4-Fluorophenol → (7R,9aS)-7-(4-Fluorophenoxy)methyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

HRID 1977029Notes

Reaction equation

HRID 1977029 reaction equation
[OH:1][CH2:2][C@H:3]1[CH2:20][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H: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>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:1][CH2:2][C@H:3]2[CH2:20][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[NH2:19])[CH2:11][C@@H:6]3[CH2:5][CH2:4]2)=[CH:24][CH:23]=1

Participants

6

Reactant 4

HCID 97324-FluorophenolHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 54443190(7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluoro-phenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Product 1

HCID 69433005(7R,9aS)-7-(4-Fluorophenoxy)methyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazineYield 30.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 4.12 g (14.8 mmol) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 2.48 g (22.2 mmol) of 4-fluorophenol and 4.65 g (17.7 mmol) of triphenylphosphine in 225 mL of THF was treated with 2.79 mL (17.7 mmol) of diethyl azodicarboxylate and stirred at room temperature for 4 days. The solvent was evaporated, the residue dissolved in 1:1 ethyl acetate:ethyl ether and the solution treated with HCl(g) in ether until precipitation ceased. The mixture was filtered and the solid washed repeatedly with ethyl acetate. The solid was dissolved in a mixture of chloroform and 1M sodium hydroxide, the layers separated, and the organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 60:40 ethyl acetate:hexane gave 1.69 g (30%) of the title compound. mp (—HCl) 144-149° C. HRMS calcd for C21H25F2N3O: 373.1966, found: 373.1958.

Workup

  1. customThe solvent was evaporated
  2. dissolutionthe residue dissolved in 1:1 ethyl acetate
  3. additionethyl ether and the solution treated with HCl(g) in ether until precipitation
  4. filtrationThe mixture was filtered
  5. washthe solid washed repeatedly with ethyl acetate
  6. dissolutionThe solid was dissolved in a mixture of chloroform and 1M sodium hydroxide
  7. customthe layers separated
  8. dry with materialthe organic phase was dried (magnesium sulfate)
  9. filtrationfiltered
  10. customevaporated
  11. customPurification by flash silica gel chromatography with 60:40 ethyl acetate

Sources & evidence

ORD record
ord-fd047472033949fcbd4344c7848e5e6e
Source dataset
uspto-grants-2001_05
Patent number
US06231833B1

Reaction notes

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