Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

Jernej Wagger,Franc Požgan,Aljaž Požes

doi:10.1039/c3ra43417f

Abstract

For the use of analytics, European pharmacopoeial impurities A, B, C, and D of cabergoline were synthesized. Ergocryptine was chosen as a starting material and synthesis was accomplished via two approaches, different in length and stereochemical outcome. A longer, indirect approach was realized through otherwise problematic oxidations of the 9,10-dihidrolysergol derivative, to the corresponding aldehyde and carboxylic acid. This was achieved by the use of activated DMSO and a Pinnick oxidation sequence. All four synthesized impurities are used as analytical standards in cabergoline manufacturing processes.

Highlights

Cabergoline (1) is a natural product-based drug, representing a complex, branched amide of 6-N-allylated 9,10-dihydrolysergic acid A (Fig. 1)
We found 9,10-dihydrolysergic acid 10 rather difficult to isolate, since it displays modest solubility in both organic solvents and water, but with acid 10 in hand, the door towards completion of the synthesis plan was open (Scheme 5)
BAIB/TEMPO mediated oxidation did not work in our case, giving only traces of the desired acid, and failure to oxidize the alcohol 14 is in agreement with the results reported in the literature.[14]

Summary

Introduction

Cabergoline (1) is a natural product-based drug, representing a complex, branched amide of 6-N-allylated 9,10-dihydrolysergic acid (cabergolinic acid) A (Fig. 1). Eur.)[3] as impurities A, B, C and D (Fig. 1) The genesis of these impurities can be found in the syntheses and other manufacturing process activities of cabergoline (Scheme 1).[4]. Since cabergoline (1), with the maximum weekly dosage of 2.0 mg, falls into low dosing drugs, the threshold for identi cation and quali cation of impurities in API is usually 0.10% and 0.15% of mass, respectively.[2] These limits are low and efficient production processes should not exceed them. O en, new synthesis routes have to be designed to obtain desired impurities and this was our task. Eur. impurities A, B, C and D of cabergoline (1) were designed and results are presented in this paper

Results and discussion

Findings

Conclusions