Hydrochloric Acid → Ethyl (3S)-3-hydroxy-3-(6-((methylamino)carbonyl))-2-naphthyl)-3-(1-trityl-1H-imidazil-4-yl) propanoate

HRID 2044806Notes

Reaction equation

HRID 2044806 reaction equation
CCC1C2CC([CH:11]([OH:22])[C:12]3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:29][NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]([C:45]3[N:46]=[CH:47][N:48]([C:50]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:49]=3)=[O:44])[CH:39]=2)[CH:34]=1)=[O:32].Cl.[O:70]1CC[CH2:72][CH2:71]1>C(OCC)(=O)C>[OH:44][C@@:43]([C:38]1[CH:37]=[CH:36][C:35]2[C:40](=[CH:41][CH:42]=[C:33]([C:31]([NH:30][CH3:29])=[O:32])[CH:34]=2)[CH:39]=1)([C:45]1[N:46]=[CH:47][N:48]([C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:49]=1)[CH2:72][C:71]([O:22][CH2:11][CH3:12])=[O:70]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 8028Tetrahydrofuran3×HCID 101711(5-Ethyl-1-azabicyclo[2.2.2]octan-2-yl)-quinolin-4-ylmethanolHCID 18769037N-methyl-6-((trityl-1H-imidazol-4-yl)carbonyl)-2-naphthamide

Product 1

HCID 57465807Ethyl (3S)-3-hydroxy-3-(6-((methylamino)carbonyl))-2-naphthyl)-3-(1-trityl-1H-imidazil-4-yl) propanoateYield 80%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

Under argon atmosphere, 0.37 g (1.25 mmol, 1.25 equivalent) of hydrocinchonine was added to 4.7 mL (2.5 mmol, 2.5 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 at 4˜5° C. 0.32 mL (4 mmol, 4 equivalents) of pyridine was added dropwise at 5˜6° C. The mixture was stirred at 3˜6° C. for 20 minutes. A solution of 0.52 g (1 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 5.2 mL of THF was added dropwise at −36˜−34° C. The mixture was stirred at −40˜−34° C. for 1 hour and 15 minutes. Further, 1.9 mL (1 mmol, 1 equivalent) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise at −40˜−35° C. The mixture was stirred at −40˜−38° C. for 2 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After concentration under reduced pressure, 5 mL of IPE was added to the concentration residue, this was recrystallized, crystals were filtered, and washed with 3 mL of IPE. After washing, vacuum drying (40° C.) to a constant weight afforded 0.49 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 80%, enantiomer excess 90.9% ee).

Workup

  1. stirringThe mixture was stirred at −40˜−34° C. for 1 hour and 15 minutes
  2. stirringThe mixture was stirred at −40˜−38° C. for 2 hours
  3. customThen, the layers were separated
  4. washThe organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution
  5. concentrationAfter concentration under reduced pressure, 5 mL of IPE
  6. additionwas added to the concentration residue
  7. customthis was recrystallized
  8. filtrationcrystals were filtered
  9. washwashed with 3 mL of IPE
  10. washAfter washing
  11. customvacuum drying (40° C.) to a constant weight

Sources & evidence

ORD record
ord-f22e048a9b21413ebb28d4c7d3d9a00c
Source dataset
uspto-grants-2013_11
Patent number
US08586762B2

Reaction notes

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