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-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

HRID 1476514Notes

Reaction equation

HRID 1476514 reaction equation
[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:36][C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[N:34][CH:33]=1)[CH3:31].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>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:36][C:32]([CH2:30][CH3:31])=[CH:33][N:34]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 672588031-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochlorideHCID 672590924-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid2×

Product 1

HCID 532461583-[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-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191.5 mg; compound B26) and HBTU (167 mg) in DCM (3 ml) is added DIPEA (0.28 ml) and the mixture is stirred for 1 h at RT. After 1 h an additional amount of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (40 mg) is added and the mixture is stirred for 15 min in order to complete the reaction. Subsequently the solvent is removed and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc/MeOH, 97.5/2.5 (v/v)] and afterwards by preparative HPLC to yield the title compound as a solid.

Workup

  1. stirringthe mixture is stirred for 15 min in order
  2. customthe reaction
  3. customSubsequently the solvent is removed
  4. customthe residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc/MeOH, 97.5/2.5 (v/v)] and afterwards by preparative HPLC

Sources & evidence

ORD record
ord-847f9b46c69949348b314afd798d9a37
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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