Thionyl Chloride → 6-(Benzyloxy)-4-chloropyrido[3,4-d]pyrimidine

HRID 564779Notes

Reaction equation

HRID 564779 reaction equation
[CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][NH:15][C:16](=O)[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16]([Cl:22])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 24386Thionyl ChlorideHCID 1358174446-Benzyloxy4-hydroxy-pyrido[3,4-d]pyrimidine

Product 1

HCID 227274286-(Benzyloxy)-4-chloropyrido[3,4-d]pyrimidine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideCatalyst

Procedure

6-Chloro-3H-pyrido[3,4-d]pyrimidine-4-one (9.08 g, 50.0 mmol) was reacted with sodium hydride (60% dispersion on mineral oil, 8.14 g, 203.5 mmol) in benzyl alcohol at 150° C. for 18 hours. The mixture was partitioned between water and ether (water layer at pH14 from the excess sodium hydride) and the layers separated. The aqueous layer was further washed with ether, and then acidified to pH1 with dilute HCl, giving a cream precipitate. This was collected by filtration and dried at 60° C. in vacuo to give 6-benzyloxy-3H-pyrido[3,4-d]pyrimidin-4-one (10.59 g, 84%); δH [2H6]-DMSO 8.71 (1H,s), 7.79 (1H,s), 7.25-7.48 (6H,m), 5.40 (2H,s); m/z (M+1)+254. 6-Benzyloxy-3H-pyrido[3,4-d]pyrimidine-4-one (1.033 g, 4.08 mmol) was reacted with thionyl chloride (10 ml) and dimethyl formamide (2 drops) at reflux under a nitrogen atmosphere for 5 hours, and then left at room temperature overnight. The mixture was concentrated in vacuo, azeotroping twice with toluene to remove the excess thionyl chloride, to give 6-benzyloxy4-chloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 8.73 (1H,s), 8.10 (1H,s), 7.25-7.55 (6H,m), 5.41 (2H,s). 6-Benzyloxy-4-chloropyrido[3,4-d]pyrimidine (ca. half the above material, ca. 2 mmol) was reacted with 4-benzyloxyaniline (0.430 g, 2.25 mmol) in acetonitrile (10 ml) according to Procedure A for 5 hours. The resulting brown solid was 6-benzyloxy4-(4-benzyloxyanilino)pyrido[3,4-d]pyrimidine (0.621 g, 71%); δH [2H6]-DMSO 8.99 (1H,s), 8.73 (1H,s), 8.22 (1H,s), 7.71 (2H,d), 7.15-7.55 (10H,m), 7.10 (2H,d), 5.50 (2H,s), 5.13 (2H, s); m/z (M+1)+435.

Workup

  1. temperatureat reflux under a nitrogen atmosphere for 5 hours
  2. concentrationThe mixture was concentrated in vacuo
  3. customazeotroping twice with toluene
  4. customto remove the excess thionyl chloride

Sources & evidence

ORD record
ord-83450e9028ce4d4b827359e6ca548e41
Source dataset
uspto-grants-2001_01
Patent number
US06169091A

Reaction notes

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