An improved synthesis of sunitinib malate via a solvent-free decarboxylation process

Abstract

To search for an economical and convenient synthesis of sunitinib and its malate salt, optimization of a scalable synthetic route was explored by designing a standard experimental protocol on laboratory scale using commercially available materials including acetyl ethyl acetate, 4-fluoroaniline, and N 1 ,N 1 -diethylethane-1,2-diamine. The optimal conditions were established based on investigating the main reaction steps, including cyclization, hydrolysis, decarboxylation, formylation, and condensation, giving optimized yields for each step of 94.4, 97.6, 98.5, 97.1, 91.0, 86.3, 85.5, 88.2, 99.1, 97.3, and 58.7 %, respectively. The synthesis process of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid as the important intermediate was significantly improved by using solvent-free decarboxylation instead of the traditional process in a high-boiling-point solvent. The subsequent formylation was conducted directly using the dichloromethane solution of the crude product from decarboxylation, leading to an almost quantitative combined yield of these two steps. The overall yields of sunitinib and its salt using the optimal synthesis process were 67.3 and 40.0 % based on acetyl ethyl acetate. The obtained data could be used as reference for future industrialization, especially for avoiding expensive solvents and reducing reaction time.Electronic supplementary material The online version of this article (

Synthesis and Characterization of Novel Copper(II)-Sunitinib Complex: Molecular Docking, DFT Studies, Hirshfeld Analysis and Cytotoxicity Studies

“…The main difference is in a broad singlet observed at 9.84 ppm for the complex, that corresponds to a proton bonded to the amine group (Figure S2). The spectrum of CuSun was similar to that reported for sunitinib malate [37,38], since in these cases Sun is found as HSun + . Lastly, we have measured the EPR spectra of a solution of CuSun and CuCl 2 •2H 2 O in DMSO at room temperature and we have found similar spectra in both cases (Figure S4).…”

Antimicrobial and antiproliferative study of chalcone clubbed 2,4‐dimethylpyrrole‐3‐carboxamide derivatives: Synthesis and in vitro evaluation

“…The 5‐formyl‐2,4‐dimethyl‐1 H ‐pyrrole‐3‐carboxylic acid (compound 5 ) was synthesized from tert‐butyl acetoacetate (compound 1 ) through multiple steps as per the reported procedure. [ 28 ] First, the oxime was synthesized by condensation of compound 1 with sodium nitrite in acetic acid followed by the reductive cyclization with ethyl acetoacetate that yielded bis‐ester 2 . Selective hydrolytic decarboxylation of compound 2 followed by formylation afforded aldehyde 4 .…”

A Practical Synthesis of Densely Functionalized Pyrroles via a Three-Component Cascade Reaction between Carbohydrates, Oxoacetonitriles, and Ammonium Acetate

“…to be used as handles to synthesize building blocks for fine chemicals, natural products, and pharmaceuticals. 50 As a demonstration and since formyl pyrroles and hydroxymethyl pyrroles are important building blocks for many natural products, 48 pyrrole 6a was converted to 5-formyl pyrrole 20 in 95% yield, which in turn was converted to 5-hydroxymethyl pyrrole 21 in almost quantitative yield (Scheme 2a). 51 Further, we demonstrated efficient synthesis of pyrroloozazine 25 in 53% overall yield from pyrrole 6b through a series of reactions, as shown in Scheme 2b.…”

“…Pyrroles − are nitrogen heterocyclic compounds embedded in many plant and marine natural products such as chlorophylls, porphyrins, , prodigiosin, and prodoginine . They possess wide bioactivities such as antitumor, − antimycobacterial, − anti-inflammatory, − and antiviral activities. , Several pyrrole-based drugs are commercially available including the blockbuster atorvastatin 1 , sunitinib 2 , and aloracetam 3 (Figure ). Therefore, the development of practical and sustainable methods for the synthesis of densely functionalized pyrroles that are amenable to easy transformations to useful intermediates or final products is of great interest.…”