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

HRID 1977026Notes

Reaction equation

HRID 1977026 reaction equation
[OH:1][CH2:2][CH:3]1[CH2:21][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[C:19]#[N:20])[CH2:11][CH:6]2[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOCC.Cl>[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:1][CH2:2][CH:3]2[CH2:21][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[C:19]#[N:20])[CH2:11][CH:6]3[CH2:5][CH2:4]2)=[CH:44][CH:43]=1

Participants

8

Reactant 4

HCID 97324-FluorophenolHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 69432665(7RS,9aSR)-7-hydroxymethyl-2-(2-cyano4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Product 1

HCID 20654284(7RS,9aSR)-7-(4-Fluorophenoxy)methyl-2-(2-cyano-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazineYield 30.4%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 0.51 g (1.8 mmol) of (7RS,9aSR)-7-hydroxymethyl-2-(2-cyano-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 0.555 g (2.12 mmol) of triphenylphosphine, and 0.296 g (2.64 mmol) of 4-fluorophenol in 8 mL of dry THF was treated with 0.368 g (2.12 mmol) of diethyl azodicarboxylate and stirred at ambient temperature for 24 h. The mixture was diluted with ether, and 1M HCl was added until a gummy residue formed. The layers were separated and the aqueous layer was washed with ether (3×). The aqueous layer was combined with the gummy residue and dissolved in a mixture of ethyl acetate and 10% ammonium hydroxide, the layers were separated and the aqueous layer was extracted with more ethyl acetate (2×). The organic layers were evaporated, the residue dissolved in chloroform, washed with 1M NaOH (3×), dried (magnesium sulfate), filtered and evaporated. The product was dissolved in absolute ethanol, filtered and evaporated to give 0.21 g of the title compound. mp (—HCl) 235-240° C. HRMS calcd for C22H23F2N3O: 383.1809, found: 383.1796.

Workup

  1. additionwas added until a gummy residue
  2. customformed
  3. customThe layers were separated
  4. washthe aqueous layer was washed with ether (3×)
  5. dissolutiondissolved in a mixture of ethyl acetate and 10% ammonium hydroxide
  6. customthe layers were separated
  7. extractionthe aqueous layer was extracted with more ethyl acetate (2×)
  8. customThe organic layers were evaporated
  9. dissolutionthe residue dissolved in chloroform
  10. washwashed with 1M NaOH (3×)
  11. dry with materialdried (magnesium sulfate)
  12. filtrationfiltered
  13. customevaporated
  14. dissolutionThe product was dissolved in absolute ethanol
  15. filtrationfiltered
  16. customevaporated

Sources & evidence

ORD record
ord-9b6ae618d18141bd8cd39b11a48eebb8
Source dataset
uspto-grants-2001_05
Patent number
US06231833B1

Reaction notes

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