Hydrogen Bromide → methyl (S)-1-((2S,4S)-2-(5-(4'-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 1751653Notes

Reaction equation

HRID 1751653 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[C:7]([N:9]1[CH2:13][C@@H:12]([S:14][CH3:15])[CH2:11][C@H:10]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[NH:37][C:36]([C@@H:38]5[CH2:42][C@H:41]([CH2:43][O:44][CH3:45])[CH2:40][N:39]5C(OCC5C=CC=CC=5)=O)=[N:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:8])=[O:4].Br.[C:60]([O:64][C:65]([NH:67][C@H:68]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:69]([OH:71])=O)=[O:66])([CH3:63])([CH3:62])[CH3:61].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[C:60]([O:64][C:65]([NH:67][C@H:68]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:69]([N:39]1[CH2:40][C@@H:41]([CH2:43][O:44][CH3:45])[CH2:42][C@H:38]1[C:36]1[NH:37][C:33]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:18]4[NH:17][C:16]([C@@H:10]5[CH2:11][C@H:12]([S:14][CH3:15])[CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:56]([CH3:58])[CH3:57])=[N:20][CH:19]=4)=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)=[CH:34][N:35]=1)=[O:71])=[O:66])([CH3:61])([CH3:62])[CH3:63]

Participants

10

Reactant 5

HCID 260Hydrogen BromideHCID 81531DiisopropylethylamineHCID 2755953(2R)-2-{[(tert-butoxy)carbonyl]amino}-2-phenylacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 86708800(2S,4S)-benzyl 2-(5-(4'-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

Product 1

HCID 86708799methyl (S)-1-((2S,4S)-2-(5-(4'-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateYield 73.2%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

(2S,4S)-benzyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (220 mg, 0.27 mmol) was dissolved in DCM (5 mL), MeOH (0.4 mL) and cooled to 0° C. HBr (33% in AcOH, 1 mL) was added dropwise. After stirring for 1 hr, the mixture was concentrated under reduced pressure, coevaporating with PhMe. The crude residue was treated with (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (68 mg, 0.27 mmol), COMU (129 mg, 0.27 mmol) and DMF (5 mL), then DIPEA (0.24 mL, 1.35 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 40% MeOH/EtOAc) to afford methyl (S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (179 mg, 73%).

Workup

  1. concentrationthe mixture was concentrated under reduced pressure
  2. waitAfter 1 h
  3. washwashed successively with saturated aqueous NaHCO3 and brine
  4. dry with materialThe organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude residue was purified by silica column chromatography (0% to 40% MeOH/EtOAc)

Sources & evidence

ORD record
ord-732b26bc62d94ccebfa47423740f4463
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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