1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 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-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

HRID 1476530Notes

Reaction equation

HRID 1476530 reaction equation
Cl.[CH2:2]([N:4]1[CH:8]=[C:7]([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])[CH:6]=[N:5]1)[CH3:3].[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.O>[CH2:33]([O:35][C:36]1[C:45]([O:46][CH3:47])=[CH:44][C:43]2[C:42]([C:48]3[CH:49]=[CH:50][C:51]([C:52]([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:7]6[CH:6]=[N:5][N:4]([CH2:2][CH3:3])[CH:8]=6)[C:11]5=[O:32])[CH2:27][CH2:28]4)=[O:53])=[CH:55][CH:56]=3)=[N:41][C@@H:40]3[CH2:57][CH2:58][S:59][CH2:60][C@@H:39]3[C:38]=2[CH:37]=1)[CH3:34]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 516920Potassium bisulfateHCID 27960291-Hydroxybenzotriazole hydrateHCID 672581211-[(1-ethyl-1H-pyrazol-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 532467473-[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-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-phenylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 1-[(1-ethyl-1H-pyrazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg; compound B42), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (253 mg; compound C10), EDCI (122 mg) and HOBT hydrate (86 mg) in DCM (10 ml) DIPEA (0.28 ml) is added. After 45 min additional 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (126 mg; compound C10) is added and the reaction mixture is stirred for 14 h at RT. Water and aqueous potassium hydrogen sulfate solution (10% w/w) are added and the mixture is extracted with DCM. The combined organic layers are dried (sodium sulfate) and concentrated under reduced pressure. The residue is purified by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC to afford the title compound as a solid.

Workup

  1. additionis added
  2. extractionthe mixture is extracted with DCM
  3. dry with materialThe combined organic layers are dried (sodium sulfate)
  4. concentrationconcentrated under reduced pressure
  5. customThe residue is purified by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC

Sources & evidence

ORD record
ord-8f3fd7a74bb9451ab9ea915baf9582aa
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

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