GB2037757A - Process for the preparation of hydroxyimino-eburananes - Google Patents

Abstract

A process for the preparation of racemic or optically active compounds of general formula I, <IMAGE> (wherein R represents a C1-6 alkyl group) and acid addition salts thereof which comprises reacting a compound of formula III, <IMAGE> (wherein R is as defined above) or a salt thereof with hydroxylamine or a salt thereof followed where required by resolution of the product obtained and/or by conversion of a compound of formula I into an acid addition salt thereof, the compound of formula III or salt thereof being obtained, if desired by oxidation of a compound of formula II, <IMAGE> (wherein R is as defined above) or a salt thereof. Compounds I where R is other than ethyl are claimed per se.

Description

SPECIFICATION Process for the preparation of hydroxyimino-eburnanes This invention relates to a process for the preparation of hydroxyimino-eburnanes of use as intermediates in the synthesis of pharmaceutically active compounds as well as themselves being biologically active.

According to the present invention we provide a process for the preparation of racemic or optically active compounds of general formula I,

(wherein R represents a C, 6 alkyl group) and acid addition salts thereof which comprises reacting a compound of formula Ill,

(wherein R is as defined above) or a salt thereof with hydroxylamine or a salt thereof followed where required by resolution of the product obtained and or by conversion of a compound of formula I into an acid addition salt thereof.

The compounds of general formula Ill or salt thereof may be obtained, if desired, by oxidation of a compound of formula II,

(wherein R is as defined above) or a salt thereof optionally after separation of the 1 5-epimers, followed where required by resolution and. or by conversion of a compound of formula Ill into a salt thereof.

Compounds of general formula I are not only useful as intermediates in the synthesis of other pharmaceutically active compounds, but also themseleves exhibit vasodiliatory activity. From the compound of formula I in which R represents an ethyl group, by treating with lower alcanols in the presence of acids or bases, apovincaminic acid ethly ester a potent cerebral vasodilator substance, can be prepared in a one-step synthesis (published Japanese Patent Application No. 53-147,000). Apovincaminic acid ethyl ester is the active substances of a pharmaceutical composition marketed as "Cavinton". The compounds of general formula I wherein R represents a methyl or C3-6 alkyl group may also be treated in an analogous way to yield compounds having vasodilatory activity.

Those compounds of the general formula I, in which R stands for an ethyl group are known in the art; the other compounds of the general formula I are new.

The term "alkyl group having from 1 to 6 carbon atoms" as used herein means straight or branched chained saturated aliphatic hydrocarbon groups, having from 1 to 6 carbon atons, e.g. methyl, ethyl, n-propyl, isopropy, n-butyl, isobutyl, tert.-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups.

The acid addition salts of the compounds of the general formula I can for example be prepared with the following acids: inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid, hydrobromic acid etc.; sulphuric acid; phosphoric acid; organic carboxylic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbinic acid, citric acid, malic acid, salicilic acid, benzoic acid, cinnamic acid; alkylsulphonic acids, such as methanesulphonic acid; aryl-sulphonic acids, such asp-toluene-sulphonic acid, cyclohexisulphonic acid; asparaginic acid; glutaminic acid etc.

The preparation of salts can be carried out in an inert organic solvent, for instance in an aliphatic alcohol of 1 to 6 carbon atoms in that way that a compound of the general formula I is dissolved in said solvent and the corresponding acid or a solution thereof prepared with the a above solvent is added into the solution obtained, until the pH of the mixture becomes acidic (up to pH 5 to 6). Thereafter the acid addition salt is separated from the reaction mixture in an appropriate manner, for example by filtration.

Compounds of the general formula II used as starting materials in the process according to the invention are partly new partly are disclosed in the following article: Cs. Szántay, L.Szab6, Gy. Kalaus: Tetrahedron 33, 1803 (1977), where the preparation of these compounds is also described. The new compounds of the general formula II can be prepared in an analogous way.

Following the procedure described in the above article compounds of the general formula II are obtained as a 1 5-epimeric mixture which can be used in the process according to the invention without further purification. Alternatively, the epimers can be separated from the crude 1 5-epimeric mixture, which step involves also a certain purification, and the reaction according to the invention can thereafter by carried out with any one of the epimers.

The separation of epimers is carried out by recrystallizing the 15-epimeric mixture from methanol. The recrystallized epimer is separated not only from the other epimer but also from the accompanying impurities (such as starting compounds, intermediates, decomposition products etc). The epimer which remains in the mother liquor is isolated by preparative thin layer chromatography (silica gel, a 14:3 mixture of benzene and methanol).

Racemic and optically active compounds of the general formula II are equally suitable for the purpose of this invention.

The preparation of compounds of the general formula I in which R represents an ethyl group was first described in the Belgian Patent Specification 765,006. According to this patent said compounds were obtained as intermediates in a process in which a suitable substituted 1-methoxycarbonylethyloctahydroquinolizine was subjected to ring closure in the presence of a strong base, such as alkali metal hydrides or amides, and the oxo-eburnane obtained was nitrosated with an alkali metal nitrite in the presence of a strong base, such as alkali metal hydrides.

The process, especially with respect to the industrial realization has numerous drawbacks. Due to the presence of alkali metal hydrides and amides, respectively water must entirely be excluded, which involves a lot of difficulties and requires an extraordinary care in large scale operations. In addition, alkali metal nitrites are detrimental to the health and can be handled only with extreme precautions.

By using the process according to the invention the above disadvantages are eliminated, since in place of the above strong bases, which can be used only under water-free conditions and of the dangerous alkali metal nitrites, the oxime group is introduced into the eburnane structure by hydroxyl amine and salts thereof, which are readily available and easy to handle. Since the total yield of the process according to the invention as well as the yields of the subsequent steps are higher than the yield of the known process, our process is not only easier to carry out but also economic.

Compounds of the general formula II can be oxidized with any oxidizing agent which is capable of conv,erting a 1 5-hydroxy-group into a corresponding oxo-group without influencing other parts of the molecule. Typical representatives of such oxidizing agents are manganese dioxide, silver carbonate precipitated on celite and chromium trioxide. Manganese dioxide is used in a 8-to 12-fold, expediently 1 0-fold amount calculated on the weight of the starting compound.

Oxidation is carried out in an inert organic solvent, e.g. halogenated hydrocarbon, such as dischloromethane.

Oxidation is performed under mild conditions, preferably at room temperatures.

When the reaction is completed, after filtering off the reactant, compounds of the general formula Ill are isolated by any one of the conventional techniques known in the preparative organic chemistry. Following a preferred method. the solution obtained is evaporated to dryness. The crude compound of the general formula Ill obtained as evaporation residue can be used in the subsequent step of the process according to the invention without further purification, but can also be subjected to purification before the subsequent reaction step.

Compounds of the general formula Ill can for example be purified by recrystallization or preparative thin layer chromatography. For recrystallization any suitable organic solvent can be used and the concrete solvent should always be selected in line with the solubility and crystallization of the compound to be recrystallized. Recrystallization is preferably accomplished in a dialkyl ether, e.g. diethyl ether. As an adsorbent in preparative thin layer chromatography for example of Merck PF254+366 silica gel plate can be used while as solvents suitable solvent mixtures can be employed, where the composition and the mutual proportion of the solvents depend on the properties of the compound to be purified. Atypical solvent is for example a suitable mixture of benzene and methanol.

In the process according to the invention compounds of the general formula Ill are preferably reacted with salts, for example hydrogen halides, e.g. hydrogen chloride of hydroxyl amine. The hydroxyl amine reactant is preferably used in a 3-to 5-fold excess.

The oxime-compound is prepared in an inert organic solvent. Since during the reaction in addition to water also an acid is formed, an acid binding agent is preferably added to the reaction mixture. For this purpose for example trialkyl amines, such as triethyl amine can be used. Alternatively, basic solvents, such as pyridine, can be used, which also act as an acid binding agent.

The preparation of oxime-compound is preferably accomplished at slightly elevated temperature, at about 80"C to 110"C.

This reaction mixture can thereafter be subject to conventional separation operations. The solvent is suitably eliminated from the reaction mixture by distillation in vacuo, the residue is dissolved in water and the acidic solution is rendered alkaline by adding an inorganic base, such as a saturated aqueous solution of ammonium hydroxide. From the basic solution compounds of the general formula I are isolated by extraction with a water-immiscible organic solvent, such as a dialkyl ether, e.g. diethyl ether. Evaporation of the extract to dryness yields compounds of the general formula I, which can be converted if desired, into acid addition salts thereof.

If desired, compounds of the general formula I can be subjected to further purification, for example recrystallization. For this purpose a suitably selected solvent, for example a dialkyl ether, such as diethyl ether can be used.

Racemic compounds of the general formula I can be resoluted in a manner known per se.

Both the intermediates and the end products obtained by the process according to the invention are well identifiable products, as proven by chemical analysis, IR and mass spectrum data.

Further details of the invention are illustrated by the following non-limiting Examples.

Example 1 (j )-cis-1 4,1 5-Dioxo-E-homo-eburane 8.0 g (24.8 mmoles) of (I )-cis-1 4-oxo-1 5-hydroxy-E-homo-eburnane are dissolved in 500 ml of dichloro methane and to the solution 80.0 g of active manganese dioxide are added. The reaction mixture is stirred at room temperature for 5 hours. It is then filtered, the filter is washed with dichloromethane and the filtrate is evaporated to dryness. The evaporation residue is recrystallized from diethyl ether. 6.4 g of title compound are obtained, melting at 156"C. Yield: 80"C.

Analysis for C20H22N202 (molar weight: 322.40): Calculated: C 74.50% H 6.87% N 8.69% Found: C74.22% H7.02% N8.83% IR spectrum (KBr): 1730 cm~ (CO), 1695 cm- (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-eburnane 4.0 g (12 mmoles) of (+)-cis-14-oxo-15-hydroxy-E-homo-eburnane are dissolved in 250 ml of dichloromethane and to the solution 40.0 g of active manganese dioxide are added. The reaction mixture is stirred at room temperature for 5 hours, whereupon it is filtered, the filter is washed with dichioromethane and the filtrate is evaporated to dryness in vacuo. The evaporation residue is purified by preparative thin layer chromatography (silica gel; a 14:3 mixture of benzene and methanol). The title compound is contained in the spot which has the highest Rf value and is eluted with diethyl ether. 2.9 g of the title compound are obtained, melting at 116 C (from diethyl ether). Yield: 73%.

[a]D = at80.3" (c = 0.90, chloroform) Example 3 (+)-cis-14-Oxo-15-hydroxyimino-E-homo-eburnane 1.00 g (3.10 mmoles) of (+)-cis-14,15-dioxo-E-homo-eburnane prepared according to Example 1 are dissolved in 5.0 ml of absolute pyridine, and to the solution 1.00 g (14.3 mmoles) of hydroxyl amine hydrochloride are added, which have previously been dried over phosphorus pentoxide. The reaction mixture is then heated on a water bath for 2 hours. The solvent is evaporated in vacuo, 15 ml of water are added to the residue, and the pH of the mixture is adjusted to 9 with a concentrated aqueous ammonium hydroxide solution. The basic solution is extracted with three 10-ml portions of ether.The combined ethereal phases are dried over magnesium sulphate, filtered and the filtrate is evaporated to dryness in vacuo.

Recrystallization of the oily evaporation residue (0.93 g) from ether yields 0.73 g of the title compound, melting at 254"C. Yield: 70.5%.

IR spectrum (KBr): 3200 cml (OH), 1705 cm~1 (lactame CO) 1642cm1 (C=N).

Analysis for C20H23N302 (molar weight: 337.40): Calculated: C71.19% H6.87% N 12.45% Found: m C71.24% H 6.68% N 12.50%.

Example 4 (+ )-3(S),1 4(S)-i 4-Oxo-1 5-hydroxyimino-E-homo-eburnane 0.40 g (1.24 mmoles) of (+)-3(S),17(S)-14,15-Dioxo-E-homo-eburnane prepared according to Example 2 are dissolved in 2.0 ml of absolute pyridine, and to the solution 0.40 g (5.75 mmoles) of hydroxyl amine hydrochloride are added, which have previously been dried over phosphorus pentoxide. The reaction mixture is then heated on a water bath for 2 hours. Pyridine is evaporated in vacuo, to the residue 10 ml of water are added, and the pH of the solution is adjusted to 9 with a concentrated aqueous ammonium hydroxide solution. The precipitated product is filtered off, washed with water and dried. 0.44 g of title compound are obtained melting at 190"C (decomp.).

[a]E250 = +61 (c = 1, dichloromethane).

The crude product (0.44 g) is dissolved in absolute methanol, and the pH of the solution is adjusted to 5 with a methanolic hydrochloric acid solution. The precipitated hydrochloride is filtered off, washed with methanol and dried. 0.34 g of the hydrochloride of the title compound are obtained, melting at 256 to 257"C (10110 uoethaioul). Yield lLt,,.

Claims (15)

1. I. A pfl)cess for the preparation of racemic or optically active compounds of general formula

   (wherein R represeilts a C1 ; alkyl group) diod acid addition salts thereof which comprises reacting a compound of formula Ill,

   (wherein R is ds deti iieti above) or a salt thereof with hydroxyclamine or a salt thereof followed where required by resolution of the product obtained and or by conversion of a compound of formula I into an acid addition salt thereof.
2. 2. A process as claimed in claim 1 wherein a compound of formula Ill is reacted with a hydroxylamine salt.
3. 3. A process as claimed in claim 1 or claim 2 wherein the reaction is effected in the presence of an acid binding agent.
4. 4. A process as claimed in claim 3 wherein the reaction is effected in the presence of a liquid organic base as both solvent and acid binding agent.
5. 5. A process as claimed in any preceding claim wherein the compound of formula Ill or salt thereof is obtained by oxidation of a compound offormula 11,

   (wherein R is as defined in claim 1) or a salt thereof followed where required by resolution andlor by conversion of a compound of formula Ill into a salt thereof.
6. 6. A process as claimed in claim 5 wherein oxidation is effected by means of manganese dioxide.
7. 7. A process as claimed in claim 5 or claim 6 wherein the oxidation is effected in the presence of a halogenated hydrocarbon as solvent.
8. 8. A process as claimed in any one of claims 5 to 7 wherein the compound of formula II or salt thereof is used in the form of a 15-epimeric mixture.
9. 9. A process as claimed in any one of claims 5 to 7 wherein the compound of formula li or salt thereof is used in the form of an optically active isomer.
10. 10. A process as claimed in any one of claims 5 to 7 wherein the compound of formula II or salt thereof is used in the form of a racemate.
11. 11. A process for the preparation of compounds of general formula I as defined in claim 1 and acid addition salts thereof as claimed in claim 1 substantially as herein described.
12. 12. A process for the preparation of compounds of general formula I as defined in claim 1 and acid addition salts thereof as claimed in claim 1 substantially as herein described with reference to the Examples.
13. 13. Compounds of general formula I as defined in claim 1 and acid addition salts thereof whenever prepared by a process as claimed in any one of claims 1 to 12.
14. 14. Compounds of general formula I as defined in claimed 1 wherein R represents a methyl or C36 alkyl group and acid addition salts thereof.
15. 15. Each and every novel method, process, compound and composition herein disclosed.