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

HRID 1476529Notes

Reaction equation

HRID 1476529 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:33][CH:34]=[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:36]=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(=O)(O)[O-].[Na+]>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:24]=[CH:23][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:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[N:36]=[C:32]([CH2:30][CH3:31])[O:33][CH:34]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[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]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 672581051-[(2-ethyl-1,3-oxazol-4-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 532467463-[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-1,3-oxazol-4-yl)methyl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The title compound is prepared analogously as described for example 11 using 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-[(2-ethyl-1,3-oxazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B41), HBTU (167 mg), DIPEA (207 mg) and DCM (8 ml). After 3 h additional HBTU (91 mg) and 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (20 mg; compound C10) are added and the mixture is stirred for 22 h at RT. Saturated aqueous sodium bicarbonate solution (2.5 ml) is added and the mixture is extracted twice with DCM (2×5 ml). The combined organic layers are applied to a phase separator and the solvent is removed under vacuo. The resulting residue is purified by flash column chromatography for three times [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] to yield the title compound as a solid.

Workup

  1. customThe title compound is prepared analogously
  2. extractionthe mixture is extracted twice with DCM (2×5 ml)
  3. customthe solvent is removed under vacuo
  4. customThe resulting residue is purified by flash column chromatography for three times [amino phase silica gel, eluation gradient: cyclohexane/EtOAc, 100/0 to 0/100 (v/v)]

Sources & evidence

ORD record
ord-292bf383e7ef4087b5de241205f46bf6
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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