Methanamine, N-methoxy-, hydrochloride (1:1) → (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate

HRID 2355303Notes

Reaction equation

HRID 2355303 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]

Participants

6

Reactant 4

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 6435161-(1,1-Dimethylethyl) (3R)-1,3-piperidinedicarboxylateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 30025965(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylateYield 82%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

(R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (25 g, 0.11 mol, 1.0 equiv), N,O-dimethylhydroxylamine hydrochloride, (10.5 g, 0.14 mol, 1.25 equiv) and EDC.HCl (26.3 g, 0.14 mol, 1.25 equiv) and diisopropylethylamine (48 mL, 0.28 mol, 2.5 equiv) were dissolved in 400 ml (400 mL) and stirred overnight at rt. The reaction mixture was diluted with EtOAc, washed with 5% aq HCl (2×150 mL), satd aq NaHCO3 (150 mL), brine (100 mL), and dried over Na2SO4. Concentration afforded (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)-piperidine-1-carboxylate (24.42 g, 82%) as a clear oil. LC-MS (3 min) tR=1.41 min, m/z 295 (M+Na). 1H NMR (CDCl3) δ 4.19-4.00 (m, 2H), 3.77 (m, 3H), 3.12 (s, 3H), 2.79 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.71-1.52 (m, 2H), 1.51-1.33 (m, 10H). Chiral HPLC indicated 100% purity. The crude product was used for next step without further purification.

Workup

  1. washwashed with 5% aq HCl (2×150 mL), satd aq NaHCO3 (150 mL), brine (100 mL)
  2. dry with materialdried over Na2SO4
  3. concentrationConcentration

Sources & evidence

ORD record
ord-9b842e14fd0c49a290cb0ccbc4f762c4
Source dataset
uspto-grants-2010_07
Patent number
US07754737B2

Reaction notes

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