Hydrochloric Acid → HCID 178495656, compound

HRID 1751708Notes

Reaction equation

HRID 1751708 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][CH2:49][CH2:48][N:47]3C(OC(C)(C)C)=O)=[N:43][CH:42]=1)=[CH:35][CH:34]=2)=[O:11])[CH:7]([CH3:9])C)=[O:4].Cl.[CH3:59][O:60][C:61]([NH:63][C@H:64]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:65]([OH:67])=O)=[O:62].CCN(C(C)C)C(C)C.C[CH2:84][O:85]C(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO.CN(C=O)C.[Li+].[OH-]>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:7]([O:85][CH3:84])[CH3:9])[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][CH2:49][CH2:48][N:47]3[C:65](=[O:67])[C@H:64]([NH:63][C:61](=[O:62])[O:60][CH3:59])[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[N:43][CH:42]=1)=[CH:35][CH:34]=2)=[O:11])=[O:4]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 178495660HCID 178495660, compound

Product 1

HCID 178495656HCID 178495656, compoundYield 61%

Reagents, catalysts & solvents 4

HCID 3939Lithium HydroxideCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl (2S)-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)pyrrolidine-1-carboxylate (0.013 g, 0.016 mmol) in a mixture of CH2Cl2 (0.5 mL) and MeOH (0.02 mL) was added HCl (in dioxanes, 4M, 0.20 mL, 0.80 mmol). The solution was stirred at room temperature for 1 h, and then concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (0.5 mL) was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.006 g, 0.029 mmol) and DIPEA (0.05 mL, 0.28 mmol). The resulting solution was cooled to 0° C. and COMU (0.012 g, 0.028 mmol) was added. The reaction was stirred at 0° C. for 30 min. The solution was diluted with DMF and aqueous LiOH (2.5 M, 2 drops) and concentrated under reduced pressure to remove the CH2Cl2. The crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced pressure afforded methyl {(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methoxybutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (0.008 g, 61%). 1H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.37 (m, 1H), 7.96-7.98 (m, 2H), 7.60-7.79 (m, 3H), 7.35-7.52 (m, 6H), 6.98-7.03 (m, 1H), 5.52 (s, 1H), 5.26-5.39 (m, 2H), 5.20 (s, 2H), 4.44 (m, 1H), 4.27 (m, 1H), 3.64 (s, 6H), 3.50-3.57 (m, 3H), 3.37 (s, 3H), 3.29-3.44 (m, 3H), 3.20 (s, 3H), 2.68-2.72 (m, 2H), 2.57-2.62 (m, 2H), 1.89-2.15 (m, 6H), 1.18 (d, 3H). MS (ESI) m/z 885.73 [M+H]+.

Workup

  1. concentrationconcentrated to dryness under reduced pressure
  2. temperatureThe resulting solution was cooled to 0° C.
  3. stirringThe reaction was stirred at 0° C. for 30 min
  4. concentrationconcentrated under reduced pressure
  5. customto remove the CH2Cl2
  6. customThe crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA)
  7. concentrationconcentrated under reduced pressure
  8. customto remove volatile organics
  9. additionThe addition of aqueous sodium bicarbonate
  10. stirringwith stirring
  11. customresulted in precipitation of a white solid
  12. filtrationThe precipitate was filtered through a membrane
  13. filtrationfilter
  14. washwashed with water
  15. customDrying under reduced pressure

Sources & evidence

ORD record
ord-9f0011f16acd4593ab77edab7b49c2ab
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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