Stille coupling reactions in the synthesis of hypoxia-selective 3-alkyl-1,2,4-benzotriazine 1,4-dioxide anticancer agents.
The introduction of a 3-alkyl substituent is a key step in the synthesis of 1,2,4-benzotriazine 1,4-dioxide hypoxia-selective anticancer agents, such as SN29751. The Stille reaction of 3-chloro-1,2,4-benzotriazine 1-oxides (BTOs) 5 was inhibited by the presence of electron donating substituents on the benzo ring, thus limiting the range of compounds available for SAR studies. The use of 3-iodo-BTOs 8 did not provide a significant improvement in the yields of 3-ethyl-BTOs 6. Microwave-assisted Stille coupling of chlorides 5 gave dramatically improved yields, which were consistently superior to those from the corresponding iodides 8. The application of microwave-assisted synthesis extended the range of substituted BTOs available for SAR studies and provided an efficient, scalable synthesis of the investigational anticancer agent, SN29751 (1).
Pchalek
Karin
K
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Hay
Michael P
MP
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D002712:Chlorides / Q000737:chemistry; D006577:Heterocyclic Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D006358:Hot Temperature; D007454:Iodides / Q000737:chemistry; D008872:Microwaves; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry
D000970:Antineoplastic Agents; D002712:Chlorides; D006577:Heterocyclic Oxides; D007454:Iodides; D014227:Triazines; D010100:Oxygen