4-Methylmorpholine → N-((1R)-2-indol-3-yl-1-(N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamide

HRID 989529Notes

Reaction equation

HRID 989529 reaction equation
CN1CCOCC1.Cl[C:9]1[N:14]=[C:13](OC)[N:12]=[C:11](OC)[N:10]=1.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:46])([CH3:45])[C:28]([NH:30][C@H:31]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:32]([OH:34])=O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.NC1N=C([CH:54]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:55]([N:57]2[CH2:61][CH2:60][CH2:59][CH2:58]2)=[O:56])NC=1>O1CCCC1>[NH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([CH2:35][C@@H:31]([NH:30][C:28](=[O:29])[C:27]([NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:25])([CH3:45])[CH3:46])[C:32](=[O:34])[NH:10][C:9]2[N:14]=[CH:13][N:12]([CH:54]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:55](=[O:56])[N:57]3[CH2:58][CH2:59][CH2:60][CH2:61]3)[CH:11]=2)=[CH:37]1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 184502-Chloro-4,6-dimethoxy-1,3,5-triazineHCID 15895387(R)-2-(2-((tert-Butoxycarbonyl)amino)-2-methylpropanamido)-3-(1H-indol-3-yl)propanoic acidHCID 178479101HCID 178479101, compound

Product 1

HCID 9830850N-((1R)-2-indol-3-yl-1-(N-[1-(2-oxo-1-phenyl-2-pyrrolidinylethyl)imidazol-4-yl]carbamoyl}ethyl)-2-[(tert-butoxy)carbonylamino]-2-methylpropanamideYield 31.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

N-Methyl morpholine (0.28 mL, 8.32 mm, 1 eq) was added to a stirred slurry of 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.46 g, 2.57 mm, 1 eq) and (2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoic acid (1 g, 2.57mm) in 10 mL of anhydrous tetrahydrofuran cooled to less than 0° C. After 1.5 hours, 2-(4-aminoimidazolyl)-2-phenyl-1-pyrrolidinylethan-1-one, hydrochloride (0.97 g, 2.82 mm, 1.1 eq) was added and stirring was continued at ice bath temperatures. The reaction was stirred for 4 hours and quenched by the addition of 15 mL of deionized water and ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate and the volatiles were removed under vacuum to give the crude product as a light purple foam (1.4 g, 84%). The crude product was purified by preparative chromatography to provide 0.52 g (31.5%) of the product as a foam. 1H nmr (CDCl3): δ 1.10-1.40 (m, 15H), 1.67-1.92 (m, 3H), 2.92-3.60 (m, %H), 4.90 (s, broad, 1H), 5.33 (s, broad, 1H), 5.85 (d, 1H), 6.80-7.05 (m, 3H), 7.13-7.39 (m, 10H), 7.44-7.80 (m, 2H), 8.96 (s, broad, 1H), 10.20 (s, broad, 1H).

Workup

  1. temperaturecooled to less than 0° C
  2. customwas continued at ice bath
  3. stirringThe reaction was stirred for 4 hours
  4. customquenched by the addition of 15 mL of deionized water and ethyl acetate
  5. washThe ethyl acetate layer was washed with a saturated sodium bicarbonate solution
  6. dry with materialdried over magnesium sulfate
  7. customthe volatiles were removed under vacuum
  8. customto give the crude product as a light purple foam (1.4 g, 84%)
  9. customThe crude product was purified by preparative chromatography

Sources & evidence

ORD record
ord-6bec6f9ef54c43089d95f1efdee70831
Source dataset
uspto-grants-2003_10
Patent number
US06639076B1

Reaction notes

Loading…