Diisobutylaluminumhydride → HCID 68380623, compound

HRID 2178704Notes

Reaction equation

HRID 2178704 reaction equation
[H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C@@H:18]([NH2:20])[CH3:19])=[C:14]([CH:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[CH:13]=1.[CH3:29][C:30]1[N:31]=[CH:32][N:33]([C:35]2[C:44](=[O:45])[N:43]3[C:38]([C:39](=[O:46])[O:40][CH2:41][CH2:42]3)=[CH:37][CH:36]=2)[CH:34]=1>O1CCCC1>[F:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:39]([C:38]2[N:43]([CH2:42][CH2:41][OH:40])[C:44](=[O:45])[C:35]([N:33]3[CH:34]=[C:30]([CH3:29])[N:31]=[CH:32]3)=[CH:36][CH:37]=2)=[O:46])[CH3:19])=[C:14]([CH:23]([CH3:28])[C:24]([F:25])([F:26])[F:27])[CH:13]=1

Participants

5

Reactant 3

HCID 21225700DiisobutylaluminumhydrideHCID 68379859HCID 68379859, compoundHCID 683801743,4-Dihydro-7-(4-methyl-1H-imidazol-1-yl)pyrido[2,1-c][1,4]oxazine-1,6-dione

Product 1

HCID 68380623HCID 68380623, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Diisobutylaluminum hydride (1.5 M in toluene, 1.63 mL, 2.44 mmol) was added to a solution of (2S)-1-[4-fluoro-2-(1,1,1-trifluoropropan-2-yl)phenoxy]propan-2-amine (P13) (fractions that were enriched in the lower Rf diastereomer were used, see step 4 of Preparation 13; 324 mg, 1.22 mmol) in tetrahydrofuran (5 mL). After the vigorous bubbling subsided, the reaction mixture was stirred for 2 hours at room temperature. 7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (299.7 mg, 1.222 mmol) was added, and the reaction mixture was heated to 60° C. for 24 hours. It was then cooled to room temperature, carefully quenched with 1 M aqueous sodium hydroxide solution, and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a sticky orange-tan oil. This was used in the following step without additional purification. Yield: 430 mg, 0.84 mmol, 69%. LCMS m/z 511.3 (M+1). On large scale, use of diisobutylaluminum hydride was less successful; in this case, simply dissolving P13 and P14 in methanol, boiling the solution down to a thick homogeneous oil and heating at 110° C. provided superior results.

Workup

  1. customstep 4 of Preparation 13
  2. customAfter the vigorous bubbling
  3. temperaturethe reaction mixture was heated to 60° C. for 24 hours
  4. temperatureIt was then cooled to room temperature
  5. customcarefully quenched with 1 M aqueous sodium hydroxide solution
  6. extractionextracted with ethyl acetate (2×30 mL)
  7. washThe combined organic layers were washed with saturated aqueous sodium chloride solution
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-5158a361b3d049b49319c37dde879a0e
Source dataset
uspto-grants-2015_06
Patent number
US09067934B2

Reaction notes

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