Cesium fluoride → HCID 12094340, compound

HRID 2358208Notes

Reaction equation

HRID 2358208 reaction equation
Br[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][NH:23]4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[NH2:26][CH2:27][C@@H:28]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:46][C:43]([O:42][C:40](=[O:41])[C@H:28]([CH2:27][NH:26][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][NH:23]4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1)[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])([CH3:44])[CH3:45]

Participants

6

Reactant 3

HCID 25953Cesium fluoride2×HCID 10803731(S)-tert-Butyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate2×HCID 57832855HCID 57832855, compound

Product 1

HCID 12094340HCID 12094340, compoundYield 83%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 312751,4-DioxaneSolvent2×

Procedure

A mixture of 317 mg (0.79 mmoles) of 4-bromo-5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 279 mg (0.95 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 168 mg (1.11 mmoles) of caesium fluoride, 36 mg (0.04 mmoles) of tris(dibenzylideneacetone)dipalladium(0), 49 mg (0.08 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 11 ml of dioxane is heated under reflux for 21 hours. After cooling down another 140 mg (0.48 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 168 mg (1.11 mmoles) of caesium fluoride, 36 mg (0.04 mmoles) of tris(dibenzylideneacetone)dipalladium(0), and 49 mg (0.08 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 2 ml of dioxane are added and the reaction medium is heated under reflux for 3.5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol 50-50-0, 25-75-0, 0-100-0, and finally 0-100-3. 400 mg (Yield=83%) of expected product is obtained in the form of an oil.

Workup

  1. temperatureis heated
  2. temperatureunder reflux for 21 hours
  3. additionare added
  4. temperaturethe reaction medium is heated
  5. temperatureunder reflux for 3.5 hours
  6. customThe reaction mixture is evaporated to dryness under reduced pressure (2 kPa)
  7. customThe organic phase is separated
  8. dry with materialdried over magnesium sulphate
  9. customthe solvent is evaporated off under reduced pressure (2 kPa)
  10. customThe residue is chromatographed
  11. washon silicagel eluting with a gradient of heptane-ethyl acetate-methanol 50-50-0, 25-75-0, 0-100-0, and finally 0-100-3

Sources & evidence

ORD record
ord-1a0d1d0d34f7497e988bdb15aee45058
Source dataset
uspto-grants-2010_07
Patent number
US07763621B2

Reaction notes

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