3-Oxo-azetidine-1-carboxylic acid tert-butyl ester → tert-Butyl 3-(4-fluoro-1-piperidyl)azetidine-1-carboxylate

HRID 1922670Notes

Reaction equation

HRID 1922670 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:18]2[CH2:19][CH2:20][CH:15]([F:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 27591584-Fluoropiperidine hydrochlorideHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 59605431tert-Butyl 3-(4-fluoro-1-piperidyl)azetidine-1-carboxylateYield 39.1%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1 g, 5.84 mmol), 4-fluoropiperidine hydrochloride (0.97 g, 6.42 mmol) and 4 Å molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0) then (Si—PPC, MeOH: DCM, 0:100 to 5:95) to give 3-(4-Fluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.59 g, 39%). 1H NMR (CDCl3, 400 MHz) δ 4.80-4.58 (m, 1H); 3.97-3.89 (m, 2H); 3.85-3.76 (m, 2H); 3.08 (t, J=6.4 Hz, 1H); 2.50-2.28 (m, 4H); 1.99-1.82 (m, 4H); 1.48-1.38 (m, 9H).

Workup

  1. stirringthe reaction mixture was stirred for 18 h at room temperature
  2. filtrationThe suspension was filtered through Celite
  3. concentrationthe filtrate was concentrated in vacuo
  4. customThe residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0)

Sources & evidence

ORD record
ord-065485e21d8a4a33950d190709fd62bd
Source dataset
uspto-grants-2012_05
Patent number
US08173650B2

Reaction notes

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