Pivaloyl chloride → 2-(4-Bromophenyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylacetamide

HRID 1472220Notes

Reaction equation

HRID 1472220 reaction equation
C(Cl)(=O)C(C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[CH3:28][C@@H:29]([NH:38][CH3:39])[C@H:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:38]([C@H:29]([CH3:28])[C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:39])=[O:18])=[CH:13][CH:14]=1

Participants

6

Reactant 4

HCID 62493Pivaloyl chlorideHCID 62946(-)-PseudoephedrineHCID 74654Benzeneacetic acid, 4-bromo-HCID 81531Diisopropylethylamine2×

Product 1

HCID 670167682-(4-Bromophenyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylacetamide

Reagents, catalysts & solvents 1

HCID 21919333Tetrahydrofurane dichloromethaneSolvent2×

Procedure

Pivaloyl chloride (7.8 ml, 63.3 mmol) was added dropwise to a DCM/THF solution (100 ml/20 ml) containing 4-bromophenylacetic acid (13.59 g, 63.2 mmol). DIEA (11.0 ml, 63.1 mmol) was then added dropwise (exotherm). After stirring at room temperature for 1 hour the solution was poured slowly into a DCM/THF solution (100 ml/20 ml) containing (1R,2R)-(−)-pseudoephedrine (10.5 g, 63.5 mmol) and DIEA (11.0 ml, 63.1 mmol). After stirring overnight at room temperature the solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with aqueous 1N NaOH (2×), aqueous 1N HCl (3×), brine and dried over MgSO4. The solution was filtered and concentrated. The oil residue was diluted with 100 ml of toluene and concentrated. The residue was then dissolved in ethyl ether and triturated with hexanes to give the title compound as a white solid. The compound is a 3:1 mixture of amide rotational isomers by proton NMR: 1H NMR (400 MHz, asterisk denotes minor rotamer, CDCl3): δ 7.42 (d, J=8.3 Hz, 2 H); 7.39-7.27 (m, 5 H); 7.11*(d, J=8.4 Hz, 2H); 7.04 (d, J=8.3 Hz, 2 H); 4.64-4.42 (m, 1 H); 4.07-3.94 (m, 1H); 3.82-3.70 (m, 1H); 2.94*(s, 3H); 3.63 (s, 2 H); 2.82 (s, 3 H); 1.12 (d, J=7.0 Hz, 3 H); 0.86*(d, 3H, J=7.0 Hz). LC1 3.23 min. (M+H)=362

Workup

  1. stirringAfter stirring overnight at room temperature the solution
  2. concentrationwas concentrated
  3. customthe residue partitioned between EtOAc and water
  4. washThe organic phase was washed with aqueous 1N NaOH (2×), aqueous 1N HCl (3×), brine
  5. dry with materialdried over MgSO4
  6. filtrationThe solution was filtered
  7. concentrationconcentrated
  8. additionThe oil residue was diluted with 100 ml of toluene
  9. concentrationconcentrated
  10. dissolutionThe residue was then dissolved in ethyl ether
  11. customtriturated with hexanes

Sources & evidence

ORD record
ord-2900df0473b1426ca3cc3cb80ab1d259
Source dataset
uspto-grants-2015_04
Patent number
US09012488B2

Reaction notes

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