GB2061940A

GB2061940A - Process for the preparation of 11-bromo-E-homoeburnane derivatives

Info

Publication number: GB2061940A
Application number: GB8034720A
Authority: GB
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1979-10-30
Filing date: 1980-10-29
Publication date: 1981-05-20
Also published as: GB2061940B; DE3040756C2; JPH0227354B2; FR2468606A1; HU181484B; CH645644A5; FR2468606B1; DE3040756A1; JPS56123984A

Abstract

A process for the preparation of racemic and optically active 11-bromo- E-homoeburnane derivatives of general formula (Ia), <IMAGE> (wherein R represents a C1-6 alkyl group) and acid addition salts thereof comprises treating a mixture of racemic or optically active brominated 14-oxo-E- homoeburnane derivatives of formulae (IIIa) and (IIIb), <IMAGE> (wherein R is as defined above) or a mixture of respective acid addition salts thereof with a nitrosating agent and subjecting the resultant mixture of racemic or optically active brominated 14- oxo-15-hydroxyimino-E- homoeburnane derivatives of formulae (Ia) and (Ib). <IMAGE> (wherein R is as defined above) or respective acid addition salts thereof to selective crystallisation, whereby the desired 11-bromo-E-homoeburnane derivative of formula (Ia) is obtained, which derivative if desired, is converted into an acid addition salt thereof or resolved.

Description

SPECIFICATION Process for the preparation of 11 -bromo-E-homoeburnane derivatives This invention relates to a new process for the preparation of 11 -bromo-E-homoeburnane derivatives.

In German Patent Application No. 2928 187 are described 1 1-bromo-E-homoeburnane derivatives of general formula (la)

wherein R represents a C16 alkyl group which compounds prepared as intermediates in the synthesis of 11 -bromovincaminic acid esters, are stated to process valuable therapeutic effects. 11 -bromovincaminic acid esters are useful in the treatment of behavioural disorders originating from damage or sclerosis of the cerebrovascular system. According to the above-mentioned German Patent Application these 11 -bromo-1 4- oxo-15-hydroximino-E-homoeburnane derivatives are obtained in a yield of 51% by reacting the corresponding 11 -bromo-14-oxo-E-homoeburnane compounds with a nitrosating agent.The preparation of these latter 1 1-bromo-14-oxo-E-homoeburnane derivatives, used as starting materials in the above reaction, is described in German Patent Application No. 2928 187. According to this method a 14-oxo-Ehomoeburnane derivative is treated with a brominating agent and the resultant stereoisomeric brominated compounds, i.e. and 11-bromo-14-oxo-E-homoeburnane derivatives, are separated from the mixture of isomers by preparative layer chromatography or crystallisation. In this way the 11 -bromo compound is obtained in a yield of 42.5% or 33.4%, respectively; the total yield over the two steps (calculated for 14-oxo-E-homoeburnane) is therefore 21.5% or 17%.

According to the above process the 9- and 11 -bromo-E-homoeburnane isomers are separated from each other either by preparative layer chromatography or by crystallisation. Preparative layer chromatography is, however, a less advantageous method of separation when applied on an industrial scale, whereas the selectivity of the crystaliisation method applied according to the cited reference is insufficient. Our investigations have shown that the mother liquor obtained in the crystallisation step contains at least as much dissolved 1 1-bromo derivative as the amount of the separated crystalline 1 1-bromo compound.

We have now found that the mixture of bromo derivatives, obtained when brominating the 14-oxo-Ehomoeburnane derivative need not be subjected to proparative layer chromatography or selective crystallisation in order to separate the desired isomer prior to performing the nitrosation step, since the mixture of 9- and 1 1-bromo isomers may itself be nitrosated very simply and with good yields. Furthermore, the separation of the desired 1 1-bromo derivative of formula (la) from the resulting stereoisomeric mixture of 9- and 11 -bromo-hydroxyimino derivatives is much more advantageous than that of the corresponding mixture obtained prior to nitrosation, good separation being attained by subjecting the stereoisomeric mixture to a simple selective crystallisation using an appropriately selected solvent pair.Thus the preparative layer chromatographic separation, which is difficu It to apply on an industrial scale, can be avoided as well. A further very important advantage is that the total yield relative to the starting material, ie the 14-oxo-E-homoeburnane derivative is almost doubled, and the desired compound of formula (la) can be prepared in a form substantially free of other bromo isomers.

Thus, according to the present invention there is provided a process for the preparation of racemic and optically active 1 1-bromo-E-homoeburnane derivatives of general formula (la) as herein before defined, as well as acid addtion salts thereof, e.g. pharmaceutically acceptable acid addition salts which comprises treating a mixture of racemic or optically active brominated 14-oxo-E-homoeburnane derivatives of formulae (lIla) and (ill),

(wherein R is as defined above), our a mixture of respective acid addition salts thereof with a nitrosating agent and subjecting the resultant mixture of racemic or optically active brominated 14-oxo-15-hydroxyimino-Ehomoeburnane derivatives of formula (la) and (lb),

(wherein R is as defined above) or respective acid addition salts thereof to selective crystallisation, whereby the desired 11-bromo-E-homoeburnane derivative of formula (la) is obtained, which derivative if desired is converted into an acid addition saltthereof and/or resolved.

The mixture of racemic or optically active brominated 14-oxo-E-homoeburnane derivatives of formulae (Illa)and (Illb) may be obtained, if desired, by treating a racemic or optically active 14-oxo-E-homoeburnane derivative of formula (II),

(wherein R is as hereinbefore defined), or an acid addition salt thereof, with a brominating agent.

The compounds of formula (la) possess interesting pharmacological properties and, in particular, they protect the cerebrum from damage during hypoxic states.

In the compounds of general formula (la) R may represent a straight-chain or branched C-6 alkyl group such as e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert.-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl group.

The compound of formula (II) is brominated preferably using elemental bromine; however, other brominating agents to the formation of the desired bromo compounds can alternatively be used.

Bromination is conveniently effected in the presence of an organic solvent or solvent mixture inert under the reaction conditions. As solvents e.g. non-polar organic liquids, such as halogenated aliphatic hydrocarbons (e.g. chloroform or dichloromethane), or polar organic solvents, such as for example organic acids (e.g. glacial acetic acid) can be used. As a solvent mixtures e.g. mixtures of an non-polar and a polar organic solvent, such as mixtures of methylene chloride and glacial acetic acid, can be used.

Particularly when bromination is performed in a mixture of a non-polar and a polar organic solvent (such as in a mixture of a halogenated aliphatic hydrocarbon and an alkanecarboxylic acid), the reaction is preferably conducted in the presence of a Lewis acid. As Lewis acid e.g. ferric chloride, zinc chloride, aluminium chloride, stannictetrachloride or boron trifluoride can be used.

In addition to the compounds of general formulae (Illa) and (Illb) a small amount of the corresponding 10-bromo-14-oxo-E-homoeburnane derivative is also formed in the bromination step. According to gas chromatographic analysis the brominated mixture consists of about 74% of the 11 -bromo compound having the formula (Illa),23% of the bromo compound having the formula (Illb) and 3% of the 10-bromo-14-oxo-Ehomoeburnane derivative.

The mixture of the compounds of formulae (Illa) and (Illb) is conveniently nitrosated with a tertiary alkyl nitrite preferably in the presence of an alkaline agent, such as, for example, an alkali metal tert.-alkoxide (e.g.

lithium, potassium or sodium tert.-butoxide) and preferably in an inert organic solvent, such as an aromatic hydrocarbon (e.g. benzene or toluene).

Thereafter the compounds of general formulae (la) and (Ib) obtained are separated from each other by selective crystallisation. Appropriately selected amounts of mixtures of a non-polar aprotic solvent and a polar protic solvent in appropriate ratios can be used for this purpose. As non-polar aprotic solvent e.g. an 'aliphatic or aromatic hydrocarbon optionally having one or more halogen substituents (such as e.g.

benzene, toluene, methylene chloride or chloroform) can be used. Polar protic solvents of use in the selective crystallisation include for example C16 aliphatic alcohols (such as e.g. methanol and ethanol). Especially 'preferred is a mixture of methylene chloride and methanol and of benzene and ethanol. The weight ratio of the aprotic and protic solvents used in the selective crystallisation will generally vary from 1:1 to 1:1.6, preferably from 1:1 to 1:1.33. The weight ratio of the aprotic and protic solvents based on the mixture to be crystallised may be from 1 to 1.6 preferably 1 to 1.43 for the aprotic non-polar solvent and from 1.1 to 1.7, preferably 1.27 to 1.55 for the protic polar solvent.

A particularly preferred solvent mixture comprises from 1.4 to 1.5 parts by weight methylene chloride and from 1.4 to 1.5 parts by weight methanol, the parts by weight being based on the mixture to be crystallised.

The selectivity of the crystallisation step can be ascertained, for example, by measuring the 9-bromo isomer content of the product. For this purpose gas chromatographic measurement is useful. Depending on the nature of the solvents used in the selective crystallisation step as well as on the weight ratio of the individual solvent components to each other and to the substance to be crystallized, the separated 1 1-bromo fraction generally contains 1.55 to 3.85% of the 9-bromo isomer. By the proper selection of the crystallisation conditions the 9-bromo isomer content of the end-product can be reduced to 1.55%. Thus the crystallisation can really be regarded as selective.

By concentrating the mother liquor obtained in the selective crystallisation step a second mixture of the compounds of general formulae (la) and (Ib) is obtained, which also contains a minor amount of the respective, 1 0-bromo-1 4-oxo-1 5-hydroxyimino-E-homoeburnane derivative. According to gas chromatog raphic analysis, the mixture generally contains about 48% of the 1 1-bromo compound of formula (la),47% of the9-bromo compound of formula (Ib) and 5%ofthe 10-bromo-14-oxo-15-hydroxyimino-E-homoeburnane derivative. This mixture can be recycled into the selective crystallisation process to obtain additional amounts of the 11 -bromo compound of formula (la) again substantially free of the respective 9-bromo isomer.In this way the economy of the process increases. The mixture can however alternatively be subjected to further synthesis steps yielding other pharmaceutically active compounds.

If desired, the racemic or optically active compounds of the general formula (la) obtained according to the invention can be subjected to further purification steps, e.g. recrystallization.

If desired, a racemic or optically active compound of formula (la) obtained according to the invention can be converted into an acid addition salt thereof e.g. a pharmaceuticaly acceptable acid addition salt by treating it with an appropriate acid. Suitable acids include for example mineral acids such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), sulfuric acid, phosphoric acid and perhaloic acids (e.g.

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 and cinnamic acid; alkylsulfonic acids such as methanesulfonic acid; arylsulfonic acids, such as p-toluenesulfonic acid; cyclohexylsulfonic acids; and aspartic acid, glutamic acid, N-acetyl-aspartic acid and N-acetylglutamic acid.

According to a preferred method of the invention the acid addition salts are formed simultaneously with the selective crystallisation. Thus the crude mixture of the compounds of general formulae (la) and (Ib), obtained after the nitrosation step may be dissolved in an appropriate amount of an appropriateiy selected mixture of an aprotic and a protic solvent, and a solution of the salt-forming acid in the protic solvent component of the crystallisation mixture is added to the former solution. In this way an acid addition salt of the compound of formula (la) separates directly and selectively from the solution.

The process of the invention can be used to prepare either racemic or optically active compounds of general formula (la). The compounds can be resolved by methods known per se. Resolution can be performed as the last step of the process according to the invention or alternatively an optically active starting compound of formula (II) may be used.

The process of the invention is elucidated in detail by the aid of the following non-limiting Examples.

EXAMPLE 1 Preparation of a mixture of3(S), 17(S)-i 1-bromo- 14-oxo-E-homoeburnane and 3(S), 17(SJ-9-bromo- 14oxo- E-homoeburnane 10.0 g of 3(S), 17(S)-14-oxo-E-homoeburnane ([a]20 = + 19.6 , c = 1% in dimethyl formamide) are dissolved in 100 ml of methylene chloride, and a solution of 10.0 g of ferric chloride hexahydrate in 50 ml of glacial acetic acid is added to the mixture. The resulting solution is cooled to 5-100C with ice water, and a solution of 2.5 ml of bromine in 50 ml of glacial acetic acid is introduced dropwise. The reaction mixture is stirred for 4 to 5 hours at the same temperature.

After the termination of the reaction 50 ml of methylene chloride and 300 ml of water are added to the mixture, and the resulting two phases are separated from each other. The aqueous layer is shaken with 50 ml of methylene chloride, and the phases are separated from each other. The organic layers are combined, washed with 100 ml of an 5% aqueous sodium bisulfite solution, 120 ml of a 2.5% aqueous ammonium hydroxide solution and then twice with 200 ml of water, dried over solid anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness.

12 g of the title mixture are obtained as a pale yellow oil which solidifies upon standing. The yield is 94%.

This mixture is applied in the next step of the process according to the invention without purification.

EXAMPLE 2 Preparation of 3(ski, 17(S)-i 1-bromo-14-oxo-15shydroxyimino-E-homoeburnane hydrochloride 12 g of a mixture of 3(5), 17(S)-il -bromo-1 4-oxo-E-homeburnane and 3(S), 17(S)-9-bromo-14-oxo-E- homoeburnane, prepared as described in Example 1, are dissolved in 100 ml of dry benzene, and 10 ml of minimum 95% tert.-butyl nitrite are added to the solution followed by 5.0 g of potassium tert.-butoxide. The reaction mixture is stirred at room temperature under exclusion of moisture for 35 to 40 minutes.

After the termination of the reaction 2.2 ml of glacial acetic acid and then 50 ml of water are added to the mixture. The phases are separated from each other, the benzene phase is washed thrice with 30 ml of water, dried over solid an hydros sodium sulfate, filtered, and the filtrate is evaporated to dryness.

13 g of a mixture of 3(S), 17(S)-Il -bromo-14-oxo-1 5-hydroxyimino-E-homoeburnane and 3(S), i7(S)-9- bromo-14-oxo-15-hydroxyimino-E-homoeburnane are obtained as an oil.

The resulting 13 g of oily mixture are dissolved in a mixture of 15 ml of methylene chloride and 20 ml of methanol, and the pH of the solution is adjusted to 2 to 3 with 5 m of methanolic hydrochloric acid. The reaction mixture is cooled for 4 to 5 hours, thereafter the separated substance is filtered off, washed twice with 5 ml of cold methanol and dried in air.

5.15 g (37%) of 3(S), 17(S)-i i-bromo-14-oxo-i5-hydroxyimino-E-homoeburnane hydrochloride are obtained as a pale yellow crystalline substance.

The total yield, calculated for 3(S), 17(S)-14-oxo-E-homoeburnane, is 35%.

The physical constants of the above product are as follows: melting point: 240"C (decomposition); specific rotation power: [al2D0 = +46.2 (c = 1%, in dimethyl formamide); 9-bromo isomer content: 1.6% (determined by gas chromatography).

The methylene chloride - methanol mother liquor obtained in the selective crystallization is evaporated to one-third of its original volume, and the concentrate is allowed to stand for 24 hours. The separated crystals are filtered off, washed twice with 5 ml of methanol each and then dried in air.

1.95 g (14%) of a mixture of (3S),17(S)-11-bromo-14-oxo-15-hydroxyimino-E-homoeburnane hydrochloride and (3S),1 7(S)-9-bromo-1 4-oxo-i 5-hydroxyimino-E-homoeburnane hydrochloride are obtained. The mixture melts at 228-232 C (decomposition). Specific rotation power: [a]2 = +8.0o (+12.0") (c = 1%, in dimethyl formamide).

According to gas chromatographic analysis, the crystal mixture contains 3(S),1 7(S)-1 1-bromo-i 4-oxo-1 5- hydroxyimino-E-homoeburnane hydrochloride in an amount of 48% and 3(S),i7(S)-9-bromo-i4-oxo-i5- hydroxyimino-E-homoeburnane hydrochloride in an amount of 47%.

EXAMPLE 3 Preparation of 3(so, 17(S)-i 1-bromo- 14-oxo- 75-hydroxyimino-E-homoeburnane hydrochloride One proceeds as described in Example 2 with the difference that 13 g of a mixture of 3(S),17(S)-11-bromo- 1 4-oxo-i 5-hydroxyimino-E-homoeburnane and 3(S),i 7(S)-9-bromo-i4-oxo-1 5-hydroxyimino-E- homoeburnane obtained in the nitrosation step are dissolved in a mixture of 11 ml of methylene chloride and 16 ml of methanol.

3(S),17(S)-11-Bromo-14-oxo-15-hydroxyimino-E-homoeburnane hydrochloride is obtained with a yield of 41.8% calculated for 3(S),17(S)-14-oxo-E-homoeburnane. The physical constants of the product are as follows: melting point: 240"C (decomposition); specific rotation power: [a]2D0 = +42.8 (c = 1%, in dimethyl-formamide); 9-bromo isomer content: 3.42% (determined by gas chromatography).

EXAMPLE 4 Preparation of 3(S), 17(S)-11-bromo- 14-oxo- 15-hydroxyimino-E-homoeburnane hydrochloride One proceeds as described in Example 2 with the difference that 13 g of a mixture of 3(S), 17(S)-11 -bromo-14-oxo-15-hydroxyimino-E-homoeburnane and 3(S), 1 7(S)-9-bromo-1 4-oxo-i 5- hydroxyimino-E-homoeburnane obtained in the nitrosation step are dissolved in a mixture of 15 ml of benzene and 17ml of ethanol, and the pH of the solution is adjusted to 2 to 3 with 5 ml of ethanolic hydrochloric acid. The reaction mixture is cooled for 4 to 5 hours, the separated substance is filtered off, washed twice with 5 ml of cold ethanol each and dried in air.

3(S),i 7(S)-il -Bromo-i 4-oxo-i 5-hydroxyimino-E-homoeburnane hydrochloride is obtained with a yield of 37.2% calculated for 3(S),17(S)-14-oxo-E-homoeburnane. The physical constants of the product are as follows: melting point: 240 C (decomposition); specific rotation power: [a]2D0 = +42.1 (c = 1%, in dimethyl formamide); 9-bromo isomer content: 3.85% (determined by gas chromatography).

EXAMPLE 5 Preparation of 3(S), 17(S)-i 1-bromo- 14-oxo- 15-hydroxyimino-E-homoeburnane hydrochloride One proceeds as describe in Example 4 with the difference that 13 g of a mixture of 3(S),17(S)-11 -bromo 14-oxo-l 5-hydroxyimino-E-homoeburnane and 3(S),17(S)-9-bromo-14-oxo-5-hydroxyimino-E- homoeburnane obtained in the nitrosation step are dissolved in a mixture of 19 ml of benzene and 20 ml of ethanol.

3(S),17(S)-11-bromo-14-oxo-15-hydroxyimino-E-homoeburnane hydrochloride is obtained with a yield ol 31.7% calculated for 3(S),17(S)-14-oxo-E-homoeburnane. The physical constants of the product are as follows: melting point: 240 C (decomposition); specific rotation power: [a]2D0 = +44.0 (c = 1%, in dimethyl formamide); 9-bromo isomer content: 2.57% (determined by gas chromatography).

Claims

1. A process for the preparation of racemic and optically active ii -bromo-E-homoeburnane derivatives of general formula (la),

(wherein R represents a C16 alkyl group) and acid addition salts thereof which comprises treating a mixture of racemic or optically active brominated 14-oxo-E-homoeburnane derivatives of formulae (Illa) and (Illb),

(wherein R is as defined above) or a mixture of respective acid addition salts thereof with a nitrosating agent and subjecting the resultant mixture of racemic or optically active brominated 14-oxo-1 5-hydroxyimino-E- homoeburnane derivatives of formulae (la) and (Ib).

(wherein R is as defined above) or respective acid addition salt thereof to selective crystallisation, whereby the desired 11-bromo-E-homoeburnane derivate of formula (la) is obtained, which derivative if desired, is converted into an acid addition salt thereof or resolved

2. A process as claimed in claim 1 wherein the nitrosating agent is a tertiary alkyl nitrite.

3. A process as claimed in claim 2 wherein the treatment is effected in the presence of an alkali metal tert.-alkoxide.

4. A process as claimed in any preceding claim wherein the selective crystallisation is effected in a mixture of an aprotic non-polar organic solvent and a protic organic solvent.

5. A process as claimed in claim 4 wherein the aprotic non-polar solvent is an aliphatic or aromatic hydrocarbon optionally having one or more halogen substituents and the protic polar organic solvent is a C16 aliphatic alcohol.

6. A process as claimed in claim 5 wherein the selective crystallisation is effected in a mixture of methylene chloride and methanol or of benzene and ethanol.

7. A process as claimed in any one of claims 4to 6 wherein the solvent mixture comprises from 1 to 1.6 parts by weight based on the mixture to be crystallised of the aprotic non-polar solvent and from 1.1 to 1.7 parts by weight based on the mixture to be crystallised of the protic polar organic solvent.

8. A process as claimed in claim 7 wherein the solvent mixture comprises from 1 to 1.43 parts by weight based on the mixture to be crystallised of the aprotic non-polar solvent and from 1.27 and 1.55 parts by weight based on the mixture to be crystallised of the protic polar organic solvent.

9. A process as claimed in claim 7 wherein the solvent mixture comprises from 1.4 to 1.5 parts by weight based on the mixture to be crystallised of methylene chloride and from 1.4 to 1.5 parts by weight based on the mixture to be crystallised of methanol.

10. A process as claimed in any preceding claim wherein the mixture of racemic or optically active brominated 14-oxo-E-homoeburnane derivative of formula (Illa) and (Illb) is obtained by treating a racemic or optically active 14-oxo-E-homoeburnane derivative of formula (II),

(wherein R is as defined in claim 1), or an acid addition salt thereof, with a brominating agent.

11. A process as claimed in claim 10 wherein the brominating agent is elemental bromine.

12. A process as claimed in claim 10 or claim 11 wherein the bromination is effected in the presence of an inert non-polar or polar organic solvent or a mixture thereof.

13. A process as claimed in any one of claims 10 to 12 wherein bromination is effected in the presence of a Lewis acid.

14. A process for the preparation of racemic and optically active 11 -bromo-E-homoeburnane derivatives of general formula (la) as claimed in claim 1 substantially as herein described.

15. A process for the preparation of racemic and optically active 1 l-bromo-E-homoeburnane derivatives of general formula (la) as defined in claim 1 substantially as herein described with reference to the Examples.

16. Racemic and optically active ii -bromo-E-homoeburnane derivatives of general formula (la) as defined in claim 1 whenever prepared by a process as claimed in any one of claims 1 to 15.

17. Each and every novel method, process, compound and composition herein disclosed.