4,6-Dichloro-5-methylpyrimidine → (1,1-Dimethylethyl)-3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-n-[(phenylmethoxy)carbonyl]alaninate

HRID 729741Notes

Reaction equation

HRID 729741 reaction equation
Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][C@@H:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[CH3:30][C:27]([O:26][C:24](=[O:25])[C@H:12]([CH2:11][NH:10][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:28])[CH3:29]

Participants

5

Reactant 2

HCID 8188604,6-Dichloro-5-methylpyrimidineHCID 10803731(S)-tert-Butyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate

Product 1

HCID 12094347(1,1-Dimethylethyl)-3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-n-[(phenylmethoxy)carbonyl]alaninateYield 53.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 81531DiisopropylethylamineSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 325 mg (2 mmoles) of 4,6-dichloro-5-methyl-pyrimidine (marketed by SPECS), 600 mg (2 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176) in 3 ml of dimethylformamide and 3 ml of diisopropylethylamine is heated at 120° C. overnight. The reaction medium is concentrated to dryness under vacuum and the residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. The residue is chromatographed on silicagel eluting with a gradient of heptane (100%) to a mixture of heptane-ethyl acetate (50-50). 450 mg (Yield=53%) of expected product is obtained in the form of an oil.

Workup

  1. concentrationThe reaction medium is concentrated to dryness under vacuum
  2. additionthe residue is taken up in a mixture of water, ethyl acetate
  3. customThe organic phase is separated
  4. dry with materialThe combined organic phases are dried over magnesium sulphate
  5. customthe solvent is evaporated off under vacuum
  6. customThe residue is chromatographed
  7. washon silicagel eluting with a gradient of heptane (100%) to a mixture of heptane-ethyl acetate (50-50)

Sources & evidence

ORD record
ord-3207d05f12e64c47b2f66cebb0dd7991
Source dataset
uspto-grants-2009_09
Patent number
US07582640B2

Reaction notes

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