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

HRID 1444945Notes

Reaction equation

Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].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.[CH3:41][NH:42][C:43]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[C:50]([C:55]([C:57]3[N:58]=[CH:59][N:60]([C:62]([C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=4)([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)[C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[CH:61]=3)=[O:56])[CH:51]=2)[CH:46]=1)=[O:44].Cl>C1COCC1.C(OCC)(=O)C.[Zn]>[OH:56][C@@:55]([C:50]1[CH:49]=[CH:48][C:47]2[C:52](=[CH:53][CH:54]=[C:45]([C:43]([NH:42][CH3:41])=[O:44])[CH:46]=2)[CH:51]=1)([C:57]1[N:58]=[CH:59][N:60]([C:62]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:61]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]

Participants

Conditions

Temperature: 25 °C

Procedure

Under argon atmosphere, 10 liters of THF and 253 mL (2 mol) of chlorotrimethylsilane were added to 2616 g (40 mol) of zinc powders. The mixture was stirred at 25° C. for 30 minutes. A solution of 2212 mL (20 mol) of ethyl bromoacetate in 25 L of THF was added dropwise at 25˜35° C. 21.2 g (72 mmol, 1.25 eq) of (+)-cinchonine was added to 431 mL (0.23 mol) of the above Reformatsky reagent at 0˜5° C. 18.6 mL (230 mmol, 4 eq) of pyridine was added dropwise at 0˜5° C. over 7 minutes. The mixture was stirred at 0˜5° C. for 20 minutes. A solution of 30 g (57.5 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 300 mL of THF was added dropwise at −42˜−40° C. over 30 minutes. The mixture was stirred at −45˜−40° C. for 1 hour. 430 mL of 1N hydrochloric acid was added dropwise, diluted with 430 mL of ethyl acetate, and stirred at 20˜25° C. for 30 minutes. After the layers were separated, the organic layer was washed successively with 290 mL of 1N hydrochloric acid, 290 mL of water and 290 mL of an aqueous saturated sodium bicarbonate solution two times, and 290 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 90 mL of ethyl acetate was added to the concentration residue, and the mixture was warmed to 50° C. to dissolve it. The solution was stirred at 20˜25° C. for 1 hour. 90 mL of IPE was added, followed by stirring at 0˜5° C. for 2 hours. Crystals were filtered, and washed with 30 mL of IPE. Vacuum drying (50° C.) to a constant weight afforded 29.2 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 83%, enantiomer excess 93.5% ee).

Workup

stirringThe mixture was stirred at 0˜5° C. for 20 minutes
stirringThe mixture was stirred at −45˜−40° C. for 1 hour
stirringstirred at 20˜25° C. for 30 minutes
customAfter the layers were separated
washthe organic layer was washed successively with 290 mL of 1N hydrochloric acid, 290 mL of water and 290 mL of an aqueous saturated sodium bicarbonate solution two times, and 290 mL of an aqueous saturated sodium chloride solution
concentrationAfter concentrated under reduced pressure, 90 mL of ethyl acetate
additionwas added to the concentration residue
temperaturethe mixture was warmed to 50° C.
dissolutionto dissolve it
stirringThe solution was stirred at 20˜25° C. for 1 hour
addition90 mL of IPE was added
stirringby stirring at 0˜5° C. for 2 hours
filtrationCrystals were filtered
washwashed with 30 mL of IPE
customVacuum drying (50° C.) to a constant weight

Sources & evidence

ORD record: ord-79eae2b408534cce84a12192f98f092a
Source dataset: uspto-grants-2010_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07662974B2

Reaction notes

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