Diisopropylethylamine → 3-[1-({4-[(4aR,10bR)-8,9-dimethoxy-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-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

HRID 1476568Notes

Reaction equation

HRID 1476568 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][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:32])=[N:5]1)[CH3:3].[CH3:33][O:34][C:35]1[C:36]([O:58][CH3:59])=[CH:37][C:38]2[C@H:39]3[CH2:57][S:56][CH2:55][CH2:54][C@H:40]3[N:41]=[C:42]([C:45]3[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=3)[C:43]=2[CH:44]=1.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(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:33][O:34][C:35]1[C:36]([O:58][CH3:59])=[CH:37][C:38]2[C@H:39]3[CH2:57][S:56][CH2:55][CH2:54][C@H:40]3[N:41]=[C:42]([C:45]3[CH:46]=[CH:47][C:48]([C:49]([N:29]4[CH2:30][CH2:31][CH:26]([N:12]5[C:13](=[O:25])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=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:32])[CH2:27][CH2:28]4)=[O:50])=[CH:52][CH:53]=3)[C:43]=2[CH:44]=1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67258712HCID 67258712, compoundHCID 70975863HCID 70975863, compound

Product 1

HCID 672591563-[1-({4-[(4aR,10bR)-8,9-dimethoxy-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-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg, compound B39), 4-[(4aR,10bR)-8,9-dimethoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (220 mg; compound C16) and HBTU (167 mg) in DCM (4.0 ml) is added DIPEA (0.28 ml). The reaction mixture is stirred at RT for 1 h. Saturated aqueous sodium bicarbonate solution (2 ml) is added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc] and subsequently by preparative HPLC and preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluent: EtOAc/MeOH/triethylamine, 91/5/4 (v/v/v)] to yield the title compound as a solid.

Workup

  1. filtrationthe mixture is filtered
  2. concentrationThe organic layer is concentrated under reduced pressure
  3. customthe residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc] and subsequently by preparative HPLC and preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluent: EtOAc/MeOH/triethylamine, 91/5/4 (v/v/v)]

Sources & evidence

ORD record
ord-1587b9694157477586849c1414b629b6
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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