Hydrochloric Acid → HCID 178502449, compound

HRID 2038841Notes

Reaction equation

HRID 2038841 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-phenyl acetyl}-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. 1H 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-dd35573eed3f438194e3f4f394b3b040
Source dataset
uspto-grants-2013_11
Patent number
US08575135B2

Reaction notes

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