Isopropanol → (7S,8aS)-7-(4-Fluorophenoxy)-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine

HRID 861342Notes

Reaction equation

HRID 861342 reaction equation
[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C@@H:7]2[CH2:22][N:10]3[CH2:11][CH2:12][N:13]([CH2:15]C4C=CC=CC=4)[CH2:14][C@@H:9]3[CH2:8]2)=[CH:4][CH:3]=1.ClC1[N:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CC(O)C>CO.C([O-])=O.[NH4+].[Pd].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:22][N:10]3[CH2:11][CH2:12][N:13]([C:15]4[N:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=4)[CH2:14][C@@H:9]3[CH2:8]2)=[CH:23][CH:24]=1

Participants

9

Reactant 4

HCID 3776IsopropanolHCID 11430Potassium CarbonateHCID 5834662-Chloro-5-fluoropyrimidineHCID 57170166(7S,8aS)-7-(4-fluorophenoxy)-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine

Product 1

HCID 70199992(7S,8aS)-7-(4-Fluorophenoxy)-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazineYield 36.1%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 2723923Ammonium formateSolvent

Procedure

A solution of 0.83 g (2.5 mmol) of (7S,8aS)-7-(4-fluorophenoxy)-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine in 10 mL of methanol and 1.8 mL of aqueous ammonium formate (5M) was treated with an aqueous slurry of 0.325 g of 10% palladium on carbon and the mixture was stirred at room temperature for 24 h. The mixture was filtered through Celite, evaporated, re-evaporated with another 100 mL of chloroform, dissolved in 100 mL of chloroform, dried (magnesium sulfate), filtered and evaporated. The crude amine (0.61 g, ca. 2.5 mmol), 0.50 g (3.75 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A.; et al. Org. Prep. Proc. Int., 1995, 27, 600-602), 0.86 g (6.2 mmol) of potassium carbonate and 15 mL of 2-propanol were refluxed for 5.5 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×). The combined organic phase was washed with water (2×) and brine (1×), dried (magnesium sulfate), filtered and evaporated. Purification by silica gel MPLC starting with 70:30 ethyl acetate:hexane and ramping to 50:50 ethyl acetate:hexane at 30 min, gave 0.30 g (36%) of the title compound. mp (.HCl) 90°-95 ° C. 13C NMR (base, CDCl3): δ 36.6, 43.6, 48.7, 60.5, 62.1, 75.6, 115.67, 115.98, 116.08, 116.18, 144.97, 145.26, 149.9, 153.2, 153.8, 155.6, 158.8. HRMS calcd for C17H19F2N4O (MH+): 333.1527, found: 333.1556.

Workup

  1. filtrationThe mixture was filtered through Celite
  2. customevaporated
  3. customre-evaporated with another 100 mL of chloroform
  4. dissolutiondissolved in 100 mL of chloroform
  5. dry with materialdried (magnesium sulfate)
  6. filtrationfiltered
  7. customevaporated
  8. temperatureThe mixture was cooled to room temperature
  9. extractionextracted with ethyl acetate (3×)
  10. washThe combined organic phase was washed with water (2×) and brine (1×)
  11. dry with materialdried (magnesium sulfate)
  12. filtrationfiltered
  13. customevaporated
  14. customPurification by silica gel MPLC
  15. waithexane and ramping to 50:50 ethyl acetate:hexane at 30 min

Sources & evidence

ORD record
ord-57836ff8934049d2a826dcc2d6577738
Source dataset
uspto-grants-1998_02
Patent number
US05714487

Reaction notes

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