Hydrochloric Acid → methyl {(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate

HRID 1751666Notes

Reaction equation

HRID 1751666 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]1[C:33]2[C:38]([CH2:39][O:40][C:27]=1[CH:26]=3)=[CH:37][C:36]([C:41]1[NH:45][C:44]([C@@H:46]3[CH2:50][C@H:49]([CH3:51])[CH2:48][N:47]3C(OC(C)(C)C)=O)=[N:43][CH:42]=1)=[CH:35][CH:34]=2)=[O:11])[CH:7](C)[CH3:8])=[O:4].Cl.[CH3:60][O:61][C@H:62]([CH3:72])[C@H:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64](O)=[O:65].CN([C:76]([O:80]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O.CN(C=O)C.CO>[CH3:76][O:80][C@H:7]([CH3:8])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]1[C:33]2[C:38]([CH2:39][O:40][C:27]=1[CH:26]=3)=[CH:37][C:36]([C:41]1[NH:45][C:44]([C@@H:46]3[CH2:50][C@H:49]([CH3:51])[CH2:48][N:47]3[C:64](=[O:65])[C@H:63]([C@@H:62]([CH3:72])[O:61][CH3:60])[NH:67][C:68]([O:70][CH3:71])=[O:69])=[N:43][CH:42]=1)=[CH:35][CH:34]=2)=[O:11]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59540170(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acidHCID 178495664HCID 178495664, compound

Product 1

HCID 178495663methyl {(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamateYield 34.1%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 21584119Ethylacetate methanolSolvent

Procedure

Tert-butyl (2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (174 mg, 0.24 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 5 h and then concentrated under reduced pressure. The crude residue was treated with ((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (92 mg, 0.48 mmol), HATU (182 mg, 0.48 mmol) and DMF (5 mL), then DIPEA (0.31 mL, 2.4 mmol) was added dropwise. After 35 min, the mixture was diluted with 10% MeOH/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 HPLC to afford methyl {(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate (72 mg, 34%). LCMS-ESI+: calculated for C46H56N8O10: 880.41; observed [M+1]+: 882.39. 1H NMR (CD3OD): 8.558 (s, 1H), 8.123-7.572 (m, 7H), 5.436-5.391 (dd, 1H, J=7.2, 3.6 Hz), 5.252 (s, 2H), 5.220 (m, 1H), 4.493-4.444 (m, 2H), 4.287-4.206 (m, 2H), 3.756-3.256 (m, 21H), 2.834 (m, 1H), 2.717-2.621 (m, 2H), 2.500 (m, 1H), 2.150 (m, 1H), 1.882 (m, 1H), 1.208 (d, 3H, J=6.4 Hz), 1.159-1.099 (m, 6H).

Workup

  1. concentrationconcentrated under reduced pressure
  2. waitAfter 35 min
  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 HPLC

Sources & evidence

ORD record
ord-0a049ba0c67c4cf9be4cc8ac8d511167
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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