Carbamate → N-{(R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-2,2-dimethyl-propionamide

HRID 1049109Notes

Reaction equation

HRID 1049109 reaction equation
[C:1](=[O:4])([O-])[NH2:2].N[C@H:6]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])=[C:11]([CH3:24])[N:10](CC2C(C(F)(F)F)=CC=CC=2F)[C:9]1=[O:37].C([O-])([O-])=O.[K+].[K+].C(=O)=O>O.CN(C=O)C>[F:23][C:16]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[C:13](=[O:14])[N:8]([CH2:7][C@H:6]([NH:2][C:1](=[O:4])[C:12]([CH3:15])([CH3:13])[CH3:11])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:9](=[O:37])[NH:10][C:11]=1[CH3:24]

Participants

7

Reactant 4

HCID 276CarbamateHCID 280Carbon DioxideHCID 11430Potassium CarbonateHCID 114214123-((R)-2-Amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione3×

Product 1

HCID 58239296N-{(R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-2,2-dimethyl-propionamideYield 70%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

DMF (anhydrous, 70 mL) was added to carbamate residue 3a (7.5 g, 19.7 mmol) and the mixture was cooled to 0° C. t-BOC-(1R)-amino-2-amino-1-phenylethane acetate salt (6.41 g, 21.6 mmol) was added followed by K2CO3 (4.08 g, 29.6 mmol). The mixture was stirred for ˜3 hours (all carbamate 3a (tR=11.5 minute in HPLC method 1) was converted to urea intermediate (tR=10.5 minute in HPLC method 1)). The temperature was raised to 60° C. to control the CO2 release. The mixture was heated for 2-3 hours then 210 mL of water was slowly added over 30-60 minutes maintaining the temperature at 60° C. The slurry was stirred for 30-60 minutes at 50-60° C. and was cooled down to 25° C. over 30-60 minutes. The slurry was filtered and the cake was washed with 210 mL water to remove the residual base. The cake was dried at 10 mm/50° C. to give 6.5 g (70% yield) of off-white fine needle crystal 3b. Alternately, the cake may be washed with acetonitrile/water 2:1 before drying.

Workup

  1. additionwas added
  2. temperatureThe mixture was heated for 2-3 hours
  3. temperaturemaintaining the temperature at 60° C
  4. temperaturewas cooled down to 25° C. over 30-60 minutes
  5. filtrationThe slurry was filtered
  6. washthe cake was washed with 210 mL water
  7. customto remove the residual base
  8. customThe cake was dried at 10 mm/50° C.

Sources & evidence

ORD record
ord-1d95333d7ac345b3b32653d666b03dc1
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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