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 1049111Notes

Reaction equation

HRID 1049111 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 75%

Reagents, catalysts & solvents 1

HCID 7915Isopropyl AcetateSolvent

Conditions

Temperature
55 °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 (19.0 kg in 59.6 L solution). Dimethylformamide (18 L) was charged and the mixture was distilled under vacuum to remove the isopropyl acetate. Ethyl-4-bromobutyrate (7.83 kg) was charged to the reactor followed by diisopropylethylamine (5.87 kg). The reactor contents were heated to 55° C. and stirred until completion of reaction. The reactor was cooled to 20° C. and isopropyl acetate (110 L) and water (96 L) 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 (95 L). The organic layer was treated with a solution of 85% phosphoric acid/H2O (10.4 kg/152 L). 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 (2.7 kg/19 L). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (21 L). After layer separation, dichloromethane (109 L) was added to the aqueous layer, followed by slow addition of a solution of potassium carbonate/water (23.2 kg/29 L) 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 EtOH/CH2Cl2 (5 L/469 L). Appropriate portions were combined and the solution was concentrated by vacuum distillation. Ethanol (80 L) was charged to provide a concentrated stock 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 (82.9 kg total, ˜17.3 kg of 4a, 75% yield) that 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 (7.83 kg) was charged to the reactor
  4. temperatureThe reactor was cooled to 20° C.
  5. additionisopropyl acetate (110 L) and water (96 L) were added
  6. stirringThe mixture was agitated
  7. customThe water layer was removed
  8. washthe organic layer was washed with water (95 L)
  9. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (10.4 kg/152 L)
  10. stirringThe mixture was agitated
  11. customthe layers were separated
  12. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (2.7 kg/19 L)
  13. stirringThe mixture was agitated
  14. customthe layers were separated
  15. washwashed with isopropyl acetate (21 L)
  16. customAfter layer separation, dichloromethane (109 L)
  17. additionwas added to the aqueous layer
  18. additionfollowed by slow addition of a solution of potassium carbonate/water (23.2 kg/29 L)
  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 by vacuum distillation
  24. additionEthanol (80 L) was charged

Sources & evidence

ORD record
ord-30b839023acd4ce49a408e51f3dc3eb2
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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