Sodium Carbonate → (7RS,8aSR)-7-(4-Fluorophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine

HRID 1594564Notes

Reaction equation

HRID 1594564 reaction equation
[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][N:14]([CH2:16]C4C=CC=CC=4)[CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+].FC1C=CC(OCC2CN3CCNCC3C2)=CC=1.ClC1[N:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][N:14]([C:16]4[N:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=4)[CH2:15][CH:10]3[CH2:9]2)=[CH:24][CH:25]=1

Participants

9

Reactant 5

HCID 10340Sodium CarbonateHCID 5834662-Chloro-5-fluoropyrimidineHCID 2723923Ammonium formateHCID 20682340(7RS,8aSR)-7-(4-fluorophenoxy)methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazineHCID 20682345(7RS,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine

Product 1

HCID 9798299(7RS,8aSR)-7-(4-Fluorophenoxy)methyl-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazineYield 36.4%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A solution of 2.00 g (5.9 mmol) of (7RS,8aSR)-7-(4-fluorophenoxy)methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 2) and 4.1 mL (20.6 mmol) of 5M aqueous ammonium formate in 50 mL methanol was treated with an aqueous slurry of 0.200 g of 10% Pd/C. The reaction was refluxed for 48 hours. The mixture was filtered and the solvent removed in vacuo to give an oily residue. The crude (7RS,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine was combined with 1.2 g (9.1 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), 2.0 g (9.1 mmol) of sodium carbonate in 100 mL of water, and the mixture was gently refluxed for 16 hours. After cooling to room temperature, the mixture was extracted with methylene chloride (3×). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated. Purification by flash silica gel chromatography eluting with 90:10 ethyl acetate:hexane gave 0.744 g (27%) of the title compound. Mp (.HCl) 120-122° C. 3C NMR (base, CDCl3): δ 31.4, 35.3, 43.8, 49.0, 51.5, 57.6, 61.5, 71.4, 115.39, 115.50, 115.62, 115.92, 144.96, 145.24, 149.9, 153.2, 155.1, 155.7, 158.8. Anal. calc'd for C18H20F2N4O: C, 62.41; H, 5.82; N, 16.18. Found: C, 62.05, H, 5.99; N, 16.33.

Workup

  1. temperatureThe reaction was refluxed for 48 hours
  2. filtrationThe mixture was filtered
  3. customthe solvent removed in vacuo
  4. customto give an oily residue
  5. extractionthe mixture was extracted with methylene chloride (3×)
  6. dry with materialThe combined organic layers were dried (magnesium sulfate)
  7. filtrationfiltered
  8. customevaporated
  9. customPurification by flash silica gel chromatography
  10. washeluting with 90:10 ethyl acetate

Sources & evidence

ORD record
ord-0ffaba416dce4545adb91a04f34d50b5
Source dataset
uspto-grants-2001_09
Patent number
US06284757B1

Reaction notes

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