2-Methoxybenzaldehyde → 2-(2-methoxyphenyl)-3-((R)-1-phenylpropan-2-yl)-5-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one

HRID 1170916Notes

Reaction equation

HRID 1170916 reaction equation
[NH2:1][C:2]1[C:7]([C:8]([NH:10][C@H:11]([CH3:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[C:6]([C:20]([F:23])([F:22])[F:21])[N:5]=[CH:4][CH:3]=1.[CH:24](=O)[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:24]1[NH:1][C:2]2[CH:3]=[CH:4][N:5]=[C:6]([C:20]([F:23])([F:21])[F:22])[C:7]=2[C:8](=[O:9])[N:10]1[C@H:11]([CH3:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1

Participants

5

Reactant 2

HCID 86582-MethoxybenzaldehydeHCID 59553895(R)-4-amino-N-(1-phenylpropan-2-yl)-2-(trifluoromethyl)nicotinamide

Product 1

HCID 595538812-(2-methoxyphenyl)-3-((R)-1-phenylpropan-2-yl)-5-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-oneYield 31.3%

Reagents, catalysts & solvents 2

HCID 6101p-Toluenesulfonic acidCatalystHCID 1140TolueneSolvent

Procedure

(R)-4-amino-N-(1-phenylpropan-2-yl)-2-(trifluoromethyl)nicotinamide (16.23 g, 50.2 mmol) and ortho-anisaldehyde (8.2 g, 60.2 mmol) were combined along with a catalytic amount of 4-toluenesulfonic acid (0.174 g, 1.0 mmol) in anhydrous toluene (550 mL). This mixture was heated at reflux overnight in a round bottom flask fitted with a Dean-Stark trap. The resultant dark solution was cooled to room temperature, then concentrated in vacuo to a dark brown paste. This paste was suspended in ethyl acetate, and the resultant solids were collected by filtration to provide the product (6.94 g). The filtrate was concentrated in vacuo then purified by silica gel column chromatography using 40-60% ethyl acetate/hexanes as eluant to give 12.1 g of additional product diastereomers (84% total yield). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, 1H), 7.1-7.3 (m, 7H), 6.9 (d, 1H), 6.8 (t, 1H), 6.5 (d, 1H), 5.95 (d, 1H), 5.7 (d, 1H), 4.8 (m, 1H), 3.95 (s, 3H), 3.0 (dd, 1H), 2.4 (dd, 1H), 1.3 (d, 3H). MS m/z 442.4 (M+H)+.

Workup

  1. temperatureThis mixture was heated
  2. temperatureat reflux overnight in a round bottom flask
  3. customfitted with a Dean-Stark trap
  4. concentrationconcentrated in vacuo to a dark brown paste
  5. filtrationthe resultant solids were collected by filtration

Sources & evidence

ORD record
ord-47c556f41eee4cb9bf9d77dd1af151be
Source dataset
uspto-grants-2010_11
Patent number
US07829572B2

Reaction notes

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