4-Methoxybenzylamine → N4-(4-chloro-3-ethynylphenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine

HRID 511816Notes

Reaction equation

HRID 511816 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:12]3[CH:20]=[C:19](F)[N:18]=[CH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[Cl:9])#[CH:2].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CS(C)=O>[Cl:9][C:8]1[CH:7]=[CH:6][C:5]([NH:10][C:11]2[C:12]3[CH:20]=[C:19]([NH:29][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[N:18]=[CH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:4][C:3]=1[C:1]#[CH:2]

Participants

4

Reactant 2

HCID 754524-MethoxybenzylamineHCID 86668946N-(3-ethynyl-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine

Product 1

HCID 86668948N4-(4-chloro-3-ethynylphenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamineYield 54%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of compound 209 (3.07 g, 10.3 mmol) and 4-methoxybenzylamine (13.5 mL, 103 mmol) in dry DMSO (27 mL) was stirred under a nitrogen atmosphere at 70° C. (bath temperature) for 141 h. The mixture was cooled and petroleum ether (300 mL) was added. It was stirred at room temperature for 30 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (300 mL). Water (300 mL) was added and the mixture was stirred at room temperature for 30 min. It was filtered and washed sticky solid with water (4×20 mL). The sticky solid was dissolved in minimum acetone (50 mL) and water (200 mL) added. The mixture was stirred at room temperature overnight (22 h). Sticky solid generated again. Thus, the product was extracted into ethyl acetate, which after washed with water several times, was dried (MgSO) and evaporated. The crude product was applied to a silica column (dichloromethane/MeOH=50:1) to give N4-(4-chloro-3-ethynylphenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (218) (2.30 g, 54%) as a greenish yellow solid, mp 201-203° C.; 1H NMR δ [(CD3)2SO] 9.72 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 8.19 (d, J=2.5 Hz, 1H), 7.96 (dd, J=8.9, 2.5 Hz, 14, 7.56 (d, J=8.9 Hz, 14, 7.39-7.28 (m, 3H), 7.17 (s, 1H), 6.93-6.82 (m, 2H), 4.59 (s, 1H), 4.49 (d, J=6.3 Hz, 2H), 3.71 (s, 34. Anal. Calcd for C23H18ClN5O.0.18hexane: C, 67.04; H, 4.80; N, 16.23%. Found C, 66.76; H, 4.79; N, 15.96%.

Workup

  1. temperatureThe mixture was cooled
  2. stirringIt was stirred at room temperature for 30 min
  3. customto separate
  4. customthe petroleum ether layer was decanted
  5. additionWater (300 mL) was added
  6. stirringthe mixture was stirred at room temperature for 30 min
  7. filtrationIt was filtered
  8. washwashed sticky solid with water (4×20 mL)
  9. dissolutionThe sticky solid was dissolved in minimum acetone (50 mL)
  10. additionwater (200 mL) added
  11. stirringThe mixture was stirred at room temperature overnight (22 h)
  12. extractionThus, the product was extracted into ethyl acetate, which
  13. washafter washed with water several times
  14. dry with materialwas dried (MgSO)
  15. customevaporated

Sources & evidence

ORD record
ord-0257abe4265a45e28a5c2e034015f78f
Source dataset
uspto-grants-2015_08
Patent number
US09101632B2

Reaction notes

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