Hydrochloric Acid → tert-Butyl 5-(benzyloxy)-2-methoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate

HRID 1190835Notes

Reaction equation

HRID 1190835 reaction equation
S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[CH2:11]([O:18]/[C:19](=[C:24](/O)\[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])/[C:20](OC)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+].Cl>CO>[CH2:11]([O:18][C:19]1[C:20](=[O:21])[NH:9][C:8]([O:7][CH3:6])=[N:10][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 169039Carbamimidic acid, methyl ester, sulfate (1:1)HCID 10942334Sodium MethoxideHCID 546790054-Tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate

Product 1

HCID 136338080tert-Butyl 5-(benzyloxy)-2-methoxy-6-oxo-1,6-dihydropyrimidine-4-carboxylateYield 60.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent3×

Procedure

To a solution of tert-butyl methyl oxalate (5.8 g, 36 mmol) and methyl 2-(benzyloxy)acetate (6.5 g, 36 mmol) in THF (80 mL) at −78° C. was added a dropwise a solution of LDA (prepared by dropwise addition of nBuLi (20 mL, 50 mmol) to diisopropylamine (7.1 mL, 50 mmol) in THF (20 mL) at 0° C. then stirring for 10 min). After the addition, the reaction mixture was stirred at −78° C. for 2 h then allowed to warm to rt over the course of 1 h. The reaction mixture was cooled to 0° C. then cold 1 N HCl (ca. 70 mL) was added. The resulting solution was extracted with EtOAc (3×), and the combined organic portions dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to give 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 49% yield) as tan viscous oil. O-Methylisourea hydrogensulfate (2.5 g, 14 mmol) and 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 17 mmol) were stirred in anhydrous MeOH (15 mL) at 0° C. under argon. Sodium methoxide (10 g, 46 mmol) in MeOH (25% wt) was added and the reaction mixture was stirred at rt for 40 h. MeOH (3 mL) was added and the mixture cooled in an ice bath. 1 N HCl (11 mL) was added to acidify the mixture and the resulting precipitate was collected and rinsed with cold H2O:MeOH (10:1). The filtrate was concentrated under reduced pressure and the residue was extracted with CH2Cl2 (2×). The organic extracts and the precipitate were combined, concentrated under reduced pressure, then purified by silica gel chromatography eluting with EtOAc/hexanes to give Compound 43c (2.8 g, 58% yield) as a white solid. LCMS=2.02 min using analytical method (Q), 333.2 (M+H-tBu). 1H NMR (400 MHz, DMSO-d6) δ 13.48-12.16 (m, 1H), 7.91-6.79 (m, 5H), 5.02 (s, 2H), 3.86 (s, 3H), 1.44 (s, 9H).

Workup

  1. temperaturethe mixture cooled in an ice bath
  2. customthe resulting precipitate was collected
  3. washrinsed with cold H2O:MeOH (10:1)
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. extractionthe residue was extracted with CH2Cl2 (2×)
  6. concentrationconcentrated under reduced pressure
  7. custompurified by silica gel chromatography
  8. washeluting with EtOAc/hexanes

Sources & evidence

ORD record
ord-a463968030a14c5186d9a5fc68de1faa
Source dataset
uspto-grants-2014_03
Patent number
US08680090B2

Reaction notes

Loading…