Oxalyl chloride → 4-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide

HRID 499239Notes

Reaction equation

HRID 499239 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=1.C(Cl)(=O)C(Cl)=O.[CH:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:31])[CH3:30]>C(Cl)Cl.CN(C=O)C>[CH2:33]([N:32]([CH:29]([CH3:31])[CH3:30])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][CH:12]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1

Participants

6

Reactant 3

HCID 65578Oxalyl chlorideHCID 66024IsopropylbenzylamineHCID 217124094-(2-Fluorophenyl)-2-morpholinopyrimidine-5-carboxylic acid

Product 1

HCID 594211924-(2-Fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To an ice-cooled solution of 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (4.321 g, 14.25 mmol) in CH2Cl2 (100 mL) and DMF (2 drops) was added oxalyl chloride (1.5 mL, 2.21 g, 17.5 mmol) dropwise. Most solids dissolved at first, later a precipitate formed. The suspension was stirred for 1 hour at 0° C., and then allowed to warm to room temperature (all solids dissolved). The solution was concentrated to a dark oil, which crystallized upon standing. The crude acid chloride was taken up in toluene (50 mL, distilled, dried over Na2SO4) and cooled in ice. N-Isopropylbenzylamine (9.5 mL, 8.5 g, 56.8 mmol) was added. The resulting suspension was stirred at room temperature for 90 minutes, washed with water and a saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (400 mL silica, EtOAc/heptanes 1:1). All fractions containing the product were combined and concentrated. Some of the excess amine eluted with the product. A solution of the mixture in CH2Cl2 (50 mL) was washed with a 10% aqueous citric acid solution (2×25 mL), water (25.mL), and saturated aqueous NaCl solution (25 mL), dried over Na2SO4, and concentrated to give pure 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide as a yellowish foam (5.685 g, 13.08 mmol, 92%).

Workup

  1. dissolutionMost solids dissolved at first, later a precipitate
  2. customformed
  3. temperatureto warm to room temperature
  4. dissolution(all solids dissolved)
  5. concentrationThe solution was concentrated to a dark oil, which
  6. customcrystallized
  7. temperaturecooled in ice
  8. stirringThe resulting suspension was stirred at room temperature for 90 minutes
  9. washwashed with water
  10. dry with materiala saturated aqueous NaCl solution, dried over Na2SO4
  11. concentrationconcentrated
  12. customThe crude product was purified by column chromatography (400 mL silica, EtOAc/heptanes 1:1)
  13. additionAll fractions containing the product
  14. concentrationconcentrated
  15. washSome of the excess amine eluted with the product
  16. washA solution of the mixture in CH2Cl2 (50 mL) was washed with a 10% aqueous citric acid solution (2×25 mL), water (25.mL), and saturated aqueous NaCl solution (25 mL)
  17. dry with materialdried over Na2SO4
  18. concentrationconcentrated

Sources & evidence

ORD record
ord-ee2d510350cd410b83126b1d92ceb238
Source dataset
uspto-grants-2010_08
Patent number
US07767680B2

Reaction notes

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