Hydrochloric Acid → methyl {(2S,3S)-1-[(2S,5S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-[(methoxycarbonyl)amino]acetyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate

HRID 590679Notes

Reaction equation

HRID 590679 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[C@@H:17]([CH3:18])[CH2:16][CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:57]=[C:56]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][CH2:46][C@H:45]([CH3:48])[N:44]7[C:49]([O:51]C(C)(C)C)=O)[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].Cl.[CH3:59][C@@H:60]1[CH2:65][CH:64]([C@H:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])C(O)=O)[CH2:63][C@@H:62]([CH3:75])[O:61]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl.CO.Cl>[CH3:59][C@@H:60]1[CH2:65][CH:64]([C@H:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])[C:49]([N:44]2[C@@H:45]([CH3:48])[CH2:46][CH2:47][C@H:43]2[C:41]2[NH:40][C:39]3[C:56]4[C:35]([CH:36]=[CH:37][C:38]=3[N:42]=2)=[CH:34][C:33]2[C:27]3[C:28]([CH2:30][O:31][C:32]=2[CH:57]=4)=[CH:29][C:24]([C:21]2[NH:20][C:19]([C@@H:14]4[CH2:15][CH2:16][C@H:17]([CH3:18])[N:13]4[C:11](=[O:12])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C@@H:7]([CH3:8])[CH2:9][CH3:10])=[N:23][CH:22]=2)=[CH:25][CH:26]=3)=[O:51])[CH2:63][C@@H:62]([CH3:75])[O:61]1

Participants

9

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 66746681(S)-2-((2R,6R)-2,6-Dimethyltetrahydro-2H-pyran-4-yl)-2-((methoxycarbonyl)amino)acetic acidHCID 178455982tert-butyl (2S,5S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidine-1-carboxylate

Product 1

HCID 178455981methyl {(2S,3S)-1-[(2S,5S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-[(methoxycarbonyl)amino]acetyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamateYield 23.3%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of tert-butyl (2S,5S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidine-1-carboxylate (0.30 g, 0.39 mmol) in a mixture of dichloromethane (4 mL) and methanol (0.5 mL) was added HCl (4M in dioxanes, 1.45 mL, 5.80 mmol). The solution was heated to 40° C. for 1 h and cooled to room temperature. The solution was then concentrated in vacuo. The resulting solid was dissolved in DMF (3 mL), followed by the addition of (S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)acetic acid (0.11 g, 0.46 mmol), HATU (0.18 g, 0.48 mmol), and diisopropylethylamine (0.3 mL, 1.72 mmol). The resulting solution was stirred at room temperature for 3 h. Aqueous HCl (6M, 4 drops) was added and the solution was purified by reverse phase HPLC (Gemini column, 10-53% MeCN/H2O/0.1% TFA). The desired fractions were combined, and the organics were concentrated in vacuo. The resulting aqueous solution was basified with saturated NaHCO3 to provide a white precipitate. The solid was filtered and dried to provide methyl {(2S,3S)-1-[(2S,5S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-[(methoxycarbonyl)amino]acetyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate (0.082 g, 23%) as a white powder. LCMS-ESI+: calc'd for C50H62N8O9: 903.08 (M+). Found: 903.84 (M+H+). 1H NMR (400 MHz, Methanol-d4) δ 8.36-8.22 (m, 1H), 7.98-7.82 (m, 1H), 7.69-7.20 (m, 8H), 5.22-5.07 (m, 3H), 5.02 (d, 1H), 4.73-4.64 (m, 1H), 4.49 (s, 3H), 4.26-3.97 (m, 4H), 3.79 (d, 1H), 3.72 (s, 1H), 3.63-3.52 (m, 4H), 3.47-3.32 (m, 1H), 2.61-2.43 (m, 1H), 2.32-1.98 (m, 4H), 1.95-1.78 (m, 1H), 1.79-1.65 (m, 1H), 1.54 (s, 4H), 1.41 (d, 2H), 1.28-1.09 (m, 3H), 1.04 (dd, 6H), 0.90 (d, 1H), 0.88-0.59 (m, 10H).

Workup

  1. temperaturecooled to room temperature
  2. concentrationThe solution was then concentrated in vacuo
  3. dissolutionThe resulting solid was dissolved in DMF (3 mL)
  4. customthe solution was purified by reverse phase HPLC (Gemini column, 10-53% MeCN/H2O/0.1% TFA)
  5. concentrationthe organics were concentrated in vacuo
  6. customto provide a white precipitate
  7. filtrationThe solid was filtered
  8. customdried

Sources & evidence

ORD record
ord-433f382ad2334a3fa7999e1e1c3340a6
Source dataset
uspto-grants-2016_01
Patent number
US09233974B2

Reaction notes

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