1,2-Dichloroethane → 4-(4-((S)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

HRID 1476350Notes

Reaction equation

HRID 1476350 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C@@H:39]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([S:55]([NH2:58])(=[O:57])=[O:56])=[CH:51][C:50]=2[S:59]([C:62]([F:65])([F:64])[F:63])(=[O:61])=[O:60])[CH2:40][S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:33][CH2:32]1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:58][S:55]([C:52]4[CH:53]=[CH:54][C:49]([NH:48][C@H:39]([CH2:38][CH2:37][N:34]5[CH2:35][CH2:36][O:31][CH2:32][CH2:33]5)[CH2:40][S:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[C:50]([S:59]([C:62]([F:65])([F:63])[F:64])(=[O:61])=[O:60])[CH:51]=4)(=[O:56])=[O:57])=[O:26])=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 111,2-DichloroethaneHCID 250584544-[[(1R)-3-(4-Morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide2×HCID 58080142(S)-4-(4-((4'-Chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid2×

Product 1

HCID 866618934-(4-((S)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamideYield 41.5%

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Procedure

(S)-4-(4-((4′-Chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 70, 137.4 mg, 0.33 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 190.3 mg, 0.34 mmol), DMAP (81.0 mg, 0.66 mmol), and EDC (134.5 mg, 0.70 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (6.5 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N aq. sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH in DCM). Clean fractions were combined, evaporated under vacuum, and dried overnight in a 40° C. vacuum oven to provide the title product as a substantially separated isomer (129.3 mg, yield: 41.5%).

Workup

  1. customflushed with nitrogen
  2. additionDCM (6.5 ml) was added
  3. additionThe reaction mixture was diluted with DCM (40 ml)
  4. washwashed with 1N aq. sodium bisulfate (35 ml)
  5. dry with materialThe organic layer was dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated under reduced pressure
  8. customThe concentrate was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH in DCM)
  9. customevaporated under vacuum
  10. customdried overnight in a 40° C. vacuum oven

Sources & evidence

ORD record
ord-0c04850b658c4c6b950f7998d7d50fae
Source dataset
uspto-grants-2015_04
Patent number
US09018381B2

Reaction notes

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