HU176817B - Process for preparing 2-bromo-alpha-ergocryptine - Google Patents

Abstract

The process for the preparation of 2-bromo-alpha-ergocryptine is characterized in that, in an inert atmosphere, alpha-ergocryptine is brominated by means of pyrrolidone hydrotribromide or N-bromosaccharin in solution in a cyclic ether. presence of a radical initiator at room temperature or slightly elevated temperature. Applicable in particular for the preparation of products that can be used in the treatment of breast cancer, and for the inhibition of the secretion of the hormone prolactin and growth hormone.

Description

The present invention relates to a novel process for the preparation of 2-bromo-a-ergocriptine.

2-Bromo-α-ergocriptine is a known compound that inhibits prolactin hormone and growth hormone secretion and is used in medicine for the treatment of amenorrhea-galactorrhea [South Pozo et al., J. Clin. Endocrinol. Metab., 38, 910 (1974)] and used to treat acromegaly [A. Liuzzi et al., J. Clin. Endocrinol. Metab., 38, 910 (1974)]. As a prolactin inhibitor, it has a beneficial effect on cancers, particularly breast cancer, in which prolactin activation and reactivation play a role [R. W. Turkington, L. E. Underwood, and J. J. Van Wyk, N. Engl. J. Med., 285, 707 (1971)]. It stimulates dopamine receptors in the central nervous system and is effective in treating Parkinson's disease [D. B. Caine et al., Brit. Med., 4, 442 (1974)].

The first process for the preparation of 2-bromo derivatives of ergot alkaloids is described by F. Troxler and A. Hofman, Helv. Chim. Acta, 40, 2160 (1957).

According to the process of Swiss Patent No. 507,249, ergocriptine is brominated in the presence of dioxane, and N-bromosuccinimide, N-bromocaprolactam, N-bromophthalimide and elemental bromine are used as brominating agents. Although large amounts of brominating agent are used, the reaction is neither selective nor quantitative. Much of the starting material is decomposed and dark colored, partially resinous products are formed which have failed to identify. In addition, some of the starting material remains unchanged.

The object of the present invention is to use a milder and more selective brominating agent in the presence of a root initiator. Given that the bromination reaction proceeds via a radical mechanism, compounds capable of forming free radicals facilitate the reaction.

According to the present invention, 2-bromo-α-ergocriptine is prepared by bromination of α-ergocriptine with pyrrolidone hydrotribromide or N-bromosaccharin under an inert atmosphere in the presence of a cyclic ether as a solvent and a radical initiator. The bromination is carried out at room temperature or slightly higher.

Cyclic ethers include, for example, tetrahydrofuran, tetrahydropyran or dioxane. A preferred cyclic ether for the process of the invention is dioxane.

In our experiments, it has been found that when the reaction is carried out in acetonitrile or chloroform, its selectivity is reduced.

2,2'-Azobis (2-methylpropionitrile) is used as the radical initiator [G. Bianchi and P. Grunanger, Tetrahedron 20 Letters, 21, 817 (1965)].

The bromination reaction is carried out at room temperature for 48 hours, while stirring at 50 ° C for 20-30 minutes is sufficient. The use substantially higher ^€ 50 C temperature is not preferred.

Any inert gas such as nitrogen may be used to provide an inert atmosphere.

The process according to the invention is carried out by adding to the solution of α-ergocriptine in a cyclic ether, with stirring under an inert atmosphere, the bromine and the root initiator. During the reaction, by-products 176817 are formed only to a very small extent, and the formation of by-products is practically negligible compared to the situation with the brominating agents used in the known processes.

In the process of the invention, 1 to 1.2 moles of brominating agent are used per mole of α-ergocriptine.

All starting compounds are known in the literature and are readily available.

The 2-bromo-α-ergocriptine formed in the bromination reaction is suitably separated from the reaction mixture by column chromatography. A column packed with a microporous glass support was used for chromatography. For example, the substrate may be a CPG-65 glass having a mesh size of 200-400 and having a pore diameter of approximately 69 A (manufactured by Electro Nucleonics, Fairfield, New Jersey, United States). Chloroform was used as eluent. The eluate was evaporated and the residue was recrystallized from diisopropyl ether to give pure 2-bromo-a-ergocriptine.

2-Bromo-α-ergocriptine is less polar than α-ergocriptine. Silicagel 60 is a thin layer of silica gel using a 100: 5 by volume mixture of chloroform and methanol as the mobile phase.

2-Bromo-a-ergocriptine has an R _{f of} 0.55 and a-ergocriptine of 0.40.

The pure 2-bromo-α-ergocriptine melts at 215-217 ° C (with decomposition) and has a specific rotation, [α] D 20 = -190- (192) (c = 1; methylene chloride).

The following examples illustrate the invention.

Example I

2.3 g (0.004 mol) of α-ergocriptine are dissolved in 100 ml of pure dioxane at 50 ° C under a nitrogen atmosphere. A solution of pyrrolidone hydrotribromide (2 g, 0.00403 mol) and 2,2'-azabis (2-methylpropionitrile) (0.12 g, 0.0007 mol) in dioxane (90 ml) was added with stirring. After 30 minutes, the reaction was stopped and the solvent was evaporated in vacuo.

The dry residue was dissolved in 100 ml of chloroform and

Extract 3 times with 80 ml of 1% aqueous sodium carbonate solution. The chloroform phase is dried over anhydrous sodium sulfate and concentrated to one-seventh of its original volume. The resulting concentrate was loaded onto a 5 cm diameter 230 mL microporous CPG-75 column filled with chloroform-wetted glass. Elute with chloroform and fractions containing 2-bromo-a-ergocriptine were combined under reduced pressure. The dry residue was recrystallized from diisopropyl ether. 2.05 g (78.2%) of 2-bromo-a-ergocriptine are obtained, m.p.

215-217 ° C, [α] D = -190 ° (c-1; methylene chloride).

Example 2

Α-Ergocriptine (2.07 g, 0.00359 mol) was dissolved in 100 ml of pure tetrahydrofuran under a nitrogen atmosphere. A solution of 2 g (0.00403 mol) of pyrrolidone hydrotribromide and 0.12 g (0.0007 mol) of 2,2'-azabis (2-methyl15-propionitrile) in 100 ml of tetrahydrofuran is added with stirring. After 2 days at room temperature, the solvent was evaporated in vacuo.

The dry residue was isolated and purified as in Example 1.

2.05 g (87.2%) of 2-bromo-a-ergocriptine are obtained, m.p.

216-218 ° C, [α] D = -190 ° (c = 1, methylene chloride).

Example 3

2.3 g (0.004 mol) of a-ergocriptine are dissolved in 100 ml of pure tetrahydrofuran under a nitrogen atmosphere. A solution of 1.08 g (0.00412 mol) of N-bromosaccharin and 0.13 g (0.00078 mol) of 2,2'-azabis (2-methylpropion pionitrile) in 90 ml of tetrahydrofuran is added with stirring. .

After 2 days at room temperature, the solvent was evaporated in vacuo. The dry residue was isolated and purified as described in Example 1.

2.1 g (80.1%) of 2-bromo-a-ergocriptine are obtained, m.p.

215-218 ° C, [α] D = -192 ° (c = 1, methylene chloride).

Claims (1)

A patent claim A process for the preparation of 2-bromo-α-ergocriptine by bromination of α-ergocriptine in a cyclic ether solvent, characterized in that the bromination is carried out under inert atmosphere at room temperature to 55 ° C with pyrrolidinone hydrotribromide or N-bromo-2-sulfobenzoic acid. in the presence of a catalytic amount of 2,2'-azobis (2-methylpropionitrile), and then separating the 2-bromo-a-ergocriptine from the reaction mixture in a known manner, preferably by column chromatography.