The present invention relates to an industrially feasible and cost-efficient process for the preparation of isomerically pure S-amlodipine besylate hemipentahydrate (1), a useful calcium antagonist inhibitor. Previous workers reported that R-amlodipine-tartrate was crystallized out preferentially from the reaction mixture when naturally occurring l-tartaric acid and racemic amlodipine base in DMSO are mixed. In order to crystallize S-amlodipine-tartrate, the use of unnatural d-tartaric acid as a resolving agent in DMSO was required. However, the cost of d-tartaric acid was not conducive to overall cost efficiency in the resolution protocol. Subsequent to the above observations, we have developed a novel resolving system in which amlodipine base with natural l-tartaric acid in DMF as a solvent gave preferentially the S-form of amlodipine tartrate directly from the reaction. The optimization of this approach by adjusting the water percentage in DMF ensured consistent purity of S-amlodipine (+99%) and satisfactory resolution efficiency.
Efforts toward a synthesis and process
optimization of canagliflozin 1 are described. Canagliflozin
synthesis was accomplished
via purified open ring intermediate 12. The process was
optimized by employing quality by design (QbD) methodologies, and
a telescopic strategy was executed for the first three and last two
steps in a total six-step sequence. Optimization of the Friedel–Craft
acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive
demethoxylation was performed to develop a robust process. These steps
were found to be critical; therefore, critical process parameters
(CPPs) were identified by employing design of experiment (DoE) methodology.
In addition, control strategies for dealing with impurities are described.
Multiple sources of anticipated degradation and process impurities of raltegravir potassium drug substance observed during the laboratory optimization and later during its bulk synthesis are described in this article. The impurities were monitored by UPLC, and their structures are tentatively assigned on the basis of fragmentation patterns in LC−MS and NMR spectroscopy. Most of the impurities are synthesized, and their assigned constitutions were confirmed by co-injection in UPLC. In addition to the formation, synthesis, and characterization, strategy for minimizing these impurities to the level accepted by ICH is also described. We feel that our study will be helpful to the generic industry for obtaining chemically pure raltegravir potassium.
A concise synthesis of (S)-propranolol and (S)metoprolol in high stereoselectivity using the readily available chiral building block (2S,2 0 S,2 00 S)-tris-(2,3-epoxypropyl)-isocyanurate (S-TGT) as the key intermediate is described.
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