CH642658A5 - RACEMIC OR OPTICALLY ACTIVE OXIMINO-E-HOMO-EBURNAN DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to racemic and optically active ox-25 imino-E-homo-eburnan derivatives, which may also be present as acid addition salts, and to a process for their preparation.

The compounds according to the invention have the following formula (IV)

(iv)

r3-o-n where

R2 for alkyl with 1-6 carbon atoms and R3 for optionally substituted alkyl with 1-8 carbon atoms, aryl with 6-14 carbon atoms, aralkyl with 7-20 carbon atoms, cycloalkyl with 5-14 carbon atoms or for optionally substituted acyl stand, and salts of these compounds, characterized in that the epimer mixture of a racemic so or optically active hydroxy-oxo-E-homo-eburnans of the general formula (II)

55

(iv)

wherein

R2 stands for alkyl with 1-6 carbon atoms and R3 for optionally substituted alkyl with 1-8 carbon atoms, aryl with 6-14 carbon atoms, aralkyl with 7-20 carbon atoms, cycloalkyl with 5-14 carbon atoms or for optionally substituted acyl.

A preferred compound is (+) - 3 (S), 17 (S) -14-oxo-15- (p-chlorobenzyloximino) -E-homo-eburnan.

The process for the preparation of the new compounds of the formula I is characterized in that the epimer mixture of a racemic or optically active hydroxy-oxo-E-homo-eburnans of the general formula II

(II)

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or its salt oxidizes, the racemic or optically active dioxo-E-homo-eburnan obtained of the general formula (III)

(iii) 10

or its salt with a hydroxylamine derivative of the general formula

R3-O-NH2

20th

or react with its salt.

Compounds obtained can, if appropriate, be converted into corresponding acid addition salts.

While the process described above is carried out, the starting compounds of the formula II can be epimerized before their further processing. In a preferred embodiment of the process according to the invention, the 30 optical antipodes are separated in the intermediate compounds of the formula III obtained before the reaction with the hydroxyl derivative.

The compound of the formula IV obtained according to the invention can be separated into Z, E isomers and / or into optical antipodes.

The compounds of the formula IV 35 according to the invention can be converted into apovincamic acid derivatives of the formula (I)

(I]

40

45

R1OOC

be transferred in which

R2 is defined above and so

Ri Ci — Co — alkyl.

It is known that the apovincamic acid esters, especially the apovincamic acid ethyl ester, have a significant vasodilatory effect.

The apovincamic acid esters have hitherto been prepared by hydrolyzing the vincamine, which also has an important curative action, forming the desired ester from the vinic acid obtained and producing the corresponding apovincamic acid ester from this by elimination of water. It is also possible first to produce apovincamine from the vinamine 60 by splitting off water, to hydrolyze it and to esterify the apovincamic acid obtained (Hungarian patent No. 163 434).

The process has the disadvantage that the vincamine must first be produced and then this compound, which is per se pharmacologically valuable for 6s, must be reacted further, the further conversion bringing a maximum yield of 60%.

With the process according to the invention, the pure end product is produced in good yield from simple and easily accessible starting materials in simple operations using readily crystallizable, thermodynamically stable new intermediaries.

In the above formulas I-IV, R 1 and R 2 represent straight or branched alkyl groups with 1-6 carbon atoms, e.g. Methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl, i-hexyl group.

The preferred acid addition salts, namely the physiologically acceptable acid addition salts, can e.g. with the following acids: inorganic acids such as hydrohalic acids, e.g. Hydrochloric acid, hydrobromic acid, etc., sulfuric acid, phosphoric acid, also organic acids, e.g. 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, furthermore alkylsulfonic acids, e.g. p-toluenesulfonic acid, cyclohexylsulfonic acids, aspartic acid, glutamic acid, N-acetylaspartic acid, N-acetylglutamic acid, etc.

Salt formation can be carried out in an inert organic solvent, for example in an aliphatic alcohol having 1-6 carbon atoms, in such a way that the racemic or optically active compound of the general formula IV is dissolved in this solvent and then the corresponding acid or its solution prepared with the same solvent is added until the mixture is slightly acidic (about pH = 5-6). Then the precipitated acid addition salt is usually separated off in a suitable manner, for example by filtration.

Some of the compounds of general formula II used as starting materials in the process according to the invention are new, and some are in the article by Cs. Szantay, L. Szabó, Gy. Kaiaus (Tetrahedron 33, 1803/1977). The connections are made in the manner described in this article.

The starting compounds of the general formula II are generally used in the form of the 15-epimer mixture formed in their preparation without intermediate purification. However, the crude 15-epimer mixture obtained in the preparation of the starting material can also be epimerized first, which at the same time means a certain purification, and then the reaction according to the invention can be carried out using a pure epimer.

The epimerization can be carried out as follows: the 15-epimer mixture is subjected to recrystallization from methanol, which at the same time also has the purpose of purification, because this not only removes the other epimer but also the product from other impurities (starting materials, Intermediates, decomposition products, etc.) exempt. The recrystallized substance is one epimer, the other can be isolated from the mother liquor using preparative layer chromatography (silica gel, benzene-methanol mixture in a ratio of 14: 3).

Both racemic and optically active compounds of the general formula II can be used in the process according to the invention.

The oxidation of the compounds of the general formula II can be carried out using any oxidizing agent which oxidizes the hydroxyl group in the 15-position to the oxo group without attacking the other parts of the molecule. Such oxidizing agents are, for example, manganese dioxide, silver carbonate precipitated on celite, chromium trioxide etc. Manganese dioxide is expediently used in a quantity of 8-12 times, preferably 10 times, based on the weight of the starting material.

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The reaction can be carried out in an inert organic solvent, for example in a halogenated hydrocarbon (dichloromethane). The oxidation is usually carried out under mild conditions, advantageously at room temperature.

At the end of the reaction, the compound of general formula III can be isolated by filtering off the reagent by any known methods of preparative organic chemistry. The solution obtained is preferably evaporated to dryness. The crude compound of the general formula III obtained as the evaporation residue can be used for the following step of the process according to the invention without purification, but it is also possible to purify the crude product before the next reaction step.

The compounds of the general formula III can be purified, for example, by recrystallization or by means of preparative layer chromatography. The solvents that can be used for recrystallization are determined by the solubility and crystallization properties of the substance to be crystallized. Dialkyl ethers, for example diethyl ether, are preferably used. If purification is carried out by means of preparative layer chromatography, silica gel Merck PF254 + 366 'can be used as the flow agent, and different solvent combinations can be used, the type and composition of which are selected depending on the properties of the substance to be separated. For example, a suitably composed mixture of benzene and methanol is suitable.

In the reaction of the compound of general formula III with the hydroxylamine derivative of the general formula R3-O-NH2, the hydroxylamine is expediently used in the form of a salt, for example a hydrohalide (hydrochloride). The hydroxylamine component is expediently used in a slight excess.

The oxime formation is preferably carried out in an organic solvent. Since the reaction not only produces water but also releases acid, it is advisable to carry out the reaction in the presence of an acid acceptor, for example a trialkylamine (triethylamine). However, it is also possible to use a solvent with basic properties, which is also able to bind the acid formed. One such solvent is pyridine.

The formation of oxime is expediently carried out at a somewhat elevated temperature (80-110 ° C.).

The reaction mixture can be worked up using the methods customary in preparative organic chemistry. The solvent is expediently removed from the reaction mixture, for example by vacuum distillation, and the residue is triturated with water. The crude compound of the general formula IV obtained is present as a mixture of the geometric Z and E isomers. The isomers can be separated from one another by recrystallizing the isomer mixture from methanol. One isomer is obtained as a recrystallization product, the other can be separated from the mother liquor by means of preparative layer chromatography. The two isomers can be easily separated from one another by layer chromatography, because of their different Rf values.

The hydroxylamine derivative of the general formula R3-O-NH2 contains as a substituent R3, for example, a group of those mentioned as the meaning of Ri and R2. R3 can moreover, as an aryl group with 6-14 carbon atoms, stand for a single or condensed aryl group containing one or more rings, for example phenyl, diphenyl or naphthyl group. R3 represents an aralkyl group with 7-20 carbon atoms, this may contain one or more fused aryl groups with 6-14 carbon atoms and a straight or branched alkyl group with 1-6 carbon atoms, i.e. Rj can be, for example, benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl or naphthylbutyl. R3 as a cycloalkyl group with 5-14 carbon atoms can mean a group consisting of one or more rings, for example cyclopentyl, cyclohexyl group etc. The acyl group R3 can be an acyl group derived from an organic acid. For example, acyl groups come into consideration which can be derived from saturated monobasic aliphatic carboxylic acids containing 1-8 carbon atoms, i.e. for example the formyl, acetyl, propionyl, valeroyl group etc. Furthermore, the acyl group Rs can also be the acyl group of an unsaturated monobasic aliphatic carboxylic acid with 1-8 carbon atoms, for example the acroyl, methacroyl, vinyl acetyl group, furthermore the Acyl group of one or more rings containing aromatic monobasic carboxylic acids with 6-10 carbon atoms in the ring system, ie for example the benzoyl, naphthyl, etc. Finally, the acyl group R3 can also be the acyl group of a carboxylic acids containing 7-20 carbon atoms containing an aralkyl group, for example phenylacetyl, phenylpropionyl, naphthylacetyl or naphthylpropionyl. The acyl group of cycloaliphatic carboxylic acids with one or more rings can also be present as the acyl group R3. The alkyl, aryl, aralkyl or acyl group contained as R3 can optionally contain one or more identical or different substituents. Preferred substituents are: halogen atoms (fluorine, chlorine, bromine, iodine), straight or branched alkoxy groups with 1-6 carbon atoms (methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i -Butoxy, tert-butoxy group etc.), also nitro, amino, trifluoromethyl group etc.

The use of the reagent of the general formula R3-O-NH2 is very advantageous because in this compound a functional group of the basic bifunctional compound is already protected, i.e. the possibility of the formation of by-products resulting from possible side reactions is less. On the one hand, the yield is higher, on the other hand, the usual cleaning operations can be omitted. It is also advantageous that the oxime formation reaction gives rise to compounds of the general formula IV which can be crystallized very well and are thermodynamically extraordinarily stable. The meaning of the substituent R3 in the reagent of the general formula R3-O-NH2 is greater, the more voluminous the group is.

The compounds of general formula IV are new and biologically active.

Both racemic and optically active compounds of the general formula IV can be prepared using the process according to the invention. If racemic compounds of the general formula IV are obtained, they can be separated into their optical antipodes in a manner known per se. However, this can also take place beforehand, in any step of the method, and the next step is then already carried out with the corresponding, optically active connection.

With the method according to the invention, both the new intermediaries and the target compounds are produced in a readily identifiable manner, as can be proven by elemental analysis, IR spectroscopy and mass spectroscopy.

The invention is explained in more detail below on the basis of exemplary embodiments.

4th

s

10th

IS

20th

25th

30th

35

40

45

SO

55

60

65

5

642 658

example 1

(±) -cis-14,15-Dioxo-E-homo-eburnan To the solution of 8.0 g (24.8mmol) (±) -cis-14-Oxo-15-hydroxy-E-homo-eburnan in 500 ml of dichloromethane are added to 80.0 g of active manganese dioxide. The mixture is stirred at room temperature for 5 hours. Then the mixture is filtered, the filtered off substance is washed with dichloromethane, the washing water is added to the filtrate and this is evaporated to dryness. The substance is recrystallized from diethyl ether. 6.4 g (80%) of product are obtained, which melts at 156 ° C.

Analysis for C20H22N2O2 (M = 322.40)

Calc .: C 74.50%; H 6.87%; N 8.69%

Found: C 74.22%; H 7.02%; N 8.83%

IR spectrum (potassium bromide): 1730 (CO); 1695 cm-1 (amide CO).

Mass spectrum (m / e%): 322 (M +, 100); 294 (86.5); 266 (80); 252 (77); 237 (41); 197 (42); 169 (40); 168 (40.6).

Example 2

(+) - 3 (S), 17 (S) -14,15-Dioxo-E-homo-eburnan To the solution of 4.0 g (12 mmol) (+) - cis-14-oxo-15-hydroxy -E-homo-eburnan in 250 ml dichloromethane are given 40.0 g active manganese dioxide. The mixture is stirred at room temperature for 5 hours. The reaction mixture is then filtered, the filter residue is washed out and the filtrate is evaporated to dryness in vacuo. The evaporation residue is purified by means of preparative layer chromatography. (Silica gel, eluent: benzene and methanol in a ratio of 14: 3). The stain with the largest Rf value contains the target product, this stain is eluted with diethyl ether.

2.9 g (73%) of product are obtained, which at 116 ° C.

melts (from diethyl ether). [a] o = + 80.3 ° (c = 0.90, chloroform).

Example 3

5 (+) - 3 (S), 17 (S) -14-oxo-15-6-chlorobenzyloximino) -E-homo-eburnan

0.33 g (1.02 mmol) of the (+) - 3 (S), 17 (S) -14.15-Dioxo-E-homo-eburnan prepared according to Example 1 are dissolved in 1.6 ml of absolute alcohol. To the solution are added 1 # 0.33 g (1.7 mmol) of 0- (p-chlorobenzyl) hydroxylamine hydrochloride and the reaction mixture is warmed on the water bath for 2 hours. Then the solvent is removed in vacuo, the residue is washed with water and then dried. 0.40 g (84.5%) of product 15 are obtained, which can be used for the following reaction without purification.

If Z and E isomers are to be separated from one another, the 0.40 g of substance obtained is recrystallized from 3 ml of methanol. This gives 0.22 g of uniform isomer, which, when chromatographed on silica gel G with benzene and methanol in a ratio of 14: 3, shows the higher Rf value and melts at 136-137 ° C. after recrystallization from methanol.

IR spectrum (potassium bromide): 1695 (lactam-CO), 1590 cm-1 m (aromatic).

Mass spectrum (m / e%): 461 (M +, 40).

Md = +1510 (c = 1, dichloromethane)

The methanolic mother liquor is worked up by means of preparative layer chromatography (KG-PF254 + 366 '30 benzene-methanol in a ratio of 14: 3), with a further 60 mg of the isomer with the higher Rf value (overall yield 0.28 g) and 35 mg of the isomer can be obtained with the smaller Rf value. Melting point: 177 ° C (ether). IR spectrum (potassium bromide): 1685 (lactam-CO), 1585 cm-1 35 (aromatic).

Mass spectrum (m / e%): 461 (M +, 40).

B

Claims (3)

642 658 2nd PATENT CLAIMS 1. Racemic or optically active oximino-E-homo-eburnan derivatives of the formula (iv) (III) r3-0-n 15 or its salt with a hydroxylamine derivative of the general formula R3-O-NH2 wherein R2 stands for alkyl with 1-6 carbon atoms and R3 for optionally substituted alkyl with 1-8 carbon atoms, aryl with 6-14 carbon atoms, aralkyl with 7-20 carbon atoms, cycloalkyl with 5-14 carbon atoms or for optionally substituted acyl, and their Salts. 2. (+) - 3 (S), 17 (S) -14-oxo-15- (p-chlorobenzyloximino) -E-homo-eburnan according to claim 1. 3. Process for the preparation of racemic or optically active oximino-E-homo-eburnan derivatives of the general formula (IV) or reacted with its salt and, if appropriate, compounds obtained are converted into acid addition salts. 20th (II) or its salt oxidizes, the racemic or optically active dioxo-E-homo-eburnan obtained of the general formula (III)