Ammonium Chloride → (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate

HRID 660393Notes

Reaction equation

HRID 660393 reaction equation
I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:21][C:22]([CH3:52])([CH2:48][CH2:49][CH2:50][CH3:51])[C:23]([NH:25][CH2:26][C@@H:27]1[O:31][C:30]([CH3:33])([CH3:32])[N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:28]1[CH2:41][C@H:42]([CH:46]=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:24].[NH4+].[Cl-]>C1COCC1>[CH3:52][C:22]([CH3:21])([CH2:48][CH2:49][CH2:50][CH3:51])[C:23]([NH:25][CH2:26][C@@H:27]1[O:31][C:30]([CH3:32])([CH3:33])[N:29]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C@H:28]1[CH2:41][C@H:42]([CH:46]([OH:47])[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1)[CH:43]([CH3:44])[CH3:45])=[O:24]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 596309716-iodo-1-(3-methoxypropyl)-1H-indazoleHCID 59630987(4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylateHCID 178418339Butyllithium

Product 1

HCID 59630984(4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylateYield 20%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 6-iodo-1-(3-methoxypropyl)-1H-indazole (1.1 g, 3.48 mmol) in anhydrous THF (15 mL) at −78° C. under N2 was added dropwise n-BuLi (2.5 M in hexanes, 1.4 mL, 3.5 mmol). After stirring at −78° C. for 2 h, the reaction mixture was added through a cannula to a solution of (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (160 mg, 0.35 mmol) in anhydrous THF (10 mL) at −78° C. The mixture was stirred at this temperature for 2 h, allowed to warm to rt and stirred overnight. Satd aq NH4Cl (25 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (45 mg, 20% yield). MS: 645 (M++1)

Workup

  1. stirringThe mixture was stirred at this temperature for 2 h
  2. temperatureto warm to rt
  3. stirringstirred overnight
  4. extractionthe mixture was extracted with EtOAc (3×15 mL)
  5. washThe combined organic extracts were washed with brine
  6. dry with materialdried over Na2SO4
  7. customevaporated
  8. customThe residue was purified by column chromatography on silica gel

Sources & evidence

ORD record
ord-98c565ef4a61496dba6c217f35b2c2cf
Source dataset
uspto-grants-2011_12
Patent number
US08084485B2

Reaction notes

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