Solid support synthesis of 6-aryl-2-substituted pyrimidin-4-yl phenols as anti-infective agents

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 22, 2005, Pages 4923-4926

  Agarwal, Anu ^a   Srivastava, Kumkum ^a   Puri, S K ^a   Sinha, S ^a   Chauhan, Prem M S ^a  

^a CENTRAL DRUG RESEARCH INSTITUTE   (India)

Author keywords

Combinatorial chemistry; Dihydrofolate reductase; Malaria; Solid support synthesis

Indexed keywords

ANTIINFECTIVE AGENT; PYRIMIDINE DERIVATIVE;

ANTIBACTERIAL ACTIVITY; ANTIMALARIAL ACTIVITY; ARTICLE; BACTERIAL STRAIN; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG SYNTHESIS; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; PLASMODIUM FALCIPARUM; SUBSTITUTION REACTION;

ANIMALS; ANTI-INFECTIVE AGENTS; MOLECULAR STRUCTURE; MYCOBACTERIUM TUBERCULOSIS; PHENOLS; PLASMODIUM FALCIPARUM; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

MYCOBACTERIUM TUBERCULOSIS; PLASMODIUM FALCIPARUM;

EID: 25844525515     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.08.020     Document Type: Article

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28. General experimental procedure: (a) Synthesis of polymer-bound aldehyde (1). A mixture of Merrifield resin (5 g, 1.6 mmol/g), 4-hydroxy benzaldehyde (5 g, 8 mol), NaH, and DMF (100 ml) was shaken at 80°C for 40 h and then washed successively with DMF (30 ml, three times), MeOH (30 ml, three times), DCM (30 ml, three times), and finally MeOH (20 ml, two times). The polymer-bound aldehyde 1 was dried at 60°C under high vacuum for 1 h. (b) Polymer-bound chalcones (2-6). The polymer-bound aldehyde (1, 1 g, 1.6 mmol/g) was further reacted with different acetophenones to give polymer-bound chalcones (2-6). The polymer-bound resin was first allowed to swell in DMF (20 ml) for 10 min and then substituted acetophenones (5 mmol) and sodium methoxide (5 mmol) were added. The reaction mixture was allowed to shake at room temperature for 48 h and then washed successively with water, DMF (10 ml two times), methanol (10 ml, two times), DCM (10 ml, two times), and finally with MeOH (10 ml, two times). Drying under high vacuum for 30 min afforded polymer-bound chalcones 2-6. (c) Polymer-bound-4-(substituted-phenyl)-6-(4-alkyloxy-phenyl)-2-substituted-1-yl- pyrimidine (7-11, 17-31, 47-56). The polymer-bound chalcones (2-6, 50 mg, 1.6 mmol/g), substituted-1-carboxamidine hydrochloride (0.3 mmol), sodium methoxide (0.3 mmol) and DMF (10 ml) as solvent were heated and shaken at 80°C for 30 h. The reaction was then washed successively with water, DMF, methanol, DCM, and finally with MeOH. Drying under high vacuum afforded polymer-bound pyrimidines. (d) 4-[6-(Substituted-phenyl)-2-substituted-1-yl-pyrimidin-4-yl]-phenol (12-16, 32-46, 57-66). The polymer-bound pyrimidines (7-11, 17-31, 47-56) were treated with a 1:1 mixture of TFA and DCM for 1 h and filtered. The filtrate was concentrated to afford a residue which on crystallized from methanol or from chloroform and hexane afforded the products 12-16, 32-46, 57-66.
29. 3, 200 MHz) δ (ppm) 8.08 (d, 2H, J = 8.7 Hz), 8.00 (d, 2H, J = 8.5 Hz), 7.30 (s,1H), 7.02 (d, 2H, J = 8.7 Hz), 6.96 (d, 2H, J = 8.5 Hz), 3.99 (t, 4H, J = 4.6 Hz), 3.87 (s, 3H, OMe), 1.68 (m, 6H).