Hydrochloric Acid → HCID 178502449, compound

HRID 1509681Notes

Reaction equation

HRID 1509681 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[C:27]3[CH2:29][O:30][C:31]4[CH:56]=[C:55]5[C:34]([CH:35]=[CH:36][C:37]6[N:41]=[C:40]([C@@H:42]7[CH2:46][C@H:45]([CH3:47])[CH2:44][N:43]7C(OC(C)(C)C)=O)[NH:39][C:38]=65)=[CH:33][C:32]=4[C:26]3=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:64]([OH:66])=O)=[O: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.CO.CCOC(C)=O.CN(C=O)C.CO>[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:64]([N:43]1[CH2:44][C@@H:45]([CH3:47])[CH2:46][C@H:42]1[C:40]1[NH:39][C:38]2[C:55]3[C:34]([CH:35]=[CH:36][C:37]=2[N:41]=1)=[CH:33][C:32]1[C:26]2[C:27]([CH2:29][O:30][C:31]=1[CH:56]=3)=[CH:28][C:23]([C:20]1[NH:19][C:18]([C@@H:13]3[CH2:14][C@H:15]([CH3:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:8])[CH3:9])=[N:22][CH:21]=1)=[CH:24][CH:25]=2)=[O:66])=[O:61]

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 178502450HCID 178502450, compound

Product 1

HCID 178502449HCID 178502449, compoundYield 53%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 21584119Ethylacetate methanolSolvent

Procedure

Tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′: 6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (257 mg, 0.34 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 3 h and then concentrated under reduced pressure. The crude residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (71 mg, 0.34 mmol), COMU (161 mg, 0.34 mmol) and DMF (6 mL), then DIPEA (0.3 mL, 1.67 mmol) was added dropwise. After 15 h, 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)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (152 mg, 53%). LCMS-ESI+: calculated for C48H52N8O7: 852.40; observed [M+1]+: 854.26. ′H NMR (CD3OD): 8.677 (s, 1H), 8.232-7.837 (m, 5H), 7.695-7.673 (m, 2H), 7.496-7.426 (m, 5H), 5.499 (s, 1H), 5.445-5.401 (m, 1H), 5.337 (s, 1H), 5.253-5.208 (q, 1H, J=7.2 Hz), 4.870 (m, 1H), 4.230 (d, 1H, J=7.2 Hz), 3.781 (m, 1H), 3.671 (s, 3H), 3.607 (s, 3H), 3.425 (m, 3H), 2.750-2.689 (m, 2H), 2.683 (m, 2H), 2.384 (m, 1H), 1.894 (quint, 2H, J=12 Hz), 1.249-1.151 (m, 6H), 0.974-0.890 (m, 6H).

Workup

  1. concentrationconcentrated under reduced pressure
  2. waitAfter 15 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 HPLC

Sources & evidence

ORD record
ord-4b0fcd5dcde54d9d927366c5c040f7aa
Source dataset
uspto-grants-2015_12
Patent number
US09221833B2

Reaction notes

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