2-Amino-5-methylpyridine → N,N-Dimethyl-3-[(2-methyl-6-{[(5-methylpyridin-2-yl)amino]-carbonyl}-1-benzofuran-4-yl)oxy]azetidine-1-carboxamide

HRID 1643768Notes

Reaction equation

HRID 1643768 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:37])[C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[C:27]3[CH:28]=[C:29]([CH3:31])[O:30][C:26]=3[CH:25]=[C:24]([C:32](OCC)=[O:33])[CH:23]=2)[CH2:18]1)=[O:16]>ClCCl>[CH3:37][N:14]([CH3:13])[C:15]([N:17]1[CH2:20][CH:19]([O:21][C:22]2[C:27]3[CH:28]=[C:29]([CH3:31])[O:30][C:26]=3[CH:25]=[C:24]([C:32]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:33])[CH:23]=2)[CH2:18]1)=[O:16]

Participants

5

Reactant 3

HCID 153482-Amino-5-methylpyridineHCID 79147ChlorodimethylaluminumHCID 59560208Ethyl 4-({1-[(dimethylamino)carbonyl]azetidin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate

Product 1

HCID 59559897N,N-Dimethyl-3-[(2-methyl-6-{[(5-methylpyridin-2-yl)amino]-carbonyl}-1-benzofuran-4-yl)oxy]azetidine-1-carboxamideYield 90.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-amino-5-methyl pyridine (203 mg, 1.88 mmol) in dichloromethane (5 mL) at 0° C. was added Al(CH3)2Cl (1.88 mL, 1M in hexanes) drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 4-({1-[(dimethylamino)carbonyl]azetidin-3-yl}oxy)-2-methyl-1-benzofuran-6-carboxylate (65 mg, 0.19 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over Na2SO4. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (95/5 to 85/15) to give the title compound (70 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 3 H) 2.37 (s, 3 H) 2.78 (s, 6 H) 3.30-3.44 (m, 2 H) 3.44-3.60 (m, 1 H) 3.88 (dd, J=12.13, 6.06 Hz, 1 H) 4.05 (dd, J=11.75, 2.40 Hz, 1 H) 6.70 (s, 1 H) 6.98 (d, J=9.60 Hz, 1 H) 7.71-7.85 (m, 1 H) 7.92 (s, 1 H) 8.17 (d, J=8.34 Hz, 1 H) 8.28-8.44 (m, 2 H); MS (ESI, pos): 409.

Workup

  1. additionAfter the addition
  2. customthe ice-bath was removed
  3. waitthe stirring was continued for 14 h
  4. customThe reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously
  5. extractionThe product was extracted with CHCl3
  6. washwashed with brine
  7. dry with materialdried over Na2SO4
  8. customThe product was purified by gradient silica gel chromatography

Sources & evidence

ORD record
ord-16ccc0ff9af14daaa3f249ccfe8dad9e
Source dataset
uspto-grants-2012_02
Patent number
US08119624B2

Reaction notes

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