Abstract
An optimization procedure for the preparation of Beraprost key intermediate 2 is described. The catalytic hydrogenation of lactone 3 was optimized by Design of Experiment (DoE) methods for minimal Ullmann type side product formation. Experiments used a fractional factorial design method followed by a central composite design allowing optimization of a number of factors as well as statistical analysis of results. The response surface analysis showed that the rate of the side reaction, in a defined experimental area, can be described by a second-order polynomial equation in which the water content and the status of the catalyst are the major influences. The results confirm the mechanistic hypothesis of dimer production as a side reaction on the surface of the catalyst.
Highlights
Prostanoids are biologically highly active compounds and are involved in the regulation of numerous physiological processes in mammalia.1 Beraprost [1] is a stabilized prostacycline derivative applied for the treatment of thrombosis and peripheral arterial occlusive disease.2 Acid 2 is the starting material for Beraprost synthesis (Scheme 1) and is required in kg scale
In the Pareto chart (Figure 1) analysis of variance (ANOVA) effect estimates are sorted from the largest absolute value to the smallest absolute value
While keeping temperature and pressure constant, water content, and pretreatment of the catalyst were identified as the most significant factors influencing the rate of the side reaction and the yield of the product
Summary
Prostanoids are biologically highly active compounds and are involved in the regulation of numerous physiological processes in mammalia.1 Beraprost [1] is a stabilized prostacycline derivative applied for the treatment of thrombosis and peripheral arterial occlusive disease.2 Acid 2 is the starting material for Beraprost synthesis (Scheme 1) and is required in kg scale. The base triethylamine proved to be more effective in neutralization of the released acid (Scheme 2) than the previously used sodium acetate.3 altered parameters led to the formation of a new side product, dimer 4 (up to 30%). A systematic design of experiment (DoE) was performed in order to evaluate and optimize the affecting factors such as solvent volume, pretreatment and water content status of the catalyst, amount of the catalyst, the base (triethylamine), the auxiliary agent (HBr salt of triethylamine), and the water content.
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