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

HRID 2044778Notes

Reaction equation

HRID 2044778 reaction equation
Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:36][NH:37][C:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:50]([C:52]3[N:53]=[CH:54][N:55]([C:57]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:56]=3)=[O:51])[CH:46]=2)[CH:41]=1)=[O:39]>C1COCC1.C(OCC)(=O)C.Cl>[OH:51][C@@:50]([C:45]1[CH:44]=[CH:43][C:42]2[C:47](=[CH:48][CH:49]=[C:40]([C:38]([NH:37][CH3:36])=[O:39])[CH:41]=2)[CH:46]=1)([C:52]1[N:53]=[CH:54][N:55]([C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:56]=1)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]

Participants

8

Reactant 4

HCID 1049PyridineHCID 7748Ethyl bromoacetateHCID 90454CinchonineHCID 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 68%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolvent2×HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Under argon atmosphere, a solution of 8.44 mL (76.5 mmol) of ethyl bromoacetate in 35 mL of THF was added to a solution of 5 g of Rieke-Zn in 105 mL of THF at 19˜21° C. over 20 minutes. The mixture was stirred at 20˜25° C. for 20 minutes, and allowed to stand for 3 hours and 30 minutes. 1.26 g (4.3 mmol, 1.25 eq) of (+)-cinchonine was added to 30 mL of the above Reformatsky reagent at 8° C. 1.1 mL (13.8 mmol, 4 eq) of pyridine was added dropwise at 5˜7° C. The mixture was stirred at 4˜7° C. for 15 minutes, and a solution of 1.79 g (3.4 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 15 mL of THF was added dropwise at −8˜−6° C. The mixture was stirred at −10˜−8° C. for 2 hours and 30 minutes. 10 mL of 1N hydrochloric acid was added dropwise, and the mixture was warmed to 0° C. After diluted with 50 mL of ethyl acetate, 10 mL of 1N hydrochloric acid was added, and the layers were separated. The organic layer was washed successively with 20 mL of 1N hydrochloric acid two times, 20 mL of water, 20 mL of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 4 mL of ethyl acetate and 2 mL of IPE were added to the concentration residue. Crystals were filtered, and washed with 2 mL of ethyl acetate three times. Vacuum drying (40° C.) to a constant weight afforded 1.41 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphty}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 68%, enantiomer excess 63.1% ee).

Workup

  1. waitto stand for 3 hours and 30 minutes
  2. stirringThe mixture was stirred at 4˜7° C. for 15 minutes
  3. stirringThe mixture was stirred at −10˜−8° C. for 2 hours and 30 minutes
  4. additionwas added
  5. customthe layers were separated
  6. washThe organic layer was washed successively with 20 mL of 1N hydrochloric acid two times, 20 mL of water, 20 mL of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution
  7. concentrationAfter concentrated under reduced pressure, 4 mL of ethyl acetate and 2 mL of IPE
  8. additionwere added to the concentration residue
  9. filtrationCrystals were filtered
  10. washwashed with 2 mL of ethyl acetate three times
  11. customVacuum drying (40° C.) to a constant weight

Sources & evidence

ORD record
ord-6b8c7fb0071740bbae51adfd179fa6a1
Source dataset
uspto-grants-2013_11
Patent number
US08586762B2

Reaction notes

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