A-Ergocryptine

The technical aspect of 2-bromo-a-ergocryptine synthesis, including the characterisation and significance of the impurities obtained in the production process, were reviewed. In the continuation new ergolene and ergoline compounds were synthesized and tested for the pharmacological activity. 

Today, 2-bromo-a-ergocryptine (bromocriptine) is the second (after dihydroergotoxine) most extensively used compound from the group of ergot alkaloids. 

Bromination of a-ergocriptine 2 with commercial N-bromosuccinimide (NBS) can lead to the formation of traces of a mysterious by-product, finally identified as 2-chloro-a-ergocryptine 4. Investigation of NBS indicated that it contains up to 1.5 % of chlorine (probably as N-chloro-succinimide, NCS). This chlorination occurs only in the presence of NBS, never with NCS alone ... 

Bromocriptine mesilate is 2-bromo-a-ergocryptine methane-sulphonate or 2-bromo-12 -hydroxy-2,-(l-methylethyl)-5 -(2-methylpropyl-5 a-ergotaman-3, 6, 18-trione methanesulphonate or Bromocriptinum (INN). It is the active ingredient in Parlodel dosage forms. 

Theoretically, with 6 chiral centers within the molecule (at 6, 9, 2, 5, 11 and 12 positions) 64 diastereomeric forms are possible. However, bromocriptine is sterically well defined at all of these positions, as it is derived from the naturally occurring a-ergocryptine. 

For the specific rotation of 2-bromo-a-ergocryptine and -inine bases see (11). 

Bromocriptine base is manufactured by bromination of a-ergocryptine with N-bromosuccinimide in dioxane solution. 

The compounds separated are visualized by uv at 254 and 366 nm, respectively, and by iodine vapour. Rf of bromocriptine is 0.27. The potential by-products yield spots at R 1.5 (2-bromo-a-ergocryptinine), and 0.55 (a-ergocryptine). 2-Bromo-lysergic acid remains at the starting point. 

Key 1 = dodecylbenzene, 2 = bromocriptinine, 3 = a-ergocryp-tinine, 4 = bromocriptine, 5 = a-ergocryptine (precursor). 

The bromination of peptide alkaloids at position 2 can be smoothly achieved by means of the 3-bromo-6-chloro 2-methylimidazo[ l,2-Z>]pyridazine-bromine complex (33) in methylene chloride solution in particular, the clinically important 2-bromo-a-ergocryptine can be prepared by this method in 75% yield.31... 

Ergocornine 4.22 Dihydroergocornine 4.38 a-Ergocryptine 5.00 Dihydro-a-ergocryptine 5.44 0-Ergocryptine 5.78 Dihydro-e-ergocryptine 5.91... 

Column Lichrosorb RP18 5 pm (150x3 mm ID), mobile phase water - acetonitrile - triethylamine (32 8 1), flow rate 1.0 ml/min, detection UV 280 nm. Peaks 1, dihydroergocornine 2, dihydro- a-ergocryptine 3, dihydroergocristine 4, dihydro-B-ergocryptine. (reproduced with permission from ref. 33, by the courtesy of Journal Pharmaceutical Sciences)... 

I J the mesylates of dihydroergocornine(6a)t dihyd-l... roergocristine(6b). dihydro-a-ergocryptine(6cJ, ... 

Janssen, G. B., R. B. Beems, L. H. Elver, and E. Speijers. 2000. Subacute toxicity of a-ergocryptin in Sprague-Dawley rats. 2 Metabohc and hormonal changes. Food Chemistry and Toxicology 38 689-695. 

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