Acetic Acid → 4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-9-(1-hydroxyethyl)-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one

HRID 626863Notes

Reaction equation

[C:1]([C:4]1[C:14]2[O:13][CH:12]([CH3:15])[C:11](=[O:16])[N:10]([CH:17]3[CH2:20][N:19]([C:21](=[O:23])[CH3:22])[CH2:18]3)[CH2:9][C:8]=2[C:7]([F:24])=[C:6]([Cl:25])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C.O>[C:21]([N:19]1[CH2:20][CH:17]([N:10]2[CH2:9][C:8]3[C:7]([F:24])=[C:6]([Cl:25])[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[C:14]=3[O:13][CH:12]([CH3:15])[C:11]2=[O:16])[CH2:18]1)(=[O:23])[CH3:22]

Participants

Conditions

Temperature: 0 °C

Procedure

A solution of 9-acetyl-4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-4,5-dihydro-1,4-benzoxazepin-3(2H)-one (112 mg, 0.304 mmol) in methanol (5.6 mL) at −10° C. was treated with sodium tetrahydroborate (17 mg, 0.456 mmol) and stirred for 30 min at 0° C. The reaction mixture was quenched with acetic acid (86 μL, 1.52 mmol) at 0° C. and then diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave two fractions. Each fraction contained a pair of enantiomers: peak 1 (30 mg, 27%) and peak 2 (50 mg, 44%). Peak 1: LCMS calculated for C17H21ClFN2O4 (M+H)+: m/z=371.1; found: 371.1. Peak 2: LCMS calculated for C17H21ClFN2O4 (M+H)+: m/z=371.1; found: 371.1.

Workup

customThe organic layer was separated
washwashed with brine
dry with materialdried over sodium sulfate
filtrationfiltered
concentrationconcentrated

Sources & evidence

ORD record: ord-0c866108e3a04a33b8c7cb711f9e1a5f
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09309251B2

Reaction notes

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