4-Methylmorpholine → HCID 131722577, compound

Temperature

-15 °C

The ketoamide (8) (227 mg, 0.5 mmol) was dissolved in ethyl acetate (10 mL) and cooled in an ice bath. Dry HCl gas was bubbled through until the solution was saturated and then the solution was stirred at r.t. until the starting material had been consumed as indicated by tlc (˜30 min). The solvent was removed under reduced pressure to give 22. To a solution of Ac—Tyr—Val—Ala—OH (197 mg, 0.5 mmol) in dry THF (10 mL) and DMF (2 mL) cooled to −15° C. was added N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) followed by iso-butyl chlorofornate (68 mg, 65 μL, 0.5 mmol) and the solution stirred at −15° C. for 5 min. A previously prepared solution of 22 and N-methyl morpholine (51 mg, 55 μL, 0.5 mmol) in dry THF (5 mL) was added, the solution stirred at −15° C. for 15-30 min and then at r.t. for 16 h. The solution was filtered and the solvent removed under reduced pressure to yield the product which was recrystallized from methanol/ether to give 340 mg (93%) of Ac—Tyr—Val—Ala—Asp(Bzl)—CONH—CH2CH2Ph: mp 192-194° C.; 1H NMR (DMSO) δ0.77 (m, 6H, Val CH3's), 1.19 (m, 3H, Ala CH3), 1.74 (s, 3H, Ac CH3), 1.93 (m, 1H, Val β-CH), 2.62 (obs, 2H, CH2Ph), 2.77 & 3.18 (m, 4H, Tyr & Asp β-CH2's), 3.37 (m, 2H, NH-CH2), 3.75, 4.09, 4.19 & 4.53 (m, 4H, α-CH's), 5.06 (s, 2H, benzyl CH2), 6.62 & 7.01 (2xd, 4H, Tyr aromatic CH's), 7.20 (m, 5H, phenethyl aromatic CH's), 7.35 (s, 5H, benzyl aromatic CH's), 7.83 (m, 1H, NH), 8.04 (m, 4H, NH's), 9.15 (s, 1H, Tyr OH); FABMS m/e 730 (M++1).

1. stirringthe solution stirred at −15° C. for 15-30 min
2. waitat r.t. for 16 h
3. filtrationThe solution was filtered
4. customthe solvent removed under reduced pressure
5. customto yield the product which
6. customwas recrystallized from methanol/ether

ORD record

ord-7e3acb5ce5a144eaba9f595710203bd1

Source dataset

uspto-grants-2001_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06235929B1