Hydrochloric Acid → HCID 178502481, compound

HRID 1751610Notes

Reaction equation

HRID 1751610 reaction equation
[CH3:1][C:2]1([CH3:35])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:32](=[CH:33][CH:34]=2)[C:15]2[NH:16][C:17]([C@@H:19]4[CH2:24][C@@H:23]5[C@@H:21]([CH2:22]5)[N:20]4[C:25]([O:27]C(C)(C)C)=O)=[N:18][C:14]=2[CH:13]=[CH:12]3)[O:3]1.Cl.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])C(O)=O)=[O:40].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>[CH3:47][CH:46]([CH3:48])[C@H:42]([NH:41][C:39](=[O:40])[O:38][CH3:37])[C:25](=[O:27])[N:20]1[C@H:19]([C:17]2[NH:16][C:15]3[C:32]4[C:11]([CH:12]=[CH:13][C:14]=3[N:18]=2)=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:1])([CH3:35])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:34][CH:33]=4)[CH2:24][C@@H:23]2[C@H:21]1[CH2:22]2

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 178452515HCID 178452515, compound

Product 1

HCID 178502481HCID 178502481, compoundYield 89%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (1R,3S,5R)-tert-butyl 3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.60 g, 1.3 mmol) in a mixture of CH2Cl2 (12.0 mL) and MeOH (2.5 mL) was added HCl (4M in 1,4-dioxane, 9.4 mL, 37.6 mmol). The solution was stirred at room temperature for 2.5 h and concentrated to dryness. The crude intermediate was suspended in CH2Cl2 (12 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.25 g, 1.4 mmol), HATU (0.58 g, 1.5 mmol), and DIPEA (0.7 mL, 4.0 mmol) were sequentially added to the reaction. The homogenous solution was then stirred at room temperature for 1.5 h. The solution was diluted with CH2Cl2 and washed with HCl (aqueous, 1N) and aqueous bicarbonate (sat.). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was then purified by silica gel chromatography (30 to 100% EtOAc (5% MeOH)/Hexanes) to provide methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (0.60 g, 89%). LCMS-ESI+: calc'd for C29H37BN4O5: 532.29 (M+); Found: 533.11 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. stirringThe homogenous solution was then stirred at room temperature for 1.5 h
  3. washwashed with HCl (aqueous, 1N) and aqueous bicarbonate (sat.)
  4. extractionThe aqueous layers were back extracted with CH2Cl2
  5. dry with materialthe combined organic layers were dried over Na2SO4
  6. concentrationconcentrated
  7. customThe crude oil was then purified by silica gel chromatography (30 to 100% EtOAc (5% MeOH)/Hexanes)

Sources & evidence

ORD record
ord-79f09769772e478d92c8c1e06c385030
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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