Piperazine → Quinazoline

HRID 1038958Notes

Reaction equation

HRID 1038958 reaction equation
[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.N1CCNCC1.C(N)C1C=CC2OCOC=2C=1.[CH:28]1[CH:29]=[N:30][C:31]([NH:34][S:35]([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[CH:42][CH:43]=2)(=[O:37])=[O:36])=[N:32][CH:33]=1.[C:45](Cl)([Cl:47])=[S:46]>N1C=CC=CC=1.O1CCOCC1.ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[Cl-:47].[N:30]1[CH:29]=[CH:28][CH:33]=[N:32][C:31]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][CH:45]=[S:46])=[CH:40][CH:39]=1)(=[O:37])=[O:36]

Participants

10

Reactant 5

HCID 4837PiperazineHCID 5215SulfadiazineHCID 9210QuinazolineHCID 10040ThiophosgeneHCID 75799Benzo-1,3-dioxole-5-methylamine

Product 2

HCID 9210QuinazolineHCID 86601004N-Pyrimidin-2-yl-4-thioformylamino-benzenesulfonamide chloride

Reagents, catalysts & solvents 3

HCID 1049PyridineSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

The synthesis of 4-piperazinylpyrimido[4,5-b]indoles (1b), benzofuranopyrimidines (2b), benzothieno[3,2-d]pyrimidines (3b), and quinazoline (4b) derivatives is depicted in FIG. 20. 4-Chloro-tricyclic and quinazoline building blocks (1a-4a) were synthesized using literature methods. (Pandey, A., et al., J. Med. Chem. 2002, 45:3772-93; Matsuno, K., et al., J. Med. Chem. 2002, 45:3057-66; Matsuno, K., et al., J. Med. Chem. 2002, 45:4513-23; and Venugopalan, B., et al., J. Heterocycl. Chem. 1988, 25:1633-39.) These were converted to the corresponding 4-piperazine derivatives by refluxing with piperazine in pyridine or dioxane. Piperonylamine or sulfadiazine were slowly added to a solution of thiophosgene in dichloromethane while cooling with an ice bath. The resulting mixture was stirred for four hours at room temperature, which gave 1c or 1d, as shown in FIG. 21. Compounds 1c or 1d were further reacted with 4-piperazine-substituted tricyclic or quinazoline derivatives in dichloromethane and stirred overnight at room temperature. To quench excess isothiocyanate, methanol was added, and after removal of solvent, the residue was purified by silica gel chromatography to give compounds 1-7 of FIG. 17 in approximately 20-40% yields.

Workup

  1. temperaturewhile cooling with an ice bath

Sources & evidence

ORD record
ord-55131f9f563b408f861bdea76df90e5d
Source dataset
uspto-grants-2013_10
Patent number
US08552018B2

Reaction notes

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