1,2-Dichloroethane → N-(4-((2R)-4-(4-(2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenyl sulfonyl)-4-(4-((R)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide

HRID 1476340Notes

Reaction equation

HRID 1476340 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.[Si:31]([O:48][C@@H:49]([CH2:86][F:87])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C@@H:59]([NH:68][C:69]2[CH:74]=[CH:73][C:72]([S:75]([NH2:78])(=[O:77])=[O:76])=[CH:71][C:70]=2[S:79]([C:82]([F:85])([F:84])[F:83])(=[O:81])=[O:80])[CH2:60][S:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:53][CH2:52]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Si](O[C@H](CF)CN1CCN(CC[C@@H](NC2C=CC(S(N)(=O)=O)=CC=2S(C(F)(F)F)(=O)=O)CSC2C=CC=CC=2)CC1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Si:31]([O:48][CH:49]([CH2:86][F:87])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C@@H:59]([NH:68][C:69]2[CH:74]=[CH:73][C:72]([S:75]([NH:78][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([N:18]4[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[OH:30])[CH2:16][CH2:17]4)=[CH:22][CH:23]=3)(=[O:77])=[O:76])=[CH:71][C:70]=2[S:79]([C:82]([F:84])([F:83])[F:85])(=[O:80])=[O:81])[CH2:60][S:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:53][CH2:52]1)([C:44]([CH3:45])([CH3:46])[CH3:47])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 58080224(R)-4-(4-((4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid2×HCID 667238514-((R)-4-(4-((R)-2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamideHCID 667238814-((R)-4-(4-((S)-2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

Product 1

HCID 86661885N-(4-((2R)-4-(4-(2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenyl sulfonyl)-4-(4-((R)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Procedure

(R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 58 mg, 0.14 mmol), 4-((R)-4-(4-((R)-2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide and 4-((R)-4-(4-((S)-2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide mixture of diastereomers (INTERMEDIATE 39, 120 mg, 0.14 mmol), DMAP (34 mg, 0.28 mmol), and EDC (53 mg, 0.28 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (2.8 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with 1N aq. sodium bisulfate followed by a saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give N-(4-((2R)-4-(4-(2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide (EXAMPLE 6, STEP 1, 180 mg), which was used in the preparation of EXAMPLE 6, STEP 2, without further purification.

Workup

  1. customflushed with nitrogen
  2. additionDCM (2.8 ml) was added
  3. additionThe reaction mixture was diluted with DCM
  4. washwashed with 1N aq. sodium bisulfate
  5. dry with materialThe organic layer was dried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-f16aacceed2d4a25a32706ef04312d13
Source dataset
uspto-grants-2015_04
Patent number
US09018381B2

Reaction notes

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