1-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acid → 1-Tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate

HRID 588042Notes

Reaction equation

HRID 588042 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].S(Cl)(O[CH2:26][Cl:27])(=O)=O>ClCCl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:26][Cl:27])=[O:15])[CH2:10][CH2:9]1

Participants

7

Reactant 3

HCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 516892Sodium BicarbonateHCID 2733556Chloromethyl chlorosulfate

Product 1

HCID 101075661-Tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylateYield 96.2%

Reagents, catalysts & solvents 3

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 g, 13.1 mmol) in dichloromethane (40 mL) and water (50 mL) was added NaHCO3 (4.4 g, 52.3 mmol) and tetrabutylammonium hydrogen sulfate (444 mg, 1.3 mmol). After stirring the mixture in an ice bath at 0° C. for ˜10 min, chloromethyl chlorosulfate (2.59 g, 15.7 mmol) in 10 mL of dichloromethane was added dropwise. The reaction mixture was allowed to warm up to rt and stirred vigorously overnight. The mixture was transferred to a separatory funnel with dichloromethane and water (200 mL, each). The organic layer was washed with additional water and brine, dried (Na2SO4), and concentrated in vacuo to give 1-tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate as a clear oil (3.5 g, 96% yield). This material was used without further purification. 1H NMR (DMSO-d6) δ 1.26-1.48 (m, 11H, CHH, CHH, tertBu), 1.83 (dd, J=3.0, 13.2 Hz, 2H, CHH, CHH), 2.58-2.75 (m, 1H, CH), 2.74-2.99 (m, 2H, CHH, CHH), 3.61-4.02 (m, 2H, CHH, CHH), 5.87 (s, 2H, CH2O); 13C NMR (DMSO-d6) δ 27.16, 27.98, 39.58, 42.35, 69.41, 78.67, 153.75, 172.25; LCMS: MH=278.

Workup

  1. temperatureto warm up to rt
  2. stirringstirred vigorously overnight
  3. washThe organic layer was washed with additional water and brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-107786752aaf4a3a8f815983e60bf592
Source dataset
uspto-grants-2016_01
Patent number
US09227954B2

Reaction notes

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