Diisopropylethylamine → 3-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

HRID 1476545Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1476545
Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]

Komponenten

6

Edukt 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 672579521-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride2×HCID 672590924-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid

Produkt 1

HCID 672584323-[1-({4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]phenyl}carbonyl)piperidin-4-yl]-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 22350042dichloromethane N,N-dimethylformamideLösungsmittel

Versuchsvorschrift

1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B79) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C10) and HBTU (304 mg) in DCM/DMF (15 ml/2 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and twice by preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluation gradient: EtOAc/methanol/triethylamine, 91/5/4 (v/v/v)] as a solid.

Quellen und Nachweise

ORD-Eintrag
ord-f9397824afcf42249c867ff1540f5ad4
Quelldatensatz
uspto-grants-2015_04
Patentnummer
US09018175B2

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