Hydrochloric Acid → methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate

HRID 2044812Notes

Reaction equation

HRID 2044812 reaction equation
C=C[C@@H]1[C@@H]2C[C@H]([C@@H]([OH:22])C3C4C(=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]1[CH2:74]C[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:70][CH3:74])=[O:22]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 8028Tetrahydrofuran3×HCID 90454CinchonineHCID 18769037N-methyl-6-((trityl-1H-imidazol-4-yl)carbonyl)-2-naphthamide

Product 1

HCID 57465809methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoateYield 92%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

Under argon atmosphere, 0.49 g (1.66 mmol, 1.25 equivalents) of (+)-cinchonine was added to 10 mL (5.4 mmol) of the solution of methyl bromozincacetate in tetrahydrofuran obtained in Example 55 at 5˜8° C. 0.43 mL (5.32 mmol, 4 equivalents) of pyridine was added dropwise at 6˜8° C. The mixture was stirred at 4˜6° C. for 20 minutes. A solution of 0.69 g (1.32 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 6.9 mL of THF was added dropwise at −35˜−40° C. The mixture was stirred at −40˜−35° C. for 1 hour. 2.5 mL (1.32 mmol) of the solution of methyl bromozincacetate in tetrahydrofuran obtained in Example 55 was added dropwise at −40° C., and the mixture was stirred at −40˜−35° C. for 1 hour. 20 mL of 1N hydrochloric acid was added dropwise at 0° C. or lower, followed by dilution with 30 mL of ethyl acetate. The layers were separated. The organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, 5 mL of water, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing and concentration under reduced pressure, 4 mL of IPE was added, crystals were loosened, filtered, and washed with 1 mL (×2) of IPE. After washing, vacuum drying (40° C.) to a constant weight afforded 0.72 g of methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 92%, enantiomer excess 93.6% ee).

Workup

  1. stirringThe mixture was stirred at −40˜−35° C. for 1 hour
  2. stirringthe mixture was stirred at −40˜−35° C. for 1 hour
  3. customThe layers were separated
  4. washThe organic layer was washed successively with 5 mL of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, 5 mL of water, and 5 mL (×2) of an aqueous saturated sodium chloride solution
  5. washAfter washing
  6. concentrationconcentration under reduced pressure, 4 mL of IPE
  7. additionwas added
  8. filtrationfiltered
  9. washwashed with 1 mL (×2) of IPE
  10. washAfter washing
  11. customvacuum drying (40° C.) to a constant weight

Sources & evidence

ORD record
ord-94d86cf6b9f540118416b8c02f0bb191
Source dataset
uspto-grants-2013_11
Patent number
US08586762B2

Reaction notes

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