Hydrochloric Acid → methyl (S)-4-((R)-1-((S)-2-(t-butoxycarbonylamino)-3-cyclohexylpropylcarbamoyl)piperidin-3-yl)-4-(3-chloro-2-fluorophenyl)-4-hydroxybutylcarbamate

HRID 451889Notes

Reaction equation

HRID 451889 reaction equation
Cl.[Cl:2][C:3]1[C:4]([F:25])=[C:5]([C@@:9]([OH:24])([C@@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[CH2:35][NH:36][C:37](=O)[O:38]C1C=CC([N+]([O-])=O)=CC=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C>CC#N.C(Cl)Cl.CCOCC>[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:49][CH:50]1[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]1)[CH2:35][NH:36][C:37]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([C@@:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=2[F:25])([OH:24])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:17])[O:15][CH3:16])[CH2:19]1)=[O:38])=[O:32])([CH3:29])([CH3:27])[CH3:28]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 59201293methyl (S)-4-(3-chloro-2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamateHCID 59382967(S)-4-nitrophenyl 2-(t-butoxycarbonylamino)-3-cyclohexylpropylcarbamate

Product 1

HCID 59201640methyl (S)-4-((R)-1-((S)-2-(t-butoxycarbonylamino)-3-cyclohexylpropylcarbamoyl)piperidin-3-yl)-4-(3-chloro-2-fluorophenyl)-4-hydroxybutylcarbamateYield 68.2%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred suspension of the HCl salt of methyl (S)-4-(3-chloro-2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate (31.6 mg, 0.08 mmol) and (S)-4-nitrophenyl 2-(t-butoxycarbonylamino)-3-cyclohexylpropylcarbamate (45 mg, 0.105 mmol) in MeCN (1 mL) and CH2Cl2 (1 mL) was added DIEA (80 μL, 0.45 mmol). The mixture was stirred at rt for 3 d, diluted with ether (90 mL), washed with 5% aq HCl (20 mL), IM aq NaOH (20 mL) and brine (20 mL), and dried over MgSO4. Removal of the solvent left a white solid (61 mg) which was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford five fractions. Fractions 4 and 5 were pooled and concentrated to afford methyl (S)-4-((R)-1-((S)-2-(t-butoxycarbonylamino)-3-cyclohexylpropylcarbamoyl)piperidin-3-yl)-4-(3-chloro-2-fluorophenyl)-4-hydroxybutylcarbamate (35 mg) as an oil.

Workup

  1. washwashed with 5% aq HCl (20 mL), IM aq NaOH (20 mL) and brine (20 mL)
  2. dry with materialdried over MgSO4
  3. customRemoval of the solvent
  4. waitleft a white solid (61 mg) which
  5. washThe cartridge was eluted sequentially with 0, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each)
  6. customto afford five fractions
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-7af8b3f4936e4b6388428b4a1c6887b6
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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