CN1140522C - 苯并二氢吡喃衍生物 - Google Patents
苯并二氢吡喃衍生物 Download PDFInfo
- Publication number
- CN1140522C CN1140522C CNB998142247A CN99814224A CN1140522C CN 1140522 C CN1140522 C CN 1140522C CN B998142247 A CNB998142247 A CN B998142247A CN 99814224 A CN99814224 A CN 99814224A CN 1140522 C CN1140522 C CN 1140522C
- Authority
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- China
- Prior art keywords
- general formula
- acid
- compound
- chroman
- otf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical class C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims description 35
- 238000005984 hydrogenation reaction Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000010948 rhodium Substances 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical group PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052741 iridium Inorganic materials 0.000 claims description 3
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 3
- CWONCLAJTVUXET-LLVKDONJSA-N n-[[(2r)-3,4-dihydro-2h-chromen-2-yl]methyl]acetamide Chemical compound C1=CC=C2O[C@@H](CNC(=O)C)CCC2=C1 CWONCLAJTVUXET-LLVKDONJSA-N 0.000 claims 1
- GOUBCYXYLMPDQA-SECBINFHSA-N n-[[(2r)-4-oxo-2,3-dihydrochromen-2-yl]methyl]acetamide Chemical compound C1=CC=C2O[C@@H](CNC(=O)C)CC(=O)C2=C1 GOUBCYXYLMPDQA-SECBINFHSA-N 0.000 claims 1
- CWONCLAJTVUXET-NSHDSACASA-N n-[[(2s)-3,4-dihydro-2h-chromen-2-yl]methyl]acetamide Chemical compound C1=CC=C2O[C@H](CNC(=O)C)CCC2=C1 CWONCLAJTVUXET-NSHDSACASA-N 0.000 claims 1
- GOUBCYXYLMPDQA-VIFPVBQESA-N n-[[(2s)-4-oxo-2,3-dihydrochromen-2-yl]methyl]acetamide Chemical compound C1=CC=C2O[C@H](CNC(=O)C)CC(=O)C2=C1 GOUBCYXYLMPDQA-VIFPVBQESA-N 0.000 claims 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 abstract description 9
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 6
- 150000002367 halogens Chemical class 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 5
- 229910052740 iodine Inorganic materials 0.000 abstract description 4
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 229910052801 chlorine Inorganic materials 0.000 abstract description 2
- 229910052731 fluorine Inorganic materials 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- 229910052717 sulfur Inorganic materials 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- -1 isobutyl- Chemical group 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 150000003624 transition metals Chemical group 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229910001868 water Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000002905 metal composite material Substances 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009905 homogeneous catalytic hydrogenation reaction Methods 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 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
- GVVCHDNSTMEUCS-UAFMIMERSA-N (2r,5r)-1-[2-[(2r,5r)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane Chemical compound CC[C@@H]1CC[C@@H](CC)P1C1=CC=CC=C1P1[C@H](CC)CC[C@H]1CC GVVCHDNSTMEUCS-UAFMIMERSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-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
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-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
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 229920004449 Halon® Polymers 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl 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
- 238000003556 assay Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000005340 bisphosphate group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- FWXAUDSWDBGCMN-ZEQRLZLVSA-N chiraphos Chemical compound C=1C=CC=CC=1P([C@@H](C)[C@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 FWXAUDSWDBGCMN-ZEQRLZLVSA-N 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
公开的是通式(I)的苯并二氢吡喃衍生物，其中R1代表具有1至6个碳原子的酰基、-CO-R5或氨基保护基；R2代表H或具有1至6个碳原子的烷基；R3、R4各自分别代表H、具有1至6个碳原子的烷基、氰基、卤素或COOR2；R5代表未被取代的苯基或被具有1至6个碳原子的烷基、OR2或卤素单取代或双取代的苯基；X代表H、H或O；卤素代表F、Cl、Br或I。所述衍生物及其盐可以作为药物合成的中间产物使用。
Description
技术领域
本发明涉及通式(I)的苯并二氢吡喃衍生物及其盐，
其中R1是具有1至6个碳原子的酰基、-CO-R5或氨基保护基，
R2是H或具有1至6个碳原子的烷基，
R3、R4各自分别代表H、具有1至6个碳原子的烷基、CN、卤素或COOR2，
R5是未被取代的苯基或被具有1至6个碳原子的烷基、OR2或卤素单取代或双取代的苯基，X是H、H或O，
卤素是F、Cl、Br或I，
本发明还涉及这些化合物的光学活性体、消旋体、对映异构体以及水合物和溶剂化物，例如醇化物。
背景技术
类似化合物在EP 0 707 007中公开。
发明内容
本发明基于发现新型化合物的目的，该化合物可被特别是作为药物合成的中间体使用。
已经发现通式(I)的化合物及其盐是药物制备中重要的中间体，特别是那些显示例如在中枢神经系统中起作用的药物。
本发明涉及通式(I)的苯并二氢吡喃的衍生物及其盐。
如果没有其它特别说明，本文上下所述的基团R1、R2、R3、R4、R5和X具有通式(I)和(II)中指出的意义。
在上述通式中，烷基具有1至6个碳原子，优选1、2、3或4个碳原子。烷基优选甲基或乙基、此外优选丙基、异丙基、另外还有丁基、异丁基、仲丁基或叔丁基。酰基具有1至6个碳原子，优选具有1、2、3或4个碳原子。酰基特别优选乙酰基、丙酰基或丁酰基。
R2优选H、另外还有甲基、乙基或丙基。
R3和R4优选H。
R5优选，例如苯基，邻、间或对甲苯基，邻、间或对羟基苯基，邻、间或对甲氧基苯基，邻、间或对氟苯基。基团R1为酰基、-CO-R5或其它本身已知的氨基保护基，特别优选乙酰基。
表示的“氨基保护基”通常是已知的，并且涉及用于保护(用于封锁)氨基、使之不发生化学反应的基团，但是在分子的其它位置上期望的化学反应完成之后，该氨基保护基很容易脱除。这一类典型的基团特别是，未取代的酰基、芳基、芳烷氧甲基或芳烷基。因为这些氨基保护基在期望的反应(或反应系列)结束后被除去，所以它们的性质和大小不是严格限定的。然而，这些基团优选具有1至20个碳原子，优选具有1至8个碳原子。表示的“酰基”在与本方法和本化合物有关方面要做最广义的解释。它包括从脂肪酸、芳香脂肪酸、芳香酸或杂环羧酸或磺酸衍生的酰基，并且特别包括烷氧羰基、芳氧羰基，尤其是芳烷氧羰基。该类型酰基的例子是，烷羰基例如乙酰基、丙酰基、丁酰基；芳烷羰基例如苯乙酰基；芳羰基例如苯甲酰基或甲苯甲酰基；芳氧烷羰基；例如苯氧乙酰基；烷氧羰基例如甲氧羰基、乙氧羰基、2，2，2-三氯乙氧羰基，BOC(叔丁氧羰基)、2-碘乙氧羰基；芳烷氧羰基；例如CBZ(苄氧羰基，也叫做“Z”)、4-甲氧苄氧羰基、FMOC(9-芴基甲氧羰基)；芳基磺酰基例如Mtr(4-甲氧-2，3，6-三甲基苯基磺酰基)。优选氨基保护基是BOC和Mtr，此外CBZ或FMOC。
通式I的化合物具有1个或多个手性中心，因此存在各种立体异构体。通式I包括所有这些异构体。
此外本发明涉及根据权利要求1的通式I的苯并二氢吡喃衍生物及其盐的制备方法，通式I中X是O，其特征为：
通式II的化合物
其中R1、R2、R3、R4具有权利要求1中指出的意义，且X是O，借助对映异构富集的催化剂的辅助进行氢化。
本发明还涉及根据权利要求1的通式I的苯并二氢吡喃衍生物及其盐的制备方法，通式I中X是H，H，其特征为：
通式II的化合物
其中R1、R2、R3、R4具有权利要求1中指出的意义，且X是O，借助对映异构富集的催化剂进行氢化，然后以常规方式还原。
尤其是，已经发现(2-乙酰氨基甲基)苯并吡喃-4-酮可以用各种对映异构纯二磷酸铑复合物氢化得到对映异构富集的(2-乙酰氨基甲基)苯并二氢吡喃-4-酮。
本发明还涉及通式I的苯并二氢吡喃衍生物的制备方法，其特征为对映异构富集的催化剂是过渡金属复合物。
特别优选，催化剂是含选自铑、铱、钌和钯的金属的过渡金属复合物。
本发明进一步涉及通式I的苯并二氢吡喃衍生物的制备方法，其特征是催化剂是过渡金属复合物，其中过渡金属是与手性二磷烷配位体复合的。
下述配位物可以实例的方式说明：(S)-EtDuphos：
BINAP：(S，S)-Chiraphos：(S，S)-DIOP：
(S，S)-Skewphos(BDpp)：
(S，S)-BPPM：
(R，R)-Norphos：
(S，R)-BPPFOH：(S，R)-PFctBu：
取决于催化剂中配位物的(R)或(S)对映体的选择，(R)或(S)对映体以过量得到。
用于手性配位物的前体是下面一些化合物，例如，Rh(COD)2OTf(环辛二烯三氟甲磺酸(triflate)铑)、[Rh(COD)Cl]2，Rh(COD)2BF4，[Ir(COD)Cl]2、Rr(COD)2BF4或[Ru(COD)Cl2]x。
通式I的化合物以及制备它们的原料通过本身已知的方法另行制备，例如如文献(即如Houben-Weyl，Methoden der organischenChemie(Mehtods of Organic Chemistry)，Georg-Thieme-Verlag，Stuttgart)上描述的，主要在已知的和适合于提到的反应的反应条件下进行。在这种情况下，还可以利用本身已知的、在此未详述的变通方法。
如果期望，原料也可以“一勺烩”的方式形成，即它们不从反应混合物中分离，而是立即进一步反应得到通式I的化合物。
有些情况中的通式II的化合物是已知的；未知化合物可以类似已知化合物的方法很容易地制备。
X为O的通式II的化合物转变为X为O的通式I的化合物是根据本发明用氢气以借助对映异构富集的催化剂在惰性溶剂，例如甲醇或乙醇中进行的。
适合的惰性溶剂还有例如烃类化合物如己烷、石油醚、苯、甲苯或二甲苯；氯化烃类如三氯乙烷、1，2-二氯乙烷、四氯化碳、氯仿或二氯甲烷；醇类如异丙醇、正丙醇、正丁醇或叔丁醇；醚类如乙醚、二异丙醚、四氢呋喃(THF)或二氧六环；乙二醇醚类如乙二醇单甲醚或单乙醚(乙二醇甲醚或乙二醇乙醚)，乙二醇二甲醚(二甘醇二甲醚)；酮类如丙酮或丁酮；酰胺类如乙酰胺，二甲基乙酰胺或二甲基甲酰胺(DMF)；腈类如乙腈；亚砜类如二甲基亚砜(DMSO)；二硫化碳；硝基化合物如硝基甲烷或硝基苯；酯类如乙酸乙酯，以及任选的提到的溶剂彼此间的混合物或溶剂与水的混合物。
对映选择性氢化的反应时间取决于使用的条件，介于几分钟至14天之间；反应温度在0至150℃之间，通常在20至130℃之间。
常规地，催化剂/底物的比例在1∶2000至1∶50之间，特别优选1∶1000和1∶100。反应时间，例如在3至20小时之间。氢化在1至200bar氢气压，优选3-100bar中进行。
X为O的通式II的化合物转变为X为H，H的通式I的化合物是根据本发明用氢气以借助对映异构富集的催化剂在惰性溶剂，例如甲醇或乙醇中进行，例如如上描述，随后根据已知条件使4-氧代基团转变为亚甲基。还原优选用氢气在过渡金属催化剂上进行(例如在Raney镍或钯/碳上、在惰性溶剂，例如甲醇或乙醇中氢化)。
R3、R4为COO烷基的通式I的化合物转变为R3、R4为COOH的通式I的化合物，例如在NaOH或KOH、水/THF或水/二氧六环中进行，温度在0至100℃。
基团R1从通式I的化合物中除去的反应取决于所使用的保护基，例如用强酸，方便地使用TFA(三氟乙酸)或高氯酸，而且也可用其它强无机酸，例如盐酸或硫酸，强有机羧酸，例如三氯乙酸或磺酸，例如苯磺酸或对甲苯磺酸。附加的惰性溶剂的存在是可能的，但不是总是必须的。适合的惰性溶剂是优选有机溶剂，例如羧酸如乙酸，醚类如四氢呋喃或二氧六环，酰胺类如二甲基甲酰胺，卤化烃如二氯甲烷，此外还有醇类如甲醇、乙醇或异丙醇以及水。另外，上述提到的溶剂的混合物是可能的。没有其它溶剂加入时优选TFA过量使用，高氯酸呈乙酸与70％高氯酸比例为9∶1的混合物形式。有利的反应温度大约在0和大约50℃之间，反应温度优选在15至30℃之间。
BOC基团优选用TFA在二氯甲烷中或用大约3N至5N盐酸在二氧六环中在15至30℃之间脱除。
乙酰基的脱除根据常规方法(P.J.Kocienski，ProtectingGroups，Georg Thieme Verilag，Stuttgart，1994)进行。
氢解可除去的保护基(例如CBZ或苄基)可以被除去，例如，通过在催化剂(例如贵金属催化剂如钯，有利的是在如碳的载体上)存在下与氢反应。在这种情况下适合的溶剂是上述表示的那些，特别是，例如醇如甲醇或乙醇，或酰胺如DMF。通常，氢解在温度为大约1与100℃之间和压力在大约1与200bar之间进行，优选在20至30℃和1-10bar之间。
通式I的碱可以用酸转变为相关的酸加合盐，例如通过当量的碱和酸在惰性溶剂如乙醇中反应，随后蒸发。对于这一反应，特别适合的酸是那些产生生理可以接受的盐的酸。因此，无机酸可以使用，例如硫酸、硝酸、氢卤酸如盐酸或氢溴酸、磷酸如正磷酸、氨基磺酸，此外，有机酸，特别是脂肪的、脂肪环的、芳香脂肪的、芳香的或杂环单或多元羧酸，磺酸或硫酸，如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、丁二酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、萘单磺酸和萘二磺酸以及月桂基硫酸。与生理可以接受的酸形成的盐，如苦味酸盐可被用于通式I的化合物的分离和/或纯化。
另一方面，通式I的化合物用碱(如氢氧化钠或氢氧化钾或碳酸钠或碳酸钾)可转变为相应的金属盐，尤其是碱金属盐或碱土金属盐，或转变为相应的铵盐。
本发明进一步涉及通式I的化合物作为药物合成中间体的应用，适合的药物，例如在EP 0 707 007中描述。
因此本发明特别涉及根据权利要求1的通式I的化合物在(R)-2-〔5-(4-氟苯基)-3-吡啶甲氨甲基〕-苯并二氢吡喃及它们的盐的合成中的应用，特征是
a)通式II的化合物
其中R1具有权利要求1表示的意义，
R2、R3和R4是H，且X是O，
借助对映异构富集的催化剂进行氢化，
b)特征还有，从获得的通式I的化合物对映异构富集的(R)和(S)的混合物中，其中
R1具有权利要求1表示的意义，
R2、R3和R4是H，且X是O，
通过结晶方法得到通式I的对映异构纯的(R)化合物，其中
R1具有权利要求1表示的意义，
R2、R3和R4是H，且X是O，
特征还有
c)然后以常规方法使通式I的对映异构纯的(R)化合物还原，其中
R1具有权利要求1表示的意义，
R2、R3和R4是H，且X是O，
特征还有
d)从得到的通式I的(R)化合物中除去基团R1，其中
R1具有权利要求1表示的意义，
R2、R3和R4是H，且X是H，H，
特征还有
e)上述得到的(R)-(苯并二氢吡喃-2-基甲基)胺转变为它的酸加成盐，该反应以已知的方式得到(R)-2-〔5-(4-氟苯基)-3-吡啶甲氨基甲基〕苯并二氢吡喃，如果合适，转变为它的酸加成盐，其中也可以在c)阶段或d)阶段之后从对映异构富集的(R，S)混合物中通过结晶回收(R)对映体。
本发明进一步还涉及通式I的化合物作为显示中枢神经系统作用的药物的合成中间体的应用。
本文上下所述的所有温度以℃表示，在下述实施例中，“常规后处理”的意义为：如果必要，加入水，取决于最终产物的结构，如果必要，调混合物的pH在2至10之间，用乙酸乙酯或二氯甲烷萃取，分离有机相，用硫酸钠干燥，蒸发，残留物用硅胶柱层析和/或结晶纯化，Rf为在硅胶板上的值。
具体实施方式
实施例
实验数据(复合物制备、氢化、分析方法)：
所有反应在惰性条件下进行(即无水和无氧反应条件)
1.催化剂/底物溶液的制备：
1.1实施例：
11.2mg Rh(COD)2OTf(环辛二烯triflate(三氟甲磺酸)铑)溶解在5ml甲醇中，冷却至0℃，然后加入冷的1.1当量的二磷烷〔例如，12.6mg的(R，R)-Skewphos〕的5ml甲醇溶液。室温搅拌10分钟后，混合物溶液用由110mg的(2-乙酰氨基甲基)苯并吡喃-4-酮和10ml的甲醇底物组成的溶液处理。
1.2实施例
51.4mg[Rh(COD)2Cl]2溶解在4ml甲苯/甲醇5∶1的混合溶剂中，混合物溶液用由5ml甲苯，1ml甲醇和1.1当量的二磷烷〔例如130.6mg的(R)-BINAP〕组成的溶液处理。1ml该催化剂复合物溶液加至510.8mg的(2-乙酰氨基甲基)苯并吡喃-4-酮溶解在15ml的甲苯和3ml甲醇的溶液中。
2.对映选择性氢化
用于氢化的催化剂/底物溶液置于高压锅内逆流保护气体中，保护气氛用氢气(1-5bar氢气压)灌充几次。物料类似于1.1，在室温及5bar氢气压下进行反应，以类似于1.2的催化剂在50℃和80bar的氢气中得到最好的结果。根据规律，氢化在15小时后结束。
3.取样和分析方法
样品置于逆流保护气氛中，对映体过量(enantiomeric excesses)测定之前，复合物通过硅胶柱层析(洗脱剂：乙酸乙酯)分离，氢化产物的对映体过量在手性HPLC柱上测定。柱： Daicel Chiralcel OJ(I.D.×长/mm：4.6×250)洗脱剂： 正己烷∶异丙醇＝9∶1流速： 0.8ml/min(18bar，28℃)检测器： UV 250nm保留时间： Rt(R)＝27min；Rt(S)＝29min
粗氢化溶液的浓缩可导致产物的沉淀，对映体过量的增加通过部分结晶测定。
4.进一步还原
完全转化测定之后，酮基还原通过钯/碳以“一锅反应”进行。均相氢化得到的粗酮溶液用10％重量水-湿Pd/C(例如100mg水-湿Pd/C至1g(2-乙酰氨基甲基)苯并吡喃-4-酮)和1ml冰醋酸处理，氢化在7bar氢气压下和50℃进行14小时。
5.后处理和分析方法
过滤除去钯/碳，氢化产物的对映体过量在手性HPLC柱上测定。柱： Daicel Chiralcel OJ(I.D.×长/mm：4.6×250)洗脱剂： 正己烷∶异丙醇＝9∶1流速： 0.8ml/min(18bar，28℃)检测器： UV 250nm保留时间： Rt(R)＝27min；Rt(S)＝27min
Pd/C还原过程中，对映体过量保持不变。
粗氢化溶液的浓缩导致产物的沉淀，对映体过量的增加通过部分结晶测定。
均相氢化的对映选择性：
合成 复合物：金属阴离子 溶剂 压力 ％ee
编号 配体(加合物)1. 18 Rh-OTf(R，R)-EtDuphos CH2Cl2 1 55S2. 13 Rh-OTf-(R，R)-EtDuphos THF 1 44S3. 14 Rh-OTf-(R，R)-EtDuphos MeOH 1 64S4. 15 Rh-OTf-(R，R)-EtDuphos EE 1 33S5. 6 Rh-OTf-(R，R)-EtDuphos iPrOH 1 20S6. 23a Rh-OTf-(R，R)-EtDuphos MeOH 1 34S7. 23b Rh-OTf-(R，R)-EtDuphos MeOH 1 36S8. 23c Rh-OTf-(R，R)-EtDuphos MeOH 5 45S9. 23d Rh-OTf-(R，R)-EtDuphos MeOH 5 31S10. 12 Ru-Cl2-(R)-BINAP iPrOH 5 50S
(AgOOCCF3) -11. 19 Rh-ClO4-(S，S)-Chiraphos iPrOH 1 消旋12. 20 Rh-OTf-(S，S)-DIOP THF 1 消旋13. 20 Rh-OTf-(S，S)-DIOP THF 3 8R14. 21 Rh-OTf-(R，R)-Skewphos THF 1 -15. 22b Rh-OTf-(S，S)-BPPM MeOH 1 7S16. 24a Rh-OTf-(R，S)-BPPFOH MeOH 1 54R17. 24b Rh-OTf-(R，S)-BPPFOH MeOH 1 54R18. 24c Rh-OTf-(R，S)-BPPFOH MeOH 5 63R19. 25a Rh-OTf-(R)-BINAP MeOH 1 1R20. 25b Rh-OTf-(R)-BINAP MeOH 5 消旋21. 26a Rh-OTf-(S，S)-Norphos MeOH 1 42R22. 26b Rh-OTf-(S，S)-Norphos MeOH 5 60R23. 26c Rh-OTf-(S，S)-Norphos iPrOH 5 12R24. 26d Rh-OTf-(S，S)-Norphos THF 5 3R25. 27a Rh-OTf-(S，S)-Norphos MeOH 8 64R26. 27b Rh-Cl-(S，S)-Norphos MeOH 8 40R27. 27c Rh-OTf-(S，S)-Norphos MeOH 30 65R28. 27d Rh-OTf-(S，S)-Norphos MeOH 60 64R29. 28a Rh-OTf-(R，R)-EtDUPhos MeOH 10 16S30. 28b Rh-OTf-(R，R)-EtDUPhos MeOH 30 28S31. 29a Rh-OTf-(R，S)-BPPFOH MeOH 10 55R32. 29b Rh-OTf-(R，S)-BPPFOH MeOH 30 56R33. 37 Rh-ClO4-(S，S)-Chiraphos MeOH 10 30R34. 38 Rh-OTf-(S，S)-DIOP MeOH 10 消旋35. 39 Rh-OTf-(R，R)-Skewphos MeOH 10 46S36. 40 Rh-OTf-(S，S)-BPPM MeOH 10 9S37. 41 Ir-Cl-(S，S)-DIOP MeOH 10 8R38. 42 Ir-Cl-(S，S)-DIOP CH2Cl2 10 7S0. 43 Ir-Cl-(S，S)-DIOP(+I) MeOH 10 -1. 44 Ir-Cl-(S，S)-DIOP(+I) MeOH 30 -2. 45 Ir-Cl-(S，S)-DIOP(+I MeOH 10 -
+CH3COOH)3. 46 Ir-OTf-(S，S)-DIOP MeOH 10 11R4. 47 Ir-OTf-(S，S)-DIOP(+I) MeOH 10 39R5. 49 Rh-OTf-(S，S)-Norphos MeOH 10，RT 57R6. 50 Rh-OTf-(S，S)-Norphos MeOH 10，50℃ 60R7. 52 Rh-BF4-(R，S)-PFctB MeOH 10，50℃ 33S8. 54 Rh-Cl-(R)-BINAP Tol∶MeOH5∶1 80，50℃ 91S9. 59 Rh-Cl-(S，S)-Norpbos Tol∶MeOH5∶1 80，50℃ 19R10. 62 粗 59//Pd/C Tol∶MeOH5∶1 7，50℃ 18R
Claims (5)
1.通式I的苯并二氢吡喃衍生物及其盐
其中
R1是具有1至6个碳原子的酰基，
R2是H，
R3是H，
R4是H，
X是H、H或O，
其中不包括N-(苯并二氢吡喃-2-基甲基)环丙酰胺。
2.根据权利要求1的通式I的化合物的对映体。
3.根据权利要求1的通式I的化合物及其盐，
a)(S)-N-(4-氧代苯并二氢吡喃-2-基甲基)乙酰胺；
b)(R)-N-(4-氧代苯并二氢吡喃-2-基甲基)乙酰胺；
c)(S)-N-(苯并二氢吡喃-2-基甲基)乙酰胺；
d)(R)-N-(苯并二氢吡喃-2-基甲基)乙酰胺。
4.权利要求1的具有通式I的苯并二氢吡喃衍生物以及它们的盐的制备方法，通式I中X是0，其特征为：
通式II化合物
其中R1、R2、R3、R4具有权利要求1中指出的意义，且X是0，
借助金属铑或铱与手性二磷烷配体所形成的复合物进行氢化，氢化是在1-200bar和0-150℃的条件下进行的。
5.权利要求1的具有通式I的苯并二氢吡喃衍生物以及它们的盐的制备方法，通式I中X是H、H，其特征为：
通式II化合物
其中R1、R2、R3、R4具有权利要求1中指出的意义，且X是0，
借助金属铑或铱与手性二磷烷配体所形成的复合物进行氢化，氢化是在1-200bar和0-150℃的条件下进行的，然后以常规方法还原，其中还原是用氢气在过渡金属催化下在惰性溶剂中进行。
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| DE19858341.9 | 1998-12-17 | ||
| DE19858341A DE19858341A1 (de) | 1998-12-17 | 1998-12-17 | Chromanderivate |
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| JP4664597B2 (ja) * | 2002-04-17 | 2011-04-06 | サイトキネティクス・インコーポレーテッド | 化合物、組成物および方法 |
| AU2003252025A1 (en) * | 2002-07-17 | 2004-02-02 | Cytokinetics, Inc. | Compounds, compositions, and methods |
| JP2005539062A (ja) * | 2002-09-13 | 2005-12-22 | サイトキネティクス・インコーポレーテッド | 化合物、組成物および方法 |
| WO2005042697A2 (en) * | 2003-10-06 | 2005-05-12 | Cytokinetics, Inc. | Compounds, compositions and methods |
| CN100424034C (zh) * | 2006-08-25 | 2008-10-08 | 华中科技大学 | 一种磷石膏复合砖及其生产方法 |
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| CN108690017B (zh) * | 2018-05-04 | 2021-06-18 | 新乡学院 | 一种铑催化的莫西沙星侧链中间体的制备方法 |
| CN113979983B (zh) * | 2021-11-03 | 2023-10-03 | 中国人民解放军空军军医大学 | 一种非达司他关键中间体的不对称合成方法 |
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