1,2-Dichloroethane → 4-(4-((R)-(tert-butyldimethylsilyloxy)(4'-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

HRID 1771232Notes

Reaction equation

HRID 1771232 reaction equation
[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]([CH2:88][CH3:89])[CH2:59][CH2:60][C@@H:61]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([S:77]([NH2:80])(=[O:79])=[O:78])=[CH:73][C:72]=1[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)C[Cl:92]>CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:92])=[CH:34][CH:33]=1)[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:80][S:77]([C:74]3[CH:75]=[CH:76][C:71]([NH:70][C@H:61]([CH2:60][CH2:59][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:54])[CH3:53])([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:88][CH3:89])[CH2:62][S:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[C:72]([S:81]([C:84]([F:86])([F:87])[F:85])(=[O:82])=[O:83])[CH:73]=3)(=[O:78])=[O:79])=[O:22])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 111,2-DichloroethaneHCID 66723539(R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide2×HCID 66723720(R)-4-(4-((tert-butyldimethylsilyloxy)(4-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid2×

Product 1

HCID 866618844-(4-((R)-(tert-butyldimethylsilyloxy)(4'-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamideYield 39.5%

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Procedure

(R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 160 mg, 0.3 mmol), (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-yl amino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 25, 216 mg, 0.27 mmol), DMAP (100 mg, 0.82 mmol), and EDC (104 mg, 0.54 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (3 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 to give a residue, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→25% EtOAc/hexanes) to give 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 4A, STEP 1, 140 mg), that was used in the preparation of EXAMPLE 4A, STEP 2, without further purification.

Workup

  1. customflushed with nitrogen
  2. additionDCM (3 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. customto give a residue, which
  9. customwas purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→25% EtOAc/hexanes)

Sources & evidence

ORD record
ord-3585239dcd6a4b3086f3dfb480750446
Source dataset
uspto-grants-2016_02
Patent number
US09248140B2

Reaction notes

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