Sodium cyanoborohydride → 4-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-9-(2-methyl-1,3-dioxolan-2-yl)-4,5-dihydro-1,4-benzoxazepin-3(2H)-one

HRID 626861Notes

Reaction equation

HRID 626861 reaction equation
[Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8](OCC)=[O:9])=[C:4]([CH:22]=O)[C:3]=1[F:24].C([BH3-])#N.[Na+].Cl.[C:30]([N:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1)(=[O:32])[CH3:31]>CO>[C:30]([N:33]1[CH2:36][CH:35]([N:37]2[CH2:22][C:4]3[C:3]([F:24])=[C:2]([Cl:1])[CH:15]=[C:14]([C:16]4([CH3:21])[O:20][CH2:19][CH2:18][O:17]4)[C:5]=3[O:6][CH:7]([CH3:13])[C:8]2=[O:9])[CH2:34]1)(=[O:32])[CH3:31]

Participants

5

Reactant 3

HCID 5003444Sodium cyanoborohydrideHCID 848193311-(3-Aminoazetidin-1-yl)ethanone hydrochlorideHCID 86697551Ethyl 2-[4-chloro-3-fluoro-2-formyl-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate

Product 1

HCID 866975524-(1-Acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-9-(2-methyl-1,3-dioxolan-2-yl)-4,5-dihydro-1,4-benzoxazepin-3(2H)-oneYield 32%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A solution of ethyl 2-[4-chloro-3-fluoro-2-formyl-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate (392 mg, 1.09 mmol) in methanol (21 mL) was treated with sodium cyanoborohydride (171 mg, 2.72 mmol) followed by 1-acetylazetidin-3-amine hydrochloride (360 mg, 2.39 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with acetic acid (200 μL) and concentrated in vacuo. The residue was diluted with toluene (60 mL) and heated at 110° C. for 2 h. The solvent was concentrated in vacuo, and the residue was purified 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) to give the desired product (142 mg, 32%) as a mixture of enantiomers. LCMS calculated for C19H23ClFN2O5(M+H)+: m/z=413.1; found: 413.1.

Workup

  1. customThe reaction mixture was quenched with acetic acid (200 μL)
  2. concentrationconcentrated in vacuo
  3. additionThe residue was diluted with toluene (60 mL)
  4. temperatureheated at 110° C. for 2 h
  5. concentrationThe solvent was concentrated in vacuo
  6. customthe residue was purified via preparative LCMS (XBridge C18 column
  7. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-1a82ff885e944fcf80edb4804d8e9719
Source dataset
uspto-grants-2016_04
Patent number
US09309251B2

Reaction notes

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