Annual Activities Report 2011 - INCT-Inofar - UFRJ

Annual Report 2011 | INCT-INOFAR
33
Synthesis of
Sunitinib and
Synthesis of
Fluoxetine
Synthesis of Sunitinib
Eliezer J. Barreiro a , Angelo C. Pinto b , Bárbara V. Silva b
a
Instituto Nacional de Ciência e Tecnologia de Fármacos
e Medicamentos, Universidade Federal do Rio de Janeiro,
CCS, Rio de Janeiro-RJ.
b
Universidade Federal do Rio de Janeiro, Instituto de
Química, Rio de Janeiro-RJ.
INTRODUCTION
The INCT-INOFAR leads projects that aim to develop new and innovative synthetic routes to generic
drugs already available in the market, as well as to those whose patents are about to expire. These projects
are in the area of incremental and radical innovation, one of the important focus of the INCT-INOFAR.
In this project, the selected drug was sunitinib. Sunitinib, marketed as Sutent by Pfizer, is an oral multitargeted
receptor tyrosine kinase, employed in the treatment of gastrointestinal stromal tumor, pancreatic
neuroendocrine tumors and renal cell carcinoma.
RESULTS AND DISCUSSION
Our initial efforts were focused on the preparation of the 5-formyl 2,4-dimethyl 1H- pirrole 3-carboxylic
acid [5], according to the route reported in the literature. Aldehyde [5] was prepared in 4 steps (55%
overall yield), according to the synthetic route in Scheme 1. Activation of the carboxylic acid with HOBt,
EDC, followed by reaction with diethylethylenediamine, furnished amide [6] in 92% yield. Oxindole [9]
was prepared from 5-fluorisatin by two methods: Wolff-Kishner reduction and hydrogenation under 62
psi (4.3 bar) using Pd/C as catalyst. Knoevenagel condensation between aldehyde [6] and oxindole [9]
using KOH or piperidine afforded 7 in 93% yield.