Nitrogen → (E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide

HRID 1887044Notes

Reaction equation

HRID 1887044 reaction equation
Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.N#N.[NH2:19][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]([C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][CH:38]=1)[C:23](=[O:36])[N:24]2[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CN(C=O)C.CC#N.C(Cl)Cl>[NH2:19][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]([C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:39][CH:38]=1)[C:23](=[O:36])[N:24]2[C:29]1[CH:30]=[C:31]([NH:35][C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])[CH:32]=[CH:33][CH:34]=1

Participants

8

Reactant 4

HCID 947NitrogenHCID 65578Oxalyl chlorideHCID 533952442-Butenoic acid, 4-(dimethylamino)-, hydrochlorideHCID 866912136-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one

Product 1

HCID 71666595(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamideYield 48.7%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To a mixture of 4-(dimethylamino)but-2-enoic acid hydrochloride (81 mg, 0.49 mmol) and 1 drop of DMF in 3 mL dry CH3CN was added 0.5 mL oxalyl chloride dropwise under N2. The reaction mixture was stirred at rt for 1 hr, then concentrated to dryness in vacuo. The resulting solid was dissolved in 2 mL dry DCM and was transferred to a stirred solution of 6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7) (100 mg, 0.24 mmol) and one drop of TEA in 3 mL dry DCM in an ice-water bath. After stirring for 2 hrs, the reaction was quenched with MeOH. The resulting mixture was concentrated to dry, pre-purified by column chromatography (silica gel, 0 to 5% methanol in DCM), followed by Gilson using 10 to 95% acetonitrile in water (0.1% TFA) to give (E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (8) (61 mg, 48%) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.79 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.58-7.32 (m, 6H), 7.25-7.07 (m, 5H), 6.84-6.65 (m, 1H), 6.46 (d, J=15.4 Hz, 1H), 5.88 (s, 2H), 4.02-3.87 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H). LC-MS (ESI): m/z (M+1) 522.

Workup

  1. concentrationconcentrated to dryness in vacuo
  2. dissolutionThe resulting solid was dissolved in 2 mL dry DCM
  3. stirringAfter stirring for 2 hrs
  4. customthe reaction was quenched with MeOH
  5. concentrationThe resulting mixture was concentrated
  6. customto dry
  7. custompre-purified by column chromatography (silica gel, 0 to 5% methanol in DCM)

Sources & evidence

ORD record
ord-b94cb9b7ed814512b6ee89cdd2a99a2a
Source dataset
uspto-grants-2013_08
Patent number
US08501724B1

Reaction notes

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