Hydrochloric Acid → HCID 178468191, compound

HRID 1509710Notes

Reaction equation

HRID 1509710 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:37]=[C:36]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6C(OC(C)(C)C)=O)[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:39][O:40][C:41]([NH:43][C@@H:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46])=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:37]=[C:36]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:45](=[O:46])[C@@H:44]([NH:43][C:41](=[O:42])[O:40][CH3:39])[CH:48]([CH3:50])[CH3:49])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1

Participants

8

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 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 178468193HCID 178468193, compound

Product 1

HCID 178468191HCID 178468191, compoundYield 90%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×

Procedure

To a solution of tert-butyl (2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.46 g, 0.9 mmol) in a mixture of CH2Cl2 (9.0 mL) and MeOH (1.5 mL) was added HCl (in dioxanes, 4M, 6.5 mL, 26.0 mmol). The resulting solution was stirred at room temperature for 2 h. The solution was concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (10.0 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.17 g, 0.9 mmol), HATU (0.41 g, 1.1 mmol), and DIPEA (0.5 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with CH2Cl2. The solution was washed with aqueous HCl (1N) and brine. The aqueous layers were backextracted with CH2Cl2 (2×). The resulting organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl {(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (0.46 g, 90%).

Workup

  1. concentrationThe solution was concentrated to dryness under reduced pressure
  2. stirringThe resulting solution was stirred at room temperature for 48 h
  3. washThe solution was washed with aqueous HCl (1N) and brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated under reduced pressure
  6. customThe crude residue was purified by silica column chromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc)

Sources & evidence

ORD record
ord-04fdb8726016444889fbf078811ff787
Source dataset
uspto-grants-2015_12
Patent number
US09221833B2

Reaction notes

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