemical compounds, such as hydroxymethylpiperazine, D-threo-l-phenyl-2-decanoylamino- 3 -morpholino-1 -propanol etc.
Claims
1. A process for producing 2,3-diaminopropanol, comprising the steps of:
(a) reacting an aziridine alcohol of formula (1) with halotrialkylsilane to carry out an regioselective ring opening reaction of aziridine, and
(b) immediately reacting the intermediate obtained from step (a) with amine
(NHR3R4) to produce 2,3-diaminopropanol of formula (2):
(1 ) (2)
wherein, R1 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; 3- triazinyl or pyrimidyl acyl; aryl; hydrocarbon residues; aralkyl; and those groups substituted with suitable substituent(s);
R2 is selected from the group consisting of hydrogen; alkyl including methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl or dodecyl; cycloalkyl including cyclohexyl or cyclopentyl; C2-C5 alkenyl including ethenyl, propenyl, butenyl or pentenyl; aralkyl; heteroaryl; and those groups substituted with suitable substituent(s); each of R3 and R4 is independently selected from the group consisting of hydrogen, C,-C12 alkyl, CrC12 alkylcarbonyl, CrC12 alkyloxycarbonyl, aryl, mono- or di(C,- C12)alkylamino, mono- or di(Cι-C,2)aminocarbonyl, wherein C,-C12 may be optionally substituted with the suitable substituent(s), or R3 and R4, together with nitrogen atom which they are attached to, may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-C12)alkylamino(C1-C4)alkylidene; with the proviso that when R3 and R4 are not both equal to hydrogen.
2. The process according to Claim 1, wherein R2 is hydrogen, lower alkyl, lower alkenyl, thiazolyl, phenyl, or phenyl which may be optionally substituted with substituent(s) selected from a group consisting of lower alkyl, lower alkoxy and halogen atom.
3. The process according to Claim 1 or 2, wherein R1 is (lR)-phenylethyl or (1S)- phenylethyl.
4. The process according to Claim 1 or 2, wherein said halotrialkylsilane is selected from a group consisting of iodotrimethylsilane, chlorotrimethylsilane and bromotriethylsilane.
5. A process for producing 2,3-diaminopropanol, comprising the steps of:
(a) reacting an aziridine alcohol of formula (1) with azidotrialkylsilane to carry out a regioselective ring opening reaction of aziridine to produce azidoaminoalcohol of formula (3), and
(b) reducing the compound of formula (3) to produce 2,3-diaminopropanol of formula
(4):
(1) (3) (4) wherein R1 and R2 are as defined in Claim 1.
6. The process according to Claim 5, wherein the reduction is selected from a group consisting of a reduction with LiAlH4, a reduction with Ph3P and a catalytic hydrogenation.
7. The process according to Claims 5 or 6, wherein the azidotrialkylsilane is azidotrimethylsilane .
8. A process for producing a compound of formula (7), comprising the steps of:
(a) reducing 2,3-diaminopropanol of formula (5) which corresponds to a formula (2) wherein R3 is hydrogen to produce a compound of formula (6); and (b) reducing the compound of formula (6) in the presence of a amino protector to produce the compound of formula (7):
(5) (6) (7) wherein Rs is an amino protecting group, and R1, R2 and R4 are as defined in Claim 1.
9. The process according to Claim 8, wherein the reducing step (a) is carried out using a compound having a dialdehyde group and a hydride reducing agent, and the reducing step (b) is carried out by a catalytic hydrogenation.
10. The process according to Claim 9, wherein the compound having a dialdehyde group is glyoxal.
11. The process according to Claims 8 or 9, wherein said amino protector is selected from a group consisting of t-butyl carbonate, methylcarbamate, ethylcarbamate or 9- fluoreny lmethylcarbamate .
12. The process according to Claims 8 or 9, wherein R4 is benzyl.
13. A process for producing a compound of formula (8), comprising the steps of: (a) reducing R1 group of a compound of formula (2); and
(b) reacting the resulting product from step (a) with alkanoyl halide(R6X) to produce the compound of formula (8):
14. The process according to Claim 13, wherein R3 and R4, together with nitrogen atom which they are attached to, form a morpholinyl group.
15. The process according to Claims 13 or 14, wherein the reduction is carried out by a catalytic hydrogenation.
16. The process according to Claims 13 or 14, wherein R6 is decanoyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001277801A AU2001277801A1 (en) | 2000-08-10 | 2001-08-10 | Process for preparing 2,3-diaminopropanols and synthesis of other compounds using 2,3-diaminopropanols |
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|---|---|---|---|
| KR1020000046394A KR20000063913A (en) | 2000-08-10 | 2000-08-10 | Process for preparing 1,2-diaminopropane alcohols from aziridines |
| KR2000/46394 | 2000-08-10 |
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| WO2002012185A1 true WO2002012185A1 (en) | 2002-02-14 |
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|---|---|---|---|
| PCT/KR2001/001362 WO2002012185A1 (en) | 2000-08-10 | 2001-08-10 | Process for preparing 2,3-diaminopropanols and synthesis of other compounds using 2,3-diaminopropanols |
Country Status (3)
| Country | Link |
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| KR (2) | KR20000063913A (en) |
| AU (1) | AU2001277801A1 (en) |
| WO (1) | WO2002012185A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20000063913A (en) * | 2000-08-10 | 2000-11-06 | 하현준 | Process for preparing 1,2-diaminopropane alcohols from aziridines |
| EP2198864A1 (en) | 2005-01-26 | 2010-06-23 | Allergan, Inc. | Pharmaceutical compositions having an analgesic effect and containing 1-benzyl-1-hydroxy-2,3-diamino-propyl amines, 3-benzyl-3-hydroxy-2-amino propionic acid amides or related compounds |
| CN103910655A (en) * | 2014-04-11 | 2014-07-09 | 太原理工大学 | Ring opening method of aziridine compounds |
| US9314466B2 (en) | 2007-03-06 | 2016-04-19 | Allergan, Inc. | Methods for treating cognitive disorders using 1-benzyl-1-hydroxy-2,3-diamino-propyl amines, 3-benzyl-3-hydroxy-2-amino-propionic acid amides and related compounds |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100420263B1 (en) * | 2001-04-16 | 2004-03-02 | 한솔케미언스 주식회사 | Process for preparing iso-serine and its derivatives from aziridine-2-carboxylates |
| KR101631481B1 (en) | 2015-04-07 | 2016-06-17 | 고려대학교 산학협력단 | Polymer using aziridine and method for preparing the same |
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| US3957823A (en) * | 1972-04-15 | 1976-05-18 | Badische Anilin- & Soda-Fabrik Aktiengesellschaft | Electrophilic substitution of nitrosamines |
| US4040838A (en) * | 1975-03-05 | 1977-08-09 | Fuji Photo Film Co., Ltd. | Processing color photographic materials |
| JPH01228946A (en) * | 1988-03-09 | 1989-09-12 | Suntory Ltd | Synthesis of beta-hydroxyphenetylamines |
| EP0736509A2 (en) * | 1995-04-07 | 1996-10-09 | Sumitomo Chemical Company, Limited | Processes for preparing optically active alcohols and optically active amines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56164129A (en) * | 1980-05-20 | 1981-12-17 | Takasago Corp | Preparation of allyl alcohol |
| JPH0791239B2 (en) * | 1988-11-22 | 1995-10-04 | 株式会社日本触媒 | Method for producing ethylenediamine |
| US6063963A (en) * | 1995-07-05 | 2000-05-16 | Pharm-Eco Laboratories, Inc. | Amino acid-derived diaminopropanols |
| KR20000063913A (en) * | 2000-08-10 | 2000-11-06 | 하현준 | Process for preparing 1,2-diaminopropane alcohols from aziridines |
-
2000
- 2000-08-10 KR KR1020000046394A patent/KR20000063913A/en active Search and Examination
-
2001
- 2001-08-10 KR KR1020037001904A patent/KR20030029816A/en not_active Application Discontinuation
- 2001-08-10 WO PCT/KR2001/001362 patent/WO2002012185A1/en not_active Application Discontinuation
- 2001-08-10 AU AU2001277801A patent/AU2001277801A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957823A (en) * | 1972-04-15 | 1976-05-18 | Badische Anilin- & Soda-Fabrik Aktiengesellschaft | Electrophilic substitution of nitrosamines |
| US4040838A (en) * | 1975-03-05 | 1977-08-09 | Fuji Photo Film Co., Ltd. | Processing color photographic materials |
| JPH01228946A (en) * | 1988-03-09 | 1989-09-12 | Suntory Ltd | Synthesis of beta-hydroxyphenetylamines |
| EP0736509A2 (en) * | 1995-04-07 | 1996-10-09 | Sumitomo Chemical Company, Limited | Processes for preparing optically active alcohols and optically active amines |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20000063913A (en) * | 2000-08-10 | 2000-11-06 | 하현준 | Process for preparing 1,2-diaminopropane alcohols from aziridines |
| US8513288B2 (en) | 2005-01-26 | 2013-08-20 | Allergan, Inc. | 1-aryl-1-hydroxy-2,3-diamino-propyl amines, 1-heteroaryl-1-hydroxy-2,3-diamino-propyl amines and related compounds having analgesic and/or immuno stimulant activity |
| US8013000B2 (en) | 2005-01-26 | 2011-09-06 | Allergan, Inc. | 3-heteroaryl-3-hydroxy-2-amino-propyl amines and related compounds having analgesic and/or immuno stimlant activity |
| US8153666B2 (en) | 2005-01-26 | 2012-04-10 | Allergan, Inc. | Compounds having analgesic and/or immunostimulant activity |
| EP2489658A1 (en) | 2005-01-26 | 2012-08-22 | Allergan, Inc. | 3-Heteroaryl-3-hydroxy-2-amino-propyl amines and related compounds having analgesic and/or immuno stimulant activity |
| US8288556B2 (en) | 2005-01-26 | 2012-10-16 | Allergan, Inc. | 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immuno stimulant activity |
| EP2198864A1 (en) | 2005-01-26 | 2010-06-23 | Allergan, Inc. | Pharmaceutical compositions having an analgesic effect and containing 1-benzyl-1-hydroxy-2,3-diamino-propyl amines, 3-benzyl-3-hydroxy-2-amino propionic acid amides or related compounds |
| US8835463B2 (en) | 2005-01-26 | 2014-09-16 | Allergan, Inc. | Compounds having analgesic and/or immunostimulant activity |
| US8927589B2 (en) | 2005-01-26 | 2015-01-06 | Allergan, Inc. | 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroaryl-3-hydroxy-2-aminopropionic acid amides and related compounds having analgesic and/or immuno stimulant activity |
| US9278943B2 (en) | 2005-01-26 | 2016-03-08 | Exonhit Therapeutics Sa | Methods of using as analgesics 1-benzyl-1-hydroxy-2, 3-diamino-propyl amines, 3-benzyl-3-hydroxy-2-amino-propionic acid amides and related compounds |
| US9399628B2 (en) | 2005-01-26 | 2016-07-26 | Allergan, Inc. | 1-aryl-1-hydroxy-2,3-diamino-propyl amines, 1-heteroaryl-1-hydroxy-2,3-diamino-propyl amines and related compounds having analgesic and/or immuno stimulant activity |
| US9828349B2 (en) | 2005-01-26 | 2017-11-28 | Exonhit Therapeutics Sa | 1-aryl-1-hydroxy-2,3-diamino-propyl amines, 1-heteroaryl-1-hydroxy-2,3-diamino-propyl amines and related compounds having analgesic and/or immuno stimulant activity |
| US9314466B2 (en) | 2007-03-06 | 2016-04-19 | Allergan, Inc. | Methods for treating cognitive disorders using 1-benzyl-1-hydroxy-2,3-diamino-propyl amines, 3-benzyl-3-hydroxy-2-amino-propionic acid amides and related compounds |
| CN103910655A (en) * | 2014-04-11 | 2014-07-09 | 太原理工大学 | Ring opening method of aziridine compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000063913A (en) | 2000-11-06 |
| AU2001277801A1 (en) | 2002-02-18 |
| KR20030029816A (en) | 2003-04-16 |
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