JPS6256875B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, R ² represents a C _1-6 alkyl group, and
represents a hydroxyimino group, an oxo group or two hydrogen atoms), or a pharmaceutically acceptable acid addition salt thereof. The compound of the present invention represented by the above general formula () has the following general formula () (wherein R ¹ and R ² each represent a C _1-6 alkyl group) or optically active 10-bromo-
It is useful as an intermediate in the production of vincamic acid esters and their pharmaceutically acceptable acid addition salts. The 10-bromo-vincamic acid ester of the general formula () can be applied to the treatment of behavioral disorders caused by senile cerebrovascular injury and sclerosis, as well as the treatment of disorientation associated with cranial injury. The compound of the present invention represented by the general formula () and the compound of the general formula () are produced as follows. (a) General formula () p-bromo-aniline is diazotized, and the resulting diazonium salt is converted into the general formula () in an alkaline medium. (In the formula, R ⁴ is an alkyl group having 1 to 6 carbon atoms, and Y represents a halogen) to obtain a general formula () (In the formula, R ⁴ and Y are as defined above) by ring-closing the phenylhydrazone derivative of the general formula () obtained. (wherein R ⁴ and Y are as defined above) is hydrolyzed in an alkaline medium and the resulting formula (a) 5-bromo-tryptaminecarboxylic acid of the above general formula () is decarboxylated in an acidic medium or
The ester of is hydrolyzed and decarboxylated in one step in an acidic medium, resulting in the general formula () 5-bromo-tryptamine of the general formula (), optionally after conversion into an acid addition salt. (wherein R ² is as defined above) to obtain a general formula () (wherein R ² is as defined above) is ring-closed and the resulting product is converted into its acid addition salt, resulting in a general formula () (wherein R ² is as defined above and A
represents an anion of an acid)
-alkyl-hexahydroindoquinolidinium salt with a base and then the general formula () (in the formula, R ³ represents a C _1-6 alkyl group), or (b) general formula (XI) (wherein R ² and A are as defined above)
The 1-alkyl-hexahydro-indoquinolidinium salt of is reacted with a brominating agent to give the general formula () (wherein R ² and A are as defined above)
9-bromo-1-alkyl-hexahydroindoquinolidinium salt of with a base and then the general formula () (in the formula, R ³ represents a C _1-6 alkyl group), or (c) general formula (XII) (wherein R ² , R ³ and A are as defined above) is treated with a brominating agent and the obtained By reducing the double bond appearing between rings C and D of the oily 1-ethyl-1-alkoxycarbonylethyl-9-halo-hexahydroindolo-quinolidine derivative, or by reducing this compound itself. This is first reacted with an alcohol of the general formula R ⁵ -OH (in the formula, R ⁵ represents a C _1-6 alkyl group), and in some cases, the obtained general formula (a) (wherein R ² , R ³ and R ⁵ are as defined above), a compound of the general formula (b) selectively reducing the alkoxide or salt obtained by converting it into an acid addition salt (wherein R ² , R ³ and A are as defined above) by any one of the methods of reducing; The obtained general formula (
a) and (b): General formula

[Formula] and general formula The individual components of an isomer mixture consisting of the 1-alkyl-1-alkoxy-carbonylethyl-9-bromo-octahydroindoquinolidine isomers of (wherein R ² and R ³ are as defined above) are separated from each other, and the obtained general formula (a)
(wherein R ² and R ³ are as defined above) 1α-alkyl-1β-alkoxycarbonylethyl-9-bromo-12bαH-octahydroindoquinolidine or its acid addition salt is treated with an alkaline agent. Then, the following general formula () of the present invention 10-bromo-14-oxo-E-homo-eburnane derivative of (wherein R ² is as defined above) [corresponds to the case where X is two hydrogen atoms in formula (). ] is obtained. When the compound of the above formula () is reacted with a nitrating agent, the following general formula () of the present invention is obtained. 10-bromo-14-oxo-15-hydroxyimino-E (wherein R ² is as defined above)
-Homo-eburnane derivative [corresponding to the case where X is a hydroxyimino group in formula ()] is obtained. When the compound of the above formula () is deoxyiminated, the following general formula () of the present invention is obtained. (wherein R ² is as defined above) 10-bromo-14·15-dioxo-E-homo-eburnane derivative [corresponds to the case where X is an oxo group in formula (). ] is obtained. Treatment of a compound of formula () above with a base in an alcohol of general formula R ¹ OH, where R ¹ is as defined above, provides a racemic product of formula (). If desired, the racemic products of the general formula () can then be resolved in a manner known per se to produce the pure optically active isomers. or, if desired, general formula (a),
(), (), (), (XI), (XII), (a
),
(b), (a), (b), (), (
Optically active isomers of formula () are prepared by resolving either the racemic intermediates of formula () or () and carrying out the next reaction step with the individual optically active intermediate. If desired, the free base of general formula () can be converted to a pharmaceutically acceptable acid addition salt thereof. In the above formula, R ¹ and R ² are linear or branched chains.
C _1-6 alkyl groups, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert-butyl, n-
It can represent pentyl, isopentyl, n-hexyl and isohexyl groups. The anion represented by the symbol A may be derived from any organic or mineral acid, of which pharmaceutically acceptable acids are preferred. Examples of applicable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perhalic acid (in particular perchloric acid), formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, succinic acid. Acid, tartaric acid, citric acid, salicylic acid, benzoic acid, lactic acid, malic acid, pyruvic acid, ascorbic acid, phenylacetic acid, anthranilic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, p-
aminosalicylic acid, fumaric acid, cinnamic acid, and also sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, halogenated sulfonic acids, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfanilic acid, as well as aspartic acid, Glutamic acid, N
- Amino acids such as acetyl-aspartic acid or N-acetyl-glutamic acid. German Patent Specification No. 2458164 reports on the preparation of some representative examples of 10-bromo-vincamic acid esters of the general formula (). According to this known method, 3-(1-ethyl-9-halo-octahydroindoquinolidin-1-yl)
-2-Methoxy-propenoic acid methyl ester is treated with acid to produce the corresponding 10-halo-vincamine and 10
-Produces a mixture of halo-apovincamine. At the end of this reaction, the 10-halo-vincamine should be separated from the by-products in an addition step. The starting material for the above process is prepared from ethyl-[3-(p-toluenesulfonyloxy)-prop-1-yl]-malonaldehyde acid ester diethylacetal in a five-step synthesis via complex intermediates. . 10-Bromo-vincamic acid esters and their analogs can be prepared by the process of the present invention from new, readily available starting materials via a simple new intermediate in five easily implemented reaction steps. Can be done. The method of the present invention produces the desired product in a pure state, which does not contain the corresponding apovincamic acid derivative.
Provide high yield. The compound of general formula () used as a starting material in embodiment (a) of the method of the present invention is a known and easily available material. The malonate compound of general formula () used as a reactant is described by E. Fischer and
It can be produced according to the method of H. Bergmann ("Ann." 398 , 120 (1913)). Bromoaniline derivatives of formula () can be diazotized with alkali nitrites, primarily sodium nitrite, in an aqueous, preferably concentrated aqueous solution of a strong mineral acid, especially concentrated aqueous hydrochloric acid, at a temperature of -10 DEG C. to +5 DEG C. A solution of the resulting diazonium salt of the bromoaniline starting material is then prepared in an inert organic solvent by the general formula ()
react with a solution of the compound. As inert organic solvent, aliphatic alcohols such as dry ethanol can preferably be used. This reaction is preferably carried out in the presence of an alkaline agent, for example an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide. Preferably, the alkaline agent is added to the alcoholic solution of the compound of formula () prior to introduction into the acidic solution of the diazonium salt. The product of the above reaction, ie the phenylhydrazone derivative of general formula (), is obtained in the form of a cis-trans isomer mixture. There is no need to separate the individual isomers from each other at this stage. This is because in the subsequent cyclization step both isomers are converted into the same compound of general formula (). This cyclization is performed using aliphatic alcohols (preferably n
-butanol) at elevated temperatures (preferably 40-180°C), optionally in the presence of small amounts of water. The compound of general formula () obtained as described above can be converted into the 5-bromo-tryptamine derivative of formula () by two different methods. According to one of these methods, the compound of general formula () is first subjected to alkaline hydrolysis and the resulting 5-
Halo-tryptamine-2-carboxylic acid (formula ()
(R ² =Hydrogen) is decarboxylated by heating in an acidic medium. This alkaline hydrolysis is suitably carried out by heating the ester in a solution of an inorganic base, preferably sodium or potassium hydroxide, preferably in an aqueous-alcoholic solution (such as an aqueous-ethanolic). Ru. When the reaction is carried out at the reflux temperature of the mixture, the hydrolysis is complete within a few hours. The subsequent decarboxylation can be carried out, for example, by boiling the carboxylic acid in aqueous sulfuric acid. According to another method, compounds of general formula () are hydrolyzed and decarboxylated in a single step in an acidic medium. This reaction is carried out in solutions of strong mineral acids, e.g.
This is carried out by boiling the mixture in 10-20% aqueous sulfuric acid for several hours. The 5-halo-tryptamine derivative of general formula () obtained by one of the above methods is then
It is reacted with a 2-alkyl-pentanolide of general formula () in an organic solvent that does not affect the reaction. Preference is given to using aromatic hydrocarbons such as xylene, toluene or benzene as inert organic solvents. The reaction is preferably carried out with heating at the reflux temperature of the mixture and is complete within about 2 to 6 hours. The resulting compound of general formula () can then preferably undergo ring closure in the reaction mixture in which it was formed. This reaction is carried out in the presence of a phosphorus compound that reacts with water, and optionally in the presence of a halogen element or a halogen hydric acid. The reaction is preferably carried out with heating at the reflux temperature of the mixture. At the end of the reaction, the mixture is treated with a base while heating. Phosphorus compounds that react with water include various phosphorus compounds generated with oxygen and/or halogens, such as phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus pentoxide in the presence of hydrochloric acid. Phosphorous trioxide in the presence of bromine can be used. These phosphorus compounds are in equimolar amounts;
Alternatively, preferably an equimolar excess is used. In this latter example, the excess of phosphorus compound is removed at the end of the reaction, for example by boiling the mixture with water or alcohol. In the above reaction, the intermediate of general formula () is dissolved or suspended in an organic solvent and reacted with the phosphorus compound as defined above at a temperature of 50°C to 250°C, preferably 110°C to 160°C.
As a solvent, it is possible to use, for example, a halogenated hydrocarbon, in particular chloroform, carbon tetrachloride, dichloroethane or chlorobenzene.
If the phosphorus compound used in this reaction is a liquid, the excess phosphorus compound also serves as the reaction medium. At the end of the reaction, the mixture is treated with a base, for example an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide or barium hydroxide, or with a base, such as sodium carbonate or trisodium phosphate. Treat with a basic alkali metal salt. This treatment can be carried out at room temperature or at elevated temperatures, such as from 30°C to 80°C, or even at the boiling point of the reaction mixture. The base can be introduced as a solid substance or as an aqueous solution or suspension. According to a preferred method of the invention, phosphorus oxychloride is used as the phosphorus compound in the ring-closing reaction and an excess of this compound is used as the reaction medium.
The reaction is carried out at the boiling point of the mixture and the excess phosphorus oxychloride is removed in a conventional manner by vacuum distillation. In the above process, in addition to phosphorus oxychloride, halogenated hydrocarbons such as dichloroethane or chloroform can be used as reaction medium, the reaction being preferably carried out in the latter case also at the boiling point of the reaction mixture. Acid addition salts of general formula () can be converted to the corresponding free bases by treatment with alcoholic solutions of inorganic bases. Among the acid addition salts of compounds of general formula (), perhalogenates such as perchlorates and perbromates are particularly preferred. However, salts formed with other suitable mineral or organic acids can be used as well. In order to liberate the free bases of general formula () from their acid addition salts, said salts are treated with a strong base in an inert organic solvent. The obtained base of general formula () can be reacted with the compound of general formula () without being separated from this solution. It is preferred to use dilute aqueous solutions of inorganic bases, such as alkali metal hydroxides, to liberate the bases of general formula () from their acid addition salts. Among the inert organic solvents applicable to this step, for example,
Chloroform, carbon tetrachloride, dichloromethane,
Mention may be made of halogenated hydrocarbons such as 1,2-dichloroethane, trichloroethylene and the like. Dichloromethane has been found to be particularly preferred. Bases of general formula () are preferably liberated from their acid addition salts in an inert gas atmosphere such as an argon or nitrogen atmosphere. This reaction proceeds within a short time at room temperature. As mentioned above, the organic solution of the free base of general formula () liberated from the acid addition salt is then converted to the organic solution of the free base of general formula ()
treatment with compounds. If desired, additional inert organic solvents such as tert.-butanol can be introduced into the reaction mixture. When the free base of general formula () liberated from oxidative salting is reacted with the acrylate of general formula (), the time and temperature of the reaction have no clear role, but for about 6 hours to 6 days at room temperature. Preferably, this reaction is carried out. This reaction can optionally be carried out in an inert gas atmosphere such as an argon or nitrogen atmosphere. The compounds of general formula (XI) used as starting materials in embodiment (b) of the process of the invention can be prepared from the corresponding tryptamine derivatives by ring closure, as described in Hungarian Patent Specification No. 167366. Compounds of general formula () can be suitably brominated with elemental bromine, although other brominating agents such as N-bromosquinimide can be used as well. Bromination is carried out in the presence of an inert organic solvent or solvent mixture. As solvents, for example non-polar organic liquids such as halogenated aliphatic hydrocarbons (eg chloroform, dichloromethane, etc.) or even polar organic liquids such as organic acids (eg glacial acetic acid, etc.) can be used. Optionally, a primary solvent (e.g. glacial acetic acid)
small amounts of aliphatic alcohols (e.g. methanol)
This reaction can also be carried out in a solvent mixture by adding another solvent such as. When carrying out the bromination in a non-polar solvent such as a halogenated aliphatic hydrocarbon, it is preferred to add a Lewis acid to the reaction mixture. As a Lewis acid,
For example, ferric chloride (valent), zinc chloride, aluminum chloride, tin chloride, boron trifluoride, etc. can be used. Bromination is preferably carried out at room temperature. This reaction proceeds within about 0.5 to 2 hours, preferably within 1 hour. 1-(2'-alkoxycarbonylethyl)-1-alkyl-1.2. of general formula () used as starting material in embodiment (c) of the process of the invention
3.4.6.7-hexahydro-12H-indolo[2.3-a]quinolidinium salt is the appropriate 1
-Alkyl-hexahydroindoquinolidines can be prepared as described in Hungarian Patent Specification No. 171,660 by reacting with acrylic esters. The starting material of general formula () is preferably brominated with elemental bromine, but other known brominating agents, such as N-
Bromosuccinimide can also be used with good results. Bromination is carried out in an organic solvent or solvent mixture that does not affect the reaction. For this purpose, halogenated aliphatic hydrocarbons can be used, for example non-polar organic solvents such as chloroform and dichloromethane, as well as polar organic solvents such as glacial acetic acid. It is also possible to add small amounts of other organic solvents, such as aliphatic alcohols, eg methanol, to the abovementioned solvents, for example glacial acetic acid, and mixtures of these solvents can also be used advantageously as reaction medium. When the bromination is carried out in a non-polar organic solvent such as a chlorinated hydrocarbon, the reaction is carried out using a Lewis acid such as ferric chloride, zinc chloride, aluminum chloride,
Preferably, the reaction is carried out in the presence of stannic tetrachloride or boron trifluoride. This reaction is preferably carried out at room temperature. This reaction generally proceeds within 0.5 to 4 hours, more often within 2 to 3 hours. The product of process (a), (b) or (c) initially forms an internal salt, but by adding an acid to this mixture, a compound of the general formula (b) (wherein R ² and R ³ is as defined above and A represents an anion of the acid). For this purpose, preference is given to using mineral acids such as hydrohalic acids (eg hydrochloric acid) or perhalogen acids (eg perchloric acid). In order to obtain a good crystalline alkoxy derivative of general formula (a) (wherein R ² , R ³ and R ⁵ are as defined above), methanol, ethanol,
The red oily inner salt can be treated directly with an aliphatic alcohol of general formula R5 ^- OH such as n-propanol, isopropanol, n-butanol, etc. The alkoxy compound precipitates out in crystalline form from the alcoholic reaction medium. The compound of general formula (a) or (b) is then subjected to selective reduction. This selective reduction saturates the double bond in ring C without simultaneously cleaving the halogen atom attached to the aromatic ring, and is carried out by a known method. It is preferred to use chemical reducing agents in the process, especially metal hydride complexes, primarily borohydrides (eg lithium borohydride, sodium borohydride or potassium borohydride). This borohydride reduction is suitably carried out in an inert solvent or suspending agent, preferably an aliphatic alcohol (such as methanol or aqueous methanol) or an aqueous aliphatic alcohol. the borohydride is in excess of the reaction mixture;
It is preferably added in a 1.5 to 7 molar excess. The time and temperature of the reaction have no definite role and can be varied depending on the reactivity of the starting materials used. However, it is generally carried out at about 0° C. by stirring the mixture at the same temperature for 15 minutes to 3 hours. According to a preferred method of the invention, the general formula (
The compound of a) is suspended in an aliphatic alcohol, the suspension is cooled to about 0° C., and at the same temperature sodium borohydride is added in portions to the mixture. This reaction mixture is worked up by conventional techniques. The excess reducing agent is first destroyed by acidifying the mixture, then the mixture is evaporated, the residue is dissolved in water, the solution is made alkaline, extracted with an inert organic solvent, and the product is is precipitated from this latter solution by evaporating the solvent. By processing this mixture, a product is produced, usually in a crystalline state. General formula (a) and (
When the product consisting of a mixture of the compounds of b) is obtained as an amorphous powder or in oily form, such as an aliphatic alcohol (e.g. methanol, ethanol or isopropanol) or an aliphatic ether (e.g. diethyl ether etc.) It can be easily crystallized from suitable solvents. The product of the selective reduction step is an isomeric mixture consisting of compounds of general formula (a) and (b). These isomeric compounds can be separated from each other by conventional physical methods such as fractional crystallization from appropriate organic solvents. For this purpose, for example, lower aliphatic carboxylates, halogenated lower aliphatic hydrocarbons, lower aliphatic alcohols (such as methanol, ethanol or isopropanol), lower aliphatic ethers or mixtures of these solvents can be used. Compounds of general formulas (a) and (b) can also be separated from each other on the basis of differences in their physical properties, for example on the basis of differences in R values. One of these methods is preparative layer chromatography,
This means that the R value of the trans compound is the R value of the cis isomer.
This takes advantage of the fact that it is higher than the value. Preferably, silica gel (such as Merck PF _254+366 grade silica gel) is used as the adsorbent. Various solvent mixtures can be used as eluents, for example 14:2 or 14:3 mixtures of benzene and methanol (see H. Halpaap: "Chemie
−Ing.Techn.” 35 , 488 (1963)). The cis and trans isomers of general formulas (a) and (b) can be obtained according to the invention by first hydrolyzing the reaction product obtained in the selective reduction step and then by fractional crystallization. They can also be separated from each other by separating the free acid forms from each other. According to our experience, the free acid forms of the esters of general formulas (a) and (b) can be separated from each other particularly easily by fractional crystallization. The release of carboxylic acids from these esters is also advantageous with respect to the production of optically active compounds. Racemic compounds with free carboxyl groups can be easily resolved by converting them into diastereomeric salt pairs with optically active bases. The esters of general formulas (a) and (b) can be prepared in a suitable solvent, for example ethanol, with an inorganic base,
For example, the ester can be converted to the corresponding free acid by conventional hydrolysis methods such as boiling the ester in the presence of sodium hydroxide. The resulting mixture of racemic or optically active cis- and trans-carboxylic acids can be fractionally crystallized such that the isomer mixture is dissolved in a hot organic solvent such as hot dimethylformamide and the solution is allowed to cool. The precipitated low-melting trans-carboxylic acid crystals are filtered and the liquid is mixed with water to precipitate the high-melting cis-carboxylic acid. The racemic or optically active cis- and trans-carboxylic acids separated from each other as described above can be converted into their esters in a conventional manner. The ester can be prepared, for example, by first combining the resulting racemic or optically active cis- or trans-carboxylic acid with
It is made by reacting with the appropriate halogenating agent and then treating the acid halide with an alcohol. In this way, many types of racemic or optically active carboxylic acid esters of general formula (a) or (b) can be produced. In the first step of the esterification process, the free carboxylic acid is reacted with a phosphorus halide, such as phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride. However, it is particularly preferred to use thionyl chloride as the halogenating agent in the above step.
Halogenation may be carried out in an inert organic solvent;
It can be carried out in the presence of an inorganic or organic base, but
If a liquid reactant is used as the halogenating agent, the reaction can also be carried out in an excess of the liquid reactant without adding an inert solvent and a base to the reaction mixture. In the second step of the esterification process, the obtained acyl halide is treated in the presence of a suitable alcohol and optionally an acid binder.
The reaction is preferably carried out at the boiling point of this mixture. Racemic or optically active free carboxylic acids corresponding to the esters of general formulas (a) and (b) can be esterified in a single step by reacting these free acids or their salts with an alkylating agent. You can also do it. Among the salts, salts formed with alkali metal ions such as sodium and potassium salts are particularly preferred. According to a preferred method, an alkyl halide such as an alkyl bromide or more preferably an alkyl iodide is used as the alkylating agent. These halogenated alkyl groups are linear or branched C _1-6 alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl,
It may also contain primary or secondary alkyl groups such as n-pentyl, isopentyl, n-hexyl or isohexyl groups. Among these alkylating agents, the following are particularly preferred: methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, isopropyl bromide, isopropyl iodide,
sec.-butyl iodide, sec.-butyl bromide, etc. Alkylation can be carried out in dipolar aprotic solvents such as hexamethylphosphoramide or dimethylformamide. If a free carboxylic acid is used as a starting material in the above method,
This reaction takes place in the presence of an inorganic base, such as sodium or potassium hydroxide, sodium hydride,
Alternatively, it is preferably carried out by adding an aqueous solution of potassium carbonate to the mixture. Alternatively, the free acid can be first reacted with a base and the resulting salt then contacted with an alkylating agent. Racemic or optically active 1α-alkyl-1β-alkoxycarbonylethyl-9-bromo-12bαH of general formula (a) obtained as above
The -octahydroindoquinolidine compound is the starting material for the next step of the synthesis according to the invention. Isomeric compounds of general formula (b) can be oxidized with alkali dichromates to form the corresponding hexahydro compounds of general formula (a) or (b), the latter being introduced as intermediates in the process of the invention. can. Details of this oxidation process are disclosed in the patent application specification corresponding to Hungarian patent application no. RI-660. In the next step of the synthesis according to the invention, the compound of general formula (a) may be an alkali metal hydride, e.g. sodium hydride, or e.g.
tert. of lithium, sodium or potassium.
- tert. of an alkali metal such as butoxide. - Reaction with an alkaline agent such as butoxide. Preference is given to using aromatic hydrocarbons such as benzene or toluene as reaction medium. The compounds of the invention of general formula () obtained can, if desired, be converted into their acid addition salts by conventional methods. The compounds of the invention of general formula () can be prepared in an inert solvent such as an aromatic hydrocarbon, for example benzene or toluene, with an alkaline agent, preferably with an alkali metal tert.-butoxide, such as lithium, sodium or potassium tert.-butoxide. can be nitrosated, for example with tertiary alkyl nitrites, in the presence of .-butoxide. In the next step of the synthesis, the obtained compound of the present invention of general formula () is deoxyiminated. Deoxyimination can be carried out by reducing methods, e.g. treatment with zinc in aqueous acetic acid, by oxidizing methods, e.g. treatment with thallium nitrate, or by so-called transoximation, e.g. treatment with acids in the presence of carbonyl compounds. It can be implemented. The latter method is particularly preferred. Transoximation is suitably carried out by dissolving the compound of general formula () in an organic acid and treating with paraformaldehyde in the presence of an aromatic sulfonic acid. As organic acids, for example C _1-6 alkanecarboxylic acids such as formic acid, acetic acid, propionic acid and the like can be used. Among the aromatic sulfonic acids that can be used in this reaction, p-toluenesulfonic acid can be mentioned. If desired, the resulting 10-bromo-14.15 of the invention of general formula ()
- the dioxo-E-homo-eburnane compounds can be converted into their acid addition salts by methods known per se and/or the racemic compounds can be resolved in a conventional manner to produce the pure optically active isomers. Can be done. In the final step of the synthesis, the compound of general formula () is converted into a compound of general formula () corresponding to the ester to be prepared.
R ¹ −OH in the presence of an alcohol with a base, preferably lithium, potassium or sodium
tert.−alkali metal tert. such as butoxide
Treat with alkoxide. This step produces the desired product of general formula (). The reaction mixtures resulting from each step of the above synthesis can be worked up by conventional methods. Depending on the solvent and the type of compound used, the desired product intermediate can be separated from the reaction mixture, for example by filtration or by evaporating the solvent, optionally under reduced pressure. can. If desired, the separated material can be purified by recrystallization from a suitable inert organic solvent. The solvent used for this purpose is selected according to the crystallization properties and solubility requirements of the compound in question. The reaction mixture is extracted from the mixture with a suitable inert organic solvent such as dichloromethane, dichloroethane, etc., the solution is dried and evaporated, and if necessary the residue is crystallized from a suitable solvent. It can also be treated by It may also be possible to precipitate the product from the reaction mixture with a suitable inert organic solvent such as ether and isolate it by filtration. If desired, the racemic or optically active compounds obtained can be further purified by additional conventional procedures such as recrystallization. The product of general formula () obtained by the above method can also be purified by preparative layer chromatography. For this purpose, silica gel, such as Merck PF _254+366 grade silica gel, is preferably used as adsorbent, and various solvent mixtures can be used as eluent. If desired, the general formulas (), (a), (), (), (), (XI
),
(XII), (a), (b), (a), (

Racemic or optically active compounds of b), (), () or () can be converted into their pharmaceutically acceptable acid addition salts by reacting their free bases with the appropriate acid. Examples of acids applicable for this purpose are hydrohalogen acids (e.g., hydrochloric acid, hydrobromic acid, etc.);
Mineral acids such as phosphoric acid and perhalogen acids (e.g. perchloric acid); also 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 or cinnamic acid; sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid or cyclohexylsulfonic acid, and aspartic acid, glutamic acid, N-acetyl-aspartic acid. , N-acetyl-glutamic acid, and the like. Salt formation occurs in inert solvents, especially in aliphatic alcohols such as methanol, using the general formulas (), (
a), (), (), (), (XI), (XII), (

a), (b), (a), (b), ()
,
Dissolve the free base of () or () in a solvent and make this solution slightly acidic (approximately
This is preferably carried out by setting PH=6).
The resulting salt precipitates out of the reaction mixture, or alternatively it can be precipitated with a suitable organic solvent such as ether. The compound of general formula () has an asymmetric carbon atom and can therefore exist in the form of optically active isomers and racemic mixtures. Optically active compounds of general formula () can be prepared either by resolving the corresponding racemic mixture by known methods or by utilizing optically active starting materials. According to a third method, the synthesis is started with a racemic compound of the general formula (), and one of the racemic intermediates is combined with the resulting compound of the general formula (a), (), () or (). resolution and the next step of synthesis is performed on the optically active intermediate. If desired, any of the optically active compounds prepared can be converted into the corresponding racemic mixture by known methods. Compounds of general formula () can be produced in high yields and as easily identified pure substances. Analytical data for the products are in good agreement with calculated values, and the characteristic infrared absorption (IR) spectra, nuclear magnetic resonance (NMR) spectra, and mass spectra of these compounds confirm the expected structure. It confirms it. General formula (), (), (a), (), (),
(), (XI), (), (a), (b),
(
a), (b), (), () and ()
The intermediate is a new compound and has not been previously described in the literature. The novel intermediates produced in the above method are biologically active substances and have useful pharmacological properties. Pharmacological studies were performed on the above intermediate products. Especially general formulas (b), (b), (a)
It was found that the compounds () and () have considerable pharmacological activity. Dogs anesthetized with chloralose-urethane were subjected to blood circulation tests. Arterial pressure, pulse rate, blood circulation in the femoral artery and internal carotid artery, and vascular resistance in both vascular regions (blood pressure divided by blood circulation) were measured and calculated. The test compound was administered intravenously at a dose of 1 mg per 1 kg of body weight. Each compound was tested in 5 to 6 parallel experiments. The results are shown in Tables 1 to 4 below. The abbreviations in the table are as follows: MABP = Median arterial pressure HR = Pulse rate CBF = Blood circulation volume in the internal carotid artery CVR = Vascular resistance in the internal carotid artery FBF = Blood circulation volume in the femoral artery FVR = Vascular resistance in the femoral artery

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【table】

【table】

[Table] The data in the above table shows that the new compound administered intravenously to anesthetized dogs at a dose of 1 mg/kg body weight causes only a small decrease in blood pressure and almost no change in pulse rate. There is. The significant activity of these compounds is demonstrated by a reduction in vascular resistance in the extremities (vasodilator effect). This activity is particularly significant in the case of the compounds of Tables 1-2 and 3, which exhibit vasodilatory activity of 50 to 70%. Blood circulation volume increases by 90 to 140% at the same time. At the carotid site these compounds induced mild vasodilation (10-25%). For comparison, the results of a blood circulation test conducted using vincamine are shown in Table 5 below.

【table】

[Table] The intermediates produced in the above method do not necessarily have to be isolated; the next steps of the synthesis can be carried out directly on the mixture containing the intermediates. Hereinafter, the compounds of the present invention [represented by formulas (), (), and ()] and specific methods for producing the compounds of formula () obtained therefrom will be explained step by step with reference to Examples. Example 1 Ethyl-5-bromo-tryptamine-2-carboxylate hydrochloride 23.70 g (0.10 mmol) of diethyl-3-chloropropylmalonate are dissolved in 70 ml of absolute ethanol and this mixture is added with 6.40 g of potassium hydroxide in 70 ml of absolute ethanol. g (0.11 mmol) of the solution was added dropwise under stirring to remove atmospheric moisture. The mixture was stirred for a further 2 hours, then cooled to -5°C and the diazonium salt solution previously cooled to -5°C was added to the mixture. The diazonium salt solution was prepared as follows: p-bromoaniline 17.20 g (0.10 mmol)
was dissolved in a mixture of 100 ml of water and 27 ml of concentrated aqueous hydrochloric acid. Cool the solution to 0-3°C and add 15 ml of water.
A solution of 7.00 g (0.11 mmol) of nitrile nitrite in the solution was added dropwise. When the diazotization reaction is completed, 10
The pH of this solution was adjusted to 6 by introducing about 77 ml of % aqueous sodium carbonate solution, and the resulting solution was cooled to -5°C. After introducing this diazonium salt solution, the pH of this solution was adjusted to 7.4 with approximately 15 ml of 10% aqueous sodium carbonate solution.
to 7.5 and the mixture was stirred for 1 hour at 0° C. under nitrogen atmosphere. Afterwards, the mixture was acidified to PH=6 with acetic acid and left overnight at room temperature. The precipitated deep red oil was extracted with dichloromethane. The organic layer was washed three times, first with 2N aqueous sodium hydroxide and then with water, dried over anhydrous magnesium sulfate, filtered,
This liquid was then evaporated to dryness in vacuo. The oily residue, which is a mixture of cis-trans isomers of 2-oxo-5-chloro-valeric acid ethyl ester p-bromo-phenylhydrazone, was purified by preparative layer chromatography (adsorbent: silica gel Merck PF254+).
366; Eluent: 14:2 benzene and methanol
The isomers were separated into individual isomers by a mixture of R _f
= 0.85 (isomer A) R _f = 0.77 (isomer B) IR spectrum (in KBr pellet): Isomer A: 3250 (NH), 1738 (-COOC ₂ H ₅ ),
1680 (C=N) 1605 (aromatic) cm ^-1 Isomer B: 3300 (NH), 1735 (-COOC ₂ H ₅ ),
1700 (C=N), 1608 (aromatic) cm ^-1 The oil obtained above was dissolved in 160 ml of n-butanol. A few drops of water were added and the mixture was refluxed under nitrogen atmosphere for 24 hours. Afterwards, the solution was cooled to 0 DEG C. and the precipitated ethyl-5-bromo-tryptamine-2-carboxylate hydrochloride was filtered off, washed with a small amount of n-butanol, and dried. 12.50g of the above compound
(34.8%). Melting point 248-249℃ (after recrystallization from ethanol) IR spectrum (in KBr pellets): 3340 (NH),
1705 (Ester CO) cm ^-1 Mass spectrum m/C%: 312 (M ⁺ , 19.6), 283
(100), 237 (54.5), 208 (25.6), 127 (34),
101 (13.1) ¹ H-NMR spectrum (in CDCl ₃ ): δ = 7.82-
7.28 (3H, m, aromatic proton), 4.44 (2H,
ester, -CH2 _{- CH3} ), 1.42 (3H, t, ester, _-CH2 - CH3 ) _Example 2 5-bromo-tryptamine-2-carboxylate Ethyl-5-bromo-tryptamine-2-carboxylate hydrochloride 1.00 g (2.87 mmol) of salt in 10 ml of ethanol and 10 ml of 4N sodium hydroxide aqueous solution
The mixture was boiled for 2 hours. The mixture was cooled with ice, acidified to pH 6 with glacial acetic acid, and the precipitated crystals were collected by filtration. Melting point at which 0.75 (91%) of 5-bromotryptamine-2-carboxylic acid was obtained
248-249℃ IR spectrum (in KBr pellet): 3320 (NH),
1585 (COO ^- ) cm ^-1 analysis C ₁₁ H ₁₁ N ₂ O ₂ Br (molecular weight = 283.13): Calculated value C = 46.63% H: 3.91% N = 9.98% Measured value C = 46.52% H: 3.85% N = 9.92% Example 3 5-bromo-tryptamine 5-bromo-tryptamine-2-carboxylic acid
A mixture of 1.00 g (3.53 mmol) and 80 ml of 10% aqueous sulfuric acid was stirred and refluxed for 30 hours. The pH of the mixture was adjusted to 9 with concentrated aqueous ammonia while cooling with ice solution, and the alkaline mixture was extracted four times with 20 ml of chloroform. The organic extracts were combined and added with a 5% aqueous sodium hydroxide solution.
It was then washed with water, dried over anhydrous magnesium sulphate, filtered and the liquid was evaporated in vacuo. 5-bromo-tryptamine 0.48g (58
%) as an oily residue. A portion of the oily residue was dissolved in ethanol and converted to formate by introducing formic acid.
After recrystallizing this formate from ethanol, 175
Melted at -176°C. Analysis C ₁₁ H ₁₂ N ₂ O ₂ Br (molecular weight = 284.14) Calculated value N: 9.86% Measured value N: 9.71% Example 4 1-Ethyl-9-bromo-1, 2, 3, 4.
6,7-hexahydro-12H-indolo [2.
3-a] Quinolidin-5-ium perchlorate 5-bromo-tryptamine 0.48 g (2.0 mmol) and 2-ethyl-pentanolide 0.30 g (2.3
mmol) in 5 ml of anhydrous xylene and the solution was refluxed for 4 hours. The reaction mixture was evaporated in vacuo and the residue was triturated twice with 3 ml each of petroleum ether and then dried in a desiccator. N-(α-ethyl-δ-hydroxy-valeroyl)-5-bromo-tryptamine 0.59 g (80
%) was obtained. IR spectrum (in KBr pellets): 3320 (NH,
OH, broadband) 1640 (acid amide CO) cm ^-1 obtained N-(α-ethyl-δ-hydroxy-
Valeroyl)-5-bromo-tryptamine 0.59g
was mixed without purification with 5 ml of phosphorus oxychloride. The mixture was refluxed for 6 hours, after which excess phosphorus oxychloride was distilled under vacuum and the residue was evaporated under ice cooling.
5 ml of 4N aqueous sodium hydroxide solution was mixed and the mixture was stirred at room temperature for 15 minutes. Separate the organic layer and add 3 ml each of the aqueous layer to dichloroethane.
Extracted three times. The organic solutions were combined, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed from the solution by evaporation in vacuo, the oily residue (0.65 g) was dissolved in 3 ml of methanol, and the pH of the solution was adjusted to 6 by introducing 70% aqueous perchloric acid. The precipitated crystals were collected by filtration, washed with cold methanol, and dried. 1-ethyl-9-bromo-1.2.3.4.
6,7-hexahydro-12H-indolo [2,3
-a] Quinolidin-5-ium perchlorate 0.40g
(46%; calculated with respect to 5-bromo-tryptamine) was obtained. Melting point: 233-234°C (after recrystallization from methanol) IR spectrum (in KBr pellets): 3250 (indole NH), 1622, 1545 (C=N) cm ^-1 analysis C ₁₇ H ₂₀ N ₂ ClBrO ₄ (molecular weight: 431.72) Calculated value C: 47.29% H: 4.67% N: 6.49% Measured value C: 47.08% H: 4.55% N: 6.36% Example 5 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo -1, 2, 3, 4, 6, 7
-hexahydro-7aH-indolo[2,3-
a] Quinolidine-5-ium-methoxide 1-ethyl-9-bromo-1.2.3.4.
6,7-hexahydro-12H-indolo [2,3
-a] Quinolidin-5-ium perchlorate 7.00g
(16.2 mmol) in 160 ml of dichloromethane, pour this solution into a separatory funnel, and add 10%
A mixture of 28 ml of sodium hydroxide aqueous solution and 111 ml of water was added. The biphasic mixture was thoroughly shaken, the organic layer was separated, dried over anhydrous potassium carbonate, and filtered. 8.90 g (103.5 mmol) of methyl acrylate was added to the solution, which was a solution of the free base in dichloromethane. The resulting mixture was left at room temperature for 2 days, after which time the solvent was evaporated in vacuo and the oily residue was crystallized from methanol. Thus, 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1.2.3.
4,6,7-hexahydro-7aH-indolo[2,3-a]quinolidine-5-ium methoxide was obtained in the form of orange-red crystals. Melting point: 140−
142℃ (from methanol) IR spectrum (in KBr pellets): 1730 (-
COOCH ₃ ), 1560, 1480 (C=N) cm ^-1 Mass spectrum: m/e (%) = 420 (8.5), 419
(9.3), 418 (M ⁺ , 11), 417 (8.8), 405
(0.8), 403 (1.1), 401 (0.6), 389 (1.7),
387 (2.5), 385 (2.9), 383 (1.9), 347
(9.9), 345 (13), 332 (43), 317 (99), 315
(100), 303(11), 301(12), 250(5.8), 249
(6.0), 248 (6.0), 247 (5.5) Under the conditions of mass spectrometry, methanol and bromine-containing compounds (molecular weight = 418) could also be detected in the vapor phase of the samples. ^1H -NMR ( _CDCl3 ): δ=7.47-7.05 (3H,
m, aromatic protons ₎ 3.55 (6H, S, _-COOCH3 , _-OCH3 ) 0.82 (3H, t, _-CH2CH3 ) ppm 0.1 g of the above product is suspended in 1 ml of methanol, and this suspension The pH of the liquid was adjusted to 6 with a 70% aqueous perchloric acid solution. Collect the precipitated crystals by filtration,
It was washed with a small amount of methanol and dried. 1-ethyl-1-(2'-methoxycarbonylethyl)-9-
Bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidine-5
0.095 g of -ium perchlorate was obtained. Melting point 221-222°C (after recrystallization from methanol) IR spectrum (in KBr pellets): 3300 (indole NH), 1718 (-COOCH ₃ ), 1620 and 1538
(C=N) cm ^-1 Example 6 1-ethyl-9-bromo-1, 2, 3, 4,
6,7-hexahydro-12H-indolo [2.
3-a] Quinolidin-5-ium perchlorate 1-ethyl-1 in 276 ml of dichloromethane
To a solution of 12.00 g (34 mmol) of 2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidin-5-ium perchlorate was added 48 ml of a 10% aqueous sodium hydroxide solution and water. Add 192ml,
This mixed solution (PH=11) was then sufficiently shaken in a separating funnel. The organic layer was separated, dried over solid potassium carbonate, filtered, and the liquid was evaporated to dryness in vacuo. The residue was dissolved in methanol, the solution was acidified to pH 6 with methanolic hydrochloric acid, and the solvent was distilled off in vacuo. Dissolve the oily residue in 70 ml of glacial acetic acid and add 5 ml of methanol.
ml and 6.55 g of bromine in 30 ml of glacial acetic acid (41
A solution of 1 mmol) was introduced into the mixture at room temperature with constant stirring. After about 1 hour, the product separated as an oil on the walls of the flask. The glacial acetic acid was decanted, the oily residue was dissolved in 30 ml of warm methanol and 2.92 ml of 70% aqueous perchloric acid was added to this solution. The pH of this mixture was thus adjusted to 5. The precipitated product was filtered, washed with a small amount of cold methanol, and dried. 1-ethyl-9-bromo-
1, 2, 3, 4, 6, 7-hexahydro-12H-
Indolo[2,3-a]-quinolizin-5-ium perchlorate was obtained. The glacial acetic acid solution decanted from this product in the above step was evaporated in vacuo and the residue was dissolved in warm methanol 10
ml and the solution was acidified to PH5 with 70% aqueous perchloric acid. The precipitated product was filtered, washed with cold methanol, and dried. A further 1.47 g of the above product was thus obtained. The total yield was thus 10.49g (71.4%). The melting point of this product was 233-234°C. IR spectrum (in KBr): 3250 (indole NH), 1622, 1545 (C=N)
cm ^-1 analysis C ₁₇ H ₂₀ N ₂ ClBrO ₄ (molecular weight = 431.72) Calculated value C: 47.29% H: 4.67% N: 6.49% Measured value C: 47.08% H: 4.55% N: 6.36% Example 7 1-Ethyl -1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7
-hexahydro-12H-indolo [2,3-
a] Quinolidine-5-ium methoxide 1-ethyl-1-(2'-methoxycarbonylethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidine-5
-Ium perchlorate 4.39g (10mmol) at 10%
It was shaken with a mixture of 5 ml aqueous ammonia and 50 ml dichloromethane. Separate the layers, dry the organic layer over 10 g of solid anhydrous sodium sulfate, filter,
The liquid was then evaporated to a final volume of approximately 40 ml and 0.1 g of dry ferric chloride was added to the concentrate.
2.08 g (0.67 ml, 13 mmol) of elemental bromine was added dropwise to this mixture at 25° C. with vigorous stirring. Addition took 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and then treated with 10% aqueous ammonia.
ml and filtered out the precipitated ferric hydroxide. The organic layer of this liquid was separated, dried over 10 g of solid anhydrous sodium sulfate, filtered,
This liquid was then evaporated. When the oily residue was mixed with 10 ml of methanol, the product precipitated out in a crystalline form containing lattice-bound methanol. thus,
3.81 g (85%) of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1.2.
3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidine-5-ium methoxide was obtained. Melting point: 140-142℃ ^1H -NMR (in CDCl ₃ ): = 0.8 (t, 3H, -CH ₂
CH3 ), 7.6 (2H, Ar10-11H), 8.1 ₍ 1H,
Ar8H) ppm Example 8 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7
-hexahydro-12H-indolo [2,3-
a] Quinolidine-5-ium methoxide 1-ethyl-1-(2'-methoxycarbonylethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-quinolidine-
4.39 g (10 mmol) of 5-ium perchlorate in 10
% aqueous ammonia and 50 ml dichloromethane. The layers were separated, the organic layer was dried over 10 g of solid anhydrous sodium sulfate, and then filtered. 0.5 g of dry gaseous hydrochloric acid was introduced into this liquor, followed by 50 ml of glacial acetic acid and the dichloromethane was distilled off in vacuo. 0.67 ml (2.08 g, 13 mmol) of elemental bromine was added dropwise to the residue at 25° C. with vigorous stirring. The reaction mixture was stirred at room temperature for 3 hours, the precipitated product was filtered off, and suction was applied thoroughly to remove any residue of acetic acid. Pour the still wet product into 40 ml of dichloromethane.
The diluted suspension was made alkaline with 14 ml of 10% aqueous ammonia and the layers were separated from each other. This organic layer is dissolved in solid anhydrous sodium sulfate.
Dry over 10g, filter and evaporate the liquid. The resulting oily residue was triturated with 10 ml of methanol, and the product precipitated out in a crystalline form with methanol lattice bound. In this way, 1
-Ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidin-5-ium methoxide 3.15 g ( 70%). Melting point: 140-142°C, NMR of this product was identical to that shown in Example 7. Example 9 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7
-hexahydro-12H-indolo [2,3-
a] Quinolidine-5-ium hydrobromide 10% aqueous ammonia 5 ml and dichloromethane 50 ml
1-ethyl-1-(2'-methoxycarbonylethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidin-5-ium perchlorine 4.39 g (10 mmol) of the acid salt was shaken. The layers were separated, the organic layer was dried over 10 g of solid anhydrous sodium sulfate, and filtered. This liquid was mixed with 50 ml of glacial acetic acid and the dichloromethane was distilled off in vacuo. 0.67 ml (13 mmol, 2.08 g) of elemental bromine was added dropwise to the residue at 25° C. with vigorous stirring. The reaction mixture was stirred at room temperature for 3 hours, and the precipitated yellow crystalline product was filtered and dried. thus
4.5 g of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1.2.3.4.6.
7-hexahydro-12H-indolo [2,3-
a] Quinolidin-5-ium hydrobromide was obtained (yield 90%). Melting point: 127-128°C. The NMR spectrum of this product had the characteristic bands shown in Example 7. Example 10 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7
-hexahydro-12H-indolo [2,3-
a] Quinolidin-5-ium perchlorate 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3. 4.6.
7-hexahydro-12H-indolo [2,3-
a) 0.1 g of quinolidine-5-ium methoxide was suspended and the pH of the suspension was adjusted to 6 by introducing a 70% aqueous perchloric acid solution. The precipitated crystalline product was filtered, washed with a small amount of methanol, and dried. Thus, 0.095 g of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidine- 5-ium perchlorate was obtained. Melting point:
221-222℃ (after recrystallization from methanol) IR spectrum (in KBr): 3300 (indole-
NH), 1718 (-COOCH ₃ ), 1620 and 1538 (C
=N) Characteristic absorption band example at cm ^-1 11 (±)-1α-ethyl-1β-(2'-methoxycarbonylethyl)-9-bromo-1.2.3.
4.6.7.12.12bα-octahydroindolo[2.3-a]quinolidine and (±)-1α
-Ethyl-1β-(2'-methoxycarbonylethyl)-9-bromo-1.2.3.4.6.
7.12.12bβ-octahydroindolo [2.
3-a] Quinolidine 1:1 mixture of dichloromethane and methanol20
1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1.2.3.4.6.
7-hexahydro-7aH-indolo [2,3-
a] Quinolidine-5-ium methoxide 6.50g
(14.4 mmol) was dissolved and 0.55 g of sodium borohydride was added portionwise to this solution at 0° C. with stirring. After the addition, the mixture was stirred for a further 30 minutes, then acidified to PH=6 with acetic acid and evaporated to dryness in vacuo. The pH of the residue was adjusted to 8-9 with 5% aqueous sodium carbonate solution, and the resulting solution was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and the liquid was evaporated in vacuo. Weight is used to separate isomers from each other.
6.10 g of the oily residue was subjected to preparative thin layer chromatography (adsorbent: silica gel Merck KG-PF _256+366 ; solvent: 14:3 mixture of benzene and methanol). The separation was based on the higher R _f value of the 12bβ isomer than _that of the 12bα derivative. By elution with a 10:1 mixture of dichloromethane and methanol, 2.70 g (44.5%) of (±)-
1α-ethyl-1β-(2′-methoxycarbonylethyl)-9-bromo-1,2,3,4,6.
7.12.12bα-octahydroindolo [2.3
-a] Quinolidine was isolated. Melting point: 166-168℃
(After recrystallization from methanol) IR spectrum (in KBr pellet): 3380 (indole NH), 2800, 2750 (Ballmann absorption band),
1720 (-COOCH ₃ ) cm ^-1 Mass spectrum: m/e (%) = 420 (81.6), 418
(M ⁺ , 81.2), 405 (8.1), 403 (8.1), 389
(9.5), 387 (5.4), 347 (95.5), 345 (100),
317 (2.6), 315 (2.6), 277 (28.9), 275
(30.7), 250 (27.9), 248 (31.6), 168 (19.5) ¹ H−NMR (DMSO−d ₆ , CDCl ₃ ): δ = 7.62−
7.12 (3H, m, aromatic proton), 3.58 (3H,
s, -COOCH ₃ ), 3.50 (1H, s, 12bH), 1.11
(3H, t, _-CH2CH3 ) ppm 0.1 _g of the above 12ba derivative was suspended in 1 ml of methanol, and the pH of this suspension was adjusted to 6 with methanolic hydrochloric acid. The precipitated crystals were collected by filtration, washed with a small amount of methanol, and dried.
(±)-1α-ethyl-1β-(2′-methoxycarbonylethyl)-9-bromo-1.2.3.4.
6.7.12.12bα-octahydroindolo[2.3-a]quinolidin-5-ium hydrochloride
0.095g was obtained. Melting point: 223-225℃ In a similar manner, (±)-1α-ethyl-1β-(2′-
methoxycarbonylethyl)-9-bromo-1.
2.3.4.6.7.12.12bβ-octahydroindolo [2.3-a] quinolidine 2.02g (33.3
%) were isolated from thin layer chromatography fractions with high R _f values. After recrystallization from methanol, the compound melted at 140-142°C. IR spectrum (in KBr pellet): 3300 (indole NH), 2830, 2750 (Bollmann absorption band),
1710 (-COOCH ₃ ) cm ^-1 Mass spectrum: m/e (%) = 420 (100), 418
(M ⁺ , 100), 405 (11.2), 403 (11.9), 389
(11.1), 387 (9.9), 347 (90.2), 345 (90.8),
317 (8.3), 315 (7.4), 277 (26.5), 275
(27.5), 250 (25.6), 248 (27.1), 168 (15) ¹ H-NMR (CDCl ₃ ): δ = 9.00 (1H, s, indole proton), 7.62-7.10 (3H, m, aromatic proton ), 3.80 (3H, s, −COOCH ₃ ),
3.33 (1H, s, 12bH), 0.68 (3H, t, -CH ₂
CH ₃ ) ppm Example 12 (±)-1α-ethyl-1β-(2'-methoxycarbonylethyl)-9-bromo-1.2.3.
4.6.7.12.12bα-octahydroindolo[2.3-a]quinolidine Isomer mixture 1.1 obtained as described in Example 11
g (2.63 mmol) in 5 ml of ethanol and 0.3 ml of water.
Dissolved in a warm mixture of To this solution was added 0.35 g of solid sodium hydroxide, and the mixture was refluxed for 1 hour. Afterwards, the solvent was evaporated in vacuo, the residue was dissolved in 13 ml of water and the pH of the solution was adjusted to 6 with 10% aqueous acetic acid. The precipitated material, consisting of a mixture of isomeric carboxylic acids, was collected by filtration, washed with water, dried and recrystallized from 10 ml of anhydrous dimethylformamide. (±)-1α-ethyl-1β-(21carboxyethyl)-9-bromo-
1, 2, 3, 4, 6, 7, 12, 12bα-octahydroindolo [2,3-a] quinolidine 0.35g
(33%). Melting point: 214-215℃ IR spectrum (in KBr pellet): 3420, 3100
(OH, NH), 1680 (acid CO) cm ^-1 0.35 g of the obtained 12α isomer was added to dichloromethane 10
ml and to this suspension was added excess diazomethane dissolved in dichloromethane. The solution obtained at the end of the reaction was evaporated to dryness and the residue was crystallized from methanol. (±)-1
α-Ethyl-1β-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7.
12・12bα-octahydroindolo [2・3-
a] 0.3 g of quinolidine was obtained. Melting point: 166-168℃
(from methanol) The physical constants of this compound are 12b obtained by Example 11.
It was the same as that of the α isomer. Example 13 (±)-10-bromo-14-oxo-E-homoebrunane-(3αH・17αC ₂ H ₅ ) [Compound of formula () of the present invention] (±)-1α-ethyl-1β-(2′- methoxycarbonylethyl)-9-bromo-1,2,3.
0.40 g (0.94 mmol) of α-octahydroindolo[2.3-a]quinolidine was suspended in 10 ml of anhydrous toluene and 0.27 g (282 mmol) of sodium tert.-butoxide.
was added to this suspension at room temperature with stirring under nitrogen atmosphere. The mixture was stirred for a further 3 hours and then mixed with 0.4 ammonium chloride in 10 ml of water.
Decomposition was carried out by introducing a solution of g. The toluene layer was separated, and the aqueous layer was extracted three times with 6 ml each of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the liquid was evaporated in vacuo. The oily residue was crystallized from methanol. (±)-10-bromo-14-oxo-E-homo-eburnan-(3αH・17α
262 mg (71.0%) _{of C2H5} was obtained. Melting point: 190℃
(from methanol). IR spectrum (in KBr pellets): 2830, 2700 (Bollmann absorption band), 1710
(lactam CO) cm ^-1 mass spectrum: m/e (%) = 386 (M ⁺ ,
100), 385 (51), 358 (6.4), 357 (9.5), 344
(3.6), 343 (4.1), 330 (13), 329 (10), 315
(5.5), 308 (4.5), 307 (5.5), 306 (2.7), 261
(5.0), 248 (5.9). ^1H -NMR ( _CDCl3 + DMSO- _d6 ): δ = 8.25 (1H, dd, 12-H), 7.60-7.20 (2H,
m, aromatic proton), 4.15 (1H, s, 3-H), 0.86 (3H, t, -
CH ₂ CH ₃ ) ppm. Example 14 (±)-10-bromo-14-oxo-15-hydroxyimino-E-homo-ebrunan-(3αH・
17αC ₂ H ₅ ) [Compound of formula () of the present invention] (±)-10-bromo-14- in 1 ml of anhydrous toluene
Oxo-E-homo-ebrunan-(3αH・17α
C ₂ H ₅ ) was dissolved and 0.24 ml of freshly distilled tert.-butyl nitrite was added to the stirred solution at room temperature under nitrogen atmosphere. After a few minutes, anhydrous toluene 1
Potassium tert.-butoxide in ml - 0.075 g
(0.67 mmol) was introduced into this mixture,
This mixture was stirred for an additional 0.5 h and then
Decomposition was effected by introducing a solution of 0.2 g of ammonium chloride in ml. The organic layer was separated and the aqueous layer was extracted three times with 2 ml each of dichloromethane. The organic solutions were combined, dried over anhydrous magnesium sulfate, filtered, and the liquid was evaporated in vacuo. The oily residue was acidified with methanolic hydrochloric acid to pH=6. Thus (±)−10−
Bromo-14-oxo-15-hydroxyimino-E
-Homo-eburnan-(3αH·17αC ₂ H ₅ ) hydrochloride 55 ml (47.0%) was obtained. Melting point: 247℃ (decomposition) IR spectrum (in KBr pellet): 3400 (OH), 1720 (lactam CO), 1630 (C
= N) cm ^-1 Mass spectrum: m/e (%) = 415 (M ⁺ , 50), 414 (25), 398 (30), 385
(100), 370 (30), 356 (10), 341 (15), 329
(20), 315(15), 247(15), 168(12), 167(10),
154(10), 141(20). Example 15 (±)-10-bromo-vincamine (±)-10-bromo-14-oxo-15-hydroxyimino-E-homo-ebrunane-(3αH.
17αC ₂ H ₅ ) 0.12 g (0.26 mmol) in glacial acetic acid 2.4
ml and to this solution 0.24 g of dry p-toluenesulfonic acid and 0.36 g of paraformaldehyde.
g was added. The mixture was kept at 110° C. for 3.5 hours with removal of atmospheric moisture, then poured onto ice and the pH of the mixture was adjusted to 9 with concentrated aqueous ammonium hydroxide. Precipitated (±)-cis-10
-Bromo-14,15-dioxo-E-homo-ebrunan-(3αH・17αC ₂ H ₅ ) was filtered and washed with water,
It was then dried over phosphorus pentoxide in a desiccator. (±)-cis-10-bromo-14,15-dioxo-E-homo-eburnan-(3αH・17α
C ₂ H ₅ ) [Compound of formula () of the present invention] 84 mg was obtained. Melting point: 184℃ (decomposition) In IR spectrum (in KBr pellet): 1720 (=C
=O), 1690 (amide CO) cm ^-1 The product was dissolved in 4 ml of dichloromethane without further purification, the solution was filtered and the liquid was evaporated in vacuo. Anhydrous methanol 0.4
A solution of 0.10 g of potassium tert.-butoxide in ml was added to the residue, the resulting mixture was warmed to 40 DEG C. and then left at room temperature for 2 hours. The precipitated crystals were filtered, washed with a small amount of cold methanol, and dried. (±)-10-bromo-vincamine 38mg
(33%). Melting point: 220-221°C (from methanol) IR spectrum (in KBr pellets): 1738 cm ^-1 (ester CO) ¹ H-NMR (CDCl ₃ ): δ = 7.68-6.85 (3H,
m, aromatic proton), 4.50 (1H, substitutable,
OH), 3.80 (3H, s, -COOCH ₃ ), 0,89
(3H, t, -CH ₂ CH ₃ ) ppm. Mass spectrum: m/e (%) = 432 (M ⁺ ,
100), 431 (47), 373 (56), 330 (89). Rf value is (±)-10-bromo-vincamine>
(±)-10-bromo-14-epivincamine > unreacted (±)-10-bromo-14,15-dioxo-E-homo-eburnan, so this mother liquor was subjected to preparative thin layer chromatography. It was purified using Graphy (adsorbent: aluminum oxide PF _254+366 , solvent: 100:1 mixture of dichloromethane and methanol).
with dichloromethane and methanol as eluents.
A 20:4 mixture was used and the eluate was worked up in a conventional manner. A further 5 g of (±)-10-bromo-vincamine were thus obtained. The total yield of this compound was therefore 43 mg (39%). (±)-10-bromo-14-epivincamine 5mg
(4%) was obtained as a by-product. Melting point: 205-206℃ (from methanol) Mass spectrum: m/e (%) = 432 (M ⁺ , 83),
431 (53), 385 (33), 373 (52), 330 (96). Example 16 (-)-1(S)・12b(S)-9-bromo-1-
Ethyl-1-(2'-methoxycarbonylethyl)-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-quinolidinedibenzoyl-D-tartrate (±)-1α-ethyl-1β-(2′-methoxycarbonylethyl)-9-bromo-1.2.3.
4.6.7.12.12bα-octahydroindolo[2.3-a]quinolidine 1.4g (0.32 mmol)
in 3 ml of dichloromethane and 1.19 g of dibenzoyl-D-tartaric acid in 7 ml of dichloromethane.
A solution of was added. The reaction mixture was heated to boiling and then left at room temperature for 1 hour and then at +10° C. for 12 hours. The precipitated product was filtered, washed with dichloromethane and dried.
0.82g (26%) of (-)-1(S)・12b(S)-1
-Ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7.
12・12b-octahydroindolo [2.3-a]
Quinolidine dibenzoyl-D-tartrate was obtained.
Melting point: 153-154°C, [α] ^22D = -98 _° (C = 1, in dimethylformamide) ^1H -NMR ( _CDCl3 ): δ = 0.9 (3H, t, _-CH2
CH3 ), 4.1 (1H, s, 12b _- H), 7.3-7.6
(2H, Ar, Ar10−11H), 8.2−8.4 (1H, Ar9
-H) ppm The optical power of the base liberated from the above salt is [α] ²² _D =
-101.9° (C=0.726 in dichloromethane). Example 17 (-)-3(S)・17(S)-10-bromo-14-oxo-E-homo-eburnane 5 ml dichloromethane and 2 ml 10% aqueous ammonia
(-)-1(S)・12b(S)-1-ethyl-1-(2'-methoxycarbonylethyl)-9
-Bromo-1, 2, 3, 4, 6, 7, 12, 12b-
0.5 g (0.65 mmol) of octahydroindolo[2.3-a]quinolidine dibenzoyl-D-tartrate was treated. The layers were separated from each other, the dichloromethane solution was dried over anhydrous sodium sulfate,
and the liquid was evaporated. anhydrous toluene
22 ml were added to the residue and 2-3 ml of this solvent was evaporated from the mixture at 107°C. The residual mixture was cooled to room temperature, 0.16 g of lithium tert.-butoxide was added thereto, and the mixture was stirred at room temperature for 60 hours. A solution of 1.5 g of ammonium chloride in 8 ml of water was then introduced, the mixture was stirred for 5 minutes and the layers were separated from each other. The organic layer was washed with 10 ml of water, dried over anhydrous sodium sulfate, filtered and the liquid was evaporated. The oily residue was dissolved in 2 ml of benzene and the solution was applied onto a column packed with 100 times the amount of aluminum oxide (activity) in benzene. The effluent was collected into 5 ml fractions and each fraction was analyzed by thin layer chromatography. Fractions containing the required product were combined and evaporated. The oily residue was dissolved in 1 ml of dichloromethane, 5 ml of ethanol was added to this solution, and the mixture was evaporated to a final volume of 1 ml. Filter the precipitated crystals, wash with ethanol,
And dried. Thus, 0.12 g (62%) of (-)-1(S).17(S)-10-bromo-14-oxo-E-homo-ebrunan was obtained. Melting point: 121−
122°C, [α] ²⁰ _D = +26° (C = 1, in dimethylformamide) ¹ H-NMR (CDCl ₃ ): δ = 7.3-7.55 (2H, Ar,
11-13H), 8.4 (1H, Ar, 9-H), 4.1
(1H, 3-H) ppm.

Claims (1)

[Claims] 1 General formula () (In the formula, R ² represents a C _1-6 alkyl group, and
represents a hydroxyimino group, an oxo group or two hydrogen atoms, or a pharmaceutically acceptable acid addition salt thereof. 2 General formula () (wherein R ² represents a C _1-6 alkyl group) or a pharmaceutically acceptable acid addition salt thereof. 3 General formula () (wherein R ² represents a C _1-6 alkyl group) or a pharmaceutically acceptable acid addition salt thereof. 4 General formula () (wherein R ² represents a C _1-6 alkyl group) or a pharmaceutically acceptable acid addition salt thereof. 5. The compound according to claim 1, which is (±)-10-bromo-14-oxo-E-homo-ebrunan-(3αH·17αC ₂ H ₅ ) or an acid addition salt thereof. 6 (±)-10-bromo-14-oxo-15-hydroxyimino-E-homo-ebrunan-(3α
The compound according to claim 1, which is H.17αC ₂ H ₅ ) or an acid addition salt thereof. 7. The compound according to claim 1, which is (±)-cis-10-bromo-14·15-dioxo-E-homo-eburnane or an acid addition salt thereof.