Hydrochloric Acid → (7RS,9aSR)-7-(4-Fluorophenoxy)methyl-2-(3,5-dichloropyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

HRID 1352673Notes

Reaction equation

HRID 1352673 reaction equation
[OH:1][CH2:2][CH:3]1[CH2:20][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1.C(OCC)(=O)C.CCOCC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH:3]2[CH2:20][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=4)[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 97324-FluorophenolHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 69431843(7RS,9aSR)-7-hydroxymethyl-2-(3,5-dichloropyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Product 1

HCID 20654286(7RS,9aSR)-7-(4-Fluorophenoxy)methyl-2-(3,5-dichloropyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazineYield 87.3%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 0.50 g (1.58 mmol) of (7RS,9aSR)-7-hydroxymethyl-2-(3,5-dichloro-pyridin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 40 mL of THF with 0.266 g (2.32 mmol) of 4-fluorophenol, 0.498 g (1.90 mmol) of triphenylphosphine, and 0.30 mL (1.90 mmol) of diethyl azodicarboxylate was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and treated with excess HCl(g) in ether. The solvent was evaporated and the residue washed repeatedly with 1:1 ethyl acetate:ether. The white powder was dissolved in chloroform, washed with 1M NaOH (2×), dried (magnesium sulfate), filtered and evaporated. The crude product was purified by flash silica gel chromatography with 50:50 ethyl acetate: hexane to give 0.566 g (87%) of title compound. mp (.HCl) 247–248° C. 13C NMR (base, CDCl3): δ 27.1, 29.0, 36.4, 49.0, 54.4, 54.8, 58.6, 60.7, 71.7, 115.36, 115.47, 115.59, 115.89, 122.3, 124.0, 138.2, 155.1, 155.6, 156.6, 158.8. HRMS calc for C20H22Cl2FN3O: 409.1124, found: 409.1141.

Workup

  1. customThe solvent was evaporated
  2. washthe residue washed repeatedly with 1:1 ethyl acetate
  3. dissolutionThe white powder was dissolved in chloroform
  4. washwashed with 1M NaOH (2×)
  5. dry with materialdried (magnesium sulfate)
  6. filtrationfiltered
  7. customevaporated
  8. customThe crude product was purified by flash silica gel chromatography with 50:50 ethyl acetate

Sources & evidence

ORD record
ord-e19bfeb9b4a545369eef21161a2133ec
Source dataset
uspto-grants-2007_05
Patent number
US07220753B2

Reaction notes

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