Hydrochloric Acid → 2-(4-((R)-3-(4-(N-(4-(4-((R)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperazin-1-yl)ethyl dihydrogen phosphate

HRID 1771236Notes

Reaction equation

HRID 1771236 reaction equation
[P:1]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C@@H:24]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](=[O:79])(=[O:78])[NH:41][C:42](=[O:77])[C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][CH:52]([C@@H:55]([O:69][Si](C(C)(C)C)(C)C)[C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:51][CH2:50]4)=[CH:45][CH:44]=3)=[CH:36][C:35]=2[S:80]([C:83]([F:86])([F:85])[F:84])(=[O:82])=[O:81])[CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:17]1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C@@H:24]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](=[O:79])(=[O:78])[NH:41][C:42](=[O:77])[C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][CH:52]([C@H:55]([C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=5[C:62]5[CH:63]=[CH:64][C:65]([Cl:68])=[CH:66][CH:67]=5)[OH:69])[CH2:51][CH2:50]4)=[CH:47][CH:48]=3)=[CH:36][C:35]=2[S:80]([C:83]([F:84])([F:86])[F:85])(=[O:81])=[O:82])[CH2:25][S:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:20][CH2:21]1)=[O:2]

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 58080246Di-tert-butyl 2-(4-((R)-3-(4-(N-(4-(4-((R)-(tert-butyl dimethylsilyloxy)(4'-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperazin-1-yl)ethyl phosphate

Product 1

HCID 866618862-(4-((R)-3-(4-(N-(4-(4-((R)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperazin-1-yl)ethyl dihydrogen phosphateYield 35%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Di-tert-butyl 2-(4-((R)-3-(4-(N-(4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoyl)sulfamoyl)-2-(trifluoromethylsulfonyl)phenylamino)-4-(phenylthio)butyl)piperazin-1-yl)ethyl phosphate (INTERMEDIATE 62,414 mg, 0.32 mmol) was dissolved in DCM (0.5 ml) and treated with a solution of HCl (4M in dioxane, 4.0 ml, 15.84 mmol) at rt, to provide a cloudy solution. The reaction mixture was concentrated under reduced pressure to provide an oily residue which was purified by reverse phase HPLC (Gilson column, eluting with 20→95% MeCN in 10 mM NH4OAc with 5% MeCN over 15 min). The collected fractions were concentrated and washed with water and filtered to remove NH4OAc and provide the title compound (120 mg, yield: 35%).

Workup

  1. customto provide a cloudy solution
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. customto provide an oily residue which
  4. customwas purified by reverse phase HPLC (Gilson column, eluting with 20→95% MeCN in 10 mM NH4OAc with 5% MeCN over 15 min)
  5. concentrationThe collected fractions were concentrated
  6. washwashed with water
  7. filtrationfiltered
  8. customto remove NH4OAc

Sources & evidence

ORD record
ord-8fbcbbecf9364d17aa77d8fdc6b3dd90
Source dataset
uspto-grants-2016_02
Patent number
US09248140B2

Reaction notes

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