p-Toluenesulfonic acid monohydrate → 2-(4-(4-Hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

HRID 591597Notes

Reaction equation

HRID 591597 reaction equation
[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]3[NH:6][C:4](=[O:5])[C:3]4[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=4[N:1]=3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1

Participants

6

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 127174464-(4-Hydroxypiperidin-1-yl)benzaldehydeHCID 23665763Sodium BisulfiteHCID 666066902-Amino-4,6-dimethoxy-nicotinamide

Product 1

HCID 1359390862-(4-(4-Hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
135 °C

Procedure

A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.0 mmol), 4-(4-hydroxy-piperidin-1-yl)-benzaldehyde (0.81 g, 3.9 mmol), p-toluenesulfonic acid monohydrate (1.25 g, 6.6 mmol) and sodium bisulfite (1.06 g, 6.0 mmol) in N,N-dimethylacetamide (8.0 mL) was stirred at 135° C. under N2 for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The precipitate was filtered and the solid was rinsed with water and air-dried. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 4% methanol in dichloromethane) to afford the title compound, as a yellow solid. Yield: 0.29 g (25.2%). MP 284-286° C. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 8.12 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.32 (s, 1H), 4.73 (d, J=4.4 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.72 (m, 3H), 3.05 (m, 2H), 1.80 (m, 2H), 1.43 (m, 2H). MS (ES+) m/z: 383.06 (M+1).

Workup

  1. temperaturecooled to room temperature
  2. concentrationThe mixture was concentrated to dryness under reduced pressure
  3. additionWater (40 mL) was added to the residue
  4. stirringstirred for 0.5 hours
  5. filtrationThe precipitate was filtered
  6. washthe solid was rinsed with water
  7. customair-dried
  8. customThe crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 4% methanol in dichloromethane)

Sources & evidence

ORD record
ord-6222928783b64f1bbad32ddeca70e0a6
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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