Hydrochloric Acid → methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4': 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate

HRID 1509667Notes

Reaction equation

HRID 1509667 reaction equation
[CH3:1][C:2]1([CH3:42])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[C:41]4[C:17](=[C:18]5[C:38](=[CH:39][CH:40]=4)[C:22]4[N:23]=[C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31](OC(C)(C)C)=[O:32])[NH:25][C:21]=4[CH:20]=[CH:19]5)[O:16][CH2:15][C:13]=3[CH:14]=2)[O:3]1.Cl.[CH3:44][O:45][C:46]([NH:48][C@@H:49]([CH:53]([CH3:55])[CH3:54])C(O)=O)=[O:47].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>C(OCC)(=O)C.C(O)C>[CH3:54][CH:53]([CH3:55])[C@H:49]([NH:48][C:46](=[O:47])[O:45][CH3:44])[C:31](=[O:32])[N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:24]1[NH:25][C:21]2[CH:20]=[CH:19][C:18]3[C:38](=[CH:39][CH:40]=[C:41]4[C:12]5[CH:11]=[CH:10][C:9]([B:4]6[O:3][C:2]([CH3:42])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]6)=[CH:14][C:13]=5[CH2:15][O:16][C:17]4=3)[C:22]=2[N:23]=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 86688819tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4': 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

Product 1

HCID 86690048methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4': 5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamateYield 73.5%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of tert-butyl (2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (0.98 g, 1.7 mmol), concentrated HCl (2 mL) and ethanol (20 mL) was heated to 60° C. for 2 hours. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off two more times. The resulting crude material was dissolved in dimethylformamide (17 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (455 mg, 2.6 mmol), HATU (955 mg, 2.5 mmol) and diisopropylethylamine (3 mL, 17 mmol). The reaction was stirred at room temperature for one hour then diluted with ethyl acetate. The organics were washed with water (×2) and brine, dried with magnesium sulfate and concentrated. The resulting residue was purified by flash column chromatography to yield Intermediate methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate (780 mg, 72% yield over 2 steps).

Workup

  1. concentrationThe reaction was concentrated
  2. dissolutionredissolved in a minimal amount of methanol
  3. additionAn equal volume of dichloromethane was added
  4. concentrationthe solution was again concentrated
  5. additionDichloromethane was added to the resulting residue
  6. concentrationconcentrated off two more times
  7. dissolutionThe resulting crude material was dissolved in dimethylformamide (17 mL)
  8. washThe organics were washed with water (×2) and brine
  9. dry with materialdried with magnesium sulfate
  10. concentrationconcentrated
  11. customThe resulting residue was purified by flash column chromatography

Sources & evidence

ORD record
ord-c8ea68bb8d7c4e6bb3f76406b714b7f3
Source dataset
uspto-grants-2015_12
Patent number
US09221833B2

Reaction notes

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