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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 1594565
Notes
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Reaction equation

HRID 1594565 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
ParticipantsProcedureWorkupSources & evidenceReaction notes

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]pyrazine
Yield 50%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A solution of 0.870 g (2.6 mmol) of (7SR,8aSR)-7-(4-fluorophenoxy)methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 2) and 1.8 mL (8.9 mmol) of 5M aqueous ammonium formate in 50 mL methanol was treated with an aqueous slurry of 0.100 g of 10% Pd/C. The reaction was refluxed for 24 hours. The mixture was filtered and the solvent removed in vacuo to give an oily residue. The crude (7SR,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7, 8,8a-octahydro-pyrrolo[1,2-a]pyrazine was combined with 0.373 g (2.8 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), 0.650 g (6.1 mmol) of sodium carbonate in 50 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 silica gel flash chromatography eluting with 85:15 ethyl acetate:hexane gave 0.444 g (50%) of the title compound. Mp (.HCl) 211-213° C. 13C NMR (base, CDCl3): δ 31.7, 35.2, 43.8, 49.1, 51.4, 56.6, 62.3, 72.5, 115.45, 115.56, 115.89, 144.95, 145.24, 149.9, 153.2, 155.1, 155.6, 158.79, 158.90. Anal. calc'd for C18H20F2N4O: C, 62.41; H, 5.82; N, 16.18. Found: C, 62.15, H, 5.99; N, 16.38.

Workup

  1. temperatureThe reaction was refluxed for 24 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 silica gel flash chromatography
  10. washeluting with 85:15 ethyl acetate

Sources & evidence

ORD record
ord-2bb26142681147b9bbd850d4e7244d67
Source dataset
uspto-grants-2001_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06284757B1

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes