Pyridine → 3-methoxy-N-[1-(methoxy-methyl-carbamoyl)-cyclopropyl]-2-methyl-benzamide

HRID 1091236Notes

Reaction equation

HRID 1091236 reaction equation
[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:9]2[O:15][C:14](=[O:16])[C:11]3([CH2:13][CH2:12]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].N1C=CC=CC=1.C(Cl)Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([NH:10][C:11]1([C:14](=[O:16])[N:20]([O:21][CH3:22])[CH3:19])[CH2:13][CH2:12]1)=[O:15]

Participants

6

Reactant 4

HCID 1049PyridineHCID 6344DichloromethaneHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 597133875-(3-Methoxy-2-methylphenyl)-6-oxa-4-azaspiro[2.4]hept-4-en-7-one

Product 1

HCID 597133853-methoxy-N-[1-(methoxy-methyl-carbamoyl)-cyclopropyl]-2-methyl-benzamideYield 69.7%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 5-(3-methoxy-2-methyl-phenyl)-6-oxa-4-aza-spiro[2.4]hept-4-en-7-one (VII, R1=2-Me-3-MeO-Ph, R2═R3═—(CH2)2—, 1.90 g, 8.2 mmol), N,O-dimethylhydroxylamine hydrochloride (0.96 g, 9.9 mmol), pyridine (0.80 mL, 9.9 mmol) and methylene chloride (30 mL) was stirred at room temperature for 1 week. The mixture was diluted with ethyl acetate (150 mL), washed with 5% aqueous HCl (2×50 mL) and saturated aqueous NaHCO3 (2×50 mL), and dried. Removal of the solvent afforded a crude product (2.54 g) as a syrup. The crude product was purified by flash chromatography on a silica gel (75 g) column eluted sequentially with 0, 20, 40, 60, 80, 100% ether in hexanes (200 mL of each) and ethyl acetate (500 mL) to afford 3-methoxy-N-[1-(methoxy-methyl-carbamoyl)-cyclopropyl]-2-methyl-benzamide (1.67 g, 69%) as a white solid, mp 173-175° C. 1H NMR (CDCl3) δ (ppm): 1.15 (m, 2H), 1.53 (m, 2H), 2.23 (s, 3H), 3.22 (s, 3H), 3.69 (s, 3H), 3.82 (s, 3H), 6.67 (s, 1H), 6.86 (d, J=7.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H); 13C NMR (CDCl3) δ 12.3, 15.1, 33.6, 35.1, 55.6, 61.0, 111.4, 118.6, 124.9, 126.5, 137.4, 157.9, 170.3, 170.9. Calculated for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58. Found: C, 61.24; H, 6.75; N, 9.30.

Workup

  1. washwashed with 5% aqueous HCl (2×50 mL) and saturated aqueous NaHCO3 (2×50 mL)
  2. customdried
  3. customRemoval of the solvent
  4. customafforded a crude product (2.54 g) as a syrup
  5. customThe crude product was purified by flash chromatography on a silica gel (75 g) column
  6. washeluted sequentially with 0, 20, 40, 60, 80, 100% ether in hexanes (200 mL of each) and ethyl acetate (500 mL)

Sources & evidence

ORD record
ord-c6d5a001cf104fcca93b7fdc26e2d7f8
Source dataset
uspto-grants-2012_03
Patent number
US08129355B2

Reaction notes

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