Methyl methoxyacetate → (R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamide

HRID 600423Notes

Reaction equation

HRID 600423 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[NH2:12].[CH3:13][O:14][CH2:15][C:16](OC)=[O:17]>COC(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH:12][C:16](=[O:17])[CH2:15][O:14][CH3:13]

Participants

4

Reactant 2

HCID 80507Methyl methoxyacetateHCID 162444038-Fluorochroman-4-amine

Product 1

HCID 59799572(R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamideYield 16%

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Procedure

A mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) was heated at reflux under argon for two hours (at which time the ratio of acylated to unacylated product was 1:1 by HPLC). The solid that formed upon cooling was collected via filtration and dissolved in EtOAc. The mixture was filtered to remove the biocatalyst and washed once with 0.5M HCl to remove any lingering (S)-amine. The solvent was evaporated and the product was recrystallized from tert-butyl methyl ether to yield (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g). The reaction solvent and recrystallization mother liquor was washed three times with 0.5 M HCl and concentrated to yield additional (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.83 g). The combined acidic aqueous layers were made basic by NaOH and extracted with methylene chloride to yield (S)-8-fluorochroman-4-amine (5a) (1.6 g). A solution of (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g) in 8M HCl in EtOH (50 mL) was heated at reflux for four hours. The solvents were removed from the cooled reaction mixture, the resulting solid was taken up in 50 mL of 0.5M NaOH, salted out with NaCl(s), and extracted four times with methylene chloride to yield (R)-8-fluorochroman-4-amine (0.48 g (87%)) (5b). The % ee was checked via chiral HPLC: Chiralcel OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) method: isocratic 5% (0.05% TFA/EtOH) 95% (0.05% TFA/Hex), Rt=7.2 min (S)-enantiomer, Rt=9.2 min (R)-enantiomer.

Workup

  1. temperaturewas heated
  2. temperatureat reflux under argon for two hours (at which time the ratio of acylated to unacylated product
  3. customThe solid that formed
  4. temperatureupon cooling
  5. filtrationwas collected via filtration
  6. dissolutiondissolved in EtOAc
  7. filtrationThe mixture was filtered
  8. customto remove the biocatalyst
  9. washwashed once with 0.5M HCl
  10. customto remove any lingering (S)-amine
  11. customThe solvent was evaporated
  12. customthe product was recrystallized from tert-butyl methyl ether

Sources & evidence

ORD record
ord-e359ccd522c642cca6a9a7d9d5ef1b89
Source dataset
uspto-grants-2011_03
Patent number
US07902187B2

Reaction notes

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