HU181372B - Process for preparing new 11-bromo-14-oxo-e-homo-eburnane derivatives - Google Patents

Description

This invention relates to new racemic and optically active formula I 11-bromo-E-homo-eburnane derivatives - wherein A represents hydroxyimino and oxo, R ₂ is ethyl and pharmaceutically acceptable acid addition salts front ₅ for producing such a way that a novel racemic or optically active II-bromo-14-oxo-E-homo-ebuman of formula H wherein R ₂ is as previously defined in formula I, with a nitrosating agent, preferably a tertiary alkyl j with nitrite and, if desired, the resulting new racemic or optically active 11-bromo-14-oxo-15-hydroxyimino-E-homo-eburnan of formula I, wherein A is hydroxyimino;

R ₂ is as defined above, converted into a pharmaceutically acceptable acid addition salt and, if desired, the resulting racemic or optically active

-Bromo-14-oxo-15-hydroxyimino-E-homo-ebumane or an acid addition salt thereof is deoxygenated and, if desired, the resulting 20 new racemic or optically active 11-bromo-14,15-dioxo compounds of formula I -E-homo-ebuman, wherein A is oxo and R ₂ is as defined above, is converted into a pharmaceutically acceptable acid addition salt. 25

In compounds of formula I

A can be hydroxyimino and oxo,

And R ₂ is ethyl. 30

The racemic or optically active 11-bromo-E-homoeburnan derivatives of the formula I are valuable novel compounds which are important intermediates for the valuable 11-bromo-vincamic acid esters having valuable therapeutic activity.

According to the process of the invention, one or two readily obtainable starting materials can be reacted in one or two easy steps to obtain the new 11-bromo-E-homo-ebuman derivatives in good yield.

There are two ways to prepare the new starting material of formula II. One method involves treating the corresponding racemic or optically active 14-oxo-E-homo-ebuman with a brominating agent, while the other method comprises treating a racemic or optically active 1-alkyl-1- (2'-alkoxycarbonylethyl) -1,2 , 3,46,7,12,12b-octahydroindolo [2,3-a] quinolizine is reacted with a brominating agent and the resulting mixture of a new racemic or optically active 10-bromo and 8-bromo derivative is cyclized by treatment with an alkaline agent. .

The nitrosation of the compound of formula II with a tertiary alkyl nitrite, preferably in the presence of an alkaline agent such as an alkali metal tertiary alcohol such as lithium, potassium or sodium tert-butylate, in an inert organic solvent such as an aromatic hydrocarbon, such as benzene, toluene, etc. we can do it. The resulting 11-bromo-14-oxo-15-hydroxyimino-E-homo181372 of formula I

-1181372

-Burnan compounds may, if desired, be converted into an acid addition salt in a manner known per se.

The deoxygenation of the 11-bromo-1-4-oxo-15-hydroxyimino-E-homoeburnan of formula I can be carried out by a reductive route such as zinc in aqueous acetic acid solution or by an oxidative route such as thallium nitrate or so-called reoximation such as carbonyl compounds. in the presence of an acid.

The deoxymation is preferably carried out by the so-called reoximation. Preferably, the 11-bromo-14-oxo-15-hydroxyimino-E-homo-eburnan of the general formula is reacted with paraformaldehyde in a solution of an organic acid in the presence of an aromatic sulfonic acid. Organic acids include, for example, C 1 -C 6 alkanoic acids such as formic acid, acetic acid, and the like. used. Examples of aromatic sulfonic acids are p-toluenesulfonic acid. The resulting 11-bromo-14,15-dioxo-E-homo-eburnan of formula I can be converted, if desired, into an acid addition salt in a manner known per se.

In any step of the process according to the invention, the reaction mixtures can be processed in a manner known per se, from the starting materials, the final product, the solvent, and the like. depending; for example, if the product precipitates at the end of the reaction, it may be isolated by filtration, if the product remains in solution, the solution is evaporated to dryness, preferably under vacuum. The dry evaporated material may be recrystallized from a suitable inert organic solvent. The choice of solvent depends on the solubility and crystallization properties of the material to be recrystallized. The reaction mixtures may be worked up by treating the reaction product with a suitable inert organic solvent such as dichloromethane, dichloroethane, and the like. the organic solvent solution is dried and evaporated, and the residue is crystallized if desired. The desired product may also be precipitated from the reaction mixture with an inert organic solvent, such as ether, and the precipitate thus formed may be isolated by filtration.

The racemic or optically active compounds of formula I obtained by the process of the invention may, if desired, undergo further purification, such as recrystallization.

The compounds of the present invention may also be purified by preparative layer chromatography. Suitable adsorbents are preferably silica gel Merck PF2 s 4-3 6 6, and various suitable solvent combinations are possible as starting materials.

The racemic or optically active compounds of the formula I prepared by the process of the present invention may be converted into pharmaceutically acceptable acid addition salts, if desired. Such acids include, for example, inorganic acids such as hydrogen halides such as hydrochloric acid, hydrobromic acid, etc .; sulfuric acid, phosphoric acid, perhalic acids such as perchloric acid; organic carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, benzoic acid, cinnamic acid; alkylsulfonic acids such as methanesulfonic acid; aryl 2

sulfonic acids such as p-toluenesulfonic acid; cyclohexylsulfonic acids; aspartic acid, glutamic acid, N-acetyl aspartic acid, N-acetylglutamic acid, and the like.

The salt formation is preferably carried out in an inert solvent, preferably an aliphatic alcohol such as methanol, by dissolving the base of formula I in the above solvent and then adding the appropriate acid until the pH of the mixture is slightly acidic (about pH = 6). up). The appropriate salt of the precipitated compound of formula I is then isolated from the reaction mixture by precipitation preferably with a water immiscible organic solvent such as diethyl ether.

The compounds of general formula I according to the invention contain asymmetric carbon atoms.

Both racemic and optically active compounds of formula I can be prepared by the process of the invention, depending on whether the starting compounds of formula II are racemic or optically active.

The process of the present invention provides compounds of Formula I in good yield, in a well identifiable form, where the location of the bands of the characteristic groups as measured by infrared spectroscopy and the mass spectra clearly demonstrate the structure of the compounds of Formula I.

The starting material of formula (II) and the final products of formula (I) according to the invention are new compounds and are themselves biologically active.

The invention also relates to the interruption of the process of the novel 11-bromo-1,4-oxo-15-hydroxyimino-E-homo-ebumane product of formula (1) or to the process according to the invention by without isolation from the reaction mixture.

The invention is illustrated in more detail by the following non-limiting examples.

Example 1

3 (S), 17 (S) -11-Bromo-14-oxo-15-hydroxyimino-E-homo-eburnan hydrochloride

Of a slurry of 0.27 g (0.69 mmol) of 3 (S), 17 (S) -bromo-14-oxo-E-homo-ebumane in 1.7 mL of absolute toluene under nitrogen with constant stirring at room temperature, 65 ml of tert-butyl nitrite, then a suspension of 0.20 g of potassium tert-butylate in 1.7 ml of absolute toluene are added, and the mixture is stirred for 1 hour under the same conditions with the exclusion of moisture, followed by thin layer chromatography (KG- G, Benzene-methanol 14: 3, Rf (starting material)) A solution of 0.54 g of ammonium chloride in 10 ml of water was added and the mixture was stirred for 10 minutes. Extract with dichloromethane (5 mL), dry the combined organic layers over magnesium sulfate, filter, and dry.

The solvent was removed in vacuo from the -2181372 filtrate. The residue (0.23 g) was dissolved in a mixture of methanol (1 ml) and dichloromethane (0.2 ml), the pH of the solution was adjusted to pH 5 with hydrochloric acid and the title compound was filtered off, washed with a little cold methanol and dried. 0.16 g of dm is thus obtained. Yield: 51%.

Melting point: 235 ° C (dec.).

IR (KBr): 3460 (OH), 1710 (lactam CO), 1622 cm @ ^-1 (C = H). 10

MS m / e (%): 415 (M +, 62), 414 (42), 399 (22), 398 (29), 385, 100, 370 (60), 358 (14), 356 (7.0) ), 341 (14), 329 (21), 317 (8.4), 315 (11), 249 (14), 141 (20).

[.Alpha.] D @ 20 = + 45.6 DEG (c = 1.14, dimethylformamide). 15

Example 2

3 (S) 17 (S) -1-Bromo-14,15-dioxo-E-homo-ebumane 20

Dissolve 0.10 g (0.22 mmol) of 3 (S), 17 (S) -11-bromo-14-oxo-15-hydroxyimino-E-homoebuman hydrochloride in 2 ml of glacial acetic acid and add 0/20 g of anhydrous p-Toluenesulfonic acid and 0.30 g of paraformaldehyde are added and the mixture is heated to 110 [deg.] C. for 3 hours with the exclusion of moisture. The mixture was then poured into ice water, basified to pH 9 with concentrated aqueous ammonia, and the resulting 86 mg of 3 (S), 17 (S) ^{-ll-bromo-14,15-dioxo-30} E-ho- mo-preparative ebumánt It was purified by thin-layer chromatography (Merck silica gel PF2 _{S4 +36} 6 elution with dichloromethane: ether 80: 20 mixture ratio, the highest value of stain is eluted with ether). Thus, the pure title compound is obtained.

155-156 ° C after recrystallization from ether.

IR (KBr): 1710 ^cm-1 (CO), 1690 ^cm-1 (amide CO).

[α] D = +44 (c = 1, dichloromethane).

Example 3

3 (S) 17 (S) -1-Bromo-14,15-dioxo-E-homo-ebuman hydrochloride mg 3 (S), 17 (S) -11-Bromo-14,15-dioxo-E- Homo-ebuman is dissolved in 0.5 ml of methanol and the pH of the solution is adjusted to 5 with hydrochloric acid methanol. The solvent was removed in vacuo and the residue crystallized from ethyl acetate to give 18 mg of dm.

Melting point: 228-230 ° C (dec.).

Claims (4)

Patent claims: CLAIMS 1. A process for the preparation of novel racemic or optically active compounds of formula I wherein A is hydroxyimino or oxo and R ₂ is ethyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that the novel racemic or optically active compounds of formula bromo-14-oxo-E-homo-ebuman, wherein R ₂ is as defined above, is preferably reacted with a nitrosating agent with a terderalkyl nitrite and, if desired, the resulting new racemic or optically active converting 11-bromo-14-oxo-15-hydroxyimino-E-homo-ebumane of formula (II) wherein A is hydroxyimino, R ₂ is as defined above into a pharmaceutically acceptable acid addition salt and, if desired, the resulting new racemic compound of formula I or optically active 11-bromo-14-oxo-15-hydroxyimino-E-homoeburnan - amel wherein A is hydroxyimino, R ₂ is as defined above - or the acid addition salt thereof is deoxygenated and, if desired, the resulting new racemic or optically active 11-bromo-14,15-dioxo-E-homoeburnan of formula I Wherein A is oxo and R ₂ is as defined above is converted into a pharmaceutically acceptable acid addition salt. Second embodiment of the method according to claim 1, characterized in that in formula II new, racemic or optically active ll-bromo-14-οχο-Ε-homo ebumánt - wherein R ₂ is as defined in claim ³⁵ 1 the nitrosating agent is reacted with a tertiary alkyl nitrite in the presence of an alkaline agent, such as an alkali metal tertiary alcoholate, in a reaction-inert organic solvent. 3. A process according to any one of claims 1 to 4, wherein the novel racemic or optically active compound of formula I 45 Deoxygenation of 11-bromo-14-oxo-15-hydroxyimino-E-homo-ebumane, wherein R ₂ is as defined in claim 1, is carried out in the presence of a carbonyl compound in an acid. 4. A process according to claim 3, wherein the deoxygenation is carried out with a paraformaldehyde bridge in an organic C 1-4 alkanoic acid in the presence of an aromatic sulfonic acid.