1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 6-(1,3-benzodioxol-5-yl)-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-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

HRID 1476556Notes

Reaction equation

HRID 1476556 reaction equation
Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[O:33][N:32]=[C:31]([CH2:34][CH3:35])[N:30]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:19][C:18]4[C:17](=[O:20])[N:16]([CH:21]5[CH2:26][CH2:25][N:24]([C:55]([C:54]6[CH:58]=[CH:59][C:51]([C:45]7[C:46]8[CH:47]=[C:48]([O:49][CH3:50])[C:39]([O:38][CH2:36][CH3:37])=[CH:40][C:41]=8[C@H:42]8[CH2:63][S:62][CH2:61][CH2:60][C@H:43]8[N:44]=7)=[CH:52][CH:53]=6)=[O:56])[CH2:23][CH2:22]5)[C:15](=[O:27])[N:14]([CH2:28][C:29]5[O:33][N:32]=[C:31]([CH2:34][CH3:35])[N:30]=5)[C:13]=4[CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3]1

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide2×HCID 757711-HydroxybenzotriazoleHCID 672590924-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acidHCID 672591926-(1,3-benzodioxol-5-yl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride

Product 1

HCID 672584666-(1,3-benzodioxol-5-yl)-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-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 6-(1,3-benzodioxol-5-yl)-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (232 mg; compound B86) and 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (191 mg; compound C10) in DMF (10 ml) is added HOBt (74 mg) and EDCI (92 mg) and the reaction mixture is stirred at RT for 48 h. One additional equivalent of EDCI (92 mg) is added in order to complete the reaction. The reaction mixture is extracted for three times with DCM/H2O/saturated sodium chloride solution (150 ml/100 ml/35 ml). The organic phase is separated and dried with Na2SO4. After filtration and evaporation of all volatiles the resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 95/5 (v/v)] and by preparative HPLC to give the title compound as a solid.

Workup

  1. customthe reaction
  2. extractionThe reaction mixture is extracted for three times with DCM/H2O/saturated sodium chloride solution (150 ml/100 ml/35 ml)
  3. customThe organic phase is separated
  4. dry with materialdried with Na2SO4
  5. filtrationAfter filtration and evaporation of all volatiles the resulting residue
  6. customis purified by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 95/5 (v/v)] and by preparative HPLC

Sources & evidence

ORD record
ord-0130fb99aaf4422aaaf9a29dfc760af8
Source dataset
uspto-grants-2015_04
Patent number
US09018175B2

Reaction notes

Loading…