CN105237464B - 用于制备2-[(2e)-2-氟-2-(3-亚哌啶基)乙基]-1h-异吲哚-1,3(2h)-二酮的改进方法 - Google Patents
用于制备2-[(2e)-2-氟-2-(3-亚哌啶基)乙基]-1h-异吲哚-1,3(2h)-二酮的改进方法 Download PDFInfo
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- CN105237464B CN105237464B CN201510691247.7A CN201510691247A CN105237464B CN 105237464 B CN105237464 B CN 105237464B CN 201510691247 A CN201510691247 A CN 201510691247A CN 105237464 B CN105237464 B CN 105237464B
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- -1 3- piperidylidenes Chemical class 0.000 title abstract description 27
- 238000000034 method Methods 0.000 title abstract description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 179
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000000126 substance Substances 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000005002 aryl methyl group Chemical group 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 abstract description 8
- 239000011737 fluorine Substances 0.000 abstract description 8
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 abstract description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 3
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 abstract 1
- 125000005594 diketone group Chemical group 0.000 abstract 1
- 125000005936 piperidyl group Chemical group 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 113
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 77
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
- 239000007787 solid Substances 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 33
- 150000003840 hydrochlorides Chemical class 0.000 description 33
- 239000000243 solution Substances 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 150000002576 ketones Chemical class 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000004679 31P NMR spectroscopy Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000000921 elemental analysis Methods 0.000 description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 6
- 0 *C(F)=C1CN(*)CCC1 Chemical compound *C(F)=C1CN(*)CCC1 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 125000004432 carbon atom Chemical group C* 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
- 238000002474 experimental method Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical class O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229910000077 silane Inorganic materials 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- RIFXIGDBUBXKEI-UHFFFAOYSA-N tert-butyl 3-oxopiperidine-1-carboxylate Chemical class CC(C)(C)OC(=O)N1CCCC(=O)C1 RIFXIGDBUBXKEI-UHFFFAOYSA-N 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- OIAVZDKLELDXNJ-UHFFFAOYSA-N 3,3-dimethoxypiperidine Chemical class COC1(OC)CCCNC1 OIAVZDKLELDXNJ-UHFFFAOYSA-N 0.000 description 2
- ONHQQEBZVXXMRC-UHFFFAOYSA-N 4,4-dimethoxypiperidine Chemical class COC1(OC)CCNCC1 ONHQQEBZVXXMRC-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-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
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229960003540 oxyquinoline Drugs 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OWXJKYNZGFSVRC-NSCUHMNNSA-N (e)-1-chloroprop-1-ene Chemical compound C\C=C\Cl OWXJKYNZGFSVRC-NSCUHMNNSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical class COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- FVTWJXMFYOXOKK-UHFFFAOYSA-N 2-fluoroacetamide Chemical compound NC(=O)CF FVTWJXMFYOXOKK-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 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
- GKECDORWWXXNRY-UHFFFAOYSA-N 2h-pyridin-3-one Chemical class O=C1CN=CC=C1 GKECDORWWXXNRY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical class COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 1
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- PXRQZUSKMQSYCW-UHFFFAOYSA-N C1(=CC=CC=C1)CC1=CC=CC=C1.[Br] Chemical compound C1(=CC=CC=C1)CC1=CC=CC=C1.[Br] PXRQZUSKMQSYCW-UHFFFAOYSA-N 0.000 description 1
- SPNZYOUVFSZDOK-UHFFFAOYSA-N COC(CF)=O.[Br] Chemical compound COC(CF)=O.[Br] SPNZYOUVFSZDOK-UHFFFAOYSA-N 0.000 description 1
- 241000522254 Cassia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- 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 1
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- 239000002244 precipitate Substances 0.000 description 1
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- 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
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 238000010792 warming Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- C—CHEMISTRY; METALLURGY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- Molecular Biology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及用于制备2‑[(2E)‑2‑氟‑2‑(3‑亚哌啶基)乙基]‑1H-异吲哚‑1,3(2H)‑二酮、或其盐的一种改进方法,所制备的该化合物是抗细菌化合物7‑[(3E)‑3‑(2‑氨基‑1‑氟亚乙基)‑1‑哌啶基]‑1‑环丙基‑6‑氟‑1,4‑二氢‑8‑甲氧基-4‑氧代3‑喹啉羧酸的合成路线中的一种中间体。
Description
________________________________________________________________
本申请为申请日为2012年9月28日、申请号为201280047324.X (PCT/EP2012/069164)、发明名称为“用于制备2-[(2E)-2-氟-2-(3-亚哌啶基)乙基]-1H-异吲哚-1,3(2H)-二酮的改进方法”的申请的分案申请。
发明领域
本发明涉及用于制备2-[(2E)-2-氟-2-(3-亚哌啶基)乙基]-1H-异吲哚- 1,3(2H)-二酮、或其盐的一种改进方法,其是抗细菌化合物7-[(3E)-3-(2-氨基- 1-氟亚乙基)-1-哌啶基]-1-环丙基-6-氟-1,4-二氢-8-甲氧基-4-氧代3-喹啉羧酸的合成路线中的一种中间体。
发明背景
WO-2006/101603描述了作为抗微生物化合物的7-氨基亚烷基-杂环羟基喹啉并且7-[(3E)-3-(2-氨基-1-氟亚乙基)-1-哌啶基]-1-环丙基-6-氟-1,4-二氢-8- 甲氧基-4-氧代3-喹啉-羧酸的合成在第20页的表1中作为化合物(303)被披露。在后文中该化合物被简称为化合物‘A’。
7-[(3E)-3-(2-氨基-1-氟亚乙基)-1-哌啶基]-1-环丙基-6-氟- 1,4-二氢-8-甲氧基-4-氧代3-喹啉羧酸
由Morrow(莫罗)B.J.等人在Antimicrobial Agents and Chemotherapy (抗菌剂和化疗),第54卷,第1995-1964(2010)页中描述了化合物‘A’的体外抗细菌特性。
WO-2008/005670披露了用于生产取代的烯丙基醇的一锅法连同用于分离某些同分异构醇产物的萃取方法,这些醇产物对于制备羟基喹啉如该抗微生物化合物7-[(3E)-3-(2-氨基-1-氟亚乙基)-1-哌啶基]-1-环丙基-6-氟-1,4-二氢-8- 甲氧基-4-氧代3-喹啉羧酸(即化合物‘A’)是有用的。
在所述抗微生物化合物‘A’的整个合成路线中的一种重要的中间体是 2-[(2E)-2-氟-2-(3-亚哌啶基)乙基]-1H-异吲哚-1,3(2H)-二酮及其盐酸盐:
2-[(2E)-2-氟-2-(3-亚哌啶基)乙基]-1H-异吲哚-1,3(2H)-二酮
化合物(1)将所希望的E-立体化学引入了对于抗微生物化合物‘A’的整个合成路线。
WO-2008/005670在第38页披露了对于化合物(1)的合成路线,如以下所述:
对于化合物(1)的详细反应程序披露于WO-2008/005670的第37至44页的实例1中,在方法A中提供了化合物(1),具有97:3的E:Z比值,大概总产率是18%(对于头3个庚烷层步骤1具有34%的产率,E:Z比值为71: 29,步骤2a具有53.4%的产率,E:Z比值为97:3,并且步骤3具有定量的产率),或在方法B中提供了化合物(1),具有94.4:5.6的E:Z比值,大概总产率是15%。
WO-2008/005670在第15页的流程2中披露了对于化合物(1)的盐酸加成盐的合成路线,如以下所述:
制备化合物(1)的HCl盐的详细反应程序披露于WO-2008/005670的第49至52页的实例4中,提供了>95%的所希望的从N-boc-3-哌啶酮起始的具有18%-22%的总产率的E-同分异构体。
WO-2008/005670中所述的对于制备化合物(1)或其HCl盐的反应程序的特征为Wadsworth-Emmons-Horner(沃兹沃思-埃蒙斯-霍纳反应)反应的选择性的缺乏,该反应生产大量不希望的Z-同分异构体。该不希望的Z-同分异构体需要另外的消耗时间的分离步骤。
因此,存在对于制备化合物(1)或其HCl盐的更高效的并且产生更少废料的程序的需要。
WO-2010/056633在第87页披露了制备叔-丁基4-(2-乙氧基-2-氧代亚乙基)哌啶基-1-羧酸酯的合成流程XIV并在第111页披露了制备(1-苄基-哌啶-4- 亚基)溴乙酸乙酯的合成流程XXVI。
在一个第一实施例中,本发明涉及用于制备具有化学式(III)的化合物的一种改进方法,这些化合物具有所希望的(E)-同分异构体对不希望的(Z)-同分异构体的改进的比值。
在一个另外的实施例中,然后该化合物(E)-(III)被转化为化合物(1)或其盐酸加成盐。
发明说明
在一方面,本发明涉及用于制备一种具有化学式(III)的化合物的一种方法,其特征为以下步骤
在一种反应惰性溶剂中,将一种具有化学式(I)的化合物与一种具有化学式(II)的化合物进行反应
其中
R1是氢、C1-4烷基、芳基、芳基甲基、芳基乙基、二苯甲基、烯丙基或 3-苯基烯丙基(肉桂基);
R2是C1-6烷基、苯基或被选自以下的一个取代基取代的苯基:卤素、羟基、C1-4烷基、C1-4烷氧基、三氟甲基、氰基或硝基;
A是C1-4烷氧基羰基、羟羰基、氨羰基、或氰基;并且
X是卤素;
其中芳基是苯基,或被一个或两个C1-4烷氧基、卤素、C1-4烷基、硝基、或二(C1-4烷基)氨基取代的苯基。
该反应惰性溶剂可以是任何溶剂如二氯甲烷、乙腈、乙酸乙酯、庚烷、四氢呋喃(THF)、环戊基甲醚(CPME)、二-n-丁基醚(DBE)、甲基环己烷(MeCy)、氯苯、氟苯、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲苯、或苯甲醚或其任何混合物。在实践中,该反应惰性溶剂通常是甲苯。
在一个第二方面,本发明涉及一种将化合物(III)还原为化合物(IV),随后将化合物(E)-(IV)或其一种盐作为沉淀物进行分离的方法,该化合物(III) 是(E)-(III)和(Z)-(III)的一种混合物,该化合物(IV)是(E)-(IV)和(Z)-(IV)的一种混合物。
在一种催化剂存在下,该还原可用领域内任一已知的还原剂如LiBH4, LiAlH4,双(2-甲氧基乙氧基)氢化铝钠(Red-Al),以及硅烷还原剂如三烷基硅烷(例如三甲基硅烷、三乙基硅烷、三(三甲基甲硅烷基)-硅烷)、三苯基硅烷、三烷氧基硅烷(例如三乙氧基硅烷)以及多聚硅氧烷类如聚(甲基氢化硅氧烷)来实施。
该还原反应可在任一适合的反应惰性溶剂例如甲苯中进行。
化合物(E)-(IV)的沉淀是通过将化合物(IV)与一种适合的溶剂如,例如二异丙醚或二-n-丁基醚(DBE)进行混合,随后进行沉淀的化合物(E)-(IV) 的分离来获得的。任选地,该溶剂是在添加化合物(IV)之后以及冷却该化合物(E)-(IV)沉淀物时升温的。
在一个第三方面,本发明涉及一种用于在三信反应条件下将一种具有化学式(E)-(IV)的化合物与化合物(V)反应,从而获得一种具有化学式(VI)的化合物的方法,通过使用领域内已知的脱保护方法(如,例如氢化作用或用氯甲酸盐处理)去除取代基R1将其转化为任选地以一种酸加成盐的形式的化合物(1)。
在一个第四方面,在进行与化合物(V)或其一种盐(例如钾盐)的反应以及使用如上所述的程序去除取代基R1之前,化合物(E)-(IV)中的伯羟基基团首先被转化为一种离去基团Y如卤素或磺酰基氧基,例如甲磺酰基氧基、苯磺酰基氧基、三氟甲磺酰基氧基、对-甲苯磺酰基氧基。
在一个第五方面,本发明还涉及具有化学式(E)-(III)或(E)-(IV)的新颖的化合物
或其酸加成盐,其中
R1a是C1-4烷基、芳基、芳基甲基、芳基乙基、二苯甲基、烯丙基或3-苯基烯丙基(肉桂基);
A是C1-4烷氧基羰基、羟羰基、氨羰基、或氰基;
其中芳基是苯基,或被一个或两个C1-4烷氧基、卤素、C1-4烷基、硝基、或二(C1-4烷基)氨基取代的苯基。
如在前述的定义中使用的:
-卤素对于氟、氯、溴和碘是通用的;
-C1-4烷基限定了具有从1至4个碳原子的直链和支链饱和烃基如,例如甲基、乙基、丙基、丁基、1-甲基乙基、2-甲基丙基等等;
-C1-6烷基意在包括C1-4烷基以及其具有5或6个碳原子的更高级同系物如,例如2-甲基丁基、戊基、己基等等。
如在上文提及的加成盐意为包括具有化学式(I)的化合物能够形成的酸加成盐形式。可以方便地通过用这种适当的酸来处理碱形式而获得这些酸加成盐。适当的酸包括例如无机酸,例如氢卤酸(例如氢氯酸或氢溴酸)、硫酸、硝酸、磷酸等酸类;或有机酸,例如像乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸(即乙二酸)、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对-甲苯磺酸、环己氨基磺酸、水杨酸、对氨基水杨酸、扑酸等酸类。
相反地,可以通过用适当的碱的处理将所述盐形式转化为游离碱形式。
本发明的感兴趣方法是那些其中以下限制中的一者或多者适用的:
a)R1是C1-4烷基、芳基、芳基甲基、芳基乙基、二苯甲基、烯丙基或 3-苯基烯丙基;或
b)R1是甲基、乙基、烯丙基、苯乙基、二苯甲基、或芳基甲基,其中芳基是苯基或甲氧基取代的苯基;具体地,R1是芳基甲基,其中芳基是苯基;或
c)R2是甲基、乙基、丁基、异丁基或苯基;具体地,R2是甲基;或
d)X是溴;并且
e)A是羟羰基、氨羰基、氰基或C1-4烷氧基羰基,其中C1-4烷基是甲基、乙基、或叔-丁基;具体地,A是C1-4烷氧基羰基,其中C1-4烷基是乙基。
化学定义。
术语“同分异构体”是指具有相同构成和分子量但是在物理和/或化学特性上不同的化合物。此类物质具有相同数量和种类的原子但在结构上不同。该结构的差异可以是在构造(几何异构体)上或可以源自分子中基团的不同空间排布(立体异构体)。
术语“立体异构体”是相同构造的同分异构体,这些同分异构体的原子在空间中的排布不同。对映异构体和非对映异构体是立体异构体,其中不对称地取代的碳原子起着手性中心的作用。术语“手性的”是指一种在其镜像上是不可重叠的分子,暗示着不存在一个轴线和一个平面或对称中心。
如果最高优先级的基团位于一个参考平面(该参考平面穿过双键并且垂直于包含将这些基团连接至这些双键化的原子的双键的平面)的相同侧,则一种同分异构体特指为处于“Z”(zusammen=“共同”)构型;另一种同分异构体特指为处于“E”(entgegen=“相对”)。此处用来确定E和Z同分异构体的术语“优先级”是指为了毫无疑义指定同分异构体的目的而制定的规则,描述于R.S.Cahn(卡恩)、C.K.Ingold(英戈尔德)和V.Prelog(普雷洛格)。
实验部分
以下缩写将被用于以下部分中:
AcOEt | 乙酸乙酯 |
MeTHF | 2-甲基四氢呋喃 |
CPME | 环戊基甲醚 |
DBE | 二-n-丁基醚 |
DBU | 1,8-二氮杂二环[5.4.0]十一-7-烯 |
DCM | 二氯甲烷 |
DIAD | 偶氮二羧酸二异丙酯 |
DIPE | 二异丙醚 |
DMA | N,N-二甲基乙酰胺 |
DMF | N,N-二甲基甲酰胺 |
MeCN | 乙腈 |
MeCy | 甲基环己烷 |
MIBK | 5-甲基-2-戊酮 |
TBAI | 碘化四丁铵 |
THF | 四氢呋喃 |
Red-Al | 双(2-甲氧基-乙氧基)氢化铝钠 |
实例1:具有化学式(I)的化合物的制备
具有化学式(I)的化合物当被分离为一种盐酸加成盐时可以呈现为酮形式(I)或呈现为偕-二醇形式(VII)(“水合物”)或呈现为以可变比值的两者的一种混合物。然而,在中和该盐的过程中(形成自由胺),该偕-二醇自发地松开一个水分子以形成该酮。
在下文中,术语“化合物(I)的HCl盐”将一直指严格地说法“化合物 (I)的HCl盐”至“化合物(VII)的HCl盐”亦或两者的一种混合物。
步骤1:3,3-二甲氧基哌啶的合成
将25g(125.5mmol)的N-boc-3-哌啶酮溶解在125ml的甲醇中。添加 9.1ml(138mmol)的甲磺酸,并将反应混合物在室温下搅拌几小时,然后在 50℃下搅拌直至完成。用15.96g(150.6mmol)的碳酸钠中和该反应混合物,用125ml的甲苯稀释,并在真空下去除甲醇。将所得的悬浮液进一步用 125ml的甲苯稀释。过滤出固体物料并且用63ml的甲苯冲洗,并且将结合的滤液在真空中浓缩。在减压(100℃-105℃,25mbar)下蒸馏残余物以获得7.61g的3,3-二甲氧基哌啶,为一种无色的液体(产率42%)(bp:100℃- 105℃,25mbar)。
1H NMR(360MHz,氯仿-d)δppm 3.12(s,6H),2.71(s,2H),2.58-2.68(m, 2H),1.63-1.70(m,2H),1.57(br.s.,1H),1.43-1.51(m,2H)。
13C NMR(91MHz,氯仿-d)δppm 96.69,51.01,47.31,45.90,31.05,24.27。
GC-MS(EI):145(M+),130(M–Me),114(M–MeO)。
步骤2:化合物(Ia)至(Ij)的合成
Bn:苄基Ph:苯基
Me:甲基烯丙基:H2C=CH-CH2-
Et:乙基
化合物(Ia).HCl盐和(Ic).HCl盐是可商购的。
化合物(Ib).HCl盐是从3-羟基吡啶遵循该文献(Lyle(莱尔),R.E.; Adel(阿德尔),R.E.,Lyle(莱尔),G.G.J.Org.Chem.(有机化学杂志) 1959,24,343)的步骤制备的。
化合物(Id).HCl盐的合成:
将19.8g(136mmol)的3,3-二甲氧基哌啶和19ml(136mmol)的三乙胺溶解在136ml的THF中。添加15.6ml(150mmol)的氯丙烯,并且将反应混合物在室温下搅拌然后在50℃下搅拌直至这些起始物料完全转化(2 天)。冷却至室温后,过滤出不溶解的物料并用几ml的甲苯洗涤。将合并的滤液和洗涤层在真空下浓缩至干燥。将该油状的残余物再溶解于20ml的乙酸乙酯中,并通过硅胶垫过滤。用100ml的乙酸乙酯冲洗该垫并将合并的滤液在真空下浓缩以得到20.5g的N-烯丙基-3,3-二甲氧基哌啶(产率:81%),其结构通过NMR和LC-MS证实。将19g的N-烯丙基-3,3-二甲氧基哌啶溶解于100ml的3M HCl水溶液和30ml THF中并在60℃下搅拌4小时。将甲苯添加到该反应混合物中并将各层进行分离。将水层在真空下浓缩至干燥并用二氯甲烷共蒸发两次。将所得固体在几ml的丙酮中进行搅拌,然后过滤并干燥,产生8.5g的化合物(Id).HCl盐(产率:47%)。
化合物(Id).HCl盐(酮/水合物比值:大约1/1):
形态:白色固体。
1H NMR(360MHz,DMSO-d6,酮和水合物的混合物)δ=12.19(br.s.,0.55 H),9.51(br.s.,0.45H),6.10-5.85(m,1H),5.62-5.42(m,2H),3.92(m,0.55H), 3.82(d,J=7.0Hz,1.1H),3.78-3.43(m,2.3H),3.39-3.04(m,1.4H),2.94- 2.73(m,0.9H),2.67-2.38(m,0.5H),2.26(br.s.,0.55H),2.12(br.s.,0.55H), 1.95-1.67(m,1.5H),1.62-1.44(m,0.55H)。
13C NMR(91MHz,DMSO-d6,酮形式的信号)δppm 200.80,126.93,125.20, 58.49,57.35,48.69,36.89,19.17
13C NMR(91MHz,DMSO-d6,水合物形式的信号)δppm 127.69,124.78, 90.20,58.41,58.02,51.35,34.25,19.72高分辨MS:对于C8H14NO(酮形式,M +H)的计算值:140.1070,发现值:140.1064。对于C8H16NO2(水合物形式,M+H)的计算值:158.1176,发现值:158.1190。
化合物(Ie).HCl盐的合成:
将8.0g(55.1mmol)的3,3-二甲氧基哌啶和7.1ml(60.6mmol)的苯乙醛溶解在83ml的MeTHF中并且该溶液是惰性的。添加2.37g湿的5% Pd/C,并将该反应混合物在室温下在6巴的氢气下搅拌5小时。在完成之后,释放压力,过滤掉催化剂并将该滤液在真空下浓缩至干燥以获得13.7g 粗制的3,3-二甲氧基-N-苯乙基哌啶(定量的粗制产率)。将该粗制的乙缩醛溶解于66ml的水性1M HCl中。将该水溶液用55ml的乙酸异丙酯进行洗涤,然后在真空下缓慢浓缩(温度:60℃)至干燥。添加110ml的MIBK,并将所得混合物在真空下缓慢蒸发。再添加110ml的MIBK,并将该混合物在室温下搅拌过夜之前回流2小时。将该悬浮液浓缩至干燥,并将该残余物从30ml的乙腈再结晶以产生5.51g的化合物(Ie).HCl盐(产率:42%),为一种淡黄色固体。
化合物(Ie):3,3-二甲氧基-N-苯乙基哌啶:
1H NMR(360MHz,氯仿-d)δ=7.30-7.23(m,2H),7.22-7.14(m,3H), 3.22(s,6H),2.88-2.78(m,2H),2.67-2.56(m,2H),2.49(d,J=15.4Hz,4H), 1.67(br.s.,4H)。
13C NMR(91MHz,氯仿-d)δppm 140.2,128.5,128.2,125.8,98.0,60.5, 57.4,53.7,47.6,33.2,31.1,22.2。
LC-MS:21.38(M–OMe),250.34(M+H)。
化合物(Ie).HCl盐(酮和水合物的混合物):
1H NMR(360MHz,DMSO-d6,酮形式的信号)δppm 12.14(br.s.,1H), 7.33-7.39(m,2H),7.24-7.33(m,3H),3.99(dd,J=15.4,8.4Hz,1H),3.87(d, J=15.4Hz,1H),3.73(d,J=12.1Hz,1H),3.27-3.48(m,3H),3.07-3.18(m,2H), 2.44-2.67(m,2H),2.24-2.42(m,1H),2.07-2.20(m,1H)
13C NMR(151MHz,DMSO-d6,酮形式的信号)δppm 200.90,137.10, 128.76,128.67,126.84,58.90,56.66,51.80,34.42,29.43,19.86
13C NMR(151MHz,DMSO-d6,水合物形式的信号)δppm 136.98,128.73, 128.67,126.84,90.21,59.14,56.39,49.50,36.88,29.19,19.27
高分辨MS:对于C13H18NO(酮形式,M+H)的计算值:204.1388,发现值:204.1395。对于C13H20NO2(水合物形式,M+H)的计算值: 222.1489,发现值:222.1551。
化合物(If).HCl盐:
将5.00g(34mmol)的3,3-二甲氧基哌啶溶解在69ml的MeTHF中。添加5.71g(41mmol)的碳酸钾和8.51g(34mmol)的溴二苯基甲烷并将该反应混合物回流过夜。冷却至室温后,用34ml的水洗涤出无机物料。向有机层中添加39ml的1M HCl水溶液,并将所得双相混合物进行回流,然后在真空下浓缩至干燥。将该半-固体残余物在39ml MIBK中进行回流。冷却至室温后,过滤该固体,用一些MIBK洗涤并干燥,产生7.48g的化合物(If).HCl 盐(产率:72%),为一种深褐色固体。
1HNMR(360MHz,DMSO-d6)δppm 13.12(br.s.,1H),7.78-8.16(m,4H), 7.20-7.56(m,6H),5.81(d,J=7.7Hz,1H),3.85(dd,J=13.2,7.0Hz,1H),3.22- 3.54(m,3H),2.55(br.s.,2H),2.50-2.53(m,1H),2.12(br.s.,1H)
13C NMR(101MHz,DMSO-d6)δppm 199.93,135.81,134.96,129.35, 129.22,128.86,128.56,127.94,73.96,58.62,49.56,36.86,18.54
高分辨MS:对于C18H20NO(酮形式,M+H)的计算值:266.1545,发现值:266.1549。对于C18H22NO2(水合物形式,M+H)的计算值: 284.1651,发现值:284.1654。
化合物(Ig).HCl盐:
向5g(25.1mmol)的N-boc-3-哌啶酮中添加37.6ml(37.6mmol)的 1M HCl水溶液,并且将该反应混合物在真空下进行浓缩之前在室温下搅拌几小时。从异丙醇再结晶该残余物以获得3.40g的化合物(Ig).HCl盐(产率: 63%),为一种固体。
1H NMR(360MHz,DMSO-d6)δppm 9.74(br.s.,2H),3.66(br.s.,2H), 3.15-3.36(m,2H),2.50(m,2H),1.95-2.22(m,2H)
化合物(Ih).HCl盐:
在59mg(0.055mmol)10w/w%Pd/C的存在下在1巴氢气下将800mg (5.51mmol)3,3-二甲氧基哌啶和750mg(5.51mmol)2-甲氧苯甲醛在8.3 ml的甲醇中的一种混合物进行搅拌。在该反应完成之后(几小时),将该反应混合物用氮气吹扫,过滤并向该滤液中添加6.6ml水性1M HCl。将该混合物在真空下浓缩至干燥。将该残余物再溶解在4.4ml的热丙酮中。向该热溶液中添加4.4ml的MIBK,将该混合物回流几小时,然后冷却至室温。过滤该悬浮液,并用几ml MIBK洗涤所收集的固体,然后在真空下干燥以得到 950mg的化合物(Ih).HCl盐(产率:68%),为一种灰白色固体。
酮/水合物比值大约95/5。
1H NMR(360MHz,DMSO-d6,酮的信号)δppm 11.88(br.s.,1H),7.63(dd, J=7.5,1.6Hz,1H),7.35-7.55(m,1H),7.14(d,J=7.7Hz,1H),7.03(td,J=7.3, 0.7Hz,1H),4.35(br.s.,2H),3.90(dd,J=15.5,9.5Hz,1H),3.86(s,3H),3.59(d, J=15.0Hz,1H),3.50(d,J=11.7Hz,1H),3.26(q,J=9.9Hz,1H),2.25-2.62(m, 3H),2.00-2.16(m,1H。
13C NMR(91MHz,DMSO-d6,酮形式的信号)δppm 200.64,148.10,133.37, 131.56,120.47,116.91,111.47,58.91,55.69,53.05,48.90,36.71,19.25。
13C NMR(91MHz,DMSO-d6,水合物形式的信号)δppm 148.10,133.37, 131.56,120.47,116.91,111.47,90.18,58.91,55.69,51.28,41.06,37.48,19.93。
高分辨MS:对于C13H18NO2(酮形式,M+H)的计算值:220.1332,发现值:220.1326。对于C13H20NO3(水合物形式,M+H)的计算值: 238.1438,发现值:238.1463。
化合物(Ii).HCl盐:
在59mg(0.055mmol)10w/w%Pd/C的存在下在1巴氢气下将800mg (5.51mmol)3,3-二甲氧基哌啶和750mg(5.51mmol)3-甲氧苯甲醛在8.3 ml的甲醇中的一种混合物进行搅拌。在该反应完成之后(几小时),将该反应混合物用氮气吹扫,过滤并向该滤液中添加6.6ml水性1M HCl。将该混合物在真空下浓缩至干燥。将该残余物悬浮在4.4ml的热丙酮中。添加4.4ml MIBK并且蒸馏掉丙酮。然后将该悬浮液冷却至室温并且进行过滤。用几ml MIBK洗涤所收集的固体,然后在真空下干燥以得到1.09g的化合物(Ii).HCl 盐(产率:77%),为一种灰白色固体。
高分辨MS:对于C13H18NO2(酮形式,M+H)的计算值:220.1332,发现值:220.1312。对于C13H20NO3(水合物形式,M+H)的计算值: 238.1438,发现值:238.1444。
酮/水合物比值:大约95/5。
1H NMR(360MHz,DMSO-d6,酮的信号)δppm 12.20(br.s.,1H),7.30- 7.42(m,2H),7.17(d,J=7.7Hz,1H),7.02(dd,J=8.2,2.4Hz,1H),4.38(br.s.,2 H),3.86(dd,J=15.0,8.8Hz,1H),3.79(s,3H),3.57(d,J=15.0Hz,1H),3.50(d, J=12.1Hz,1H),3.11-3.33(m,1H),2.41-2.63(m,2H),2.21-2.41(m,1H), 2.10(br.s.,1H)
13C NMR(91MHz,DMSO-d6)δppm 200.55,159.32,130.70,129.83,123.30, 116.63,115.26,58.70,58.39,55.20,48.88,36.88,19.09
实例2
化合物(IIa):
将74g(400mmol)溴氟乙酸乙酯缓慢添加到在甲苯中的400ml(400 mmol)的1M三甲基膦溶液,并将该反应混合物在室温下搅拌过夜。过滤化合物(IIa),用80ml甲苯洗涤,并在40℃下在真空下进行干燥。产量:90.97 g(87%产率)。
形态:白色固体。
1H-NMR(360MHz,CDCl3)δ=7.34(dd,J=7.0,43.5Hz,1H),4.52–4.33 (m,2H),2.49(d,J=15.0Hz,6H),1.39(t,J=7.1Hz,3H)。
13C-NMR(90.6MHz,CDCl3)δ=163.51(dd,J=1.8,20.7Hz),83.80(dd,J=63.0,206.3Hz),64.05,14.11,6.81(d,J=52.6Hz)。
31P-NMR(162MHz,CDCl3)δ=35.05(d,2JP-F=64.6Hz)。
19FNMR(376MHz,氯仿-d)δppm-212.30(dd,J=65.2,43.9Hz,1F)。
化合物(IIb):
将74g(400mmol)溴氟乙酸乙酯缓慢添加到溶解于400ml甲苯中的 58.8ml(400mmol)的三乙基膦中。将该反应混合物在室温下搅拌过夜,然后在过滤化合物(IIb)之前在0℃下搅拌几小时,用80ml甲苯洗涤并干燥。产量:102g(84%)。
形态:白色固体(mp:135℃-210℃)。
1H NMR(400MHz,CDCl3)δ=7.47(dd,J=6.8,43.3Hz,1H),4.25(q,J= 7.1Hz,2H),2.65(qddd,J=7.7,13.6,15.6,51.8Hz,6H),1.21(t,J=7.0Hz,3H), 1.22(td,J=7.8,19.1Hz,9H)。
13C-NMR(101MHz,CDCl3)δ=163.3(dd,J=1.5,20.5Hz),83.60(dd,J= 52.8,206.9Hz),63.53,13.55,11.3(d,J=44.8Hz),5.6(d,J=5.9Hz)。
19F-NMR(377MHz,CDCl3)δ=-209.53(d,2JP-F=55.6Hz)。
31P-NMR(162MHz,CDCl3)δ=44.07(d,2JP-F=56.7Hz)。
化合物(IIc)(以下文献中所述的化合物:Thenappan(冉那潘),A.; Burton(伯顿),D.J.J.Org.Chem.(有机化学杂志)1990,55,2311-2317):
将3.71g(20mmol)溴氟乙酸乙酯添加到5ml(20mmol)的三丁基膦在50ml乙酸乙酯中的一种溶液中。在真空下浓缩之前将该溶液在室温下搅拌过夜以获得粗化合物(IIc)(粗制产率:定量),为一种半-固体化合物。
1H NMR(400MHz,氯仿-d)δppm 7.55(dd,J=43.3,6.5Hz,1H),4.42(q, J=7.1Hz,2H),2.53-2.89(m,6H),1.62-1.74(m,6H),1.49-1.59(m,6H),1.39 (t,J=7.2Hz,3H),0.98(t,J=7.3Hz,9H)
13C NMR(101MHz,氯仿-d)δppm 163.77(dd,J=20.9,1.8Hz),83.17(dd, J=208.3,53.5Hz),63.74,23.74(d,J=16.1Hz),23.43(d,J=5.1Hz),17.94(d, J=43.3Hz),13.85,13.11
31PNMR(162MHz,氯仿-d)δppm 38.94(d,2JP-F=55.3Hz)。
19FNMR(376MHz,氯仿-d)δppm-208.67(dd,J=56.1,43.4Hz,1F)。
化合物(IId):
将4.57g(24.7mmol)溴氟乙酸乙酯添加到5g(24.7mmol)的三异丁基膦在25ml THF中的一种溶液中。在真空下浓缩之前将该溶液在室温下搅拌4天。将该残余物在高真空下干燥以形成一种固体。将该固体重悬于几ml 甲苯中,过滤,洗涤并在真空下干燥以得到1.07g的化合物(IId)(产率: 11%)。
形态:白色固体(mp:101℃)。
1H NMR(400MHz,氯仿-d)δ=7.64(dd,J=6.5,42.6Hz,1H),4.39-4.07 (m,2H),2.71(ddd,J=6.0,13.4,15.5Hz,3H),2.50(ddd,J=6.5,14.2,15.5Hz,3 H),2.24-2.04(m,3H),1.24(t,J=7.2Hz,3H),1.03(d,J=6.8Hz,9H),1.00(d, J=6.5Hz,9H)
13C NMR(101MHz,氯仿-d)δ=163.8(dd,J=2.5,20.5Hz),83.2(dd,J= 53.6,210.5Hz),63.4,27.8(d,J=38.9Hz),24.5,24.4,24.3,24.2,23.2(d,J=4.4 Hz),13.6
19F-NMR(377MHz,CDCl3)δ=-123.75(d,2JP-F=56.4Hz)。
31P-NMR(162MHz,CDCl3)δ=37.82(d,2JP-F=56.7Hz)。
高分辨MS(磷阳离子):对于C16H33FO2P(磷阳离子)的计算值: 307.2202;发现值:307.2225。
化合物(IIe)(以下文献中所述的化合物:Thenappan(冉那潘),A.; Burton(伯顿),D.J.J.Org.Chem.(有机化学杂志)1990,55,2311-2317)
将3.52g(19mmol)溴氟乙酸乙酯添加到5g(19mmol)的三苯基膦在 15ml二氯甲烷中的一种溶液中。在真空下浓缩之前将该反应混合物在室温下进行搅拌。将该残余物重悬于热乙酸乙酯-异丙醇(80/20)中,然后在冷却至室温之后进行过滤,并在真空下干燥以得到4.54g的化合物(IIe)(产率: 54%)。
形态:白色固体。
1H NMR(360MHz,氯仿-d)δppm 9.71(dd,J=41.7,5.9Hz,1H),8.01(dd, J=13.2,8.1Hz,6H),7.79-7.89(m,3H),7.71(td,J=7.9,3.7Hz,6H),4.11(q, J=7.2Hz,2H),1.00(t,J=7.1Hz,3H)
13C NMR(91MHz,氯仿-d)δppm 163.34(dd,J=21.5,2.8Hz,1C),135.70 (d,J=3.5Hz,3C),134.75(d,J=10.4Hz,6C),130.34(d,J=13.1Hz,6C),114.53- 115.85(m,3C),83.61-86.96(m,1C),63.60(s,1C),13.56(s,1C)
化合物(IIf):
将4.27g(25mmol)溴氟乙酸甲酯添加到三甲基膦在甲苯中的一种25 ml(25mmol)的1M溶液中。将该反应混合物在室温下搅拌过夜,过滤并用几ml甲苯洗涤所收集的固体,然后在真空下干燥以得到5.88g的化合物(IIf) (产率:95%),为一种白色固体。
形态:白色固体(mp:110℃)。
1HNMR(400MHz,DMSO-d6)δ=6.88(dd,J=7.4,43.4Hz,1H),3.87(s,3 H),2.18(d,J=15.6Hz,9H)
13C NMR(101MHz,DMSO-d6)δppm 163.51(d,J=22.7Hz),83.82(dd, J=199.5,58.7Hz),54.01,5.47(d,J=51.4Hz)
19FNMR(376MHz,DMSO-d6)δ=-212.44(dd,J=64.9,43.6Hz,1F)
31PNMR(162MHz,DMSO-d6)δ=35.75(d,J=65.2Hz,1P)
高分辨MS(磷阳离子):对于C6H13FO2P(磷阳离子)的计算值: 167.0637;发现值:167.0645。
化合物(IIg):
将10.65g t-溴氟乙酸丁酯添加到三甲基膦在甲苯中的一种50ml(50 mmol)的1M溶液中,并将该反应混合物在室温下搅拌过夜,然后在0℃搅拌几小时。将产生的固体进行过滤,用几ml甲苯进行洗涤并在真空下干燥。获得10.55g的化合物(IIg)(产率:73%)。
形态:白色固体(mp:97.8℃)。
1HNMR(400MHz,DMSO-d6)δ=6.69(dd,J=7.3,43.6Hz,1H),2.14(d,J =15.4Hz,9H),1.51(s,9H)
13C NMR(101MHz,DMSO-d6)δ=161.9(d,J=21.3Hz),86.4,83.4(dd,J= 200.3,58.7Hz),27.5,5.7(d,J=51.4Hz)
19FNMR(376MHz,DMSO-d6)δ=-209.98(dd,J=65.6,43.7Hz,1F)
31PNMR(162MHz,DMSO-d6)δ=35.17(d,J=65.2Hz,1P)
高分辨MS(磷阳离子):对于C9H19FO2P(磷阳离子)的计算值: 209.1107;发现值:209.1111。
化合物(IIh):
将三甲基膦在甲苯中的一种100ml(100mmol)的1M溶液添加到15.60 g(100mmol)溴氟乙酰胺在150ml MeTHF中的一种溶液中。将该反应混合物在室温下搅拌过夜,然后过滤化合物(IIh),用几ml甲苯洗涤并在真空下干燥。产量:7.60g(33%)。
形态:白色固体(mp:166.5℃)。
1H NMR(400MHz,DMSO-d6)δ=8.33(br.s.,1H),8.28(br.s.,1H),6.49 (dd,J=6.0,44.8Hz,1H),2.08(dd,J=0.5,15.4Hz,9H)
13C NMR(101MHz,DMSO-d6)δ=165.1(d,J=52.1Hz),84.9(dd,J=63.8,209.1Hz),5.7(d,J=18.3Hz)
19FNMR(376MHz,DMSO-d6)δ=-205.4(dd,J=44.9,64.8Hz,1F)
31PNMR(162MHz,DMSO-d6)δ=65.2(d,J=65.2Hz,1P)
高分辨MS(磷阳离子):测量值:152.069,理论值:152.0641
元素分析:计算值:C(25.88%),H(5.21%),N(6.04%),发现值:C (25.78%),H(5.24%),N(5.90%)。
实例3
化合物(III)形成的结果报道于下表中。
化合物(IIIa):
30g(124mmol)的94w/w%化合物(Ia)。将HCl盐悬浮在124ml的甲苯中。添加124ml水和13.14g碳酸钠,并且在倾析之前将所得混合物在室温下搅拌几分钟。分离这两层并将该有机层经硫酸钠干燥,然后过滤以给出142 g的16.6w/w%的化合物(Ia)在甲苯中的溶液。在0℃下,将这样获得的化合物(Ia)的溶液添加至38.8g(148mmol)化合物(IIa)的一种悬浮液中。添加 22.5g(148mmol)DBU,并在用62ml水淬灭之前将该反应混合物在0℃下搅拌过夜。分离这两层并将该有机层用62ml水洗涤,经硫酸钠干燥,并过滤以给出在甲苯中的251.7g的12.9w/w%的化合物(IIIa)溶液,将其就这样用于下一步骤中。(产率:96%,E/Z比值:80/20)。
在不同溶剂中并在不同温度下使用相同步骤。
在真空下将50.5mmol化合物(IIIa)在甲苯中的一种溶液进行浓缩,并将该残余物通过色谱法进行纯化以给出11.36g的化合物(IIIa)((E)-和(Z)-同分异构体的混合物),为一种具有有限的稳定性的油。产率:81%。
向8.12g化合物(IIIa)在MIBK中的一种溶液中添加5.56g p-甲苯磺酸一水合物,并将该反应混合物升温至完全溶解,然后冷却至室温。在过滤、洗涤并在真空下干燥之后,获得化合物(IIIa)的12g的甲苯磺酸酸盐,为一种稳定的固体(E/Z比值:85/15)。
通过制备型HPLC在ChiralPak AD柱上将12g的化合物(IIIa)进行纯化以得到4.16g的化合物(E)-(IIIa)和820mg的化合物(Z)-(IIIa)。
向溶解于34ml MIBK中的4.16g(15mmol)的化合物(E)-(IIIa)中添加 2.85g(15.0mmol)的p-甲苯磺酸一水合物。将该混合物加温直至该盐溶解,热过滤,然后让其冷却至室温。将这样获得的固体进行过滤,用几ml MIBK进行洗涤并干燥。获得5.23g的化合物(E)-(IIIa).TsOH盐(产率: 78%),为一种白色固体。
向溶解于10ml MIBK和3ml乙醇中的820mg(2.96mmol)的化合物 (Z)-(IIIa)中添加0.57g(3mmol)的p-甲苯磺酸一水合物。将该混合物加温直至该盐溶解,热过滤,然后让其冷却至室温。将这样获得的固体进行过滤,用几ml MIBK进行洗涤并干燥。获得790mg的化合物(Z)-(IIIa).TsOH 盐(产率:59%),为一种白色固体。
化合物(E)-(IIIa):
形态:淡黄色液体,迅速变黑。
1H NMR(361MHz,氯仿-d)δppm 7.17–7.46(m,5H),4.19(q,J=7.0Hz, 2H),3.56–3.66(m,4H),2.52–2.55(m,2H),2.37–2.40(m,2H),1.69–1.75 (m,2H),1.22(t,J=7.1Hz,3H)
19FNMR(377MHz,氯仿-d)δ=-128.28(s,1F)。
化合物(E)-(IIIa).TsOH盐:
形态:白色固体(mp:103.5℃)。
1HNMR(400MHz,氯仿-d)δ=10.66(br.s.,1H),7.74(d,J=8.1Hz,2H), 7.52(d,J=7.1Hz,2H),7.44-7.36(m,1H),7.36-7.30(m,2H),7.16(d,J=8.1 Hz,2H),4.85(d,J=13.6Hz,1H),4.31(d,J=5.3Hz,2H),4.20-4.04(m,2H), 3.89(ddd,J=4.2,8.1,13.7Hz,1H),3.58-3.44(m,1H),3.22-3.04(m,1H), 2.72(td,J=4.2,14.5Hz,1H),2.35(s,3H),2.25(tdd,J=4.3,10.3,14.5Hz,1H), 2.14-1.98(m,1H),1.95-1.82(m,1H),1.18(t,J=7.2Hz,3H)
13C NMR(101MHz,氯仿-d)δppm 159.68(d,J=35.2Hz),145.06(d, J=259.7Hz),142.57,139.91,131.17,129.90,129.15,128.72,128.41,125.79, 121.84(d,J=19.8Hz),61.96,59.27,50.85,49.40(d,J=5.1Hz),22.74(d,J=8.1Hz), 21.21,20.85,13.79。
19FNMR(376MHz,氯仿-d)δppm-118.96(br.s.,1F)
LC-高分辨MS:对于C16H21FNO2(化合物E-(IIIa)+H)的计算值: 287.1551;发现值:278.1563
元素分析:对于C23H28FNO5S的计算值:C(61.45%),H(6.28%),N (3.12%);发现值:C(60.67%),H(6.24%),N(3.14%)
化合物(Z)-(IIIa):
形态:淡黄色液体,迅速变黑。
1H NMR(400MHz,氯仿-d)δppm 7.22–7.34(m,5H),4.28(q,J=7.2Hz, 2H),3.62(s,2H),3.25(d,J=3.0Hz,2H),2.73–2.80(m,2H),2.51–2.58(m,2 H),1.72(dt,J=11.5,5.5Hz,2H),1.33(t,J=7.0Hz,3H)
13C NMR(101MHz,氯仿-d)δppm 161.40(d,J=35.2Hz,),141.78(d, J=250.9Hz),137.38(d,J=2.9Hz),129.14,128.30,127.26,62.45,61.18,52.84, 51.88(d,J=11.7Hz),25.46(d,J=1.5Hz),24.95,14.14
19FNMR(377MHz,氯仿-d,)δ=-128.47(s,1F)
化合物(Z)-(IIIa).TsOH:
形态:白色固体(mp:167.1℃)
1H NMR(400MHz,氯仿-d)δppm 10.63(br.s.,1H),7.74(d,J=8.3Hz,2 H),7.52(d,J=6.8Hz,2H),7.34-7.42(m,1H),7.26-7.34(m,2H),7.15(d, J=7.8Hz,2H),4.33(d,J=5.3Hz,2H),4.20-4.28(m,3H),4.17(d,J=13.6Hz,1 H),3.70(ddd,J=13.6,7.7,2.6Hz,1H),3.39-3.53(m,1H),3.08-3.30(m,2H), 2.43-2.59(m,1H),2.35(s,3H),1.94-2.09(m,1H),1.87(s,1H),1.30(t,J=7.2 Hz,3H)。
13C NMR(101MHz,氯仿-d)δppm 159.83(d,J=35.2Hz),144.46(d, J=263.4Hz),142.50,139.92,131.16,129.91,129.15,128.72,128.32,125.79, 121.54(d,J=10.3Hz),61.80,59.19,50.84,48.35(d,J=11.7Hz),23.07,21.20, 21.16,13.89。
19FNMR(376MHz,氯仿-d)δppm-120.65(br.s.,1F)
LC-高分辨MS:对于C16H21FNO2(化合物(Z)-(IIIa)+H)的计算值: 287.1551;发现值:278.1559
元素分析:对于C23H28FNO5S的计算值:C(61.45%),H(6.28%),N (3.12%);发现值:C(60.91%),H(6.34%),N(3.15%)
化合物(IIIb):
将1.0g(6.68mmol)化合物(Ib).HCl盐、2.09g(8.02mmol)化合物 (IIa)和924mg(6.68mmol)碳酸钾悬浮于13ml甲苯中。冷却至0℃之后,添加1.21ml(8.02mmol)DBU并且将该反应混合物在0℃下搅拌过夜。向该反应混合物中添加13ml水,并在搅拌几分钟后分离这两层。用13ml甲苯萃取水层,并将合并的有机层经硫酸钠干燥,并过滤以给出化合物(IIIb)在甲苯中的50.6g的0.94w/w%的溶液(原位产率:35%)。将该溶液在真空下进行浓缩,并将该残余物通过硅胶垫(洗脱液:丙酮)过滤进行纯化以获得404 mg的纯化的产物(产率:30%)。E/Z比值:96/4。
形态:淡橘色油。
化合物(E)-(IIIb):
1HNMR(400MHz,氯仿-d)δppm 4.27(q,J=7.2Hz,2H),3.52(d,J=2.0Hz, 2H),2.47-2.51(m,2H),2.34-2.39(m,1H),2.34(s,3H),1.71-1.79(m,2H), 1.34(t,J=7.1Hz,3H)
13C NMR(101MHz,氯仿-d)δppm 161.04(d,J=35.9Hz,1C),142.15(d, J=250.9Hz,1C),130.39(d,J=13.9Hz,1C),61.21,55.40,54.36(d,J=5.1Hz,1 C),46.13(s,1C),24.90(d,J=2.2Hz,1C),24.53(d,J=8.8Hz,1C),14.08
19FNMR(376MHz,氯仿-d)δppm-129.72(br.s.,1F)
高分辨MS:对于C10H17FNO2(化合物(IIIb)+H)的计算值: 202.1238;发现值:202.1225
化合物(Z)-(IIIb):
1HNMR(400MHz,氯仿-d)δppm 3.12(d,J=3.0Hz,2H)
13C NMR(101MHz,氯仿-d)δppm 61.13,55.49,53.78(d,J=11.7Hz,1C), 25.29(d,J=2.2Hz,1C)
19FNMR(376MHz,氯仿-d)δppm-129.12(br.s.,1F)
化合物(IIIc):
从化合物(Ic).HCl盐和(IIa)使用如对于化合物(IIIa)的相同程序获得化合物(IIIc)。产率:65%。E/Z比值:85/15。
形态:淡黄色液体,迅速变黑。
化合物(E)-(IIIc):
1H NMR(360MHz,氯仿-d)δppm 1.13(t,J=7.32Hz,3H)1.34(t,J=7.14 Hz,3H)1.77(dd,J=6.59,5.12Hz,2H)2.40(td,J=6.40,2.56Hz,2H)2.48-2.56 (m,2H)2.60(d,J=5.49Hz,2H)3.62(d,J=1.46Hz,2H)4.28(q,J=7.32Hz,3H)
化合物(Z)-(IIIc):
1H NMR(360MHz,氯仿-d)δppm 1.13(t,J=7.32Hz,3H)1.34(t,J=7.14 Hz,3H)1.77(dd,J=6.59,5.12Hz,2H)2.52(q,J=7.32Hz,2H)2.56-2.62(m,2 H)2.73-2.81(m,2H)3.21(d,J=2.93Hz,2H)4.28(q,J=7.32Hz,2H)
化合物(IIId):
从化合物(Id).HCl盐和(IIa)使用与对于化合物(IIIa)的相同程序获得化合物(IIId)。产率:40%,E/Z比值:90/10
形态:淡黄色液体,迅速变黑。
化合物(E)-(IIId):
1HNMR(400MHz,氯仿-d)δppm 1.33(t,J=7.05Hz,3H)1.68-1.81(m,2 H)2.33-2.46(m,2H)2.50-2.61(m,2H)3.02-3.14(m,2H)3.57(d,J=2.01Hz, 2H)4.27(d,J=7.05Hz,2H)5.12-5.29(m,2H)5.77-5.99(m,1H)
13C NMR(91MHz,氯仿-d)δppm 14.42(s,1C)20.91(s,1C)23.50(d, J=7.61Hz,1C)49.69(d,J=4.84Hz,1C)50.99(s,1C)58.28(s,1C)62.67(s,1C) 125.91(s,1C)127.17(s,1C)145.65(d,J=260.90Hz,1C)160.47(d,J=31.80Hz, 1C)
19FNMR(377MHz,氯仿-d,)δ=-128.85(s,1F)
化合物(IIIe):
从化合物(Ie).HCl盐和(IIa)使用与对于化合物(IIIa)的相同程序获得化合物(IIIe)。产率:86%。E/Z比值:93/7。
形态:淡黄色液体,迅速变黑。
化合物(E)-(IIIe):
1H NMR(400MHz,氯仿-d)δ=7.28-7.24(m,2H),7.19-7.15(m,3H), 4.26(q,J=7.2Hz,2H),3.69(d,J=2.0Hz,2H),2.85-2.81(m,2H),2.68-2.63 (m,2H),2.63-2.60(m,2H),2.38(dt,J=2.6,6.5Hz,2H),1.77-1.73(m,2H), 1.31(t,J=7.1Hz,3H)。
13C NMR(101MHz,氯仿-d)δ=160.9(d,J=35.4Hz),142.0(d,J=251.3 Hz),139.9,130.3(d,J=13.4Hz),128.5,128.1,125.8,61.0,59.8,53.3,52.1(d,J= 4.6Hz),33.6,25.0(d,J=8.1Hz),24.6(d,J=1.7Hz),13.9。
19FNMR(377MHz,氯仿-d,)δ=-128.85(s,1F)。
化合物(Z)-(IIIe):
1H NMR(400MHz,氯仿-d,Z-同分异构体的信号)δ=7.28-7.24(m,2H), 7.19-7.15(m,3H),4.25(q,J=7.1Hz,2H),3.26(d,J=3.0Hz,2H),2.85–2.81 (m,2H),2.80-2.73(m,4H),2.68-2.63(m,2H),1.77-1.71(m,2H),1.31(t,J= 7.1Hz,3H)。
13C NMR(101MHz,氯仿-d,Z-同分异构体的信号)δ=161.1(d,J=35.8 Hz),141.5(d,J=250.9Hz),139.9,130.1(d,J=11.7Hz),128.5,128.1,125.8, 60.9,59.8,53.2,51.7(d,J=11.6Hz),33.5,25.4(d,J=1.5Hz),24.6(d,J=1.7 Hz),13.9。
19FNMR(377MHz,氯仿-d,Z-同分异构体的信号)δ=-128.48(s,1F)。
化合物(IIIf):
从化合物(If).HCl盐和(IIa)使用与用于化合物(IIIa)的那种相同的程序获得化合物(IIIf)。
形态:淡黄色液体,迅速变黑。
化合物(IIIg):
从化合物(Ig).HCl盐和(IIa)使用与用于化合物(IIIa)的那种相同的程序获得化合物(IIIg)。
形态:淡黄色液体,迅速变黑。
化合物(IIIh):
从化合物(Ih).HCl盐和(IIa)使用与用于化合物(IIIa)的那种相同的程序获得化合物(IIIh)。
形态:淡黄色液体,迅速变黑。
化合物(E)-(IIIh):
1H NMR(360MHz,氯仿-d)δppm 7.32(dd,J=7.5,1.6Hz,2H),7.23(td, J=7.9,1.8Hz,2H),6.92(td,J=7.5,1.1Hz,2H),6.86(d,J=8.4Hz,2H),4.20(q, J=7.3Hz,2H),3.81(s,3H),3.62-3.68(m,4H),2.54-2.63(m,2H),2.37(td, J=6.5,2.7Hz,2H),1.68-1.79(m,2H),1.24(t,J=7.1Hz,3H)
13C NMR(91MHz,氯仿-d)δppm 160.97(d,J=36.7Hz,1C),157.73(s,1 C),142.06(d,J=247.7Hz,1C),130.62(s,1C),128.07(s,1C),125.67(s,1C), 120.16(s,1C),110.29(s,1C),61.04(s,1C),55.51(s,1C),55.28(s,1C),52.76 (s,1C),52.47(d,J=4.8Hz,1C),25.00(d,J=8.3Hz,1C),24.59(d,J=2.1Hz,1C), 13.95(s,1C)
化合物(IIIk):
从化合物(Ia).HCl盐和(IIf)使用与对于化合物(IIIa)的相同程序获得化合物(IIIk)。
形态:淡黄色液体,迅速变黑。
化合物(E)-(IIIk):
1HNMR(600MHz,氯仿-d)δppm 7.28-7.34(m,4H),7.23-7.28(m,1H), 3.70(s,3H),3.59(br.s,4H),2.48-2.56(m,2H),2.39(td,J=6.4,2.6Hz,2H), 1.67-1.76(m,2H)
13C NMR(151MHz,氯仿-d)δppm 161.50(d,J=36.2Hz),142.05(d, J=248.1Hz),137.69,130.82(d,J=13.2Hz),129.25,128.21,127.16,62.61,52.78, 52.63(d,J=5.5Hz),51.93,25.14(d,J=8.8Hz),24.65.
高分辨MS:对于C15H18FNO2(M+°)的计算值:263.1322,发现值: 263.1325。
化合物(Z)-(IIIk):
1HNMR(600MHz,氯仿-d)δppm 7.28-7.34(m,5H),3.81(s,3H),3.59(s, 2H),3.22(d,J=3.0Hz,2H),2.76(td,J=6.4,1.9Hz,2H),2.48-2.56(m,2H), 1.67-1.76(m,2H)。
13C NMR(151MHz,氯仿-d)δppm 161.85(d,J=35.1Hz),141.50(d, J=250.3Hz),137.64,130.97(d,J=12.1Hz),129.06,128.27,127.18,62.58,52.89, 52.63(d,J=5.5Hz),52.00,25.52(d,J=2.2Hz),25.09。
高分辨MS:对于C15H18FNO2(M+°)的计算值:263.1322,发现值: 263.1328。
实验4
化合物(E)-(IVa):
将437mmol化合物(IIIa)在甲苯中的溶液冷却至0℃。添加在甲苯中的 212g(682mmol)的65w/w%双(2-甲氧基乙氧基)氢化铝钠(Red-Al)溶液,并将该反应混合物在0℃下搅拌1小时,过量的Red-Al用77ml的丙酮淬灭,并允许该反应混合物加温至室温。添加568ml水和235ml的50w/w%的氢氧化钠水溶液,并且在倾析之前将所得混合物加温至50℃。分离这两层,并将该有机层用437ml水洗涤,经硫酸钠干燥,过滤并在真空下进行浓缩。向油状残余物中添加1170ml庚烷,并将所得固体过滤,并从188ml二异丙醚中再结晶以给出53.5g化合物(E)-(IVa)。产率:52%,E/Z比值>99/1 。
形态:固体(mp:92.0℃)。
1H NMR(360MHz,氯仿-d)δppm 1.51-1.71(m,2H)2.20-2.30(m,2H) 2.51(t,J=5.90Hz,2H)2.96(d,J=1.46Hz,2H)3.54(s,2H)4.15(d,J=23.05Hz, 2H)7.13-7.36(m,5H)
13C NMR(91MHz,氯仿-d)δppm 24.18(d,J=7.61Hz,1C)25.39(s,1C) 53.97(d,J=7.61Hz,1C)54.15(s,1C)57.87(d,J=31.83Hz,1C)63.21(s,1C) 116.05(d,J=16.61Hz,1C)127.73(s,1C)128.75(s,2C)129.69(s,2C)137.85 (s,1C)152.75(dd,J=248.43,1.00Hz,1C)
19FNMR(377MHz,氯仿-d)δppm-120.14(s,1F)
元素分析:计算值:C(71.46%),H(7.71%),F(8.07%),N(5.95%),O (%);发现值:C(71.38%),H(7.91%),N(5.99%)
化合物(E)-(IVe):
将双(2-甲氧基乙氧基)氢化铝钠(Red-Al)在甲苯中的5.6ml(19.5 mmol)的70w/w%溶液添加至化合物(IIIe)在甲苯中的保持在0℃的38g (10.2mmol)的7.8w/w%溶液中。在0℃下一小时后,将过量的Red-Al用 1.2ml(16.4mmol)的丙酮淬灭,并将该反应混合物在室温下搅拌过夜。将该反应混合物加温至50℃,并添加14ml水和5.5ml(105mmol)的 50w/w%氢氧化钠水溶液。分离各层,并将该有机层用14ml水洗涤,经硫酸钠干燥,并过滤。将该滤液在真空下蒸发至干燥以给出2.40g的粗化合物 (IVe)(LC-测定:94.1w/w%,E/Z比值:92/8,产率:89%)。从6ml DBE 再结晶该粗产物以获得1.87g的化合物(E)-(IVe)(产率:73%,E/Z比值: 98/2),为一种固体产物。母液的LC分析显示40/60的E/Z比值,作为化合物(E)-(IVe)的选择性沉淀的一个证据。
形态:深褐色固体(mp:110.5℃)。
1H NMR(400MHz,氯仿-d)δppm 7.25-7.32(m,2H),7.15-7.23(m,3H), 4.20(d,J=23.2Hz,2H),3.89(br.s.,1H),3.04(d,J=1.3Hz,2H),2.76-2.86(m, 2H),2.55-2.68(m,4H),2.27(td,J=6.2,1.8Hz,2H),1.62-1.75(m,2H)
13C NMR(101MHz,氯仿-d)δppm 152.80(d,J=247.9Hz),139.94,128.61,128.42,126.11,115.20(d,J=16.1Hz),60.27,57.04(d,J=31.5Hz),53.88(d,J=8.1Hz),53.81,33.39,25.06(d,J=1.5Hz),23.76(d,J=8.1Hz)
19F NMR(376MHz,氯仿-d)δppm-119.40(t,J=23.0Hz,1F)
高分辨MS:对于C15H21NOF(M+H)的计算值:250.1607,发现值: 250.1604。
元素分析:计算值:C(72.26%),H(8.09%),F(7.62%),N(5.62%),O(6.42%);发现值:C(71.29%),H(8.20%),N(5.51%)
实验5
经化合物(IIIa)的甲磺酸盐的化合物(VIa):
在0℃下将28.2g(120mmol)的化合物(E)-(IVa)和18.4ml(132 mmol)的三乙胺溶解在180ml甲苯中。缓慢添加14.4g(125.8mmol)甲磺酰氯,并将该反应混合物在0℃下搅拌1小时。用120ml的冷水将该形成的三乙胺盐酸化物洗涤出,并将该有机层经硫酸钠干燥、过滤并添加至22.2g (120mmol)邻苯二甲酰亚胺钾(化合物(V),M=K)和2.43g(6.6 mmol)TBAI在60ml甲苯中的一种悬浮液中。将该反应混合物在室温下搅拌过夜,然后用120ml水进行洗涤、过滤并在真空下浓缩。从30ml异丙醇中结晶该残余物以给出33g白色固体。产率:76%。
形态:白色固体(mp:125.1℃)。
1H NMR(360MHz,氯仿-d)δppm 1.47-1.76(m,4H)2.20-2.28(m,2H) 2.47-2.56(m,2H)3.22(d,J=1.46Hz,2H)3.63(s,2H)4.40(d,J=20.90Hz,2H) 7.12-7.42(m,5H)7.72(dd,J=5.49,3.29Hz,2H)7.85(dd,J=5.49,2.93Hz,2H)
13C NMR(91MHz,氯仿-d)δppm 24.14(s,1C)25.24(d,J=1.38Hz,1C) 35.39(d,J=32.52Hz,1C)53.94(s,1C)54.35(d,J=7.61Hz,1C)63.31(s,1C) 117.42(d,J=12.46Hz,1C)123.83(s,1C)125.73(s,1C)127.53(s,1C)128.68 (d,J=4.15Hz,2C)129.46(s,1C)129.67(s,1C)132.47(s,1C)134.45(s,254C) 134.26-134.58(m,2C)138.46(s,1C)147.70(d,J=248.43Hz,1C)168.04(s,1 C)
19F NMR(377MHz,氯仿-d)δppm-118.91(s,1F)
元素分析:计算值:C(72.51%),H(5.81%),F(5.21%),N(7.69%),O (8.78%);发现值:C(72.68%),H(5.84%),N(7.66%)
经三信反应的化合物(VIa):
将8.43ml(42.5mmol)DIAD逐滴添加至10g(42.5mmol)化合物 (E)-(IVa)、6.25g(42.5mmol)邻苯二甲酰亚胺和11.15g(42.5mmol)三苯基膦在85ml甲苯中的冷(-10℃)溶液中。在-10℃下24小时之后,添加水。过滤掉不溶解的物料并且允许该滤液倾析。分离这两层,并将该有机层经硫酸钠干燥,过滤并在真空下进行浓缩。从异丙醇再结晶该残余物以获得10.2g的化合物(VIa)(产率:66%)。
NMR和MS谱与经化合物(IIIa)的甲磺酸盐获得的化合物(VIa)的那些相同。
经化合物(IIIe)的甲磺酸盐的化合物(VIe):
将0.49ml(6.32mmol)甲磺酰氯经10分钟添加至1.50g(6.02mmol) 化合物(IVe)以及0.92ml(6.62mmol)三乙胺在9ml甲苯中的保持在0℃的溶液中。在0℃下1小时之后,添加6ml水。分离各层,并将该有机层经硫酸钠干燥,并过滤。将这样获得的甲磺酸盐的溶液经5分钟添加至1.17g (6.32mmol)邻苯二甲酰亚胺钾(化合物(V),M=K)和133mg(0.36 mmol)TBAI在3ml甲苯中的一种悬浮液中。将该反应混合物在10℃下搅拌 2小时然后在室温下搅拌过夜。添加6ml水,过滤掉不溶解的物料,允许该滤液倾析,丢弃水层,并将该有机层经硫酸钠干燥,并过滤以给出化合物 (VIe)在甲苯中的25.12g的4.6w/w%的溶液(原位产率:51%)。将该溶液在真空下进行浓缩,从n-丙醇再结晶该残余物以获得1.02g的化合物(VIe)。将该母液在真空下进行浓缩,并通过硅胶垫(洗脱液:庚烷–乙酸乙酯1/1至 1/3)过滤以产生多于0.11g的化合物(VIe)。合并产率:47%。
形态:白色固体(mp:97.0℃)。
1H NMR(600MHz,氯仿-d)δppm 7.85(dd,J=5.3,3.0Hz,2H),7.72(dd, J=5.7,3.0Hz,2H),7.28-7.32(m,2H),7.24-7.27(m,2H),7.21(t,J=7.2Hz,1 H),4.50(d,J=21.9Hz,2H),3.29(s,2H),2.89-2.94(m,2H),2.69-2.74(m,2 H),2.59-2.63(m,2H),2.26(t,J=5.5Hz,2H),1.63-1.73(m,2H)
13C NMR(151MHz,氯仿-d)δppm 167.60,147.56(d,J=247.0Hz),140.27,134.04,131.98,128.71,128.39,126.03,123.41,117.02(d,J=15.4Hz),60.50, 53.95,53.84(d,J=7.7Hz),34.99(d,J=32.9Hz),33.73,24.92,23.71(d,J=7.7Hz)
19F NMR(377MHz,氯仿-d,)δ=-117.73(s,1F)。
高分辨MS:对于C23H24N2O2F(M+H)的计算值:379.1822,发现值: 379.1820。
元素分析:计算值:C(73.00%),H(6.13%),F(5.02%),N(7.40%),O (8.46%);发现值:C(72.53%),H(6.42%),N(7.32%)
实验6
来自化合物(VIa)的化合物(1).HCl盐:
将9.8ml(90.6mmol)1-氯甲酸氯乙酯缓慢添加至30g(82.3mmol)化合物(E)-(Va)在165ml甲苯中的保持在0℃的溶液中。将该反应混合物在室温下搅拌1小时,然后在80℃下搅拌1小时,并过滤。向该滤液中添加24 ml乙醇和在异丙醇中的15.35ml(90.6mmol)6M HCl溶液,并将所得混合物回流4小时,然后冷却至0℃。过滤沉淀物,用16ml丙酮和16ml甲苯洗涤,并在在真空下进行干燥以给出21.94g化合物(1).HCl盐。产率:86%。
NMR和MS数据与文献的那些相同。
Claims (2)
1.具有化学式(E)-(IV)的化合物
或其酸加成盐,其中
R1a是芳基甲基、芳基乙基或二苯基甲基;并且
其中芳基是苯基,或被一个或两个C1-4烷氧基、卤素、C1-4烷基、硝基或二(C1-4烷基)氨基取代的苯基。
2.在权利要求1中所述的具有化学式(E)-(IV)的化合物,其中R1a是芳基甲基,其中芳基是苯基。
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CN101248070A (zh) * | 2005-03-21 | 2008-08-20 | 詹森药业有限公司 | 7-氨基亚烷基-杂环喹诺酮和萘啶酮 |
WO2010056633A2 (en) * | 2008-11-11 | 2010-05-20 | Janssen Pharmaceutica Nv | 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones |
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WO2008005670A2 (en) * | 2006-07-05 | 2008-01-10 | Janssen Pharmaceutica N.V. | One-pot condensation reduction methods for preparing substituted allylic alcohols |
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