CS215105B2 - Method of making the 2-brom-alpha-ergocryptin - Google Patents

Description

The invention relates to a process for the preparation of 2-bromo-α-ergocryptine.

2-Bromo-α-ergocryptine is a known compound that inhibits the secretion of prolactin hormone and growth hormone. It is used therapeutically in the treatment of amenorrhea in galactorrhea (Del Pozo et al., J. Clin. Endocrinol. Metab., 38: 910,1974) and acromegaly (A. Liuzzi et al., J. Clin. Endocrinol. Metab. 38: 910, 1974). It preferably acts as a prolactin inhibitor to those cancers, particularly breast cancers, in which activation and reactivation are prolactin-dependent [R. Turkington, W. E. Underwood, and J. J. Van Wyk, N. Engl. J. Med. 285 (1971) 707]. It stimulates dopamine receptors in the central nervous system and is successful in the treatment of Parkinson's disease [D. B. Caine et al., Brit. Copper. 4 (1974) 442.

The first process for the preparation of 2-bromo derivatives of ergotamine alkaloids was disclosed by F. Troxler and A. Hofman in Helv Chim. Acta 40 (1957) 2160. U.S. Patent 507,249 discloses as brominating agents for ergocryptine N-bromosuccinimide, N-bromocaprolactam, N-bromophthalimide and elemental bromine in dioxane. Despite the large excess of the brominating agent, the reaction is not selective and quantitative.

Due to the high sensitivity of ergocryptine, the reactions proceed uncontrollably in other directions, so that much of the starting material disintegrates into dark colored, partially resinous and unidentifiable products, and some of the starting materials also remain unreacted.

It is an object of the present invention to use a milder and more selective brominating agent in the presence of radical initiators. Since these reactions are carried out by a radical mechanism, they can be facilitated by compounds which can form free radicals.

The principle of the process for the preparation of 2-bromo-α-ergocryptine according to the invention by bromination of α-ergocryptine is characterized in that α-ergocryptine is brominated in an inert atmosphere with pyrrolidone hydrotribromide or N-bromosaccharin in cyclic ether solution in radical initiators at room temperature up to 55 ° C.

As cyclic ethers, for example, tetrahydrofuran, tetrahydropyran or dioxane can be used.

Dioxane is preferred. The reaction in acetonitrile or chloroform is less selective.

2,2‘-Azobis- (2-methylpropionitrile) may be used as the radical initiator [G. Bianchi and P. Grunager, Tetrahedron Letters 21 (1965) 817]. The reaction is complete at room temperature in 48 hours, at 50 degrees Celsius with stirring for 20 to 30 minutes.

Temperatures above 50 ° C are not recommended.

Any inert gas such as nitrogen may be used as the inert atmosphere. The reaction is carried out by adding a brominating agent and a radical initiator to a solution of α-ergocryptine in cyclic ether with stirring under an inert atmosphere. In this reaction, the formation of by-products is very sparse, in any case much less than if another brominating agent is used.

1 to 1.2 mol of brominating agent is used per mole of α-ergocryptine.

All starting materials are described in the literature and can be obtained on the market.

2-Bromo-alpha-ergocryptine from the reaction mixture by separation on a column filled with microporous glass carrier, e.g., glass CPG-75 with 200 to 400 holes and a pore diameter of about 69.10 ^-10 M, product of Electro Nucleonics, Fairfield, New Jersey, USA. Chloroform is used as eluent.

Pure 2-bromo-α-ergocryptine is obtained from the eluate after evaporation of the solvent and recrystallization from diisopropyl ether.

2-Bromo-α-ergocryptine is less polar than α-ergocryptine. On a silica gel plate Merck 60 when developing mobile phase chloroform / methanol (100: 5, v.) Comprises 2-bromo-.alpha.-ergocryptine value _of R = 0.55 and α-ergokryptm value R _R ~ 0.40.

Pure 2-bromo-α-ergocryptine melts at 215 degrees Celsius to 217 ° C (decomposition), its specific rotation being [α] _D ²⁰ = -190 to 192 ° (c = 1), methylene chloride.

2-Bromo-crergocryptine is in the free base form insoluble and unsuitable for therapeutic use. Therefore, it is converted into a water-soluble acid addition salt, physiologically harmless, preferably a methanesulfonic acid salt.

The method is explained in more detail by the following examples, but is not limited thereto.

Example 1

2.3 g (4.0 mmol) of α-ergocryptine are dissolved in 100 ml of pure dioxane at 50 ° C under nitrogen. A solution of 2 g (4.03 mmol) of pyrrolidone hydrotribromide and 0.12 g (0.7 mmol) of 2,2'-azo-bis- (2-methylpropionitrile) in 90 ml of dioxane was added with stirring. The reaction was quenched after 30 minutes and the solvent was evaporated in vacuo.

The dry residue is dissolved in 100 ml of chloroform and extracted three times with 80 ml of a 1% solution of sodium carbonate in water. The chloroform phase is dried over sodium sulphate and evaporated to the seventh of the original volume. The concentrate was applied to a 5 cm diameter column packed with 230 mL of CPG-75 microporous glass moistened with chloroform. Elute with chloroform. Fractions containing 2-bromo-α-ergocryptine were combined and evaporated to dryness in vacuo. The residue is recrystallized from diisopropyl ether. 2.05 g or 78.2% of theory are obtained. 215 DEG-217 DEG C. and [.alpha.] D @ ²⁰ = -190 DEG (c = 1, methylene chloride).

Example 2

2.07 g (3.59 mmol) of α-ergocryptine are dissolved in 100 ml of pure tetrahydrofuran under a nitrogen atmosphere. A solution of 2 g (4.03 mmol) of pyrrolidone hydrotribromide and 0.12 g (0.7 mmol) of 2,2 ' -azobis (2-methylpropionitrile) in 100 ml of tetrahydrofuran was added with stirring. After standing at room temperature for two days, the solvent was evaporated in vacuo.

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

2.05 g or 87.2% of theory are obtained. 216 DEG-218 DEG C. and [ _.alpha. ] _D @ 20 = -190 DEG (c = 1, methylene chloride).

Example 3

..... ...............

2.3 g (41.0 mmol) of α-ergocryptine are dissolved in 100 ml of pure tetrahydrofuran under a nitrogen atmosphere. A solution of 1.08 g (4.12 mmol) of N-bromosaccharin and 0.13 g (0.78 mmol) of 2,2'-azo-bis- (2-methylpropionit-1) in 10 ml of tet- ahyd-ofu-anu. After standing at room temperature for two days, the solvent was evaporated in vacuo.

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

2.1 g and 80.1% of theory are obtained. 215 DEG-218 DEG C. and [ _.alpha. ] _D @ ²⁰ = -112 DEG (c = 1, methylene chloride).

Claims (3)

the subject of the invention Process for the preparation of 2-bromo-α-ergokryptine by bromination of α-ergocryptine, characterized in that the bromination of α-ergocryptine is carried out in an inert atmosphere with pyrrolidone hydrotribromide or N-bromosaccharin in a cyclic ether solution in the presence of a radical initiator at room temperature High: 55 ° C. 2. A process according to claim 1 wherein the cyclic ether is dioxane. 3. The process of claim 1, wherein the radical initiator used is 2,2 ' -azobis (2-methylpropionitrile).