Citric Acid → ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoate

HRID 922725Notes

Reaction equation

HRID 922725 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]([S:50]([C:53]4[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=4)(=[O:52])=[O:51])[CH:49]=3)=[O:44])[CH:39]=2)[CH:34]=1)=[O:32].C(O)(=O)[CH2:61][C:62](CC(O)=O)(C(O)=O)[OH:63]>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]([S:50]([C:53]2[CH:54]=[CH:55][C:56]([CH3:57])=[CH:58][CH:59]=2)(=[O:51])=[O:52])[CH:49]=1)[CH2:61][C:62]([O:22][CH2:11][CH3:12])=[O:63]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 1049PyridineHCID 90454CinchonineHCID 86715406N-methyl-6-[(1-tosyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide

Product 1

HCID 86715405ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoateYield 97%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

The Reformatsky reagent was obtained according to the method described in Example 14. The obtained Reformatsky reagent (27.1 mL, corresponding to 2.5 eq.) was cooled to 0° C., cinchonine (2.1 g, 7.2 mmol) and pyridine (1.9 mL, 23.0 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was cooled to −25° C., N-methyl-6-[(1-tosyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (2.5 g, 5.76 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hr. To the obtained reaction mixture was added the Reformatsky reagent (10.9 mL, corresponding to 1.0 eq.) at −25° C., and the mixture was stirred for 1 hr. The Reformatsky reagent (5.4 mL, corresponding to 0.5 eq.) was added again −25° C., and the mixture was stirred for 1 hr. To the obtained reaction mixture were added ethyl acetate (35 mL) and 20 w/v % aqueous citric acid solution (35 mL) at 10° C. or below. The separated organic layer was washed with 10% sodium chloride-containing 20 w/v % aqueous citric acid solution (35 mL) at 5° C. (twice), 5 w/v % aqueous sodium bicarbonate (35 mL) (three times), and water (35 mL). The separated organic layer was concentrated under reduced pressure to give ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoate (2.92 g, 5.6 mmol). yield: 97%.

Workup

  1. customThe Reformatsky reagent was obtained
  2. temperatureThe reaction mixture was cooled to −25° C.
  3. stirringthe mixture was stirred at the same temperature for 1 hr
  4. customTo the obtained reaction mixture
  5. additionwas added the Reformatsky reagent (10.9 mL, corresponding to 1.0 eq.) at −25° C.
  6. stirringthe mixture was stirred for 1 hr
  7. additionThe Reformatsky reagent (5.4 mL, corresponding to 0.5 eq.) was added again −25° C.
  8. stirringthe mixture was stirred for 1 hr
  9. customTo the obtained reaction mixture
  10. washThe separated organic layer was washed with 10% sodium chloride-
  11. additioncontaining 20 w/v % aqueous citric acid solution (35 mL) at 5° C. (twice), 5 w/v % aqueous sodium bicarbonate (35 mL) (three times), and water (35 mL)
  12. concentrationThe separated organic layer was concentrated under reduced pressure

Sources & evidence

ORD record
ord-f75e70d3c96848fab8662fd9f437b3c6
Source dataset
uspto-grants-2016_03
Patent number
US09278938B2

Reaction notes

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