1,2-Dichloroethane → Di-tert-butyl 2-(((R)-3-(4-(N-(4-(4-((R)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(ethyl)amino)ethyl phosphate

HRID 1771189Notes

Reaction equation

HRID 1771189 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.C(Cl)CCl.C(N(CC)CC)C.[P:42]([O:54][CH2:55][CH2:56][N:57]([CH2:87][CH3:88])[CH2:58][CH2:59][C@@H:60]([NH:69][C:70]1[CH:75]=[CH:74][C:73]([S:76](=[O:79])(=[O:78])[NH2:77])=[CH:72][C:71]=1[S:80]([C:83]([F:86])([F:85])[F:84])(=[O:82])=[O:81])[CH2:61][S:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[P:42]([O:54][CH2:55][CH2:56][N:57]([CH2:58][CH2:59][C@@H:60]([NH:69][C:70]1[CH:75]=[CH:74][C:73]([S:76](=[O:79])(=[O:78])[NH:77][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[CH:72][C:71]=1[S:80]([C:83]([F:85])([F:86])[F:84])(=[O:82])=[O:81])[CH2:61][S:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:87][CH3:88])([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:43]

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 58080224(R)-4-(4-((4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid2×HCID 66723800(R)-di-tert-butyl 2-(ethyl(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)amino)ethyl phosphate2×

Product 1

HCID 87125282Di-tert-butyl 2-(((R)-3-(4-(N-(4-(4-((R)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)(ethyl)amino)ethyl phosphateYield 59.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 88 mg, 0.20 mmol), EDC (77 mg, 0.40 mmol), and DMAP (49 mg, 0.40 mmol), triethylamine (28 μl, 0.20 mmol) in 5 ml of DCM was added (R)-di-tert-butyl 2-(ethyl(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)amino)ethyl phosphate (INTERMEDIATE 50, 150 mg, 0.20 mmol). The mixture was stirred at r.t overnight. The reaction solution was diluted with DCM (20 ml) and washed with water (30 ml). The aqueous layer was extracted with DCM (30 ml) and the combined organic layers were dried over sodium sulfate, and concentrated in vacuo to an oil. This material was purified by column chromatography (ISCO, 0→100% EtOAc/hexane followed by 0→10% MeOH/EtOAc) to provide the title compound (137 mg, yield: 59%).

Workup

  1. washwashed with water (30 ml)
  2. extractionThe aqueous layer was extracted with DCM (30 ml)
  3. dry with materialthe combined organic layers were dried over sodium sulfate
  4. concentrationconcentrated in vacuo to an oil
  5. customThis material was purified by column chromatography (ISCO, 0→100% EtOAc/hexane followed by 0→10% MeOH/EtOAc)

Sources & evidence

ORD record
ord-247a7b85eaed47ec9b3286bc7a2c02c5
Source dataset
uspto-grants-2016_02
Patent number
US09248140B2

Reaction notes

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