proline dl-form → HCID 54767260, compound

HRID 1522903Notes

Reaction equation

HRID 1522903 reaction equation
BrC1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([C:26]3[CH:41]=[CH:40][C:29]([O:30][CH2:31][C@@H:32]([N:34]4[CH2:38][CH2:37][C@@H:36]([CH3:39])[CH2:35]4)[CH3:33])=[CH:28][CH:27]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([O:19]C2CCCCO2)=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[CH3:42][S:43]([O-:45])=[O:44].[Na+].N1CCC[CH:48]1C(O)=O.[OH-].[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu](I)I>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH:9]([C:26]2[CH:41]=[CH:40][C:29]([O:30][CH2:31][C@@H:32]([N:34]3[CH2:38][CH2:37][C@@H:36]([CH3:39])[CH2:35]3)[CH3:33])=[CH:28][CH:27]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:42]([S:43]([CH3:48])(=[O:45])=[O:44])=[CH:3][CH:4]=1

Participants

8

Reactant 4

HCID 614proline dl-formHCID 14798Sodium HydroxideHCID 2733271Sodium methanesulfinateHCID 86682922HCID 86682922, compound

Product 1

HCID 54767260HCID 54767260, compound

Reagents, catalysts & solvents 3

HCID 83717Copper iodideCatalystHCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of (3R)-1-((2S)-1-(4-(3-(4-bromophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-2-yl)phenoxy)propan-2-yl)-3-methylpyrrolidine (32 mg, 0.052 mmol; intermediate from the synthesis of Example 54), sodium methanesulfinate (12 mg, 0.118 mmol), copper iodide (11 mg, 0.058 mmol), DL-proline (12 mg, 0.104 mmol), and sodium hydroxide (5 mg, 0.125 mmol) in DMSO (0.5 mL) was heated at 95° C. overnight. The reaction mixture was diluted with ethyl acetate (20 mL), washed (50 mL sat'd NaHCO3, 50 mL brine), and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was stirred in 80% AcOH/water (0.5 mL) overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase HPLC to give 4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(4-(methylsulfonyl)phenyl)-2H-chromen-6-ol. 1H NMR (DMSO-d6; TFA salt): δ 11.60 (br, 1H), 7.93 (d, 2H), 7.62 (d, 2H), 7.34 (d, 2H), 6.92 (d, 1H), 6.83 (d, 2H), 6.64 (dd, 1H), 6.60 (br, 1H), 6.56 (d, 1H), 6.00 (s, 1H), 3.84 (m, 2H), 3.60 (m, 1H), 3.36 (m, 1H), 3.13 (s, 3H), 2.93 (m, 1H), 2.50 (m, 2H), 2.23 (m, 2H), 2.13 (s, 3H), 1.70 (m, 1H), 1.54 (m, 3H), 1.11 (m, 3H); LCMS: 534.9 (M+H)+.

Workup

  1. washwashed (50 mL sat'd NaHCO3, 50 mL brine)
  2. dry with materialdried (Na2SO4)
  3. customThe solvent was removed under reduced pressure
  4. customThe solvent was removed under reduced pressure
  5. customthe residue was purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-a94d31bc9e62410e92f1a509ad588035
Source dataset
uspto-grants-2015_07
Patent number
US09078871B2

Reaction notes

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