Ethylene → N-(benzyloxycarbonyl)-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester

To a suspension of zinc dust (15 mmol, 0.98 g) in THF (1.5 mL) was added 1,2-dibromoethane (1 mmol, 0.13 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased. Then, the suspension was cooled to room temperature and trimethylchlorosilane (0.5 mmol, 70 uL) was added and the mixture was stirred for 15 min. A suspension of 5-iodo-1,3,6-trimethyl uracil (2.5 mmol, 700 mg) in DMA (2 mL) was warmed to obtain a clear solution and was added in one portion to the reaction mixture. The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which, had been quenched with saturated ammonium chloride, indicated the absence of starting material. Then, the reaction mixture was diluted with THF (3 mL) and the excess zinc dust was allowed to settle. The above prepared solution containing the zinc compound (2.5 mmol) was added to a solution of Pd(dba)2 (0.05 mmol, 27 mg), trifurylphosphine (TFP) (0.2 mmol, 50 mg) and N-(benzyloxycarbonyl)-4-iodo-3-methyl-L-phenylalanine methyl ester (0.5 mmol, 227 mg) in THF (2 mL) at room temperature and the light yellow mixture was stirred for 15 h at 45° C. Then, the reaction mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 71 mg (30% yield) of N-(benzyloxycarbonyl)-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as an yellow oil. ES-HRMS m/e calcd for C26H29N3O6 (M+Na) 502.2173, found 502.2174.

1. temperaturewas warmed
2. customto obtain a clear solution
3. additionwas added in one portion to the reaction mixture
4. stirringThe reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which
5. customhad been quenched with saturated ammonium chloride
6. additionThen, the reaction mixture was diluted with THF (3 mL)
7. customThe above prepared solution
8. stirringthe light yellow mixture was stirred for 15 h at 45° C
9. extractionwas extracted with ethyl acetate (3×30 mL)
10. washThe combined extracts were washed with brine solution (50 mL)
11. dry with materialwere dried over anhydrous magnesium sulfate
12. filtrationFiltration of the drying agent and concentration
13. customgave the crude product which
14. customwas purified by silica gel chromatography

ORD record

ord-cb3a5060de254b9f9ee4283674e3f082

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06380387B1