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 1771233Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1771233
[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

Komponenten

6

Edukt 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

Produkt 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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 142844-(Dimethylamino)pyridineKatalysator

Versuchsvorschrift

(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.

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-41ef8ac94f904f878263da9e36151a67
Quelldatensatz
uspto-grants-2016_02
Patentnummer
US09248140B2

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