4-Methylmorpholine → 3-Ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

HRID 1912541Notes

Reaction equation

HRID 1912541 reaction equation
[O:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:12]([C:17](=O)[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:21][C:22]([NH2:29])=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CN1CCOCC1>C(O)(C)C>[NH2:21][C:22]1[NH:29][C:17]([CH3:18])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[O:1][CH2:2][CH2:3][CH2:4]3)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 124946853,3-Diamino-acrylic acid ethyl ester hydrochlorideHCID 78036909Methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate

Product 1

HCID 712088353-Ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (8.27 g, 31.8 mmol), ethyl 3,3-diaminoacrylate, hydrochloride (5.29 g, 31.8 mmol) and 4-methylmorpholine (3.49 mL, 31.8 mmol) in Isopropanol (76.0 mL) was heated to 90° C. overnight. The mixture was concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to provide crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.00-6.87 (m, 3 H), 6.64-6.58 (m, 1 H), 6.20 (br. s., 2 H), 4.83-4.77 (m, 1 H), 4.15-4.05 (m, 4 H), 3.71-3.63 (m, 3 H), 2.71 (t, J=6.3 Hz, 2 H), 2.27-2.16 (m, 3 H), 1.99-1.93 (m, 2 H), 1.27-1.22 (m, 3 H); LC/MS (m/z) ES+=373.3 (M+1). A solution of crude 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate in dichloromethane (DCM) (216 mL) was treated with DDQ (7.22 g, 31.8 mmol) and then stirred at ambient temperature (mixture turned dark within one minute). The mixture was filtered over Celite™. The filtrate was diluted with saturated sodium bicarbonate and the layers were separated. The aqueous phase was extracted with DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-100% hexane/EA) to afford 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methylpyridine-3,5-dicarboxylate (7.64 g, 20.63 mmol, 64.9% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.86 (d, 1 H), 6.81 (s, 1 H), 6.73 (d, J=8.4 Hz, 1 H), 6.23-6.02 (m, 2 H), 4.17 (t, J=4.7 Hz, 2 H), 3.99-3.77 (m, 2 H), 3.52-3.43 (m, 3 H), 2.73 (br. s., 2H), 2.45-2.35 (m, 3 H), 1.98 (br. s., 2 H), 0.83-0.67 (m, 3 H); LC/MS (m/z) ES+=371.3 (M+1).

Workup

  1. concentrationThe mixture was concentrated
  2. dissolutiondissolved in ethyl acetate
  3. washwashed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-656776e40f4740b2a0a9afedfe7d1e4f
Source dataset
uspto-grants-2013_12
Patent number
US08609653B2

Reaction notes

Loading…