tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate → Tert-butyl 4-(4-methoxy-3-methylbenzoyl)piperidine-1-carboxylate

HRID 713415Notes

Reaction equation

HRID 713415 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][C:23]=1[CH3:30]>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:30])[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

4

Reactant 2

HCID 11065582tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylateHCID 178491913HCID 178491913, compound

Product 1

HCID 71212195Tert-butyl 4-(4-methoxy-3-methylbenzoyl)piperidine-1-carboxylateYield 51%

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

Procedure

A solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 11.02 mmol in 30 mL THF) was cooled to 0° C., then (4-methoxy-3-methylphenyl)magnesium bromide was added dropwise via a syringe under N2 and the reaction mixture was stirred at the same temperature for 1.5 h, then gradually warmed up to room temperature over 1 h when the reaction was judged complete by LCMS. 40 mL of saturated aqueous NH4Cl was added slowly then the aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed to yield the crude product. Purification by flash chromatography gave the title compound as a white solid (1.97 g, 5.62 mmol, 51% yield). MS (ESI) m/z 334.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.57 min. 1H NMR (400 MHz, CDCL3) δ ppm 1.48 (s, 9H) 1.62-1.91 (m, 4H) 2.27 (s, 3H) 2.78-3.02 (m, 2H) 3.27-3.46 (m, 1H) 3.91 (s, 3H) 4.12-4.27 (m, 2H) 6.87 (d, J=8.59 Hz, 1H) 7.77 (t, 2H).

Workup

  1. extractionthe aqueous solution was extracted with ethyl acetate (2×50 mL)
  2. washThe combined organic phases were washed with brine
  3. dry with materialdried over Na2SO4
  4. customthe solvent was removed
  5. customto yield the crude product
  6. customPurification by flash chromatography

Sources & evidence

ORD record
ord-2560cebbafb4484ea3cf27f3738337d5
Source dataset
uspto-grants-2015_11
Patent number
US09181266B2

Reaction notes

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