Hydrochloric Acid → Ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)butanoate hydrochloride

HRID 1049115Notes

Reaction equation

HRID 1049115 reaction equation
[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][NH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:12]1=[O:40])[CH3:2].[ClH:48].CCCCCCC>C(OC(C)=O)(C)C.O>[ClH:48].[CH2:1]([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][NH:8][C@H:9]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:12]1=[O:40])[CH3:2]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 8900HeptaneHCID 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

Product 1

HCID 87270797Ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)butanoate hydrochlorideYield 87%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 7915Isopropyl AcetateSolvent

Procedure

To a 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 (=6.55 g, 9.94 mmol) in i-PrOAc (140 mL) was added conc. HCl (12 N, 0.88 mL, 10.6 mmol) solution in water dropwise at room temperature over 2 min. Approximately 95 mL of water and i-PrOAc mixture was removed by distillation under reduced pressure. Isopropyl alcohol (1.28 mL) was added to provide a homogeneous solution at 28 oC. The reaction mixture was added dropwise into a vigorously stirred solution of n-heptane (65 mL) at 5 oC. A white precipitate was formed immediately and the mixture became thick upon completion of addition. The white slurry was stirred for 18 h at room temperature. The white solid was collected by pressure filtration under nitrogen and dried by passing nitrogen through the filter cake for 1 h to provide 6.0 g (87%) 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 HCl salt 4a.HCl as a white solid, LCMS (ESI) m/z 660.2 (MH+ of free base). Elemental analysis: Cl, 5.21%

Workup

  1. customApproximately 95 mL of water and i-PrOAc mixture was removed by distillation under reduced pressure
  2. additionIsopropyl alcohol (1.28 mL) was added
  3. customto provide a homogeneous solution at 28 oC
  4. customA white precipitate was formed immediately
  5. additionthe mixture became thick upon completion of addition
  6. filtrationThe white solid was collected by pressure filtration under nitrogen
  7. customdried
  8. customfor 1 h

Sources & evidence

ORD record
ord-94887e68799948f7972e8c5f9145712c
Source dataset
uspto-grants-2016_07
Patent number
US09382214B2

Reaction notes

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