Aluminium lithium hydride → (4-Benzyl-3-methyl-1,4-oxazepan-6-yl)methanol

HRID 467487Notes

Reaction equation

HRID 467487 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C:20](=O)[CH:19]([C:22](OC)=[O:23])[CH2:18][O:17][CH2:16][CH:15]1[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][O:17][CH2:16][CH:15]1[CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1

Participants

4

Reactant 2

HCID 21226445Aluminium lithium hydride2×HCID 67369976Methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate

Product 1

HCID 58405257(4-Benzyl-3-methyl-1,4-oxazepan-6-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
23 °C

Procedure

A solution of LAH in THF (2.0 M, 3.25 mL, 6.49 mmol, 3.00 equiv) was added to a solution of methyl 4-benzyl-3-methyl-5-oxo-1,4-oxazepane-6-carboxylate (4-4, diastereomeric mixture, 600 mg, 2.16 mmol, 1 equiv) in THF (30 mL) at −78° C. and the resulting mixture was warmed to 23° C. and stirred for 60 h. Additional LAH solution (2.0 M, 3.25 mL, 6.49 mmol, 3.00 equiv) was added and the mixture was heated at 60° C. for 4 h. The mixture was cooled to 0° C. and excess LAH was quenched with 100 uL of H2O, followed by 100 uL of 15% aqueous sodium hydroxide solution, and lastly 300 uL of H2O. The mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was concentrated and the residue purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to afford (4-benzyl-3-methyl-1,4-oxazepan-6-yl)methanol (4-5) as a mixture of diastereomers (TFA salts). 1H NMR (300 MHz, CD3OD) δ 7.62-7.45 (m, 5H), 4.70-4.30 (br m, 2H), 4.10-3.75 (br m, 3H), 3.65-3.30 (br m, 6 H), 2.45 (m, 1H), 1.45 (d, 3H,J=7.3 Hz). LRMS m/z (M+H) 236.3 found, 236.2 required. The TFA salts were free based by elution through an ion exchange column (Strata™ X-C, water loading, washing with CH3OH followed by elution of free base with 5% NH4OH in methanol).

Workup

  1. temperaturethe mixture was heated at 60° C. for 4 h
  2. temperatureThe mixture was cooled to 0° C.
  3. customexcess LAH was quenched with 100 uL of H2O
  4. additionThe mixture was diluted with EtOAc (100 mL)
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated
  7. customthe residue purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present)

Sources & evidence

ORD record
ord-175d5c978cba45b2b803f8ad8a464042
Source dataset
uspto-grants-2014_01
Patent number
US08623863B2

Reaction notes

Loading…