Methyl iodide → Valsartan Impurity 92

HRID 588322Notes

Reaction equation

HRID 588322 reaction equation
[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].CI.C(OC(C)C)(=O)C>O.CN(C)C=O>[CH3:29][O:12][C:11](=[O:13])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1

Participants

7

Reactant 4

HCID 6328Methyl iodideHCID 7915Isopropyl AcetateHCID 10796Cesium carbonateHCID 46193546(2R,4S)-2-methyl-4-((2-methylpropan-2-yl)oxycarbonylamino)-5-(4-phenylphenyl)pentanoic acid

Product 1

HCID 66958074Valsartan Impurity 92

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

2 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) prepared according to Example 2 in WO/2008/031567 is added to 2.55 g caesium carbonate. Dimethylformamide (4 ml) is then added. Methyl iodide (0.55 ml) is then added and the mixture is stirred for 16 h at room temperature. Water (10 ml) and isopropyl acetate (10 ml) are added. The phases are separated. The aqueous phase is washed with isopropyl acetate (2×10 ml). The combined organic phases are washed with 20% aqueous sodium chloride solution (15 ml) and then dried (MgSO4). The mixture is concentrated under reduced pressure to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1=Boc, R2=H, R3=CO2Me). 1H NMR (CDCl3): 1.18 (3H), 1.41 (9H), 1.51 (1H), 1.95 (1H), 2.66 (1H), 2.85 (2H), 3.70 (3H), 3.94 (1H), 4.36 (1H), 7.25 (2H), 7.35 (1H), 7.45 (2H), 7.53 (2H), 7.59 (2H).

Workup

  1. customThe phases are separated
  2. washThe aqueous phase is washed with isopropyl acetate (2×10 ml)
  3. washThe combined organic phases are washed with 20% aqueous sodium chloride solution (15 ml)
  4. dry with materialdried (MgSO4)
  5. concentrationThe mixture is concentrated under reduced pressure

Sources & evidence

ORD record
ord-375854639d2a4fa68f7871c6b48e2697
Source dataset
uspto-grants-2016_01
Patent number
US09227934B2

Reaction notes

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