Triethylamine → (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate

HRID 1254402Notes

Reaction equation

HRID 1254402 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].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:37][NH:38][O:39][CH3:40]>C1COCC1>[CH3:40][O:39][N:38]([CH3:37])[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 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 6435161-(1,1-Dimethylethyl) (3R)-1,3-piperidinedicarboxylate

Product 1

HCID 30025965(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylateYield 90.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred, ice-cold solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol) under stirring. The mixture was stirred for 1 h in the ice-water bath. A suspension of triethylamine (207 mL, 1.41 mol) and N,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to rt and stirred overnight. Tlc showed the reaction was complete. Solvent was evaporated, and the residue was dissolved in CH2Cl2 (1.2 L), washed successively with 0.5 N aq HCl, satd aq Na2CO3 and brine, dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 g, 90.6%), which was used in the next step directly without further purification. Chiral HPLC indicated that the product had an enantiomeric excess of 96%˜98%. 1H NMR (400 MHz, CDCl3): 4.05-4.19 (m, 2H), 3.71 (s, 3H), 3.16 (s, 3H), 2.75-2.85 (m, 2H), 2.65 (t, 1H), 1.90 (d, 1H), 1.60-1.78 (m, 2H), 1.44 (s, 9H).

Workup

  1. additionwas added
  2. stirringstirred overnight
  3. customSolvent was evaporated
  4. dissolutionthe residue was dissolved in CH2Cl2 (1.2 L)
  5. washwashed successively with 0.5 N aq HCl
  6. dry with materialdried over Na2SO4
  7. customevaporated

Sources & evidence

ORD record
ord-870ffbf743164774875d57f7ca977968
Source dataset
uspto-grants-2013_06
Patent number
US08455521B2

Reaction notes

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