IL97309A - Intermediates for hexahydrobenz Úcd¾ indoles and process for the preparation of pure enantiomers thereof - Google Patents

Intermediates for hexahydrobenz Úcd¾ indoles and process for the preparation of pure enantiomers thereof

Info

Publication number: IL97309A
Authority: IL; Israel
Prior art keywords: hexahydrobenz; formula; indole; amino; compound
Prior art date: 1990-02-26

Application number

IL9730991A

Other languages

English (en)

Other versions

IL97309A0 (en

Original Assignee

Lilly Co Eli

Priority date (The priority date 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 date listed.)

1990-02-26

Filing date

1991-02-20

Publication date

1996-11-14

1991-02-20 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

1992-05-25 Publication of IL97309A0 publication Critical patent/IL97309A0/xx

1994-09-22 Priority to IL11102794A priority Critical patent/IL111027A/en

1996-11-14 Publication of IL97309A publication Critical patent/IL97309A/en

Links

238000000034 method Methods 0.000 title abstract description 33
239000000543 intermediate Substances 0.000 title abstract description 18
238000002360 preparation method Methods 0.000 title abstract description 13
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 title abstract description 3
150000002475 indoles Chemical class 0.000 title description 7
150000001875 compounds Chemical class 0.000 claims abstract description 66
-1 hydroxy, carboxy Chemical group 0.000 claims description 33
239000000203 mixture Substances 0.000 claims description 21
239000001257 hydrogen Substances 0.000 claims description 20
229910052739 hydrogen Inorganic materials 0.000 claims description 20
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
125000000217 alkyl group Chemical group 0.000 claims description 8
125000003545 alkoxy group Chemical group 0.000 claims description 5
RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 3
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
125000004414 alkyl thio group Chemical group 0.000 claims description 3
125000004093 cyano group Chemical group *C#N 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
125000001475 halogen functional group Chemical group 0.000 claims 3
WFIHFVABJQXZDE-UHFFFAOYSA-N 1,2,2a,3,4,5-hexahydrobenzo[cd]indol-4-amine Chemical class C1NC2=CC=CC3=C2C1CC(N)C3 WFIHFVABJQXZDE-UHFFFAOYSA-N 0.000 abstract description 4
150000002576 ketones Chemical class 0.000 abstract description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 51
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 26
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 26
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 26
VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
239000002904 solvent Substances 0.000 description 24
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
238000006243 chemical reaction Methods 0.000 description 17
239000011541 reaction mixture Substances 0.000 description 17
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
229910052799 carbon Inorganic materials 0.000 description 16
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
238000007327 hydrogenolysis reaction Methods 0.000 description 13
239000000243 solution Substances 0.000 description 13
239000000047 product Substances 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
150000001414 amino alcohols Chemical class 0.000 description 11
238000003786 synthesis reaction Methods 0.000 description 11
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
229940086542 triethylamine Drugs 0.000 description 11
150000003335 secondary amines Chemical class 0.000 description 10
238000004809 thin layer chromatography Methods 0.000 description 10
NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 9
230000015572 biosynthetic process Effects 0.000 description 9
230000000707 stereoselective effect Effects 0.000 description 9
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
239000000706 filtrate Substances 0.000 description 8
238000004458 analytical method Methods 0.000 description 7
150000002118 epoxides Chemical class 0.000 description 7
150000002431 hydrogen Chemical group 0.000 description 7
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
101150041968 CDC13 gene Proteins 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
238000002425 crystallisation Methods 0.000 description 6
230000008025 crystallization Effects 0.000 description 6
229910052757 nitrogen Inorganic materials 0.000 description 6
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 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
239000012359 Methanesulfonyl chloride Substances 0.000 description 5
150000001412 amines Chemical class 0.000 description 5
239000003054 catalyst Substances 0.000 description 5
229910052736 halogen Inorganic materials 0.000 description 5
125000005843 halogen group Chemical group 0.000 description 5
150000002367 halogens Chemical class 0.000 description 5
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
229960000583 acetic acid Drugs 0.000 description 4
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
150000003141 primary amines Chemical class 0.000 description 4
239000000377 silicon dioxide Substances 0.000 description 4
229910052938 sodium sulfate Inorganic materials 0.000 description 4
235000011152 sodium sulphate Nutrition 0.000 description 4
239000007787 solid Substances 0.000 description 4
239000007858 starting material Substances 0.000 description 4
125000001424 substituent group Chemical group 0.000 description 4
239000000725 suspension Substances 0.000 description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
125000003277 amino group Chemical group 0.000 description 3
239000012267 brine Substances 0.000 description 3
230000003197 catalytic effect Effects 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
239000006260 foam Substances 0.000 description 3
229910052740 iodine Inorganic materials 0.000 description 3
239000011630 iodine Substances 0.000 description 3
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
239000012074 organic phase Substances 0.000 description 3
125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 3
239000002244 precipitate Substances 0.000 description 3
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
238000001953 recrystallisation Methods 0.000 description 3
238000000926 separation method Methods 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
150000003512 tertiary amines Chemical class 0.000 description 3
MFVFAPQCEUCUSG-UHFFFAOYSA-N 1,2,2a,3,4,5-hexahydrobenzo[cd]indole Chemical class C1CCC2CNC3=CC=CC1=C32 MFVFAPQCEUCUSG-UHFFFAOYSA-N 0.000 description 2
UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 2
IJJWOSAXNHWBPR-HUBLWGQQSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-hydrazinyl-6-oxohexyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)NN)SC[C@@H]21 IJJWOSAXNHWBPR-HUBLWGQQSA-N 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
HMQSYBGBCXSTTH-UHFFFAOYSA-N [2-amino-4-hydroxy-5-(1-phenylethyl)-2a,3,4,5-tetrahydro-2h-benzo[cd]indol-1-yl]-phenylmethanone Chemical compound C=1C=CC=CC=1C(C)C(C=1C=CC=C2C3=1)C(O)CC3C(N)N2C(=O)C1=CC=CC=C1 HMQSYBGBCXSTTH-UHFFFAOYSA-N 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
125000002252 acyl group Chemical group 0.000 description 2
150000001298 alcohols Chemical class 0.000 description 2
239000000935 antidepressant agent Substances 0.000 description 2
150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
150000001541 aziridines Chemical class 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
229910052794 bromium Inorganic materials 0.000 description 2
239000002178 crystalline material Substances 0.000 description 2
HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
238000006073 displacement reaction Methods 0.000 description 2
238000004090 dissolution Methods 0.000 description 2
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
238000001914 filtration 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
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
125000006239 protecting group Chemical group 0.000 description 2
238000010956 selective crystallization Methods 0.000 description 2
YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
238000012800 visualization Methods 0.000 description 2
239000008096 xylene Substances 0.000 description 2
150000003738 xylenes Chemical class 0.000 description 2
RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
ZYVORBSWPVDTCX-UHFFFAOYSA-N 1,2,2a,3-tetrahydrobenzo[cd]indole Chemical compound C1=CCC2CNC3=CC=CC1=C32 ZYVORBSWPVDTCX-UHFFFAOYSA-N 0.000 description 1
HLRMNQPUEPLRBJ-UHFFFAOYSA-N 1-amino-2a,3,4,5-tetrahydro-2H-benzo[cd]indol-6-ol Chemical compound NN1CC2C=3C(=C(C=CC1=3)O)CCC2 HLRMNQPUEPLRBJ-UHFFFAOYSA-N 0.000 description 1
125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 1
125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
NDVDJYHPROIWDW-UHFFFAOYSA-N 2a,3,4,5-tetrahydro-2H-benzo[cd]indol-1-amine Chemical compound C1CCC2=CC=CC3=C2C1CN3N NDVDJYHPROIWDW-UHFFFAOYSA-N 0.000 description 1
125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
YKDGRGQHSOGQJV-UHFFFAOYSA-N 4,5-dihydro-3H-benzo[cd]indol-1-amine Chemical compound NN1C=C2C=3C(=CC=CC1=3)CCC2 YKDGRGQHSOGQJV-UHFFFAOYSA-N 0.000 description 1
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
241000400611 Eucalyptus deanei Species 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
208000027089 Parkinsonian disease Diseases 0.000 description 1
206010034010 Parkinsonism Diseases 0.000 description 1
102000003946 Prolactin Human genes 0.000 description 1
108010057464 Prolactin Proteins 0.000 description 1
229940123796 Prolactin inhibitor Drugs 0.000 description 1
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
239000002249 anxiolytic agent Substances 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
125000004069 aziridinyl group Chemical group 0.000 description 1
125000001246 bromo group Chemical group Br* 0.000 description 1
244000309464 bull Species 0.000 description 1
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
239000001569 carbon dioxide Substances 0.000 description 1
229910002092 carbon dioxide Inorganic materials 0.000 description 1
229950005499 carbon tetrachloride Drugs 0.000 description 1
UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 description 1
210000003169 central nervous system Anatomy 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
239000000460 chlorine Substances 0.000 description 1
125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
239000013078 crystal Substances 0.000 description 1
FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
239000003480 eluent Substances 0.000 description 1
FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
239000000284 extract Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
125000000524 functional group Chemical group 0.000 description 1
239000007789 gas Substances 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
230000026030 halogenation Effects 0.000 description 1
238000005658 halogenation reaction Methods 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
239000000852 hydrogen donor Substances 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
238000004811 liquid chromatography Methods 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
239000000463 material Substances 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
229910000510 noble metal Inorganic materials 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
125000000286 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
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
229940097325 prolactin Drugs 0.000 description 1
125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000007017 scission Effects 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
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
230000002311 subsequent effect Effects 0.000 description 1
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 description 1
FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
238000001665 trituration Methods 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
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000010792 warming Methods 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
- 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
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Indole Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

IL9730991A 1990-02-26 1991-02-20 Intermediates for hexahydrobenz Úcd¾ indoles and process for the preparation of pure enantiomers thereof IL97309A (en)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
IL11102794A IL111027A (en)	1990-02-26	1994-09-22	Hexahydrobenz [cd] indoles and processes for their preparation

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US48519490A	1990-02-26	1990-02-26

Publications (2)

Publication Number	Publication Date
IL97309A0 IL97309A0 (en)	1992-05-25
IL97309A true IL97309A (en)	1996-11-14

Family

ID=23927262

Family Applications (2)

Application Number	Title	Priority Date	Filing Date
IL9730991A IL97309A (en)	1990-02-26	1991-02-20	Intermediates for hexahydrobenz Úcd¾ indoles and process for the preparation of pure enantiomers thereof
IL11102794A IL111027A (en)	1990-02-26	1994-09-22	Hexahydrobenz [cd] indoles and processes for their preparation

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
IL11102794A IL111027A (en)	1990-02-26	1994-09-22	Hexahydrobenz [cd] indoles and processes for their preparation

Country Status (13)

Country	Link
EP (1)	EP0444851B1 (de)
JP (1)	JP2968070B2 (de)
KR (2)	KR0176247B1 (de)
AT (1)	ATE127454T1 (de)
CA (1)	CA2037098C (de)
DE (1)	DE69112670T2 (de)
DK (1)	DK0444851T3 (de)
ES (1)	ES2078434T3 (de)
GR (1)	GR3017777T3 (de)
HU (1)	HU215965B (de)
IE (1)	IE68887B1 (de)
IL (2)	IL97309A (de)
PH (1)	PH31173A (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5302612A (en) *	1990-02-26	1994-04-12	Eli Lilly And Company	6-substituted-hexahydrobenz[cd]indoles
IL97308A (en) *	1990-02-26	1996-10-31	Lilly Co Eli	6-Substituted-hexahydrobenz (cd) indoles process for their preparation and pharmaceutical compositions containing them

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4110339A (en) *	1977-11-25	1978-08-29	Eli Lilly And Company	4-(Di-n-propyl)amino-1,3,4,5-tetrahydrobenz[cd]indole
IL74222A (en) *	1984-02-06	1988-07-31	Lilly Co Eli	6-substituted-4-dialkylamino tetrahydrobenz(c,d)indoles,their preparation and pharmaceutical compositions comprising them
IL97308A (en) *	1990-02-26	1996-10-31	Lilly Co Eli	6-Substituted-hexahydrobenz (cd) indoles process for their preparation and pharmaceutical compositions containing them
TW219933B (de) *	1990-02-26	1994-02-01	Lilly Co Eli
US5039820A (en) *	1990-02-26	1991-08-13	Eli Lilly And Company	4-amino-6-iodo-hexahydrobenz(cd)indoles

1991
- 1991-02-20 IL IL9730991A patent/IL97309A/en not_active IP Right Cessation
- 1991-02-25 KR KR1019910003031A patent/KR0176247B1/ko not_active Expired - Fee Related
- 1991-02-25 HU HU91631A patent/HU215965B/hu unknown
- 1991-02-25 IE IE62491A patent/IE68887B1/en not_active IP Right Cessation
- 1991-02-25 KR KR1019910003030A patent/KR0171418B1/ko not_active Expired - Fee Related
- 1991-02-26 EP EP91301500A patent/EP0444851B1/de not_active Expired - Lifetime
- 1991-02-26 DE DE69112670T patent/DE69112670T2/de not_active Expired - Fee Related
- 1991-02-26 CA CA002037098A patent/CA2037098C/en not_active Expired - Fee Related
- 1991-02-26 DK DK91301500.4T patent/DK0444851T3/da active
- 1991-02-26 AT AT91301500T patent/ATE127454T1/de not_active IP Right Cessation
- 1991-02-26 JP JP3055928A patent/JP2968070B2/ja not_active Expired - Fee Related
- 1991-02-26 ES ES91301500T patent/ES2078434T3/es not_active Expired - Lifetime
- 1991-04-26 PH PH42055A patent/PH31173A/en unknown
1994
- 1994-09-22 IL IL11102794A patent/IL111027A/en not_active IP Right Cessation
1995
- 1995-10-18 GR GR950402879T patent/GR3017777T3/el unknown

Also Published As

Publication number	Publication date
IL97309A0 (en)	1992-05-25
IL111027A (en)	1996-05-14
DE69112670T2 (de)	1996-03-07
IE68887B1 (en)	1996-07-24
KR0171418B1 (ko)	1999-02-01
JP2968070B2 (ja)	1999-10-25
EP0444851A2 (de)	1991-09-04
CA2037098C (en)	2006-04-18
EP0444851A3 (en)	1992-02-19
ATE127454T1 (de)	1995-09-15
IL111027A0 (en)	1994-11-28
DE69112670D1 (de)	1995-10-12
DK0444851T3 (da)	1995-10-23
GR3017777T3 (en)	1996-01-31
HU215965B (hu)	1999-03-29
HU63191D0 (en)	1991-09-30
KR0176247B1 (ko)	1999-03-20
HUT68729A (en)	1995-07-28
CA2037098A1 (en)	1991-08-27
KR910021376A (ko)	1991-12-20
KR910021404A (ko)	1991-12-20
ES2078434T3 (es)	1995-12-16
JPH04211653A (ja)	1992-08-03
IE910624A1 (en)	1991-08-28
EP0444851B1 (de)	1995-09-06
PH31173A (en)	1998-03-20

Legal Events

Date	Code	Title
1997-04-15	FF	Patent granted
1997-07-13	KB	Patent renewed
2001-06-14	KB	Patent renewed
2005-03-20	KB	Patent renewed
2010-05-17	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
US5536832A (en)	1996-07-16	N-acyl-2,3-benzodiazepine derivatives pharmaceutical compositions containing them and process for preparing same
US5008400A (en)	1991-04-16	Bicyclic aminoacids as intermediates
US4749718A (en)	1988-06-07	Carbazole derivatives and their use as 5HT-induced antagonists
US5039820A (en)	1991-08-13	4-amino-6-iodo-hexahydrobenz(cd)indoles
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US5559245A (en)	1996-09-24	Intermediates to 4-amino- hexahydrobenz (cd) indoles and processes therefor
Mohri et al.	1999	A synthesis of 4-quinolone-3-carboxylic acids via pyrolysis of N-aryldioxopyrrolines
AU661076B2 (en)	1995-07-13	Indole derivatives
EP0444851B1 (de)	1995-09-06	Hexahydrobenzo[cd]indole und Verfahren zu deren Herstellung
Eberle et al.	1987	Intramolecular Diels-Alder reactions of indole-3-acrylates
US4353911A (en)	1982-10-12	Indolo(2,3-a)quinolizidines, useful in increasing femoral and vertebral blood flow
HU204257B (en)	1991-12-30	Process for producing new substituted quinoline derivatives and pharmaceutical compositions containing them
IL133782A (en)	2006-12-31	Steoselective process for the preparation of gabapentin analogues
US4885364A (en)	1989-12-05	Resolution process for benzazepine intermediates
US3925382A (en)	1975-12-09	Process for preparing quinazoline derivatives
US4784996A (en)	1988-11-15	Pyrimidoindoles useful as hypoglycaemics
GB1567997A (en)	1980-05-21	Biologically active tetracyclic compounds and pharmaceutical compositions containing same
US4965356A (en)	1990-10-23	Resolution process for benzazepine intermediates
EP0916657B9 (de)	2006-05-17	Optisch aktive 1-Phenylpyrrolidonderivate
JPS5846515B2 (ja)	1983-10-17	インド−ル誘導体の製造方法
HU218218B (hu)	2000-06-28	Sztereoszelektív eljárás 1-benzoil-4-hidroxi-5-(1-fenil-etil)-amino-1,2,2a,3,4,5-hexahidrobenz[cd]indol optikai izomerjeinek előállítására
Hwang et al.	1979	The Synthesis of 12‐Methyl‐1, 2, 3, 4, 6, 7, 12, 12B‐Octahydroindolo [2, 3‐A] Quinolizine (1), 1‐Benzoyl‐1, 2, 3, 4, 6, 7, 12, 12B‐Octahydroindolo [2, 3‐A] Quinolizine (2), and 1‐Phenylcarbinol‐1, 2, 3, 4, 6, 7, 12, 12B‐Octahydroindolo [2, 3‐A] Quinolizine (3)
HU206698B (en)	1992-12-28	Process for producing n-benzyl-tetrahydro-furane-carboxamide derivatives
SK1262003A3 (en)	2004-03-02	Process for the preparation of 9-amino substituted 9,10-dihydropyrrolo [2,1-B][1,3]benzothiazepines