2,4-Dimethylbenzaldehyde → N-{(1S, 2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-(2R/S)-2-methyl-N'-(3-trifluoromethyl-phenyl)-malonamide

HRID 2377549Notes

Reaction equation

HRID 2377549 reaction equation
C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([C:22](=[O:34])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[CH3:21])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:9][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([CH3:21])[C:22]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1)=[O:34])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]

Participants

6

Reactant 3

HCID 618142,4-DimethylbenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 69288737{(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester

Product 1

HCID 131726491N-{(1S, 2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-(2R/S)-2-methyl-N'-(3-trifluoromethyl-phenyl)-malonamide

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (173 mg, 0.46 mmol, prepared as described in WO PCT 0250019) was dissolved in 5 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with 2-methyl-malonic acid (54 mg, 0.46 mmol), meta-trifluoromethylaniline (0.06 mL, 0.46 mmol), N,N-diisopropylethylamine (0.8 mL, 4.6 mmol) and HATU (434 mg, 1.1 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 17% yield). MS found: (M+Na)+=528.4. (25b) A solution of {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 0.08 mmol) in MeOH (2 mL) was charged with 5% Pd/C, Degussa style (8 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.009 mL, 0.06 mmol) and sodium cyanoborohydride (5 mg, 0.08 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=494.4.

Workup

  1. filtrationfiltered
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in MeOH (2 mL)
  4. stirringstirred for 12 h at RT
  5. customquenched with sat. NaHCO3
  6. extractionextracted twice with EtOAc
  7. washwashed with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification of the residue by reverse-phase HPLC

Sources & evidence

ORD record
ord-602baf9b1cdc4fd2a71a690195ae9cfe
Source dataset
uspto-grants-2008_12
Patent number
US07468440B2

Reaction notes

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