Isopropyl Acetate → 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 1049112Notes

Reaction equation

HRID 1049112 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].C(N(C(C)C)CC)(C)C.[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55]Br)[CH3:50].C(OC(C)C)(=O)C>O.CN(C)C=O>[CH2:49]([O:51][C:52](=[O:57])[CH2:53][CH2:54][CH2:55][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])[CH3:50]

Participants

7

Reactant 4

HCID 7915Isopropyl AcetateHCID 76300Ethyl 4-bromobutyrateHCID 81531DiisopropylethylamineHCID 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)butanoate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
82.5 °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 (3000 g) and dimethylformamide (4.5 L). The mixture was stirred and diisopropylethylamine (924 g) and ethyl-4-bromobutyrate (1287 g) were charged to the reactor and the reactor contents were heated to 80-85° C. After completion of the reaction (4 hr) the contents were cooled to 25-30° C. and isopropyl acetate (15.0 L) and water (9.0 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 citric acid/water (300 g/6.0 L). The layers were separated and the organic layer was treated with a solution of 85% phosphoric acid/H2O (1055 g/21.0 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 (422 g/6.0 L). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (2×6.0 L). After layer separation, isopropyl acetate (15.0 L) was added to the aqueous layer, followed by slow addition of a solution of potassium carbonate/water (3.04 kg/4.5 L) while mixing. The layers were separated and the aqueous layer was extracted with i-PrOAc (6.0 L). After layer separation, the combined organic layers were washed with sodium bicarbonate/water (1.20 kg/15.0 L). Reagent alcohol (6.0 L) was added to the organic layer and the solution concentrated by vacuum distillation until the reactor volume was ˜9.0 L. Reagent alcohol (12.0 L) was added and distillation was resumed until the volume was 9.0 L. 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 was used in the next step. LCMS (ESI) m/z 660.2 (MH+)

Workup

  1. customAfter completion of the reaction (4 hr) the contents
  2. temperaturewere cooled to 25-30° C.
  3. stirringThe mixture was agitated
  4. customThe water layer was removed
  5. washthe organic layer was washed with citric acid/water (300 g/6.0 L)
  6. customThe layers were separated
  7. additionthe organic layer was treated with a solution of 85% phosphoric acid/H2O (1055 g/21.0 L)
  8. stirringThe mixture was agitated
  9. customthe layers were separated
  10. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (422 g/6.0 L)
  11. stirringThe mixture was agitated
  12. customthe layers were separated
  13. washwashed with isopropyl acetate (2×6.0 L)
  14. customAfter layer separation, isopropyl acetate (15.0 L)
  15. additionwas added to the aqueous layer
  16. additionfollowed by slow addition of a solution of potassium carbonate/water (3.04 kg/4.5 L)
  17. additionwhile mixing
  18. customThe layers were separated
  19. extractionthe aqueous layer was extracted with i-PrOAc (6.0 L)
  20. customAfter layer separation
  21. washthe combined organic layers were washed with sodium bicarbonate/water (1.20 kg/15.0 L)
  22. additionReagent alcohol (6.0 L) was added to the organic layer
  23. concentrationthe solution concentrated by vacuum distillation until the reactor volume
  24. additionReagent alcohol (12.0 L) was added
  25. distillationdistillation

Sources & evidence

ORD record
ord-8e730e7335da425cac96ef1b43a975b6
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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