Tris(hydroxymethyl)aminomethane → (+)-(6S)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine

HRID 429956Notes

Reaction equation

HRID 429956 reaction equation
C(O)C(N)(CO)CO.[CH3:9][O:10][C:11]([C:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[NH:17][C:16](=[O:27])[NH:15][C:14]=1[CH2:28][O:29][CH3:30])=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([C:13]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[NH:17][C:16](=[O:27])[NH:15][C:14]=1[CH2:28][O:29][CH3:30])=[O:12]

Participants

4

Reactant 2

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 108050354-(3,4-Difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester

Product 1

HCID 10852560(+)-(6S)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A 100-L reaction vessel was charged with 50 mM Tris buffer (Tris HCl (77.4 g) and Tris Base (196.7 g) in deionized water (42.3 L)), 12.0 L of subtilisin (PURAFECT® 4000 L, available from Genencor International), acetonitrile (5.7 L), and (±)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine, (2), (120 g, 0.38 mol) and the mixture was allowed to react at 37° C., pH 8.3 for 9 days. The reaction mixture was extracted with toluene (10 L). The aqueous layer was separated and washed with toluene (5 L). The combined organic extracts were washed with brine (10 L). The organic layer was concentrated by rotary evaporation, filtered, then adjusted to 400 mL volume with toluene. The (+)-2 was crystallized by adding heptane (80 mL), followed by seeding. The mixture was stirred for 1 hr, then heptane (520 mL) was added over 8 hrs. The crystals were filtered, washed with 3:2 heptane-toluene (150 mL), then dried under high vacuum to yield (+)-(6S)-5-methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxopyrimidine, ((+)-2) as a white solid.

Workup

  1. customto react at 37° C.
  2. extractionThe reaction mixture was extracted with toluene (10 L)
  3. customThe aqueous layer was separated
  4. washwashed with toluene (5 L)
  5. washThe combined organic extracts were washed with brine (10 L)
  6. concentrationThe organic layer was concentrated by rotary evaporation
  7. filtrationfiltered
  8. customThe (+)-2 was crystallized
  9. additionby adding heptane (80 mL)
  10. additionheptane (520 mL) was added over 8 hrs
  11. filtrationThe crystals were filtered
  12. washwashed with 3:2 heptane-toluene (150 mL)
  13. customdried under high vacuum

Sources & evidence

ORD record
ord-ae17505ce83d4fc0aface7fbb4000c33
Source dataset
uspto-grants-2001_11
Patent number
US06320049B1

Reaction notes

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