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

HRID 591596Notes

Reaction equation

HRID 591596 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].[C:15]([N:18]1[CH:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH:19]1[CH3:33])(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:15]([N:18]1[C@@H:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]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:31][CH:32]=2)[CH2:20][C@H:19]1[CH3:33])(=[O:17])[CH3:16]

Participants

6

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 23665763Sodium BisulfiteHCID 666066902-Amino-4,6-dimethoxy-nicotinamideHCID 866620144-(4-Acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde

Product 1

HCID 1359390852-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-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 (0.25 g, 1.26 mmol), 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (0.43 g, 1.64 mmol), p-toluenesulfonic acid monohydrate (0.53 mg, 2.77 mmol) and sodium bisulfite (0.45 g, 2.52 mmol) in N,N-dimethylacetamide (5.0 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 dried over Na2SO4. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 2.5% methanol in dichloromethane) to afford the title compound as yellow solid. Yield: 90 mg (16.3%). MP 279-279.8° C. 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.20 (s, 1H), 4.78 (bs, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 3.70 (d, J=12.0 Hz, 2H) 3.11 (d, J=10 Hz, 2H), 2.18 (s, 3H), 1.40 (bs, 6H).

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. dry with materialdried over Na2SO4
  8. customThe crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 2.5% methanol in dichloromethane)

Sources & evidence

ORD record
ord-a36ff95092fe4a35972b78ba2556eede
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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