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

HRID 420262

Reaction equation

HRID 420262 reaction equation
C=C[C@@H]1[C@@H]2C[C@H]([C@@H:11]([OH:22])[C:12]3C=CN=C4C=CC=CC=34)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.C[O:71][CH:72]1CCC[CH2:73]1>C(OCC)(=O)C.C1COCC1>[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)[CH2:73][C:72]([O:22][CH2:11][CH3:12])=[O:71]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 90454CinchonineHCID 138539Cyclopentyl methyl ether2×HCID 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 93%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

75.0 mL (75.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise to 100 mL of THF at −15˜−5° C. 11.0 g (37.5 mmol) of cinchonine was added at −15˜−5° C., 9.7 mL (120 mmol) of pyridine was added dropwise, and the mixture was stirred for 20 minutes. 15.6 g (30.0 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide was added at once by assisting by 25 mL of flowing THF at −15˜−5° C., and the mixture was stirred at the same temperature for 1 hour. 30.0 mL (30.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise at −15˜−5° C. over 40 minutes, and the mixture was stirred at the same temperature for 1 hour. 420 mL of ethyl acetate and 210 mL of 1N hydrochloric acid were added in this order at −15˜10° C., and the mixture was stirred at 15˜25° C. for 30 minutes. The organic layer was washed with 210 mL of 1N hydrochloric acid, and further 210 mL (×3) of water, 210 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 210 mL of water. After washing, the organic layer was concentrated to about 50 mL under heating and reduced pressure (inner temperature 20˜40° C.). 50 mL of ethyl acetate was added, followed by re-concentration procedure two times. 50 mL of ethyl acetate was added to the residue, the mixture was stirred at room temperature for 1 hour, 50 mL of IPE was added, and the mixture was stirred at room temperature. After stirred at 0˜10° C. for 1 hour, crystals were filtered, washed with 16 mL (×2) of IPE, and dried to obtain 17.0 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 93%, enantiomer excess 94.3% ee).

Workup

  1. stirringthe mixture was stirred at the same temperature for 1 hour
  2. stirringthe mixture was stirred at the same temperature for 1 hour
  3. stirringthe mixture was stirred at 15˜25° C. for 30 minutes
  4. washThe organic layer was washed with 210 mL of 1N hydrochloric acid, and further 210 mL (×3) of water, 210 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 210 mL of water
  5. washAfter washing
  6. concentrationthe organic layer was concentrated to about 50 mL
  7. temperatureunder heating
  8. customreduced pressure (inner temperature 20˜40° C.)
  9. addition50 mL of ethyl acetate was added
  10. concentrationfollowed by re-concentration procedure two times
  11. addition50 mL of ethyl acetate was added to the residue
  12. stirringthe mixture was stirred at room temperature for 1 hour
  13. addition50 mL of IPE was added
  14. stirringthe mixture was stirred at room temperature
  15. stirringAfter stirred at 0˜10° C. for 1 hour
  16. filtrationcrystals were filtered
  17. washwashed with 16 mL (×2) of IPE
  18. customdried

Sources & evidence

ORD record
ord-e30221024c7c4617905fa5b7350bf1e1
Source dataset
uspto-grants-2012_01
Patent number
US08093403B2

Linked notes

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