CN1305459A - 制备4-取代-1h-吲哚-3-乙醛酸酰胺的方法 - Google Patents
制备4-取代-1h-吲哚-3-乙醛酸酰胺的方法 Download PDFInfo
- Publication number
- CN1305459A CN1305459A CN99807248A CN99807248A CN1305459A CN 1305459 A CN1305459 A CN 1305459A CN 99807248 A CN99807248 A CN 99807248A CN 99807248 A CN99807248 A CN 99807248A CN 1305459 A CN1305459 A CN 1305459A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- formula
- compound
- alkoxyl group
- aryl
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 238000002360 preparation method Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims description 43
- 229910052760 oxygen Inorganic materials 0.000 claims description 37
- 239000001301 oxygen Substances 0.000 claims description 37
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 230000029936 alkylation Effects 0.000 claims description 10
- 238000005804 alkylation reaction Methods 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000006351 sulfination reaction Methods 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 230000026030 halogenation Effects 0.000 claims description 6
- 238000005658 halogenation reaction Methods 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 3
- PKBSYKUAXVIELQ-UHFFFAOYSA-N (4-methylphenyl)sulfinyl 2-methylpropanoate Chemical group CC(C)C(=O)OS(=O)C1=CC=C(C)C=C1 PKBSYKUAXVIELQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- -1 3-indoleacetic acid compound Chemical class 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 150000002475 indoles Chemical class 0.000 description 10
- 230000002378 acidificating effect Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- MPRWIVBRDAXEAF-UHFFFAOYSA-N acetyloxy ethaneperoxoate Chemical compound CC(=O)OOOC(C)=O MPRWIVBRDAXEAF-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- KLUDQUOLAFVLOL-UHFFFAOYSA-N acetyl propanoate Chemical compound CCC(=O)OC(C)=O KLUDQUOLAFVLOL-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- KCKIKSJECTZLJA-UHFFFAOYSA-N indol-4-one Chemical class O=C1C=CC=C2N=CC=C12 KCKIKSJECTZLJA-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- NJZQOCCEDXRQJM-UHFFFAOYSA-N 1-benzylindole Chemical class C1=CC2=CC=CC=C2N1CC1=CC=CC=C1 NJZQOCCEDXRQJM-UHFFFAOYSA-N 0.000 description 1
- PTXVSDKCUJCCLC-UHFFFAOYSA-N 1-hydroxyindole Chemical compound C1=CC=C2N(O)C=CC2=C1 PTXVSDKCUJCCLC-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical class C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
- UNNGUFMVYQJGTD-UHFFFAOYSA-N 2-Ethylbutanal Chemical compound CCC(CC)C=O UNNGUFMVYQJGTD-UHFFFAOYSA-N 0.000 description 1
- UMDWJYHTZUWTET-UHFFFAOYSA-N 2-amino-1-(1h-indol-3-yl)ethanol Chemical class C1=CC=C2C(C(O)CN)=CNC2=C1 UMDWJYHTZUWTET-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- QRAFJHXNLQTXQW-UHFFFAOYSA-N 2-methylpropyl hydrogen carbonate Chemical compound CC(C)COC(O)=O QRAFJHXNLQTXQW-UHFFFAOYSA-N 0.000 description 1
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 1
- FXJVNINSOKCNJP-UHFFFAOYSA-N 4-methylbenzenesulfinic acid Chemical compound CC1=CC=C(S(O)=O)C=C1 FXJVNINSOKCNJP-UHFFFAOYSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- AWMHRVHGKOFCNI-UHFFFAOYSA-N C(CCCC)OC(C(C)(C)C)OOCCC(C)C Chemical compound C(CCCC)OC(C(C)(C)C)OOCCC(C)C AWMHRVHGKOFCNI-UHFFFAOYSA-N 0.000 description 1
- GKRYOTUQPZKDFB-UHFFFAOYSA-N C1=CC=CC=C1C(=O)OO.[Cl] Chemical compound C1=CC=CC=C1C(=O)OO.[Cl] GKRYOTUQPZKDFB-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- FQODPPSFOYMQMV-UHFFFAOYSA-N FC=1C(=C2C(=C(NC2=CC1)C)F)F Chemical compound FC=1C(=C2C(=C(NC2=CC1)C)F)F FQODPPSFOYMQMV-UHFFFAOYSA-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
- SEOVTRFCIGRIMH-UHFFFAOYSA-N Indole-3-acetic acid Natural products C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- GTZOZDOTOWNSJH-UHFFFAOYSA-N [O].CCCCCCC Chemical compound [O].CCCCCCC GTZOZDOTOWNSJH-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 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
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- UKPXULFIISGBHG-UHFFFAOYSA-N cyclopropene Chemical compound [CH]1C=C1 UKPXULFIISGBHG-UHFFFAOYSA-N 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 125000002704 decyl 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])* 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical compound CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- DDTGNKBZWQHIEH-UHFFFAOYSA-N heptalene Chemical compound C1=CC=CC=C2C=CC=CC=C21 DDTGNKBZWQHIEH-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- MGPLBSPZSIFUQX-UHFFFAOYSA-N methyl 4-methylbenzenesulfinate Chemical class COS(=O)C1=CC=C(C)C=C1 MGPLBSPZSIFUQX-UHFFFAOYSA-N 0.000 description 1
- PSNSVDSRLUYDKF-UHFFFAOYSA-N methyl benzenesulfinate Chemical class COS(=O)C1=CC=CC=C1 PSNSVDSRLUYDKF-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 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
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- GUVXZFRDPCKWEM-UHFFFAOYSA-N pentalene Chemical compound C1=CC2=CC=CC2=C1 GUVXZFRDPCKWEM-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- KFZUDNZQQCWGKF-UHFFFAOYSA-M sodium;4-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=C(S([O-])=O)C=C1 KFZUDNZQQCWGKF-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005991 sulfenylation reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-O tert-butylammonium Chemical compound CC(C)(C)[NH3+] YBRBMKDOPFTVDT-UHFFFAOYSA-O 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 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
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—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
- C07D209/22—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 with an aralkyl radical attached to the ring nitrogen atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
制备用于抑制SPLA2的1H-吲哚-3-乙醛酸酰胺和在制备这种化合物中使用的新中间体的方法。
Description
本发明涉及制备某些用于抑制由于脓毒性休克引起的sPLA2介导的脂肪酸释放的1H-吲哚-3-乙醛酸酰胺(glyoxamides)和在制备这类化合物中使用的中间体的方法。
已知某些1H-吲哚-3-乙醛酸酰胺为哺乳动物的sPLA2的有效的选择性抑制剂,可用于治疗疾病,如脓毒性休克、成人呼吸窘迫综合症、胰腺炎、损伤、支气管哮喘、过敏性鼻炎、风湿性关节炎和相关的sPLA2引起的疾病。例如在EPO公开号0675110中公开了这些化合物。
在各种专利和公开中描述了使用4-羟基吲哚中间体制备这些化合物的方法。
在Marc Julia、Jean Igolen和Hanne Igolen的文章“Recherches enserie indolique.Ⅵ sur tryptamines substituees”,Bull,Soc.Chim.France,1962,第1060-1068页中描述了某些吲哚-3-乙醛酸酰胺和它们成为色胺衍生物的转化。
在E.Romeo等的文章“2-Aryl-3-Indoleglyoxylamides(FGIN-1):ANew Class of Potent and Specific Ligands for the Mitochondrial DBIReceptor(MDR)”,The Journal of Pharmacology and ExperimentalTherapeutics,第262卷,第3期,(第971-978页)中描述了某些已经在哺乳动物的中枢神经系统中研究应用的2-芳基-3-吲哚乙醛酸酰胺。
在摘要“Fragmentation of N-benzylindoles in Mass Spectrometry”;Chemical Abstracts,第67卷,1967,73028h中报导了包括那些在引哚环的3号位具有乙醛酸酰胺基的各种苄基取代酚。
在美国专利号3,449,363中描述了在吲哚环的3号位具有乙醛酸酰胺基的三氟甲基吲哚。
在美国专利号3,351,630中描述了α-取代的3-吲哚基乙酸化合物和它们(包括乙醛酸酰胺中间体)的制备。
在美国专利号2,825,734中描述了采用3-吲哚乙醛酸酰胺中间体如1-苯乙基-2-乙基-6-羧基-N-丙基-3-吲哚乙醛酸酰胺制备3-(2-氨基-1-羟乙基)吲哚(参见实施例30)。
在美国专利号4,397,850中采用乙醛酸酰胺吲哚作为中间体制备异噁唑基吲哚胺(indolamines)。在美国专利号3,801,594中描述了采用3-吲哚乙醛酸酰胺中间体制备的止痛药。
在A.Alemanhy,E.Fernandez Alvarez,O.Nieto Lopey and M.E.Rubio Herraez的文章“No.565.-Inhibiteurs d’enzymes.Ⅻ.-Preparationde(propargylamino-2 ethyl)-3 indoles”Bullentin De La Societe ChimiqueDe France,1974,第12期,第2883-2888页中描述了在吲哚环的6员环上氢取代的各种吲哚-3乙醛酸酰胺。
在Gert Kollenz和Christa Labes的文章“Indol-Umlagerung von1-Diphenylamino-2,3-dihydro-2,3-pyrrolidonen”,Liebig Ann, Chem.,1975,第1979-1983页中描述了苯基取代的3-乙醛酸酰胺。
这些方法中很多应用了4-羟基吲哚中间体。例如在美国专利号5,654,326(这里通过引用其整体结合到本文中来)中公开了制备4-取代-1H-吲哚-3-乙醛酸酰胺衍生物的方法,包括在室温(20-25℃)下在二甲基甲酰胺中使适当取代的4-甲氧基吲哚(如在Clark,R.D.等,Synthesis,1991,第871-878页中的描述制备,所述公开通过引用结合到本文中来)与氢化钠反应,随后在室温下采用芳基甲基卤化物处理得到1-芳基甲基吲哚,接着在二氯甲烷中采用三溴化硼将所得产物邻位脱甲基(Tsung-Ying Shem and Charles A.Winter,Adv,Drug Res.,1977,12,176,所述公开通过引用结合到本文中来)得到4-羟基引哚。在二甲基甲酰胺中采用氢化钠作为碱使用α溴链烷酸酯进行羟基引哚的烷基化。通过将α-[(吲哚-4-基)氧]链烷酸酯首先与草酰氯,随后与氨反应,接着在甲醇中采用氢氧化钠水解而转化为乙醛酸酰胺。
如上所述的制备4-取代-1H-吲哚-3-乙醛酸酰胺衍生物的方法是有用的。然而这个方法使用了昂贵的试剂和对环境有害的有机溶剂,生产了含呋喃的副产品并导致所需产品的相对低的产率。
在作为选择的制备方法中,采用磺酰氯卤化适当取代的丙酰乙酸。通过采用氢氯酸处理将所述卤化中间体水解并脱羧基,随后与适当取代的环己二酮反应。采用适当的胺处理所述烷基化二酮得到4-氧代-吲哚,在催化剂(如在碳上的钯)存在下,通过在高沸点极性烃溶剂(如卡比醇)中回流氧化所述4-氧代-吲哚制备4-羟基吲哚,接着可将4-羟基吲哚按如上的描述进行烷基化和转化为所需的乙醛酸酰胺。
然而这个方法因需要高温氧化及回收贵重的金属催化剂而受到限制。
虽然上述制备4-羟基吲哚中间体的方法是令人满意的,然而需要更有效的转化。
本发明提供了用于制备1H-吲哚-3-乙醛酸酰胺的改进方法。本发明的方法可在较温和的条件下,用不昂贵、容易获得的试剂来进行并得到更好的总产率。另外,本发明的方法允许在吲哚环上用更多种取代基进行转化。通过以下的描述和附加的权利要求书,本发明的其它目标、特征和有利之处将变得显而易见。
本发明提供了用于制备式Ⅰ的化合物或它们的药物可接受的盐或前体药物衍生物的方法;其中:R1选自C7-C20的烷基;和其中;R10选自卤素、C1-C10的烷基、C1-C10的烷氧基、-S-(C1-C10的烷基)和
卤代(C1-C10)的烷基,t为0至5的整数(包括0和5);R2选自氢、卤素、C1-C3的烷基、C3-C4的环烷基、C3-C4的环烯基、-
O-(C1-C2的烷基)、-S-(C1-C2的烷基)、芳基、芳氧基和杂环(HET);R4选自-CO2H、-SO3H和-P(O)(OH)2或它们的盐或前体药物衍生物;
和R5选自氢、(C1-C6)的烷基、(C1-C6)的烷氧基、卤代(C1-C6)的烷氧基、
卤代(C2-C6)的烷基、溴、氯、氟、碘和芳基;所述方法包括以下步骤:
a)采用SO2Cl2将式Ⅹ的化合物
f)采用具有式XCH2R4a的烷基化试剂(其中X为离去基团和R4a为-CO2R4b、-SO3R4b、-P(O)(OR4b)2或-P(O)(OR4b)H,其中R4b为酸保护基团)将式Ⅳ的化合物烷基化形成式Ⅲ的化合物g)将式Ⅲ的化合物与草酰氯和氨反应形成式Ⅱ的化合物h)任选将式Ⅱ的化合物水解形成式Ⅰ的化合物;和
i)任选将式Ⅰ的化合物成盐。
在本发明的另一个实施方案中提供了制备式Ⅰ的化合物的方法,包括以下步骤:
b)采用具有式XCH2R4a的烷基化试剂(其中X为离去基团和R4a为-CO2R4b、-SO3R4b、-P(O)(OR4b)2或-P(O)(OR4b)H,其中R4b为酸保护基团)将式Ⅳ的化合物烷基化形成式Ⅲ的化合物c)将式Ⅲ的化合物与草酰氯和氨反应形成式Ⅱ的化合物d)任选将式Ⅱ的化合物水解形成式Ⅰ的化合物;和
e)任选将式Ⅰ的化合物成盐。
本发明的化合物所用的一些定义的术语如下:
除非另外声明,否则这里所用的术语“烷基”本身或作为其它取代基的一部分是指直链或支链单价烃原子团,如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、庚基、己基、辛基、壬基、癸基等。
这里使用的术语“(C1-C10)的烷氧基”是指如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、异戊氧基、新戊氧基、庚氧基、己氧基、辛氧基、壬氧基、癸氧基等基团,它们通过氧原子连接到所述分子的残基上。
术语“(C3-C4)的环烷氧基”包括环丙基和环丁基基团。
术语“(C3-C4)的环烯基”包括在1-或2-号位含有双键的环丙烯基或环丁烯基环。
术语“卤素”是指氟、氯、溴或碘。
术语“卤代(C1-C10)烷基”是指被1至3个卤素原子取代的(C1-C10)烷基基团,通过烷基基团与所述分子的残基连接。所述术语卤代(C1-C10)烷基包括术语卤代(C2-C6)烷基。
术语“卤代(C1-C6)的烷氧基”是指卤素取代的烷氧基基团,该基团通过烷氧基的氧原子与所述分子的残基连接。
术语“芳基”是指具有苯、并环戊二烯、茚、萘、奥、庚搭烯、菲、蒽等环结构特征的基团。任选所述芳基被选自(C1-C6)烷基(优选甲基)、(C1-C6)烷氧基或卤素(优选氟或氯)的1至3个取代基取代。
术语“芳氧基”是指通过氧连接基连接到所述分子的残基的芳基基团。
术语“离去基团”是指在亲核取代反应中离开基体的具有非共享电子对的取代基。术语“离去基团”包括氢卤酸根、磺酸根、乙酸根等。
术语杂环包括吡啶、吡嗪、嘧啶、哒嗪、吡咯、吡唑、呋喃、噻吩、噻唑、异噻唑、噁二唑、噻二唑、咪唑、三唑和四唑。所述杂元环可通过杂环上的任何碳连接到所述分子的残基上。
本发明的另外一方面为式Ⅰ的化合物的盐。在那些例子中本发明的化合物具有的酸性官能团可形成各种盐,它们比其母体化合物更具水溶性和生理适应性。代表性的药物可接受盐包括(但不限于此)碱金属和碱土金属盐,如锂、钠、钾、钙、镁、铝等的盐。通过在溶液中采用碱处理游离酸或将所述酸暴露于离子交换树脂中可方便地得到盐。
包括在所定义的范围内的药物可接受盐为本发明化合物的相对无毒、无机和有机的碱加成的盐,例如具有足够碱性的衍生自含氮的碱的铵、叔铵和胺阳离子与本发明的化合物形成的盐(如参见S.M.Berge等“Pharmaceutical Salts”,J.Phar.Sci.,66:1-19(1977))。
在这里使用的术语“酸保护基团”,就象它在有机合成化学中经常使用的一样,是指能够阻止酸基参与分子上的一些其它功能基团的反应而又在需要时能够除去的基团。T.W.Greene在ProtectiveGroup in Organic Synthesis,John Wiley and Sons,New York,1981的第五章中描述了这些基团,其整体部分通过引用结合到本文中来。
酸保护基团的例子包括所述酸基团的酯或酰胺衍生物、如甲基、甲氧基甲基、甲基-硫代甲基、四氢呋喃基、甲氧基乙氧基甲基、苄氧基甲基、苯基芳基、乙基、2,2,2-三氯乙基、2-甲基硫代乙基、叔丁基、环戊基、三苯基甲基、对溴苄基、三甲基甲硅烷基、N,N-二甲基、吡咯烷基、哌啶基或邻硝基苯胺。优选的酸保护基为甲基。
前体药物为本发明的化合物的衍生物,具有化学或代谢可解离基团并通过溶剂分解形成,或者是在生理条件下在体内具有药物活性的本发明的化合物。本发明的化合物的衍生物在它们的酸和碱衍生物形式中均具有活性,但酸衍生物形式经常提供在哺乳动物的有机体中的溶解性、组织相容性或缓慢释放的有利之处。(参见Bundgard,H.,Design of Prodrugs,第7-9、21-24页,Elsevier,Amsterdam,1985)。前体药物包括酸衍生物,如通过母体酸性化合物与适合的醇反应制备的酯,或通过母体酸性化合物与适合的胺反应制备的酰胺。衍生自本发明的化合物的侧酸基的简单的脂族酯(如甲酯、乙酯、丙酯、异丙酯、丁酯、仲丁酯、叔丁酯)或芳香酯均为优选的前体药物。其它优选的酯包括吗啉代乙氧基、二乙基乙醛酸酰胺和二乙氨基羰基甲氧基。
在一些情况下需要制备具有双酯基类型的前体药物,如(酰氧基)烷基酯或((烷氧基羰基)氧)烷基酯。
R4为-CO2H;和
R5、R6和R7为H。
可通过本发明的方法制备的化合物包括:((3-(2-氨基-1,2-二氧乙基)-2-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸;dl-2-((3-(2-氨基-1,2-二氧乙基)-2-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)丙
酸;((3-(2-氨基-1,2-二氧乙基)-1-(((1,1’-联苯)-2-基甲基)-2-甲基-1H-吲哚-
4-基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-1-((1,1’-联苯)-3-基甲基)-2-甲基-1H-吲哚-4-
基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-1-((1,1’-联苯)-4-基甲基)-2-甲基-1H-引哚-4-
基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-1-((2,6-二氯苯基)甲基)-2-甲基-1H-吲哚-4-
基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-1-((4-氟苯基)甲基)-2-甲基-1H-吲哚-4-基)氧)
乙酸;((3-(2-氨基-1,2-二氧乙基)-2-甲基-1-((萘基)甲基)-1H-吲哚-4-基)氧)乙
酸;((3-(2-氨基-1,2-二氧乙基)-2-乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-1-((3-氯苯甲基)-2-乙基-1H-吲哚-4-基)氧)乙
酸;((3-(2-氨基-1,2-二氧乙基)-1-((1,1’联苯)-2-基甲基)-2-乙基-1H-吲哚-4-
基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-1-((1,1’联苯)-2-基甲基)-2-丙基-1H- 引哚-4-
基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-2-环丙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙
酸;((3-(2-氨基-1,2-二氧乙基)-1-((1,1’联苯)-2-基甲基)-2-环丙基-1H-吲哚-
4-基)氧)乙酸;4-((3-(2-氨基-1,2-二氧乙基)-2-乙基-1-(苯基甲)-1H-吲哚-4-基)氧)丁
酸;((3-(2-氨基-1,2-二氧乙基)-2-乙基-1-(苯甲基)-1H-吲哚-4-基)氧乙酸;((-3-(2-氨基-1,2-二氧乙基)-2-乙基-6-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)
乙酸;((-3-(2-氨基-1,2-二氧乙基)-2,6-二甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙
酸;((3-(2-氨基-1,2-二氧乙基)-2-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-6-乙基-2-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)
乙酸;((3-(2-氨基-1,2-二氧乙基)-2,6-二乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙
酸;((3-(2-氨基-1,2-二氧乙基)-2-甲基-6-苯氧基-1-(苯甲基)-1H-吲哚-4-基)
氧)乙酸;((3-(氨基氧代乙酰基)-2-乙基-6-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙
酸;和((3-(2-氨基-1,2-二氧乙基)-2-乙基-6-苯氧基-1-(苯甲基)-1H-吲哚-4-基)
氧)乙酸或它们的药物可接受盐。
对于这些化合物,优选的化合物包括:((3-(2-氨基-1,2-二氧乙基)-2-乙基-1-(苯甲基-)-1H-吲哚-4-基)氧)乙酸;((-3-(2-氨基-1,2-二氧乙基)-2-乙基-6-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)
乙酸;((-3-(2-氨基-1,2-二氧乙基)-2,6-二甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙
酸;((3-(2-氨基-1,2-二氧乙基)-2-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸;((3-(2-氨基-1,2-二氧乙基)-6-乙基-2-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)
乙酸;((3-(2-氨基-1,2-二氧乙基)-2,6-二乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙
酸;((3-(2-氨基-1,2-二氧乙基)-2-甲基-6-苯氧基-1-(苯甲基)-1H-吲哚-4-基)
氧)乙酸;((3-(氨基氧代乙酰基)-2-乙基-6-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙
酸;和((3-(2-氨基-1,2-二氧乙基)-2-乙基-6-苯氧基-1-(苯甲基)-1H-吲哚-4-基)
氧)乙酸或它们的药物可接受盐。
对于这些化合物,更优选的为:((3-(2-氨基-1,2-二氧乙基)-2-甲基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸和((3-(2-氨基-1,2-二氧乙基)-2-乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸。
可通过本发明的方法制备的最优选的化合物为((3-(2-氨基-1,2-二氧乙基)-2-乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸或它们的药物可接受盐。
本发明的方法提供了如以下的方案Ⅰ中显示的使用不昂贵、容易获得的试剂合成式Ⅰ的化合物的改进方法。
方案Ⅰ将酮(Ⅴ)溶解在适合的溶剂,优选对质子有惰性的溶剂如四氢呋喃(THF)中。其它适合的溶剂包括(但不限于此)二甲基甲酰胺(DMF)、二氧杂环己烷或甲苯。如果需要可将所述基体/溶剂溶液进行超声波处理或轻微加热以便于溶解。
所用的溶剂的量应足以确保所有的化合物停留在溶液中直至完成所需的反应。
采用碱,优选如氢化钠的强碱处理所述溶液,随后采用式
的亚磺化试剂(其中R为-(C1-C6)烷基、芳基或取代芳基并且X为(C1-C6)的烷氧基、卤素或-OCO2(C1-C6)烷基)处理。所述亚磺化试剂可根据J.W.Wilt等,J.Org.Chem,1967,32,2097的方法制备。优选的亚磺化试剂包括对甲苯基亚磺酸甲酯、苯亚磺酸甲酯或对甲苯基亚磺酸异丁酸酐。其它适合的碱包括(但不限于此)LDA、甲醇钠或甲醇钾。优选使用两种等当量的碱。当使用氢化钠时,优选在加入亚磺化试剂前加入该碱。当使用甲醇钠时试剂添加顺序并不重要。
可在大约25℃至回流的温度下,优选在回流下进行所述反应,在1至24小时内基本完成反应。
亚磺化试剂的量并不关键,然而,使用相对于吡咯原料(1)摩尔当量或过量可最好地完成反应。
可采用“单罐”方法进行上述反应,将所述反应剂以上述顺序加入反应容器中。
在“单罐”方法中,二氧杂环己烷是优选的溶剂。如果使用如下的方案Ⅰ(a)描述的“两罐”方法,THF和甲苯分别为优选的溶剂。
可使用标准的结晶或色谱方法将中间体Ⅳ分离和纯化。
可使用如TLC或HPLC等标准分析技术监控所述反应以测定原料和中间体转化为产品的时间。
在作为选择的制备方法中,可采用式R20SSR20(其中R20为烷基或芳基)的二硫化物代替所述亚磺化试剂。随后可使用适当的氧化剂,如过氧化氢或间-氯过苯甲酸容易地将硫化物中间体氧化。
随后可在碱的存在下,采用具有式XCH2R4a的烷基化试剂(其中X为适合的离去基团和R4a为保护的羧基、磺酰酸基或膦酰酸基,优选采用酯基保护)将吲哚(Ⅳ)容易地烷基化。溴化乙酸甲酯为优选的烷基化试剂。适合的碱包括碳酸钾、碳酸钠、碳酸锂、碳酸铯、碳酸氢钠、碳酸氢钾或氢氧化钾。优选碳酸钾。烷基化试剂的量不是关键的,然而使用相对于原料为摩尔过量的烷基化试剂可最好地完成所述反应。优选在有机溶剂如丙酮、乙腈或二甲基甲酰胺中进行所述反应。其它适合的溶剂包括四氢呋喃、甲乙酮、乙腈、甲苯或叔丁基甲基醚。在大约0℃至100℃的温度下,优选在室温下进行所述反应,根据所用的试剂和如反应温度等条件在大约1至24小时内基本完成反应。
任选使用如溴化叔丁基铵的相转移试剂。
乙醛酸酰胺Ⅱ的制备通过两步方法容易地完成:首先采用浓度为大约0.2至1.5mmol,优选相对于原料为等摩尔浓度的草酰氯处理中间体Ⅲ。优选二氯甲烷、氯仿、三氯乙烯、四氯化碳、醚或甲苯作为溶剂。大约-20℃至室温的温度是适合的,优选大约-5℃。
在第二步中,采用氨处理所述溶液;所述氨可作为气体鼓泡或优选使用摩尔过量的30%的氨水。所述反应一般在大约-25℃至25℃,优选在大约-2℃至0℃的温度下进行,并在10分钟至1小时内基本完成。
在如甲醇、乙醇、异丙醇等低级醇溶剂或如四氢呋喃、二氧杂环己烷和丙酮溶剂中,使用如氢氧化钾、氢氧化锂或氢氧化钠(优选氢氧化钠)的碱进行Ⅱ的水解。
使用如HPLC的标准分析技术监控方案Ⅰ的反应以测定原料和中间体转化为产物的时间。
以下的方案Ⅰ(a)说明了上述制备中间体Ⅳ的两罐方法。可使用标准色谱方法将中间体Ⅳ(a)分离和纯化。
熟练的技术人员可容易认识到上述方法的原料可为商业可得的或可通过已知技术由商业可得的原料容易地制备得到。例如可根据Patai等,The Chemistry of sulfphinic acids,ester and their derivatives;John Wiley and sons,1990第217-236 & 557-600页的方法制备亚磺化试剂和亚磺酰化试剂。
根据以下方法制备原料Ⅴ。
在大约0℃至25℃,优选低于15℃的温度下,通过采用磺酰氯,优选采用相对于原料为等摩尔的浓度处理首先将适当取代的丙酰乙酸Ⅹ卤化制备Ⅸ。
与如氢氯酸的含水酸一起回流大约1至24小时进行Ⅸ的水解和脱羧基。中和含有所述脱羧基产物Ⅷ的溶液,调整pH值至大约7.0至7.5,随后使其与环己二酮Ⅶ(优选为等摩尔浓度)和碱(优选氢氧化钠)反应得到作为沉淀物的三酮一水合物Ⅵ,如果需要可将其纯化和分离。优选在-20℃至室温的温度下进行所述反应并在大约1至24小时内基本完成。
优选采用“单罐”方法进行上述反应,将所述反应剂以上述顺序加入反应容器中。优选在不对式Ⅸ或Ⅷ的化合物分离下进行所述反应,由此避免了对这些挥发性催泪剂的暴露。
通过在与水形成共沸物的高沸点非极性溶剂(优选甲苯)中,将 Ⅵ与等摩尔量的式R1NH2的胺(其中R1如上所定义)一起回流进行Ⅴ的制备。
优选使用具有沸点为至少100℃的溶剂,如甲苯、二甲苯、甲基异丙苯、苯、1,2-二氯乙烷或1,3,5-三甲基苯,由此免去了压力容器的需要。所用的溶剂的量应足以确保所有的化合物停留在溶液中直至在大约1至24小时内反应基本完成。
以下实施例进一步说明本发明的方法。这些实施例还说明了本发明的中间体化合物的制备。这些实施例仅仅是说明而并不意味对本发明的范围作任何的限定。
实施例1
((2-乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸甲酯的制备A.2-(2-氧代丁基)-1,3-环己二酮的制备
将1-苄基-2-乙基-4-氧代-4,5,6,7-四氢吲哚(1000g,4.995mol)悬浮在甲苯中(6000ml,6体积)。将所述混合物加热至85℃并搅拌5分钟。在~30-45分钟内逐滴加入苄基胺(562.6g,5.25mol,1.05当量)。随着滴加的进行,所述混合物变成琥珀色溶液。加热所述溶液使水共沸蒸出直至反应温度达到110℃。在110℃下搅拌所述反应液2小时,在这段时间中在大气压力下蒸出~4000ml的溶剂。将所述溶液转移到烧瓶中并进一步挥发得到琥珀色的粘性油,可直接在以下步骤中使用。油重量=1372.24g理论重量=1253.7g产率=87%摩尔产率=95.2%B.2-乙基-(苯甲基)-1H-吲哚-4-醇的制备
将氢化钠(400g,9.96mol,2.5当量)悬浮在THF(5000ml,5体积)中。往所述悬浮液中加入上述部分A的化合物(1149g,3.98mol,1当量)并在20-25℃下搅拌直至鼓泡减弱。加入甲苯亚磺酸甲酯(1121g,6.59mol,1.65当量)并将所得混合物加热至30℃。经过~2.5小时,观察到随着气体的挥发所述混合物变成深色并且放热使温度升高至47℃。TLC表明原料已被全部消耗。随后缓慢加入去离子水(5000ml,5体积)骤冷,将反应物冷却至0至5℃。进一步采用冰醋酸(600g,10mol,2.5当量)骤冷所述反应物。采用甲苯(5000ml,5体积)稀释所述混合物并采用饱和碳酸氢钠(2500ml,2.5体积)洗涤。将上层有机层采用另外2500ml饱和碳酸氢钠洗涤。将含水层合并并采用甲苯(5000ml,5体积)反萃取。将有机层结合并加热至轻微回流(~80℃)并搅拌2小时,此时由TLC证实反应的完成。在大气压下将所述深色溶液浓缩至~4000ml并采用饱和碳酸氢钠(1500ml×2)洗涤。将所述有机物采用硫酸镁干燥并在真空下浓缩成深色粘性油,在以下步骤中直接使用。C.((2-乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸甲酯的制备
将上述部分B的化合物溶解在丙酮(7500ml,7.5体积)中并在20至25℃下搅拌。加入粉末碳酸钾(1360g,9.84mol,2.5当量)和溴化乙酸甲酯(780g,5.09mol,1.3当量)并在20至25℃下将棕褐色的混合物搅拌16小时,此时由TLC确定反应的完成。通过聚丙烯将所得固体过滤并采用丙酮(1500ml,1.5体积)洗涤。在真空下将所述滤液挥发得到深色油。将所述油溶解在异丙醇(10,000ml,10体积)中并将所得的淤浆加热至回流30分钟。使所述溶液自冷却,在~38℃时发生结晶。将所述淤浆冷却至0至5℃并搅拌2小时。将所述淤浆过滤并采用3-500ml的冷的异丙醇分次洗涤。在真空烘箱中,在50℃下将所述棕褐色固体干燥16小时。干燥物重量=691.53g。理论克数=1288.4g产率(重量)=53.7%
实施例 2
2-乙基-(苯甲基)-1H-吲哚-4-醇的制备A.4-甲基-苯亚磺酸酸酐的制备
将4-甲基-苯亚磺酸钠盐(0.9g,5mmol)悬浮在苯(5ml)中。加入HCl(1当量)。单独将氯甲酸异丁酯(0.65ml,5mmol)加入冷的吡啶(1.2ml,15mmol)的苯(5ml)溶液中。将所述亚磺酸溶液分次加入。在室温下将所得的溶液搅拌30分钟。将溶剂挥发,剩余物分配在MTBE和水之间。将有机层采用硫酸钠干燥、过滤并挥发得到无色油。再次将所述油溶解在MTBE中并采用0.1N的HCl溶液洗涤直至将吡啶除去。经过硫酸钠干燥和过滤后,将所述溶液挥发得到无色液体(0.30g)。1HNMR(500MHz,CDCl3),7.64(d,2H),7.35(d,2H),3.83(m,1H),3.37(m,1H),2.45(s,3H),1.94(m,1H),0.95(m,6H)。B.2-乙基-(苯甲基)-1H-吲哚-4-醇的制备
将上述实施例1B的原料(0.3g,1.2mmol)溶解在5ml的THF中。加入氢化钠(0.1g,2.6mmol)。加入与碳酸氢异丁酯形成酸酐的4-甲基-苯亚磺酸(0.3g,1.25mmol)的THF溶液1ml。将所述混合物回流1小时,此时没有观察到原料。继续回流得到产物。
Claims (6)
代(C1-C10)的烷基,t为0至5的整数(包括0和5);R2选自氢、卤素、C1-C3的烷基、C3-C4的环烷基、C3-C4的环烯基、-
O-(C1-C2的烷基)、-S-(C1-C2的烷基)、芳基、芳氧基和杂环;R4选自-CO2H、-SO3H和-P(O)(OH)2或它们的盐或前体药物衍生物;和R5选自氢、(C1-C6)的烷基、(C1-C6)的烷氧基、卤代(C1-C6)的烷氧基、
卤代(C2-C6)的烷基、溴、氯、氟、碘和芳基;所述方法包括以下步骤:
a)采用SO2Cl2将式Ⅹ的化合物其中R8为(C1-C6)的烷基、芳基或杂环;卤化形成式Ⅸ的化合物b)将式Ⅸ的化合物水解并脱羧基形成式Ⅷ的化合物c)采用式Ⅷ的化合物将式Ⅶ的化合物烷基化形成式Ⅵ的化合物
f)采用具有式XCH2R4a的烷基化试剂(其中X为离去基团和R4a为-CO2R4b、-SO3R4b、-P(O)(OR4b)2或-P(O)(OR4b)H,其中R4b为酸保护基团)将式Ⅳ的化合物烷基化形成式Ⅲ的化合物g)将式Ⅲ的化合物与草酰氯和氨反应形成式Ⅱ的化合物h)任选将式Ⅱ的化合物水解形成式Ⅰ的化合物;和
i)任选将式Ⅰ的化合物成盐。
2.用于制备式Ⅰ的化合物或它们的药物可接受的盐或前体药物衍生物的方法;其中:R1选自C7-C20的烷基;和其中;R10选自卤素、C1-C10的烷基、C1-C10的烷氧基、-S-(C1-C10的烷基)和
卤代(C1-C10)烷基,t为0至5的整数(包括0和5);R2选自氢、卤素、C1-C3的烷基、C3-C4的环烷基、C3-C4的环烯基、-
O-(C1-C2的烷基)、-S-(C1-C2的烷基)、芳基、芳氧基和杂环;R4选自-CO2H、-SO3H和-P(O)(OH)2或它们的盐或前体药物衍生物;和R5选自氢、(C1-C6)的烷基、(C1-C6)的烷氧基、卤代(C1-C6)的烷氧基、
卤代(C2-C6)的烷基、溴、氯、氟、碘和芳基;
所述方法包括以下步骤:
f)采用具有式XCH2R4a的烷基化试剂(其中X为离去基团和R4a为-CO2R4b、-SO3R4b、-P(O)(OR4b)2或-P(O)(OR4b)H,其中R4b为酸保护基团)将式Ⅳ的化合物烷基化形成式Ⅲ的化合物g)将式Ⅲ的化合物与草酰氯和氨反应形成式Ⅱ的化合物h)任选将式Ⅱ的化合物水解形成式Ⅰ的化合物;和
i)任选将式Ⅰ的化合物成盐;和
e)任选将式Ⅰ的化合物成盐。
3.权利要求1或2的方法,其中所述亚磺化试剂为对甲苯基亚磺酸异丁酸酐。
4.权利要求1至3的任何一项的方法,该方法用于制备((3-(2-氨基-1,2-二氧乙基)-2-乙基-1-(苯甲基)-1H-吲哚-4-基)氧)乙酸。
5.用于制备式Ⅰ的化合物或它们的药物可接受的盐或前体药物衍生物的方法;当通过权利要求1的方法制备时,其中:R1选自C7-C20的烷基;和其中;R10选自卤素、C1-C10的烷基、C1-C10的烷氧基、-S-(C1-C10的烷基)和
卤代(C1-C10)的烷基,t为0至5的整数(包括0和5);R2选自氢、卤素、C1-C3的烷基、C3-C4的环烷基、C3-C4的环烯基、-
O-(C1-C2的烷基)、-S-(C1-C2的烷基)、芳基、芳氧基和杂环;R4选自-CO2H、-SO3H和-P(O)(OH)2或它们的盐或前体药物衍生物;和R5选自氢、(C1-C6)的烷基、(C1-C6)的烷氧基、卤代(C1-C6)的烷氧基、
卤代(C2-C6)的烷基、溴、氯、氟、碘和芳基。
6.用于制备式Ⅰ的化合物或它们的药物可接受的盐或前体药物衍生物的方法;基本如以上的任何一个实施例所描述,其中:R1选自C7-C20的烷基;和其中;R10选自卤素、C1-C10的烷基、C1-C10的烷氧基、-S-(C1-C10的烷基)和
卤代(C1-C10)的烷基,t为0至5的整数(包括0和5);R2选自氢、卤素、C1-C3的烷基、C3-C4的环烷基、C3-C4的环烯基、-
O-(C1-C2的烷基)、-S-(C1-C2的烷基)、芳基、芳氧基和杂环;R4选自-CO2H、-SO3H和-P(O)(OH)2或它们的盐或前体药物衍生物;和R5选自氢、(C1-C6)的烷基、(C1-C6)的烷氧基、卤代(C1-C6)的烷氧基、
卤代(C2-C6)的烷基、溴、氯、氟、碘和芳基。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8211098P | 1998-04-17 | 1998-04-17 | |
US60/082,110 | 1998-04-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1305459A true CN1305459A (zh) | 2001-07-25 |
Family
ID=22169126
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN99807248A Pending CN1305459A (zh) | 1998-04-17 | 1999-04-15 | 制备4-取代-1h-吲哚-3-乙醛酸酰胺的方法 |
Country Status (27)
Country | Link |
---|---|
US (1) | US6265591B1 (zh) |
EP (1) | EP1071663A4 (zh) |
JP (1) | JP2002512225A (zh) |
KR (1) | KR20010042741A (zh) |
CN (1) | CN1305459A (zh) |
AR (1) | AR015767A1 (zh) |
AU (1) | AU750368B2 (zh) |
BR (1) | BR9909697A (zh) |
CA (1) | CA2326515A1 (zh) |
CO (1) | CO5080803A1 (zh) |
DZ (1) | DZ2770A1 (zh) |
EA (1) | EA003582B1 (zh) |
EG (1) | EG22139A (zh) |
HK (1) | HK1039120A1 (zh) |
HR (1) | HRP20000685A2 (zh) |
HU (1) | HUP0101344A3 (zh) |
ID (1) | ID26021A (zh) |
IL (1) | IL138827A0 (zh) |
NO (1) | NO20005148L (zh) |
NZ (1) | NZ507175A (zh) |
PE (1) | PE20000430A1 (zh) |
PL (1) | PL343487A1 (zh) |
SK (1) | SK15372000A3 (zh) |
SV (1) | SV1999000043A (zh) |
TR (1) | TR200002999T2 (zh) |
WO (1) | WO1999054300A1 (zh) |
ZA (1) | ZA200005294B (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999054295A1 (en) * | 1998-04-17 | 1999-10-28 | Eli Lilly And Company | Process for preparing 4-hydroxy indole, indazole and carbazole compounds |
US6407261B1 (en) | 1998-04-17 | 2002-06-18 | Eli Lilly And Company | Process for preparing 4-hdyroxy indole, indazole and carbazole compounds |
DE19962300A1 (de) * | 1999-12-23 | 2001-06-28 | Asta Medica Ag | Substituierte N-Benzyl-Indol-3-yl-glyoxylsäure-Derivate mit Antitumorwirkung |
US20030225149A1 (en) * | 2002-04-30 | 2003-12-04 | Blazecka Peter G. | Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids |
EP2424521A4 (en) | 2009-04-29 | 2015-03-04 | Amarin Pharmaceuticals Ie Ltd | PHARMACEUTICAL COMPOSITIONS COMPRISING EPA AND CARDIOVASCULAR AGENT AND METHODS OF USE |
AR088377A1 (es) | 2011-10-20 | 2014-05-28 | Siena Biotech Spa | Proceso para la preparacion de 6-cloro-2,3,4,9-tetrahidro-1h-carbazol-1-carboxamida y compuestos intermedios de esta |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CO4370099A1 (es) * | 1994-04-01 | 1996-10-07 | Lilly Co Eli | 1H-INDOL-3-GLIOXILAMIDAS INHIBIDORAS DE sPLA2 |
WO1999054295A1 (en) * | 1998-04-17 | 1999-10-28 | Eli Lilly And Company | Process for preparing 4-hydroxy indole, indazole and carbazole compounds |
-
1999
- 1999-04-14 DZ DZ990070A patent/DZ2770A1/xx active
- 1999-04-15 TR TR2000/02999T patent/TR200002999T2/xx unknown
- 1999-04-15 SK SK1537-2000A patent/SK15372000A3/sk unknown
- 1999-04-15 SV SV1999000043A patent/SV1999000043A/es not_active Application Discontinuation
- 1999-04-15 IL IL13882799A patent/IL138827A0/xx unknown
- 1999-04-15 CN CN99807248A patent/CN1305459A/zh active Pending
- 1999-04-15 EA EA200001076A patent/EA003582B1/ru not_active IP Right Cessation
- 1999-04-15 EP EP99917556A patent/EP1071663A4/en not_active Withdrawn
- 1999-04-15 BR BR9909697-8A patent/BR9909697A/pt not_active IP Right Cessation
- 1999-04-15 WO PCT/US1999/008332 patent/WO1999054300A1/en not_active Application Discontinuation
- 1999-04-15 KR KR1020007011468A patent/KR20010042741A/ko not_active Application Discontinuation
- 1999-04-15 US US09/647,471 patent/US6265591B1/en not_active Expired - Fee Related
- 1999-04-15 CA CA002326515A patent/CA2326515A1/en not_active Abandoned
- 1999-04-15 AR ARP990101753A patent/AR015767A1/es not_active Application Discontinuation
- 1999-04-15 ID IDW20002058A patent/ID26021A/id unknown
- 1999-04-15 HU HU0101344A patent/HUP0101344A3/hu unknown
- 1999-04-15 AU AU35648/99A patent/AU750368B2/en not_active Ceased
- 1999-04-15 PL PL99343487A patent/PL343487A1/xx not_active Application Discontinuation
- 1999-04-15 NZ NZ507175A patent/NZ507175A/xx unknown
- 1999-04-15 EG EG104099D patent/EG22139A/xx active
- 1999-04-15 JP JP2000544641A patent/JP2002512225A/ja not_active Withdrawn
- 1999-04-15 PE PE1999000312A patent/PE20000430A1/es not_active Application Discontinuation
- 1999-04-16 CO CO99022895A patent/CO5080803A1/es unknown
-
2000
- 2000-09-29 ZA ZA200005294A patent/ZA200005294B/en unknown
- 2000-10-13 NO NO20005148A patent/NO20005148L/no not_active Application Discontinuation
- 2000-10-17 HR HR20000685A patent/HRP20000685A2/hr not_active Application Discontinuation
-
2002
- 2002-01-23 HK HK02100522.5A patent/HK1039120A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
DZ2770A1 (fr) | 2003-12-01 |
HUP0101344A3 (en) | 2002-12-28 |
AU750368B2 (en) | 2002-07-18 |
EA200001076A1 (ru) | 2001-04-23 |
NO20005148L (no) | 2000-11-09 |
WO1999054300A1 (en) | 1999-10-28 |
AR015767A1 (es) | 2001-05-16 |
HUP0101344A2 (hu) | 2001-09-28 |
IL138827A0 (en) | 2001-10-31 |
HK1039120A1 (zh) | 2002-04-12 |
CO5080803A1 (es) | 2001-09-25 |
EP1071663A1 (en) | 2001-01-31 |
TR200002999T2 (tr) | 2001-01-22 |
ID26021A (id) | 2000-11-16 |
NZ507175A (en) | 2002-12-20 |
AU3564899A (en) | 1999-11-08 |
BR9909697A (pt) | 2000-12-19 |
KR20010042741A (ko) | 2001-05-25 |
SV1999000043A (es) | 2000-05-02 |
EA003582B1 (ru) | 2003-06-26 |
HRP20000685A2 (en) | 2001-10-31 |
PE20000430A1 (es) | 2000-05-24 |
SK15372000A3 (sk) | 2001-08-06 |
PL343487A1 (en) | 2001-08-27 |
EG22139A (en) | 2002-08-30 |
JP2002512225A (ja) | 2002-04-23 |
CA2326515A1 (en) | 1999-10-28 |
ZA200005294B (en) | 2001-10-01 |
EP1071663A4 (en) | 2002-06-19 |
US6265591B1 (en) | 2001-07-24 |
NO20005148D0 (no) | 2000-10-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2008526936A (ja) | 置換インドールの新規製造方法 | |
US20030166946A1 (en) | Process for the preparation of indole derivatives and intermediates of the process | |
CN1305459A (zh) | 制备4-取代-1h-吲哚-3-乙醛酸酰胺的方法 | |
CN88103507A (zh) | 具有苯并噻唑或其它杂环支链的氧代-2,3-二氮杂萘基乙酸的制备方法 | |
CN1052979C (zh) | 恩丹西酮的制备方法 | |
CN1184109A (zh) | 对映体纯环烷醇吲哚羧酸和氮杂吲哚羧酸和嘧啶并[1,2-a]-吲哚羧酸及其活性衍生物的制备方法 | |
CN1247562C (zh) | 制备螺环季酮酸衍生物的方法 | |
AU735516B2 (en) | Process for preparing 4-substituted-1H-indole-3-glyoxamides | |
JP5675800B2 (ja) | 4−(アセチルアミノ))−3−[(4−クロロ−フェニル)チオ]−2−メチル−1h−インドール−1−酢酸の製造のための中間体および方法 | |
WO2018061034A1 (en) | Novel process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine | |
CN1205204C (zh) | 3-羟甲基-苯并[b]噻吩衍生物及其制备方法 | |
US8080663B2 (en) | Process for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine | |
US6617460B1 (en) | Process for preparing toluenesulfinates | |
US6380397B1 (en) | Process for preparing 4-substituted-1H-indole-3-glyoxamides | |
CN112047865B (zh) | 一种在水中合成n-烷基磺酰胺的方法 | |
US6570023B1 (en) | Process for preparing toluenesulfinates | |
CA2347718A1 (en) | Process for preparing 4-substituted-1h-indole-3-glyoxamides | |
TWI588146B (zh) | 恩替卡韋的合成方法及其中間體化合物 | |
CZ20003824A3 (cs) | Způsob přípravy 4-substituovaných-lH-indol-3- glyoxamidů | |
JPH11152282A (ja) | 新規なカルボン酸誘導体およびその製造方法 | |
KR20090082463A (ko) | N-[3-[(2-메톡시페닐)설파닐]-2-메틸프로필]-3,4-디하이드로-2h-1,5-벤즈옥사티에핀-3-아민 제조 방법 | |
MXPA00009955A (en) | Process for preparing 4-substituted-1h-indole-3-glyoxamides | |
JP2007204372A (ja) | ニコチン酸エステル化合物の製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1039120 Country of ref document: HK |