CH650508A5 - Process for preparing 14-oxo-(E)-homo-eburnamenine derivatives - Google Patents

Abstract

The isomeric mixture of optically active compounds of the formulae <IMAGE> in which R<1> denotes C1-C6-alkyl, is prepared. An optically active tryptophane ester derivative of the formula <IMAGE> in which R<2> = R<1> and A represents an acid radical, is reacted with an alkylvaleroyl halide in the presence of an acid-binding agent to give the optically active halopentanoyl tryptophane ester derivative. This latter is converted by cyclic dehydration and treatment with a base into an optically active hexahydroindoloquinolizinium salt derivative, which is reacted with acrolein to give the hydroxy-dehydro-(E)-homo-eburnameninecarboxylic acid ester derivative. The latter is oxidised to the 14-oxo compound. This compound is selectively reduced, with the isomeric mixture of optically active oxo-(E)-homoeburnamenine- carboxylic acid ester being obtained. This latter is initially treated with an inorganic oxyhalide and then selectively reduced. Using II compounds as the starting material, Ib compounds are obtained after a further process. The conversion of Ia + Ib, as well as of Ib, compounds into Ia compounds is described. The optically active compounds of the Formula Ia are novel. The optically active compounds of the Formula Ib can be used in the preparation of vincamine, which dilates cerebral blood vessels, and of ethyl (+)-apovincaminate.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 
EMI4. 1
 oxidized, wherein Rl is defined above and X4 represents an acid residue, and then selectively reducing the compound of general formula XI to the compound of general formula Ia and optionally converting a compound obtained into an acid addition salt. 



   5.  Process for the preparation of the optically active trans14-oxo -E-homo-eburnamenin derivative of the general formula
EMI4. 2nd
 wherein Rl is an alkyl group with 1-6 carbon atoms and acid addition salts of this compound, characterized in that from the isomer mixture prepared according to the process of claim 1 from optically active compounds of the general formulas
EMI4. 3rd
 wherein Rl is defined above, separates the optically active compound of the general formula Ib, to the optically active oxodehydro -E-homo-eburnamenin derivative of the general formula
EMI4. 4th
 oxidized, in which R 'is defined further above and X4 stands for an acid residue and then reduces the compound of general formula Ia and, if appropriate, converts a compound obtained into an acid addition salt. 



   The invention relates to a process for the preparation of the isomer mixture from optically active 14-oxo -E-homoeburnamenin derivatives of the general formula Ia and Ib
EMI4. 5
 wherein Rl is an alkyl group with 1-6 carbon atoms and process for the preparation of the pure optically active compounds.  The compounds mentioned can also be present as acid addition salts. 



   The process for the preparation of the isomer mixture from compounds of the formulas Ia and Ib is characterized in that an optically active tryptophan ester derivative of the general formula
EMI5. 1




  in which formula R2 represents an alkyl group with 1-6 carbon atoms and A represents an acid residue, with an alkylvaleric acid halide derivative of the general formula
EMI5. 2nd
 wherein Rl has the meaning given in the general formulas Ia and Ib and X1 and X2 represent identical or different halogen atoms, in the presence of an acid binder, the resulting optically active halopentanoyl-tryptophan ester derivative of the general formula
EMI5. 3rd
 in which R1 is subjected to a cyclizing dehydration and is then treated with a weak base in the general formulas Ia and Ib, R2 in the general formulas II and X 'have the meanings given in the general formula III, and then treated with a weak base,

   the optically active hexahydroindoloquinolizinium salt derivative of the general formula obtained
EMI5. 4th
 wherein Rl have the meanings given in general formulas Ia and Ib, R2 in general formula II and X1 the meanings given in general formula IV, in the presence of a catalytic amount of an alkali metal tert. alcoholate with acrolein of the formula CH2 = CH-CHO (VI), the resulting optically active hydroxy-dehydro -Ehomo-eburnamenin-carboxylic acid ester derivative of the general formula
EMI5. 5
 in which R 1 has the meaning given in general formulas Ia and Ib and R2 has the meaning given in general formula II and X3 represents an acid residue,

   the new optically active oxodehydro -E- homo-eburnaminincarboxylate derivative obtained derivative of the general formula
EMI5. 6
 wherein Rl selectively reduces the meanings given in general formulas Ia and Ib R2 in general formulas II and X3 the meanings given in general formula VII, the mixture of isomers obtained from compounds of general formulas
EMI5. 7

EMI5. 8th
  wherein R 'hydrolyzes the meaning given for the general formulas Ia and Ib and R2 for the general formula II, the mixture of isomers obtained from compounds of the general formulas
EMI6. 1
 and
EMI6. 2nd
 wherein Rl has the meaning given in the general formulas Ia and Ib, first treated with an inorganic oxyhalide and then reduced in a selective manner. 



   A second process relates to the preparation of the optically active 14-oxo -E-homo-eburnamenin derivatives of the formula Ib given above.  This process is characterized in that, as described above, compounds of the formula II are used to prepare optically active compounds of the formula VIII. 

  These compounds are then subjected to a basic treatment, the optically active carboxyethyl-hexahydroindoloquinolizine-carboxylic acid derivative obtained of the general formula
EMI6. 3rd
   wherein Rl is defined above and X5 represents an acid residue, is selectively decarboxylated, the optically active carboxyethyl-hexahydro -indoloquinolinium salt obtained of the general formula
EMI6. 4th
 wherein Rl and X5 are defined above is first esterified and then reduced or first reduced and then esterified, the resulting alkoxycarbonyl-octahydroindoloquinolizine isomer mixture of the general formula
EMI6. 5
 wherein R 'is defined above and R3 represents an alkyl group with 1-6 carbon atoms,

   is separated into the isomeric compounds and the optically active cis (la, 12ba,) - alkoxycarbonyl-octahydro-indoloquinolizine falling under the general formula XIV is finally cyclized to the compound of the general formula Ib. 



   Another new process relates to the conversion of the isomer mixture from compounds of the formulas Ia and Ib into optically active compounds of the formula Ia. 



  This process is characterized in that the isomer mixture mentioned is an optically active oxodehydro -E-homo-eburnamenin derivative of the general formula
EMI6. 6
 oxidized, wherein Rl is defined above and X4 represents an acid residue, and then selectively reducing the compound of general formula XI to the compound of general formula Ia and optionally converting a compound obtained into an acid addition salt. 



   The same method is also used to convert an optically active compound of the formula Ib into an optically active compound of the formula Ia.   



   The present invention also relates to the separation of the isomer mixture from the optically active compounds of the formulas Ia and Ib into the individual compounds. 



   All of the compounds obtained according to the invention can be converted into acid addition salts. 



   The C16 alkyl groups present as symbols R1, R2 and R3 in the general formulas Ia, Ib, II, III, IV, V, VII, VIII, Ma, IXb, Xa, XI, XII, XIII and XIV can be straight-chain or branched and e.g. B.  for methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert.  Butyl, isobutyl, n-pentyl, i-pentyl, n-hexyl and i-hexyl are available. 



   Symbol A in the compounds of the general formula II, symbol X3 in the compounds of the general formulas VII and VIII, symbol X4 in the compounds of the general formula XI and symbol X5 in the compounds of the general formulas XII and XIII can be any organic or inorganic acid radicals - e.g. B.  a halide such as chloride, iodide, bromide, etc. , advantageously chloride. 



   The symbols X 'and X2 in the general formulas III, IV and V can represent any halogen atom, namely fluorine, chlorine, bromine or iodine, preferably chlorine. 



   The optically active compounds of general formula Ia are new, the racemic compounds are known (Bull.  So.  Chim.  France 1976, 1961).    



   The optically active compounds of the general formula Ib are known and can be used as an intermediate in the preparation of the valuable vinkamine and (+) -apovinkamic acid ethyl ester (Cavinton®), which has a cerebral vasodilating effect. 



   Several processes are known for the preparation of the (+) -Vinkamin and the (+) -Apovinaminic acid ethyl ester [see e.g. B.  J.  At the.  Chem.  Soc.    1540 (1979)].     The majority of the known processes are characterized in that a racemic intermediate product is separated into the optically active antipodes in the course of the synthesis and in the further stages of the process only the cheap antipode is introduced and the other antipode is discarded.  This results in a material loss of at least 50%.  This loss of material could be reduced by an enantioselective synthesis used to prepare the (+) -Vinkamine and / or the (+) -Apovinkaminic acid ethyl ester. 

  The purpose of the present invention is to develop such an enantioselective synthesis, which is based on the principle that an optically active starting material with the suitable selected configuration in the course of the process proves the optical activity of the molecule formed therefrom until it is only necessary during the process is. 



   Attempts have previously been made to apply the above principle, and attempts have been made to carry out the asymmetric synthesis of the (+) -vinkamine [Acta Chim.  Hung.  99, 73 (1979)].  In the process described in this article, the naturally occurring optically active tryptophan with L configuration was used as the starting material, which was converted into the isopropyl ester (a compound of the general formula II, in which R2 stands for isopropyl). 

  The L-trypthophane isopropyl ester was reacted with an ethylvaleric acid chloride derivative falling under the general formula III; The chloropentanoyl tryptophan isopropyl ester obtained, which falls under the general formula IV, was subjected to a ring shot with phosphorus oxychloride in benzene and then in
Treated methylene chloride with a weak base; in this way, the optically active 1-ethyl-hexahydro-indoloquinolizine-6-carbonic acid isopropyl ester perchlorate, which came under the general formula V, was prepared.  To the next
Stage of the process used to make the Vinkamin - d. H.  for the reaction with the acrylic ester derivative - however, the base had to be released from this perchlorate first. 

  The base was released in methylene chloride with a 2% aqueous sodium hydroxide solution; however, the product obtained has been found to be racemic.  In a higher pH range, the optical activity of the carbon atom adjacent to the ester group is lost.  However, the base cannot be released from the perchlorate in a lower pH range. 



   It has been found that, if the optically active hexahydro -indoloquinolilicon perchlorate is used instead of the previously used acrylic acid ester derivative with a compound of very active electrophilic properties - such as the acrolein of formula VI - the base is released from the perchlorate is superfluous and the result of the reaction is an optically active compound of the general formula VII, also in the form of the perchlorate salt. 



   In the further stages of the method according to the invention, the optical activity of the optically active remains
Tryptophanester originating at the junction of the
Carboxy group present chiral center so long until another chiral center corresponding to the configuration of the end product is formed.  According to the inventive method, this takes place in the implementation of the optically active compound of the general formula V with the acrolein of the formula VI; In the resulting compound of the general formula VII, a new chiral center corresponding to the configuration of the end product is formed at the linking point of the substituent R1 in position 16. 

  The one that is used to preserve the optical activity and is already unnecessary in the desired end product
Carboxy group can then be used in any later
Stage of synthesis can be removed. 



   As a result, this works at the junction of the
The chiral center present in the carboxy group is lost, but the molecule already has the desired optical activity. 



   Implementation of the compounds of general
Formula V-like racemic compounds with acrolein were first developed by Schut and co-workers [J.  Org.    Chem.  34, 330 (1969)] describes racemic desalkyl-desalkoxycarbonyl derivatives and by Buzäs et al. [Tetrahedron 34, 3001-3004 (1978)] for racemic desalkoxycarbonyl derivatives.  In none of the cited references, however, optically active starting materials were used and optically active end products were produced; furthermore, none of the above processes was carried out by the methods according to the invention
Procedures occurring, mostly new optically active inter mediate products performed. 



   In other areas of alkaloid chemistry, attempts have already been made to elaborate asymmetric syntheses that arise from the naturally occurring L-tryptophan.  In these syntheses, however, the removal of the carboxylic ester group present at the chiral center and the optical activity with the carboxylic acid group at the end of the synthesis caused a major problem.  According to one method, an acid amide was first prepared from the ester with methanolic ammonia, which was converted into the nitrile using phosphorus oxychloride in pyridine and dimethylformamide; in the next step the nitrile propyl group was removed with sodium borohydride in ethanol and pyridine.  The overall yield of the above three stages was 36% [Okamura and co-workers:
Chem.  Pharm.  Bull    26, (8), 2305-2311 (1978)].  

  According to another method, the ester group was first converted into the carboxylic acid, from which a
Carbamate prepared and the latter group was removed by heating to boiling with sodium borohydride in ethanol [Yamada and coworkers: Tetrahedron 19, 1605-1608 (1976)]
The starting materials of the general formula II can be prepared from optically active tryptophan by the process described in the Journal of Physiological Chemistry 52 214 (1907); the optically active tryptophan can e.g. B.  treated with the appropriate alcohol in the presence of an acid - suitably hydrochloric acid - at room temperature. 

  An advantage of the method according to the invention is that optically active starting materials with the configuration occurring in nature are suitable for producing optically active end products with the desired configuration. 



   The starting material of the general formula III can be obtained using the valeric acid derivative obtained from the corresponding 2-alkyl pentoxide [Tetrahedron 33, 1803 (1977)] z. B.  can be prepared with thionyl chloride [Acta Chim. 99.73-80 (1979)].    



   The reaction of the compounds of general formulas II and III can be carried out in an inert organic solvent.  For this purpose, e.g. B. 



  aromatic hydrocarbons (such as benzene, toluene, etc. ) serve.  According to the invention, the reaction is carried out in the presence of an acid binder.  Various bases (such as trialkylamines, e.g. B.  Triethylamine etc. ) are used.  According to an advantageous embodiment of this process, the compounds of the general formulas II and III are reacted in the presence of pyridine, which serves both as a solvent and as an acid binder. 



   The reaction temperature is usually around 20-25 "C.    



   The dehydration of the optically active compounds of the general formula IV which leads to the cyclization is preferably carried out with the aid of a strong dehydration agent.  Asl strong dehydrating agents can be used with oxygen and / or halogen formed phosphorus compounds comprising phosphorus pentoxide, phosphorus pentachloride, polyphosphoric acid or anhydrous zinc chloride, advantageously phosphorus chloride.  The dehydration of the compounds of the general formula IV which leads to the cyclization is normally carried out in an inert solvent.  Optionally substituted aromatic hydrocarbons (e.g. B.  Benzene, toluene, xylene, nitrobenzene), optionally substituted aliphatic or cycloaliphatic hydrocarbons (e.g. B.  Tetralin, chloroform, etc. ) serve. 

  The dehydration which takes place under cyclization is generally carried out with the exclusion of water, preferably at a temperature of 80-90.degree.  Subsequent treatment usually uses a dilute aqueous solution of an alkali metal bicarbonate (e.g. B. 



  Sodium bicarbonate) is used.  The treatment with the weak base is expediently carried out at 10-25 C for a period of, for example, 10-24 hours. 



   The reaction of the optically active compound of the general formula V with the acrolein is usually carried out in an inert organic solvent with the exclusion of water.  As a reaction medium optionally substituted by one or more halogen atom (s) aliphatic or aromatic hydrocarbons (z. B.  Dichloromethane, dichloroethane, chloroform, chlorobenzene, etc. ) be used.  The reaction is tert in the presence of a catalytic amount of an alkali metal. -butylate (advantageously potassium tert. -butylate).  The reaction temperature is usually 10-25 "C.    



   The oxidation of the optically active compounds of the general formula VII can, for. B.  be carried out with chromium trioxide, manganese dioxide, pyridine chlorochromate or pyridine dichromate complex or chromium trioxide deposited on silica gel.  The oxidation is preferably carried out under mild reaction conditions with the exclusion of water in an inert organic solvent.  As a reaction medium such. B.  aliphatic or aromatic hydrocarbons substituted by one or more halogen atoms (e.g. B.  Dichloromethane).  The reaction temperature is usually 15-25 "C.    



   The selective reduction of the optically active compounds of the general formula VIII is carried out, for example, with a reducing agent which is suitable for saturating the double bond present in the ring without impairing the other reducible groups of the molecule.  For this purpose, e.g. B.  Sodium borohydride in alcohol, zinc in a mixture of acetic acid and water can be used.  The selective reduction can also be carried out catalytically in the presence of a palladium / carbon catalyst.  Is used as a reducing agent such. B.  Sodium borohydride, only the optically active trans compound of the general formula IXa is obtained.  When using z. B. 

  Zinc as a reducing agent is generally obtained from a mixture of the compounds of the general formulas IXa and IXb with a predominant proportion of the optically active cis compound of the general formula IXb.  If you reduce the z. B.  carried out by catalytic hydrogenation, a mixture is also obtained, in which, however, the trans compound of the general formula IXa predominates.  The mixture of the compounds of the general formulas IXa and IXb obtained can be separated into the two isomers by methods known per se and the individual isomers can be introduced into the next step of the process according to the invention.  According to the invention, however, the mixture of the two compounds of the general formulas IXa and IXb is used without isolation in the next stage of the process according to the invention. 

  The reduction is usually carried out in an inert organic solvent.  The choice of solvent depends on the reducing agent used.  If the reduction is e.g. B.  carried out with sodium borohydride or catalytically, can be used as the reaction medium, for. B.  aliphatic alcohols with 1-6 carbon atoms (e.g. B.  Methanol) are used.  The z. B.  Reduction carried out with zinc can advantageously be carried out in an alkane carboxylic acid having 1-6 carbon atoms (such as acetic acid) or a mixture of such an acid with water.  The reaction temperature is usually between - 5 reason + 25 "C.    



   The hydrolysis of the mixture of optically active compounds of the general formulas IXa and IXb is advantageously carried out in the presence of an alkaline agent.  As alkaline agents such. B.  aqueous solutions of alkali metal hydroxides (such as lithium hydroxide, potassium hydroxide, sodium hydroxide) or alkaline earth metal hydroxides (e.g. B. 



  Calcium hydroxide, barium hydroxide) etc.  Find use.  According to an advantageous embodiment of the hydrolysis, the compounds are dissolved in an aliphatic alcohol having 1-6 carbon atoms, an aqueous alkali metal hydroxide solution is added to the solution obtained and the mixture is boiled at 70-100 ° C. for 24 hours. 

 

   The mixture of optically active compounds of the general formulas Xa and Xb is treated with an inorganic oxyhalide - such as thionyl chloride or advantageously phosphorus oxychloride; the reaction is preferably carried out in an excess of phosphorus oxychloride as solvent.  The temperature of the decarbonylation reaction is generally 20-100 "C.     The selective reduction of the product obtained after the decarbonylation is carried out, for example, with sodium borohydride in an aliphatic alcohol containing 1-6 carbon atoms - advantageously in methanol.  The reaction temperature is usually between - 5 C and +5 "C.    



   The oxidation of the optically active compound of formula Ib or of the isomer mixture of compounds Ia and
Ib to compounds of formula XI is, for example, with
Lead tetraacetate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.  The oxidation is usually carried out in an inert organic solvent.  In the case of the oxidation carried out with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, an aliphatic or aromatic hydrocarbon which is optionally substituted by one or more halogen atoms, such as, for. B.  Dichloromethane.  In the preferred use of lead tetraacetate as the oxidizing agent, alkane carboxylic acid optionally substituted by one or more halogen atoms, such as, for. B.  Acetic acid, trifluoroacetic acid, etc.  serve. 

  The oxidation is usually carried out at a temperature of 0-25 ° C. 



   The selective reduction of the optically active compounds of the general formula XI is carried out, for example, with a reducing agent which is capable of saturating the double bond present in the ring, but without adversely affecting the other reducible groups of the molecule.  For this purpose, e.g. B.  Sodium borohydride in alcohol, or zinc in a mixture of acetic acid and water, or you can catalytically hydrogenate in the presence of a palladium-carbon catalyst.  In the preferred use of sodium borohydride, only the trans compounds of the general formula Ia are obtained. 



   If you use e.g. B.  as the reducing agent zinc and an acid, a mixture of the compounds of the general formulas Ia and Ib is obtained, in which the cis product of the general formula Ib is contained as the predominant component.  The catalytic hydrogenation usually gives a mixture of compounds of the general formulas Ia and Ib, with a predominant proportion of the trans compound of the general formula Ia.     A mixture of the compounds of the general formulas Ia and Ib obtained can be separated into the two isomers by methods known per se. 



   The basic treatment of a compound of general formula VIII can be carried out with the aid of an aqueous solution of an alkali metal hydroxide (e.g. B.  Potassium hydroxide, sodium hydroxide, etc. ) in an inert, water-miscible organic solvent (such as aliphatic alkanols containing 14 carbon atoms, etc. ) be performed. 



  The reaction can be carried out at room temperature (between 15 C and 35 C). 



   The selective decarboxylation of the compounds of the general formula XII can advantageously be carried out thermally, at a temperature of 15> 200 C, advantageously between 165 and 175 C, in a high-boiling inert organic solvent.  Any inert organic solvent boiling between 150 and 200 C can be used as the reaction medium (e.g. B.  Decalin, tetralin, quinoline, isoquinoline, etc.).  The selective thermal decarboxylation of the compounds of the general formula XII can advantageously be carried out in decalin. 



   The reduction of the compounds of the general formula XII can be carried out using catalytically activated hydrogen or using chemical reducing agents.  If the reduction with catalytically activated
Hydrogen is carried out as a hydrogenation catalyst metals (e.g. B.  Palladium, platina, iron, copper, cobalt, chromium, zinc, molybdenum, tungsten) and oxides thereof can be used.  The catalytic hydrogenation can also be carried out in the presence of catalysts applied to the surface of a support.  Above all, carbon (in particular bone carbon), silica, aluminum oxide, alkali metal sulfates or alkali metal carbonates can be used as carriers.  The catalytic hydrogenation can be carried out in an inert solvent (e.g. B. 

  Water, watery
Alkali metal hydroxide solutions, alcohols, ethyl acetate, di oxane, glacial acetic acid, dimethylacetamide, dimethylformamide or mixtures thereof) are carried out.  The reduction can also be carried out using chemical reducing agents.  For this purpose, e.g. B.  Complex metal hydrides (e.g. B.  Borohydrides such as alkali metal borohydrides, e.g. B.  Sodium borohydride; or aluminum hydrides such as aluminum aluminum hydrides e.g. B.  Lithium aluminum hydride) are used.  Any solvent (e.g. B.  Water, aqueous alcohols, acetonitrile, advantageously aliphatic alcohols such as methanol) are used. 



   According to a particularly advantageous embodiment of the process according to the invention, the compounds of the general formula XIII can be reduced using a palladium / bone carbon catalyst in an inert solvent (such as dimethylformamide).  The catalytic hydrogenation of the compound of the general formula XIII produces an epimer mixture which predominantly contains the cis isomer.  If the hydrogenation is carried out in the presence of palladium / bone carbon as a catalyst in dimethylformamide, the corresponding C / D cis-fused l2baH epimer is formed in a stereoselective manner, the corresponding 12bpH epimer being formed only as a by-product. 



   In another embodiment of the process according to the invention, the carboxylic acid of the general formula XIII is first converted into an appropriate ester and then subjected to the reduction described above. 



   The esterification of both the compounds of the general formula XIII and the corresponding octahydro derivatives can be carried out on the basis of the method described in Hungarian patent no.  171 660 described embodiment can be performed.  The corresponding methyl ester can advantageously be prepared in a known manner so that the corresponding acid in an inert organic solvent (z. B.  halogenated hydrocarbons, such as dichloromethane) with diazomethane. 



   The mixture of the isomers of the general formula XIV can in a manner known per se (e.g. B.  after preparative layer chromatography) are separated into the individual isomers. 



   The cyclization of the optically active cis (la, 12a) compound falling under the general formula XIV can be carried out in a manner known per se (e.g. B.  using an alkali metal hydride, e.g. B.  of sodium hydride). 



   If desired, the optically active compounds of the general formulas Ia and Ib obtained by the process according to the invention can be subjected to further cleaning measures (e.g. B.  Recrystallization). 

 

   The optically active compounds of the general formulas Ia and Ib prepared by the process according to the invention can, if desired, be converted into their acid addition salts.  As a salt-forming acid, inorganic acids (such as hydrogen halides, e.g. B.  Hydrochloric acid, hydrogen bromide, etc. ; Sulfuric acid, phosphoric acid, perhalic acid, such as perchloric acid), organic carboxylic acid (formic acid, acetic acid, propionic acid, oxalic acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, benzoic acid, cinnamic acid, etc. ), Alkylsulfonic acids (such as methanesulfonic acid), arylsulfonic acids (such as p-toluenesulfonic acid) cyclohexylsulfonic acids; Aspartic acid, glutamic acid, N-acetyl-aspartic acid, N-acetylglutamic acid etc.  be used. 



   Salt formation is advantageously carried out in an inert organic solvent (e.g. B.  conveniently in an aliphatic alcohol containing 1-6 carbon atoms, such as methanol etc. ) carried out by dissolving the optically active base of the general formula Ia or Ib in the solvent mentioned and making the mixture slightly acidic (about pH = 6) by adding the corresponding acid.  The salt formed of the optically active compound of the general formula Ia or Ib can be removed from the reaction mixture by adding an water-immiscible organic solvent (e.g. B.  Diethyl ether) precipitated and then isolated. 



   The compounds of the general formula Ib can be referred to in the Hungarian patent application no.  RI-634 described manner e.g. B.  be converted into the corresponding (+) -apovinic acid esters. 



   The optically active intermediates of the general formulas VII, VIII, IXa, IXb, Xa, Xb, XI, XII and XIII produced by the process according to the invention are new compounds.  The optically active intermediates of the general formulas IV and V, in which R2 is different from the isopropyl group, are also new. 



   Further details of the method according to the invention can be found in the examples below, without restricting the scope of protection to these examples. 



   Example I (preparation of starting material) (+) -L-tryptophan-methyl ester hydrochloride
20.0 g (0.098 mol) of L-tryptophan are stirred at room temperature with 180 ml of methanol saturated with hydrogen chloride gas until completely dissolved (about 2 hours).  The hydrochloride which has separated out is filtered off and washed three times with 20 ml of ether each time.  27.0 g of the compound mentioned in the title are obtained.  Yield 87.8%. 



  F. : 214 C (is identical to the value given in the literature). 



   IR (KBr): 3250 (only); 1740- '(CO). 



     
24 = +160 (c = l, O0 water). 



  (a),
Example 2 (+) -L-N- (2-ethyl -5-chloropentanoyl) tryptophan methyl ester
10.0 g (0.039 mol) of the (+) -L-tryptophan-methyl ester hydrochloride prepared according to Example 1 are dissolved in 75 ml of anhydrous pyridine, the solution is cooled to 0 C, whereupon 8.05 g (0.044 mol) of 2- Ethyl -5-chloro-valeric acid chloride are added dropwise.  The reaction mixture is left to stand at room temperature for 4 days.  The solvent is removed under reduced pressure and the residue is triturated three times with 5 ml of water.  It will contain 11.22 g of the compound mentioned in the title.  Yield 77.8%.  F. : 97-100 C (methanol-water). 



     20 = + 24 "(c = 1.00, dichloromethane); (?) D
20 (α) 2546 = +41 (c = 1.00 dichloromethane).    



  Analysis for the formula C19H26N203C1 (mol.       Weight  365.87) calculated: C 62.37%, H 7.16%, N 7.65%, Cd 9.69; found: C 62.56%, H 6.99%, N 7.67%, Cd 9.52.    



  IR (KBr): 3250 (NH); 1720 (CO2CH3); 1630 cm-1 (CH-CO). 



   Example 3 (+) - 1-ethyl-6-methoxycarbonyl-1,2,3,4,6,7-hexahydro
12H-indolo [2,3-a] quinolizine -5-ium perchlorate
5.00 g (13.7 millimoles) of the (+) -LN- (2-ethyl-5-chloropentanoyl) -tryptophan methyl ester prepared according to Example 2 are suspended in 100 ml of anhydrous benzene, after which 5.81 ml ( 9.75 g, 63.75 millimoles) of phosphorus oxychloride are added.  The mixture is refluxed for 5 hours with constant stirring and then concentrated under reduced pressure. 

  The residue is washed twice with 10 ml of petroleum ether, in
100 ml of dichloromethane dissolved and the solution made alkaline with a 5% aqueous sodium bicarbonate solution (pH = 7.5).  The organic phase is separated off, dried over anhydrous magnesium sulfate, filtered and the filtrate is left to stand overnight.  The solvent is removed under reduced pressure, the residue is dissolved in 6 ml of methanol and the solution is acidified with about 1 ml of a 70% aqueous perchloric acid solution (pH = 5).  The deposited crystals are filtered, washed twice with 1 ml of methanol and dried.  2.3 g of the compound mentioned in the title are obtained.  Yield 40.85%. 



   24 (a) 546 = + 119 "(c = 1.00, dichloromethane).    



   After concentrating the mother liquor, a further amount (1.0 g, 17.76%) of the compound mentioned in the title is obtained. 



     
22 = +80 "(a) 546 overall yield: 58.61%; optical purity 83%. 



   The product obtained (2.3 g) is recrystallized several times from methanol.  The product obtained is visually the most traveled. 



   F. : 219-220 C (methanol) 22 = +92 "(c = 1.11, dichloromethane); (a),
22 = +129 "(c = 1.00, dichloromethane). 



  (a) 546 Analysis for the formula C19H23N206C1 (mol.       Weight  410.85) calculated: C 55.54%, H 5.64%, N 6.82%; found: C 55.34%, H 5.84%, N 7.08%. 



  IR (KBr): 3200 (NH); 1735 (CO2CH3); 1600 cm-1 (C = N). 



   Example 4 (+) -14-Hydroxy -5- methoxycarbonyl -3- dehydro -E- homoeburnamenin -4- ium perchlorate
2.0 g (4.87 millimoles) of the (+) - 1 -ethyl-6-methoxycarbonyl -1,2,3,4,6,7-hexahydro12H-indolo [2,3-a] quinolizine prepared according to Example 3 -5- ium perchlorate is dissolved in 12 ml of anhydrous dichloromethane, and 0.6 ml of freshly distilled acrolein (0.506 g, 9.04 millimoles) are added to the solution.  The solution obtained is cooled to 0 ° C.  After adding a suspension of 28 g (0.25 millimoles) of potassium tert. -butylate and 6 ml dichloromethane, the reaction mixture is left to stand at room temperature for 2 hours, shaken twice with 10 ml of water each time, and the phases are separated.  

  The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is removed from the filtrate under reduced pressure.  The weight of the residue is 2.0 g. 



  Yield: 88.1% of the compound mentioned in the title.  The product can be processed without cleaning. 



      . 22 = + 42 "(c = 1.00 dichloromethane) (a) 546 IR (KBr): 3350 (OH); 1740 (CO2CH3); 1590 cm- (C = H).      



   Example 5 Preparation of (+) -14-hydroxy -5- isopropoxycarbonyl -3dehydro -E- homo-eburnamenin -4- ium perchlorate
The procedure is as in Example 4, with the difference that 2.0 g (4.56 millimoles) of (+) - 1-ethyl -6-isopropoxycarbonyl -1,2,3,4,6,7-hexahydro are used as the starting material -12 Hindolo [2,3-a] quinolizine -5- ium perchlorate (Acta Chim. 



     Hung.  99.73 (1979)).  The oily crude product obtained is crystallized from 5 ml of a mixture of ethanol and isopropanol (1: 1).  1.00 g of the compound mentioned in the title are obtained.  Yield 44.2%.  F. : 182-183 "C.    



   22 = 126;
22 = 172 "(c = 0.952, dichloromethane) (a) 546 IR (KBr): 3400 (OH); 1730 (CO); 1580 cm - zu (C = (C = N).    



  Analysis for the formula C24H31N207C1 (mol.       Weight  494.97) calculated: C 58.23%, H 6.31%, N 5.66%; found: C 58.18%, H 6.28%, N 5.44%. 



   The mother liquor is left to stand.  A further amount of 0.6 g (overall yield 70.8%) of the compound mentioned in the title, but racemic, is eliminated.  F. : 171-172 C
22 = 0 '.    



   Example 6 Preparation of (+) 5-methoxycarbonyl -14- oxo -E- homoeburnamenin (3kl, 16a)
A solution of 2.0 g (4.28 millimoles) of the (+) - 14-hydroxy -5-methoxycarbonyl -3- dehydro -E- homo-eburnamenin -4- ium perchlorate prepared in Example 4 in 80 ml of anhydrous dichloromethane a KG-HR adsorbent containing 8.0 g of freshly prepared chromium trioxide is added [E.  Santiello, F.  Ponti, A.  Momrocchi: synth.  1978 534].  The reaction mixture is stirred at room temperature for 8-10 hours.  The oxidizing agent is filtered, washed three times with 20 ml of a dichloromethane-methanol mixture containing 2% methanol.  The solution obtained is evaporated to dryness under reduced pressure. 

  1.69 g of (+) - 5-methoxycarbonyl -14- oxo -3- dehydro -Ehomo-eburnamenin are obtained in the form of an oily residue. 



   IR (KBr): 1740 (ester CO); 1720 (amide CO); 1610 and 1540 cm-l (C = N). 



   The product obtained is dissolved in a mixture of 20 ml of methanol and 5 ml of dichloromethane and reduced at 0-5 C with cooling with 200 mg of sodium borohydride.  0.5 ml of acetic acid are added to the solution.  The reaction mixture is evaporated to dryness under reduced pressure.  The oily residue is dissolved in 10 ml of water and the resulting solution is made alkaline with a 5% aqueous sodium carbonate solution (pH = 7.5) and extracted three times with 10 ml of dichloromethane each.  The phases are separated, the organic layer is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure.  The residue (1.2 g) can be purified by two different methods. 



   A) The crude compound mentioned in the title is purified by preparative layer chromatography (KGPF254 + 366; benzene-methanol 14: 3; elution with ether).  700 mg (44.8%) of the chemically pure title compound is made from the higher value zone
22 = + 65 (c = 1.00, dichloromethane) (a) 546 Optical purity 62.5%. 



   B) The crude product obtained after the reduction was recrystallized from 6 ml of ethanol.  500 mg (32.1%) of the title compound are obtained. 



     (a) 22 90 '546 = 90 (c = 1.00, dichloromethane). 



  Optical purity 86.5%. 



  After a second recrystallization: 23 = 104 "(c = 1.00, dichloromethane) (a) 546 This value does not change after further recrystallizations. 



     F. : 168-170'C IR (KBr): 1735 (CO2CH3); 1695 cm- '' (acid amide CO). 



  MS (m / e%): 366 (M +, 27); 365 (3); 351 (%); 337 (4.5); 307 (100); 305 (10); 263 (8); 251 (3). 



   From the mother liquor from the first recrystallization, 200 mg of the compound mentioned, but racemic, are obtained. 



   22 = 0 '.    



      (C1) 546 F. : 133-134 C.    



   Total chemical yield (based on 700 mg) 46.2%. 



   Example 7 Optically active and racemic 14-oxo -5-isopropoxycarbonyl -3- dehydro -E- homo-eburnamenin -4- ium perchlorate
A solution of 400 mg (0.81 millimoles) of the (+) -14-hydroxy -5-isopropoxycarbonyl -3- dehydro -E- homo-eburnamenin -4- ium perchlorate and 20 ml of anhydrous dichloromethane prepared according to Example 5 becomes 1 , 8 g of a KG-HR absorbent freshly prepared according to Example 6 and containing chromium trioxide were added.  The reaction mixture is stirred at room temperature for 8-10 hours, the oxidizing agent is filtered off and washed three times with 4 ml of dichloromethane containing 2% methanol.  The filtrate is evaporated to dryness under reduced pressure. 



  230 mg of the oily title compound are obtained as residue. 



   Yield: 57.5%. 



   IR (KBr): 1730, 1710 (CO ester; N-CO); 1601 cm- '(C = N).    



   The optically active title compound cannot be purified by crystallization.  To determine the structure of this compound, the above oxidation reaction is therefore carried out using 400 mg of optically inactive (racemic) (+) -14-hydroxy -5- isopropoxycarbonyl -3- dehydro -E- homo-eburnamenin -4- ium-perchlorate as starting material carried out.  After recrystallization of the crude product from 2 ml of a mixture of ethanol and isopropanol (1: 1), 200 mg (+) -14-oxo -5- isopropoxycarbonyl -3- dehydro -E-homo-eburnamenin -4- ium perchlorate are obtained. 

 

   Yield: 50.1%. 



      F. : 198-201 C.    



   MS ("each,%): 392 (14); 363 (29); 305 (100); 276 (12). 



   Example 8 Preparation of (+) -isopropoxycarbonyl -14-oxo -E- homoeburnamenin (3ss, 16a)
230 mg (0.47 millimoles) of the optically active 14-oxo -5-isopropoxycarbonyl -3- dehydro -E- homo-eburnamenin -3- ium perchlorate prepared according to Example 7 are dissolved in 4 ml of methanol and at a temperature between 0 and 5 C reduced with 30 mg sodium borohydride.  0.1 ml of acetic acid is added to the reaction mixture.  The mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 2 ml of water and the resulting solution is adjusted to pH 7.5 with a 5% aqueous sodium bicarbonate solution.  The alkaline solution is extracted three times with 3 ml of dichloromethane, dried over anhydrous magnesium sulfate and the filtrate is made solvent-free under reduced pressure. 

  The residue is purified by preparative layer chromatography (KG-PF254 + 366; benzene-methanol 14: 3; elution with ether). 



   165 mg of the oily title compound are obtained from the zone with the highest Rf value. 



   Yield 90%. 



   22 = + 57 (c = 0.172, dichloromethane). 



     c) D IR (KBr): 1720-1695 cm-l (EsterCO, acid amideCO). 



      MS (m / e,%): 394 (M +, 21) 366 (0.4); 351 (5.4); 337 (2.5); 307 (100); 263 (3.6). 



   Example 9 Preparation of (+) - la-ethyl -1ff carboxyethyl -6-carboxy -1,2,3,4,6,7,12,12bss-octahydro-indolo [2,3-a] quinolizine
A) 500 mg of the (+) -5- methoxycarbonyl -14- oxo -E- homo-eburname prepared by method A) from Example 6, purified by preparative layer chromatography
22 nin- (313, 16α) -s (α) 546 = 65) are dissolved in 6 ml of ethanol. 



  After adding a solution of 340 mg (6.06 millimoles) of potassium hydroxide and 0.8 ml of water, the mixture is heated to boiling for 3 hours.  The reaction mixture is evaporated under reduced pressure, 2 ml of ice-cold water are added to the residue and the mixture is acidified to pH 5 with constant cooling with a 50% aqueous acetic acid solution.  The precipitated product is filtered off, washed five times with 2 ml of water and dried, five times with 2 ml of water and dried.  410 mg of the compound mentioned in the title are obtained.  F. : 81.5%. 



     (?) 22 = +41 (c = 1.00, dimethylformamide). 



  (a) 546 IR (KBr): 340 (r3200 (OH, NH); 1600 cm- Ú (CO). 



  MS (rn / e,%): 370 (9.8); 352 (17.6); 326 (31.4); 311 (15.7); 308 (56.2); 307 (98.2); 267 (48.2); 169 (30.1); 168 (28); 44 (100). 



   B) (500) (1.36 millimoles) produced according to method B) from Example 6 (+) -5- methoxycarbonyl -14 oxo -E- homo-eburnamenin (3ss, 16a) 22 = 90 ') (a) D obtained by method A) from example 9430 mg of the compound mentioned in the title.  Yield 83.3%.    



   F. : 170 C (decomposition of 170 "C).    



   22 = +54 '; (a>,
22 = + 62.5 (c = 0.528, dimethylformamide). 



  (a) 546
Example 10 Preparation of (+) -14- Oxo -E- homo-eburnamenin (3ss, 16a)
250 mg (0.676 millimoles) of the (+) -la-ethyl -113-carboxyethyl -6-carboxy-1,2,3,4, 22 6,7,12, l2b ss-octahydro-indolo prepared according to Example 9 [2 , 3-a] quinolizins (a) 2546 = + 41 ') are dissolved in 3 ml of phosphorus oxychloride at 0 ° C. 



  The solution is left to stand at room temperature for one day.  The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 2 ml of water and the solution obtained is adjusted to pH 9 with cooling using a concentrated aqueous ammonium hydroxide solution; the aqueous phase is separated off, extracted three times with 4 ml of dichloromethane.  The organic phase is separated off, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure.  The residue is dissolved in 4 ml of methanol and reduced at 0-5 C with 20 mg of sodium borohydride.  0.1 ml of acetic acid is added to the residue and the mixture is concentrated to dryness under reduced pressure. 

  The residue is dissolved in 2 ml of water, the residue is adjusted to pH 7.5 with a 5% aqueous sodium carbonate solution and extracted three times with 3 ml of dichloromethane.  The organic phase is separated, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness.  The residue is purified by preparative layer chromatography. 



  [KG-PF254 + 366; Benzene-methanol 14: 3; RF end product RF starting material; Eluent: ether (end product), methanol (starting material)]
13 mg of the title compound and 40 mg of the unchanged starting material are obtained. 



   CD (EtOH, BmaXs nm, (A e)) = 301.5 (-0.203); 288 (0); 272 (+0.97); 237 (+ 1.66); 223.5 (0); 212 (- 2.5). 



   That from the (+) -14- oxo -E- homo-eburnamenin 3ss,
16a) prepared hydrochloride melts at 237-238 C (from methanol). 



   Example 11 (+) -14- Oxo -3- dehydro -E- homo-eburnamenin -4- iumperchlorate
A) A solution of 500 mg (1.62 millimoles) (+) - oxo -E-homo-eburnamenin (3a, 16a) (prepared according to Hungarian patent application no.  RI-634) and 5 ml of trifluoroacetic acid are added with ice cooling and stirring, 850 ml (1.62 millimoles) of 85% lead tetraacetate.  The resulting homogeneous solution is left to stand at this temperature for one hour.  The mixture is poured into 10 ml of ice-cold water.  Hydrogen sulfide gas is passed into the solution, the precipitated lead (II) sulfide is filtered and washed with 2 ml of water. 

  The aqueous mother liquor is adjusted to pH 9 with a concentrated ammonium hydroxide solution while cooling with ice and with stirring and extracted three times with 5 ml of dichloromethane.  The combined organic phases are dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure.  The remaining oil (456 mg) is dissolved in 2 ml of methanol, the pH of the solution is adjusted to 5 with a 70% aqueous perchloric acid solution. 



  The title compound which has separated out is filtered off, washed with 1 ml of methanol and dried.  380 mg of the compound mentioned in the title are obtained.  Yield 57.6%. 



  F. : 215-217 C (from methanol). 



   20 (α) D = +153;
20 = + 196 (c = 0.82, dichloromethane). 

 

  (a) 546
IR (KBr): 1705 (amide CO); 1605 and 1540 cm- I N). 



   B) The procedure is as in Example 11 A) with the difference that 100 mg (0.32 millimoles) of the (+) -14-oxo -E-homoeburnamenin (3ss, 16a) prepared according to Example 10 are used as the starting material.  72 mg of the title compound are obtained.  F. : 203 "C.     Yield 55%. 



     20 = +77 '; 20 = +98 '(c = 0.82, dichloromethane). 



  (a) 546 Optical purity 50%. 



   The IR spectrum of the compound produced in this way is identical to that of the product produced according to method A) with an optical purity of 100%. 



   Example 12 (+) -14- Oxo -E- homo-eburnamenin (3ss, 16a)
A solution of 500 mg (1.62 millimoles) of the according to Hungarian patent application no.  RI-634 manufactured (+)
14- Oxo -E- homo-eburnamenins (3a, 16a) and 10 ml of di-chloromethane is cooled with ice, a solution of 408 mg (1.8 millimoles) of 2,3-dichloro-5,6-dicyano-benzoquinone and
10 ml of dichloromethane are added dropwise.  The reaction mixture is left to stand at room temperature for 2 days and then extracted with 10 ml of a 5% aqueous sodium carbonate solution.  The organic phase is separated off, dried over anhydrous magnesium sulfate, filtered, the filtrate is concentrated and the residue is dissolved in a mixture of 5 ml of methanol and 10 ml of dichloromethane. 



   40 mg of sodium borohydride are added to the solution at 0 ° C., and 0.2 ml of acetic acid is added after 15 minutes, whereupon the resulting solution is evaporated to dryness under reduced pressure.  The residue is dissolved in 4 ml of water and the pH of the solution is adjusted to 7.5 with a 5% aqueous sodium carbonate solution.  The weakly alkaline solution is extracted three times with 5 ml dichloromethane each time. 



  The separated and combined organic phases are dried over anhydrous magnesium sulfate and filtered, the filtrate is evaporated to dryness under reduced pressure.  The residue is purified by preparative column chromatography (KG-PF254 + 366; benzene-methanol
14: 3; Eluent ether; RF end product> RF starting material). 



   100 mg (25%) of the compound mentioned in the title and 220 mg (44%) of the starting material are obtained. 



   F. : 121-122 C (isopropanol) 22 = +138 '; (a) D2 = +138;
22 = + 179 '(c = 1.00, dichloromethane). 



  (a) 546
The IR and MS values of the product are identical to those of the corresponding racemic compound (see Hungarian patent application no.  RI-634). 



   CD (EtOH, A max, nm, (A 8)) = 301.5 (-0.69); 288 (0); 272 (+2.54); 237 (+ 4.77); 223.5 (0); 212 (- 6.3). 



   On the basis of the CD Spectra, the product has proven identical to the compound prepared according to Example 10. 



   Example 13 (+) -14- Oxo -E- homo-eburnamenin (3ss, 16a)
A solution of 250 mg (0.61 millimoles) of the (+) -14- oxo -3dehydro -E- homo-eburnamenin -4- ium perchlorate and 10 ml of methanol prepared according to method A) of Example 11 and 10 ml of methanol are cooled with ice constant stirring 30 mg sodium borohydride added.  After 15 minutes, 0.1 ml of acetic acid is added to the reaction mixture and the solution is evaporated to dryness under reduced pressure.  The residue is partitioned between 2 ml of a 5% aqueous sodium carbonate solution and 4 ml of dichloromethane.  The organic phase is separated, dried over anhydrous solid magnesium sulfate, filtered and the solvent is removed from the filtrate under reduced pressure.  The oily residue is crystallized from 1 ml of isopropanol. 

  170 mg of the compound mentioned in the title are obtained.  The product is identical to the compound described in Example 12 in all chemical and physical properties.  Yield 90%. 



   Example 14 (+) -14- Oxo -E- homo-eburnamenin (3ss, 16a)
200 mg (0.49 millimoles) of the (+) -14- oxo -3- dehydro -E- homoeburnamenin -4- ium perchlorate prepared according to method A) of Example 11 are mixed in a mixture of 5 ml of acetic acid and 10 ml Water dissolved.  700 mg of zinc dust are added to the solution with constant stirring.  The stirring is continued for 24 hours, whereupon the mixture is filtered and the filtrate is washed three times each
3 ml of dichloromethane is extracted.  The combined organic phases are with 10 ml of a 10% aqueous
Sodium hydroxide solution shaken out, the organic
The phase is separated off, washed with 3 ml of water, dried on anhydrous anhydrous magnesium sulfate and filtered. 



   The filtrate is made solvent-free.  The oily residue obtained (140 mg) is purified by preparative column chromatography (KG-PF254 + 366; benzene-methanol
14: 2; Eluent: acetone; RF / 3ss, 16a 9 RF / 32.       162-
After separation, 60 mg of the compound mentioned in the title are obtained.  The product is certified according to the Hungarian patent application no.  RI-634 manufactured connection identical in all chemical and physical properties.  Yield 38%. 



   40 mg (26.4%) of the (+) -14-oxo -E-homo-eburnamenin (3ss, 16a) can also be isolated from the reaction mixture.  The product is compatible with the one in example 12 or  13 described compound in all chemical and physical properties identical. 



   Example 15 Optically active and racemic 5-methoxycarbonyl -14-oxo3-dehydro -E- homo-eburnamenin -4- ium-perchlorate
The procedure is as in Example 7, with the difference that the starting material is 2.00 g (4.28 millimoles) of the (+) -14- hydroxy -5-methoxycarbonyl -3- dehydro-eburnamenin -4- prepared according to Example 4 ium perchlorate used. 



  After removal of the oxidizing agent and evaporation of the filtrate, the oily residue (1.40 g) is crystallized from 5 ml of a methanol-dichloromethane mixture (5: 1).  0.30 g of the racemic title compound are obtained. 



  Yield 15.2%.  F. : 179-181 C.    



   IR (KBr): 1740 (CO2CH3); 1720 (acid amide CO); 1540 cm¯l (C = N). 



   The mother liquor obtained in the recrystallization is evaporated to dryness.  1.1 g of (+) -5- methoxycarbonyl -14- oxo -3dehydro -E- homo-eburnamenin -4- ium perchlorate are obtained in the form of an oily residue.  Yield 55.7%.  Overall yield 70.9%. 



   20 (a) 546 = + 204 '(c = 1.08 dichloromethane).    



   Example 16 (+) -1a- ethyl-lss carboxyethyl -6-carboxy -1,2,3,4,6,7-hexahydro -12H-indolo [2,3-a] quinolizine -5- ium perchlorate
750 ml (1.60 millimoles) of the optically active (+) -5-methoxy-carbonyl -14- oxo -3- de hydro-eburnamenin -4- ium-perchlorate (a) 52426 = 204 ') prepared according to Example 15 -
AL dissolved in 15 ml of ethanol, whereupon a solution of 310 mg (7.75 millimoles) of sodium hydroxide in 1.5 ml of water was added and the reaction mixture was left to stand at room temperature for 2 days.  The reaction mixture is evaporated to dryness under reduced pressure.  

  5 ml of ice-cold water are added to the residue, after which the pH is adjusted to 5 with a 70% aqueous perchloric acid solution with constant cooling.  The precipitated product is filtered off, washed twice with 2 ml of water and dried.  480 g of the compound mentioned in the title are obtained.  Yield 68%. 



     . 22 = +40 "(c = 0.45, methanol). 



     (a) 546
IR (KBr): 3350 (OH, NH); 1680, 1600 cm- '(COOH). 



   F. : 185-190 C (decomposition)
Example 17 (-) -Jethyl-lss carboxyethyl -1,2,3,4,6,7-hexahydro12H-indolo [2,3-a] quinolizine -5-ium perchlorate
460 mg (0.95 millimoles) of the (+) - 1 a-ethyl-lss-carboxyethyl -6-carboxy -1,2,3,4,6,7-hexahydro -12H- indolo prepared according to Example 16 [2, 3-a] Quinolizine -5- ium perchlorate ((1) 25426 = + 40) are suspended in 5 ml of decalin and the suspension is stirred in an oil bath of 18F185 C for 20 minutes under nitrogen.  The reaction mixture is cooled, filtered, washed twice with 2 ml ether and dried. 

  390 mg of the compound mentioned in the title are obtained.  Yield 96%. 



     22 = - 18 '(c = 1.00, methanol). 



     (U) 546
IR (KBr): 3350 (NH, OH); 1720, 1620 (COOH);
1530 cm- (C = N).    



   Example 18 (-) -Jethyl-lss methoxycarbonyl-1,2,3,4,6,7,12,12b a oktahp, dro-indolo [2,3-a] quinolizine hydrochloride and (+) - la - A thyl -P methoxycarbonyl -1,2,3,4,6, 7,12,12b ss-octahydro-indolo [2,3-a] quinolizine
390 mg (0.92 mole) of the (-) la-ethyl-lss-carboxyethyl prepared according to Example 17 -1,2,3,4,6,7- hexahydro -12H- indolo [2,3-a] quinolizine - 5-ium perchlorate are dissolved in a mixture of 2 ml of methanol and 2 ml of dichloromethane. 



  The solution is cooled to 0 ° C., whereupon a diazomethane solution prepared from 1.2 g of N nitroso -N-methylurea in dichloromethane is added with stirring.  (A. 



  Vogel: Practical Organic Chemistry 971 3.  Output) The solvent is distilled off from the reaction mixture under reduced pressure.  The residue is dissolved in 5 ml of anhydrous dimethylformamide and hydrogenated in the presence of 0.3 g of a palladium / carbon catalyst.  The catalyst is removed by filtration and the filtrate is evaporated to dryness under reduced pressure.  The oily residue is dissolved in 5 ml of dichloromethane and the solution is brought to pH 8 with a saturated aqueous sodium carbonate solution.  The organic phase is separated off, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure.  The residue is purified by preparative layer chromatography (Kg-PF254 + 366; benzene-methanol 14: 3; eluent acetone). 



     RF / la, 12bal <RFiia, 12b0 /
30 mg (10%) of the compound mentioned in the title are isolated from the cis ester (la, 12ba) isolated in the form of an oil using methanol saturated with hydrogen chloride gas.



   The turning capacity of the base is: 22 = -114 '(c = 1.10, dichloromethane) Optical purity 94%.



   The product is identical in all its physical and chemical properties to the compound described in Hungarian Patent Application No. RI-634.



   The trans compound mentioned in the title (la, 12bss) was also isolated by purification using preparative layer-chromatographic methods. Yield 10 mg (3%).



     22 = + 78 (c = 0.52, dichloromethane).



     (a, 546 Optical purity 86%.



   The IR and MS data of the product are consistent with those of the corresponding racemic compound described in Hungarian Patent Application No. RI-634.



   Example 19 (+) -14- Oxo -E- homo-eburnamenin (3a, 16a)
58 mg (17.4 millimoles) of the (-) -la-ethyl-lss-methoxycarbonyl -1,2,3,4,6,7,12,12b-octahydro-indolo [2,3-a ] Quinolizins are dissolved in 5 ml of anhydrous toluene. A 50% oily suspension of 10 mg of sodium hydride is added to the solution, and the reaction mixture is heated to boiling for 5 hours with stirring and under nitrogen. The mixture is cooled, extracted three times with 2 ml of a 2.5% aqueous sulfuric acid solution. The combined aqueous phases are adjusted to a pH of 8 with a concentrated ammonium hydroxide solution.

  The alkaline solution is extracted three times with 3 ml of dichloromethane, the combined organic layers are dried over anhydrous solid magnesium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure. The solid residue is recrystallized from 1.5 ml of methanol.



  34 mg of the compound mentioned in the title are obtained. Yield 65%.



   22 = + 32.5 (c = 1.35, dichloromethane) F .: 152-154 C.


    

Claims (5)

 PATENT CLAIMS 1. Process for the preparation of the isomer mixture of optically active 14-oxo -E-homo-eburnamenin derivatives of the general formulas EMI1.1  wherein R1 is an alkyl group with 1-6 carbon atoms and acid addition salts of these compounds, characterized in that an optically active triyptophan ester derivative of the general formula EMI1.2  wherein R2 represents an alkyl group with 1-6 carbon atoms and A represents an acid residue, with an alkylvaleric acid halide derivative of the general formula EMI1.3  wherein R1 is defined above and X1 and X2 represent identical or different halogen atoms, in the presence of an acid binder,  the optically active halogen pentanoyl tryptophan ester derivative obtained of the general formula EMI1.4  wherein R1, R2 and X1 are defined above, subject to cyclizing dehydration and then treated with a weak base, the optically active hexahydroindoloquinolizium salt derivative obtained of the general formula EMI1.5  wherein R1, R2 and X1 are defined above, in the presence of a catalytic amount of an alkali metal tert-alcoholate with acrolein of the formula CH2 = CH-CHO (VI), the optically active hydroxy-dehydro -Ehomo-eburnamenin-carboxylic acid ester obtained Derivative of the general formula EMI1.6  where R1 and R2 are defined above and X3 represents an acid residue,  oxidized, the new optically active oxodehydro -E-homo-eburnamenin -carboxylic acid ester obtained derivative of the general formula EMI1.7  wherein Rl, R2 and X3 are defined above, selectively reduced, then the mixture of isomers obtained from compounds of the general formulas EMI2.1  wherein Rl and R2 are defined above, hydrolyzed, the resulting isomer mixture of compounds of the general formulas EMI2.2  wherein Rl is defined above, first treated with an inorganic oxyhalide and then selectively reduced and the compounds obtained are optionally converted into acid addition salts.  2. Process for the preparation of optically active 14-oxo-ehomo-eburnamenin derivatives of the general formula EMI2.3  and EMI2.4  wherein Rl is an alkyl group having 1-6 carbon atoms, and the acid addition salts of these compounds, characterized in that the isomer mixture is prepared from compounds of the general formulas Ia and Ib by the process according to claim 1 and this is converted into the optically active isomers of the formulas Ia and Ib separates and the compounds obtained are optionally converted into acid addition salts.  3. Process for the preparation of the optically active cis -14 oxo -E-homo-burnamenin derivative of the general formula EMI2.5  wherein Rl is an alkyl group with 1-6 carbon atoms and acid addition salts of this compound, characterized in that an optically active compound of the general formula is obtained from optically active compounds of the general formula II by the process defined in claim 1 EMI3.1  in which R1 is defined above, R2 is an alkyl group with 1-6 carbon atoms and X3 is an acid radical, this compound is subjected to a basic treatment,  the resulting optically active carboxyethyl-hexahydro-indoloquinolizine-carboxylic acid derivative of the general formula EMI3.2  wherein Rl is defined above and Xs represents an acid residue, selectively decarboxylated, the optically active carboxyethyl hexahydro -indoloquinolizinium salt obtained of the general formula EMI3.3  wherein Rl and X5 are defined above, first esterified and then reduced or first reduced and then esterified, the resulting alkoxycarbonyl-octahydro-indoquinolizine isomer mixture of the general formula EMI3.4  wherein Rl is defined above and R3 represents an alkyl group with 1-6 carbon atoms,  separates into the isomeric compounds and cyclizes the optically active cis (la, 12ba, -alkoxycarbonyl -octahydro-indoloquinolizine falling under the general formula XIV to the compound of the general formula Ib and, if appropriate, converts the compound obtained into an acid addition salt.  4. Process for the preparation of the optically active trans14-oxo -E-homo-eburnamenin derivative of the general formula EMI3.5  wherein Rl is an alkyl group with 1-6 carbon atoms and acid addition salts of this compound, characterized in that the isomer mixture prepared according to the process of claim 1 from optically active compounds of the general formulas EMI3.6  and EMI3.7  wherein R 'is defined above, for the optically active oxodehydro -E-homo-eburnamenin derivative of the general formula EMI4.1  oxidized, wherein Rl is defined above and X4 represents an acid residue, and then selectively reducing the compound of general formula XI to the compound of general formula Ia and optionally converting a compound obtained into an acid addition salt.  5. Process for the preparation of the optically active trans14-oxo -E-homo-eburnamenin derivative of the general formula EMI4.2  wherein Rl is an alkyl group with 1-6 carbon atoms and acid addition salts of this compound, characterized in that from the isomer mixture prepared according to the process of claim 1 from optically active compounds of the general formulas EMI4.3  wherein Rl is defined above, separates the optically active compound of the general formula Ib, to the optically active oxodehydro -E-homo-eburnamenin derivative of the general formula EMI4.4  oxidized, in which R 'is defined further above and X4 stands for an acid residue and then reduces the compound of general formula Ia and, if appropriate, converts a compound obtained into an acid addition salt.    The invention relates to a process for the preparation of the isomer mixture from optically active 14-oxo -E-homoeburnamenin derivatives of the general formula Ia and Ib EMI4.5  wherein Rl is an alkyl group with 1-6 carbon atoms and process for the preparation of the pure optically active compounds. The compounds mentioned can also be present as acid addition salts.  The process for the preparation of the isomer mixture from compounds of the formulas Ia and Ib is characterized in that an optically active tryptophan ester derivative of the general formula ** WARNING ** End of CLMS field could overlap beginning of DESC **.