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-(4-fluorophenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

HRID 1476550Notes

Reaction equation

HRID 1476550 reaction equation
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]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])=[N:5]1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].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>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=7)=[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:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 672590924-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acidHCID 672596901-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Product 1

HCID 709763533-[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-(4-fluorophenyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagents, catalysts & solvents 1

HCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (108 mg; compound B82) 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 (88 mg; compound C10) and HBTU (183 mg) in DCM/DMF (18 ml/1 ml) in the presence of DIPEA (227 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, 60/40 to 40/60 (v/v)] and 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.

Sources & evidence

ORD record
ord-32b92787327a4811a03bb5e48537ca8d
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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