Hydrochloric Acid → HCID 178495694, compound

HRID 1751709Notes

Reaction equation

HRID 1751709 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@H:17]([C:18]2[NH:22][C:21]3[C:23]4[C:28]([CH:29]=[CH:30][C:20]=3[N:19]=2)=[CH:27][C:26]2[C:31]3[C:36]([CH2:37][O:38][C:25]=2[CH:24]=4)=[CH:35][C:34]([C:39]2[NH:43][C:42]([C@@H:44]4[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]4C(OC(C)(C)C)=O)=[N:41][CH:40]=2)=[CH:33][CH:32]=3)[CH2:16][C@H:15]2[C@@H:13]1[CH2:14]2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH3:60][O:61][C:62]([NH:64][C@H:65]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:66]([OH:68])=O)=[O:63].CCN(C(C)C)C(C)C.CCOC(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]([CH3:9])[CH3:8])[C:10]([N:12]1[C@H:17]([C:18]2[NH:22][C:21]3[C:23]4[C:28]([CH:29]=[CH:30][C:20]=3[N:19]=2)=[CH:27][C:26]2[C:31]3[C:36]([CH2:37][O:38][C:25]=2[CH:24]=4)=[CH:35][C:34]([C:39]2[NH:43][C:42]([C@@H:44]4[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]4[C:66](=[O:68])[C@H:65]([NH:64][C:62](=[O:63])[O:61][CH3:60])[C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[N:41][CH:40]=2)=[CH:33][CH:32]=3)[CH2:16][C@H:15]2[C@@H:13]1[CH2:14]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 178495695HCID 178495695, compound

Product 1

HCID 178495694HCID 178495694, compoundYield 55%

Reagents, catalysts & solvents 4

HCID 3939Lithium HydroxideCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl (2S,4S)-2-[5-(2-{(1S,3S,5S)-2-[N-(methoxycarbonyl)-L-valyl]-2-azabicyclo[3.1.0]hex-3-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (0.025 g, 0.032 mmol) in a mixture of CH2Cl2 (1.0 mL) and MeOH (0.25 mL) was added HCl (in dioxanes, 4M, 0.50 mL, 2.0 mmol). The solution was stirred at room temperature for 12 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 (0.012 g, 0.057 mmol) and DIPEA (0.05 mL, 0.28 mmol). The resulting solution was cooled to 0° C. and COMU (0.023 g, 0.054 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,4S)-2-(5-{2-[(1S,3S,5S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (0.015 g, 55%). 1H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.35 (m, 1H), 7.94-7.96 (m, 2H), 7.54-7.78 (m, 6H), 6.93-7.00 (m, 1H), 5.72 (m, 1H), 5.46 (s, 1H), 5.19 (s, 2H), 5.14-5.16 (m, 1H), 3.95 (m, 1H), 3.67 (s, 3H), 3.63 (s, 3H), 3.42-3.49 (m, 2H), 3.24 (s, 3H), 2.67-2.78 (m, 2H), 2.41-2.62 (m, 3H), 2.01-2.13 (m, 2H), 1.86-1.99 (m, 3H), 0.99-1.03 (m, 2H), 0.90 (d, 3H). MS (ESI) m/z 882.23 [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-85ea79a20ae14641a1d78c2b224f7074
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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