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

HRID 1771246Notes

Reaction equation

HRID 1771246 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][C@H:57]1[N:62]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61][CH2:60][O:59][CH2:58]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:94]>C(Cl)Cl.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:94])=[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:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:62]4[CH2:61][CH2:60][O:59][CH2:58][C@H:57]4[CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[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

6

Reactant 3

HCID 111,2-DichloroethaneHCID 667234854-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-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 866618984-(4-((R)-(tert-butyldimethylsilyloxy)(4'-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamideYield 253%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 183 mg, 0.34 mmol) in DCM (3 ml) were added sequentially DMAP (125 mg, 1.02 mmol), 4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-yl amino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 105, 280 mg, 0.34 mmol) and EDC (131 mg, 0.68 mmol). The resulting solution was stirred at room temperature overnight. Evaporation of the volatiles under reduced pressure gave a residue which was purified by column chromatography (ISCO, 27 g silica gel column, eluting with 0→20% EtOAc/hexanes) to give 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((S)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 24, STEP 1,153 mg) which was used in the preparation of EXAMPLE 24, STEP 2 without further purification.

Workup

  1. customEvaporation of the volatiles under reduced pressure
  2. customgave a residue which
  3. customwas purified by column chromatography (ISCO, 27 g silica gel column, eluting with 0→20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-c54c986951d448aea21f044223e7aa20
Source dataset
uspto-grants-2016_02
Patent number
US09248140B2

Reaction notes

Loading…