4-Methylmorpholine → tert-butyl 4-(2-{hydroxy-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-yl]methyl}-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate

HRID 252401Notes

Reaction equation

HRID 252401 reaction equation
C([Mg]CCCC)CCC.C([Li])CCC.Br[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30].CN1CCOCC1.[CH:38]([CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:39]>O1CCCC1>[OH:39][CH:38]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 231494685-bromo-3-(3-methoxypropyl)-1-methyl-1H-indole2×HCID 86618882Tert-butyl 4-(2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylateHCID 178418339ButyllithiumHCID 178448196HCID 178448196, compound

Product 1

HCID 66888806tert-butyl 4-(2-{hydroxy-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-yl]methyl}-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

A solution of 12.51 ml of dibutylmagnesium (1M in heptane) in 70 ml of tetrahydrofuran is cooled to 0° C. and admixed with 7.80 ml of n-butyllithium (1M in hexane). After 10 minutes, the mixture is admixed with a solution of 3.60 g of 5-bromo-3-(3-methoxypropyl)-1-methyl-1H-indole (residue 3) and 0.14 ml of N-methylmorpholine in 15 ml of tetrahydrofuran and stirred at 0° C. for 30 minutes. The reaction mixture is cooled to −78° C. and admixed with the solution of 3.02 g of tert-butyl 4-(2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine -3-carboxylate in 15 ml of tetrahydrofuran over 2 minutes. The resulting mixture is stirred at −78° C. for another 45 minutes and subsequently successively quenched with 1M ammonium chloride solution, diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are washed successively with 0.5N HCl (cold)(2×), water and brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound (diastereomer mixture) is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:2 EtOAc-heptane). Rt=24.2/25.4 (gradient II).

Workup

  1. temperatureThe reaction mixture is cooled to −78° C.
  2. stirringThe resulting mixture is stirred at −78° C. for another 45 minutes
  3. customsubsequently successively quenched with 1M ammonium chloride solution
  4. additiondiluted with water
  5. extractionextracted with tert-butyl methyl ether (3×)
  6. washThe combined organic phases are washed successively with 0.5N HCl (cold)(2×), water and brine
  7. dry with materialdried over sodium sulphate
  8. filtrationfiltered
  9. concentrationthe filtrate is concentrated by evaporation

Sources & evidence

ORD record
ord-91e56152c0e041e399a836c919414b97
Source dataset
uspto-grants-2011_01
Patent number
US07868036B2

Reaction notes

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