Compounds based on the ergoline ring system: ##STR1## have a suprising variety of pharmaceutical activities. For example, lysergic and isolysergic acid are D-8-carboxy-6-methyl-.DELTA..sup.9 -ergolines (9,10-didehydroergolines or 9-ergolenes.) The amides of lysergic acid have valuable and unique pharmacologic properties, and include the naturally-occurring peptide alkaloids; ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine, etc.; synthetic oxytocic alkaloids such as methergine; and the synthetic hallucinogen - lysergic acid diethylamide or LSD. Ergotamine, a 9-ergolene, with a "peptide" side chain, has been used in the treatment of migraine and recently, both ergocornine and 2-bromo-.alpha.-ergokryptine have been shown to be inhibitors of prolactin and of dimethylbenzanthracene (DMBA)-induced tumors in rats, according to Nagasawa and Meites, Proc. Soc. Exp'tl. Bio. Med. 135, 469 (1970) and to Heuson et al., Europ. J. Cancer, 353 (1970). (See also U.S. Pat. Nos. 3,752,888 L and 3,752,814).
Non-peptide ergot derivatives, both naturally occurring and totally or partially synthetic, share these multiple pharmacological properties with the peptide derivatives. For example, D-6-methyl-8-cyanomethylergoline, was prepared by Semonsky and co-workers, Coll. Czech. Chem. Commun., 33, 577 (1968), and was found to be useful in preventing pregnancy in rats - Nature, 221, 666 (1969). (See also U.S. Pat. No. 3,732,231) - by interfering with the secretion of hypophysial leuteotropic hormone and the hypophysial gonadotropins or by inhibiting the secretion of prolactin. [See Seda et al., Reprod. Fert., 24, 263 (1971) and Mantle and Finn, id. 441)]. Semonsky and co-workers, Coll. Czech. Chem. Comm., 36, 220 (1971), have also prepared D-6-methyl-8-ergolinylacetamide, a compound which is stated to have anti-fertility and anti-lactating effects in rats. The 2-halo derivatives of D-6-methyl-8-cyanomethylergoline and of D-6-methyl-8-ergolinylacetamide have been prepared and found to be active prolactin inhibitors (M. J. Sweeney, J. A. Clemens, E. C. Kornfeld and G. A. Poore, 64 th Annual Meeting Amer. Assoc. Cancer Research, April, 1973 - See also U.S. Pat. No. 3,920,664).
D-2-chloro-6-methyl-8-cyanomethylergoline (generic name, lergotrile), one of the aforementioned 2-halo derivatives, can be prepared by chlorinating D-6-methyl-8-cyanomethylergoline with such halogenating agents as N-chlorosuccinimide, N-chloroacetanilide, N-chlorophthalimide, N-chlorotetrachlorophthalimide, 1-chlorobenzotriazole, N-chloro-2,6-dichloro-4-nitroacetanilide, N-chloro-2,4,6-trichloroacetanilide, and sulfuryl chloride. Lergotrile can also be prepared by chlorinating any of the intermediate compounds used by Semonsky et al. (loc. cit.) for the preparation of D-6-methyl-8-cyanomethylergoline including methyl dihydrolysergate or D-6-methyl-8-hydroxymethylergoline, or with the novel intermediate of Example 6 of U.S. Pat. No. 3,920,664 such as, D-6-methyl-8-methylsulfonyoxylmethylergoline.
It is an object of this invention to provide a method of chlorinating any of the above ergoline derivatives to provide either lergotrile or a compound readily convertible thereto in higher yield than with any of the chlorinating agents heretofor provided by the art.