Dimethylformamide → Ethyl 4-(((1R)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl)-1-phenylethyl)amino)butanoate

HRID 1049110Notes

Reaction equation

HRID 1049110 reaction equation
[NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].CN(C)[CH:42]=[O:43]>C(OC(C)C)(=O)C>[CH2:9]([O:10][C:42](=[O:43])[CH2:3][CH2:2][CH2:34][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])[CH3:8]

Participants

4

Reactant 2

HCID 6228DimethylformamideHCID 114214123-((R)-2-Amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methyl-1H-pyrimidine-2,4-dione

Product 1

HCID 67105103Ethyl 4-(((1R)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl)-1-phenylethyl)amino)butanoateYield 80%

Reagents, catalysts & solvents 1

HCID 7915Isopropyl AcetateSolvent

Conditions

Temperature
52 °C

Procedure

To a reactor was charged a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in isopropyl acetate (30.7 kg in 125.4 kg solution). Dimethylformamide (28.8 kg) was charged and the mixture was distilled under vacuum to remove the isopropyl acetate. Ethyl-4-bromobutyrate (11.8 kg) was charged to the reactor followed by diisopropylethylamine (8.87 kg). The reactor contents were heated to 52° C. and stirred until completion of reaction. The reactor was cooled to 22° C. and isopropyl acetate (144 kg) and water (144 kg) were added. The mixture was agitated and the layers allowed to settle. The water layer was removed and the organic layer was washed with water (144 kg). The organic layer was treated with a solution of 85% phosphoric acid/H2O (15.6 kg/173 kg). The mixture was agitated, allowed to settle, and the layers were separated. The organic layer was treated with a solution of 85% phosphoric acid/H2O (4.03 kg/28.8 kg). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (28.8 kg). After layer separation, isopropyl acetate (144 kg) was added to the aqueous layer, followed by slow addition of a solution of potassium carbonate/water (35.1 kg/43.2 kg) while mixing. The layers were separated and the organic layer was concentrated by vacuum distillation. The solution was passed through a silica gel plug pre-conditioned with CH2Cl2 and the plug eluted using i-PrOAc/CH2Cl2 (31 kg/190 kg) in four portions. Appropriate portions were combined and the solution was concentrated initially by atmospheric pressure distillation followed by vacuum distillation. The concentrated solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a (86.4 kg total, ˜29.8 kg of 4a, 80% yield) was used in the next step. LCMS (ESI) m/z 660.2 (MH+)

Workup

  1. distillationthe mixture was distilled under vacuum
  2. customto remove the isopropyl acetate
  3. additionEthyl-4-bromobutyrate (11.8 kg) was charged to the reactor
  4. temperatureThe reactor was cooled to 22° C.
  5. additionisopropyl acetate (144 kg) and water (144 kg) were added
  6. stirringThe mixture was agitated
  7. customThe water layer was removed
  8. washthe organic layer was washed with water (144 kg)
  9. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (15.6 kg/173 kg)
  10. stirringThe mixture was agitated
  11. customthe layers were separated
  12. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (4.03 kg/28.8 kg)
  13. stirringThe mixture was agitated
  14. customthe layers were separated
  15. washwashed with isopropyl acetate (28.8 kg)
  16. customAfter layer separation, isopropyl acetate (144 kg)
  17. additionwas added to the aqueous layer
  18. additionfollowed by slow addition of a solution of potassium carbonate/water (35.1 kg/43.2 kg)
  19. additionwhile mixing
  20. customThe layers were separated
  21. concentrationthe organic layer was concentrated by vacuum distillation
  22. washthe plug eluted
  23. concentrationthe solution was concentrated initially by atmospheric pressure distillation
  24. distillationfollowed by vacuum distillation

Sources & evidence

ORD record
ord-f5ce853e82d74ae881142ad4a4abdf20
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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