DE1096363B - Process for the production of reserpine - Google Patents

Description

Process for the preparation of reserpine The present invention relates to a process for the preparation of reserpine of the formula Reserpine is a major component of the Rauwolfia heterophylla Roem. and Schult separate ingredients (see R. Paris and R. Mendoza-Daza, Bulletin des Sciences Pharmacologiques, Vol. 48, 1941, p. 146; R. Mendoza-Daza, dissertation from the University of Paris, Pharmaceutical Faculty, 1940; C. Dj erassi, M. Gorman, AL Nussbaum and J. Reynoso, Journal of the American Chemical Society, Vol. 75, 1953, p. 5446, and Vol. 76, 1954, p. 4463). Reserpine was separated from the so-called "oleoresin fractions" of Rauwolfia serpentina Benth by JM Müller, E. SchlittIer and HJ Bein (cf. Experientia, Vol. 8, 1952, p. 338) in a crystalline state.

Reserpine has a calming and antihypertensive effect of long duration. It also has a temperature-lowering effect and increases the periodic Bowel movements. Because of these various properties, reserpine is an important one Remedies of low toxicity, especially a very powerful remedy against Mental illness.

Used in the process of the invention for the manufacture of reserpine the starting compound is the dextrorotatory 5ß-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-iß-carboxylic acid, which has not yet been described, and obtained as intermediates the the following, also not yet described connections: The counterclockwise Lactone of 5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid (II), the dextrorotatory lactone 8ß-Oxy-2a-bromo-3ß, 5ßoxido - 1,2,3,4,4aa, 5,8,8aa - octahydronaphthalene - lßcarboxylic acid (III), the ozonide of the levorotatory methyl ester of 3ß-acetoxy-2a-methoxy-7-oxo -1, 2,3,4,4aa, 7,8,8aaoctahydronaphthalene-1ß-carboxylic acid (IV), the dextrorotatory 18ß - oxy - 11,17a - dimethoxy-3-oxo-16ß-carboxy-2,3-seco-20α-yohimbane (V), the levorotatory lactone of 18fl-oxy-11, 17a-dimethoxy-3-oxo-16ß-carboxy-2,3-seco-20α-yohimbans (VI), the lactone of 18β-oxy-11,17α-dimethoxy-16β-carboxy-3,4-dehydro-20a-yohimbane (VII).

The method of the invention, which is illustrated in the equation, is characterized in that the dextrorotatory 5ß-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1ß-carboxylic acid (I) by the optical resolution of the corresponding racemate with an optically active base such as quinine, brucine, cinchonine or l-ephedrine is obtained with Sodium acetate and acetic acid hydride in methylene chloride with refluxing converts, the resulting left-rotating lactone of 5ß-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1ß-carboxylic acid (II) with aluminum isopropylate in isopropanol to form the levorotatory 1,8-lactone of 5 [beta], 8 [beta] -dioxy - 1,4,4aα, 5,8,8aα - hexahydronaphthalene - 1ß - reduced carboxylic acid, this after the separation with the calculated amount of an N-bromimide, such as N-bromosuccinimide, an N-bromamide or N-bromohydantoin at ordinary temperature in one opposite Reacts bromine inert solvent, the resulting clockwise Lactone of 8β-oxy-2α-bromo-3β, 5β-oxido-1,2,3,4, 4aα-5,8,8aα-octahydronaphthalene-1β-carboxylic acid (III) separated by precipitation with water and after customary work-up and with sodium methylate in methanol in the dextrorotatory lactone of 8ß-oxy-2α-methoxy-3ß, 5ßoxido - 1,2,3,4,4aα, 5,8,8aα - octahydronaphthalene-1ß-carboxylic acid transferred, this separates and reacts with N-bromosuccinimide in dilute sulfuric acid, the resulting levorotatory 1,8-lactone of 6a-bromo-7ß, 8B-dioxy-2a-methoxy-3B, 58- oxido -4aa, 8aa- decahydro naphthalene-1,1-carboxylic acid is separated off and treated with chromic acid oxidized in acetic acid, the resulting levorotatory lactone of 6α-bromo-8ß-oxy-2α-methoxy-3ß, 5 (3-oxido-7-oxo -4aa, 8aa-decahydronaphthalene-lß-carboxylic acid separated off and with Zinc powder in acetone and acetic acid in the levorotatory 3ß-oxy-2α-methoxy-7-oxo-1,2, 3,4,4aα - 7,8,8aα - octahydronaphthalene - 1ß - carboxylic acid transferred, from which one first prepares the methyl ester with diazomethane in dioxane, which one then acetylated with acetic anhydride in pyridine, this levorotatory methyl ester of 3β-acetoxy-2α-methoxy-7-oxo-1,2,3,4,4aα, 7,8,8aα-octahydronaphthalene-1β-carboxylic acid in an organic solvent such as ethyl acetate or methylene chloride, Treated with ozone at temperatures between 0 and -60 ° C, the resulting ozonide IV either with water or iodic acid or periodic acid directly into the levorotatory 1β-Carboxymethyl-2β-methoxycarbonyl-3α-methoxy-4β-acetoxy-6β-formylcyclohexane transferred or by treating the ozonide IV with zinc powder in Hydrate of 1ß- (2'3'-dioxopropyl) -2ß-methoxycarbonyl-3α-methoxy-4ß-acetoxy-6ß-formylcyclohexane obtained in the presence of acetic acid oxidized with chromic acid or periodic acid, the resulting levorotatory 1,1-carboxymethyl - 2,1-methoxycarbonyl - 3a - methoxy-4ß-acetoxy-6ß-formylcyclohexane with diazomethane methylated in methylene chloride and ether, the ester obtained with 6-methoxytryptamine condensed, the condensation product with sodium borohydride and then with alcoholic sodium hydroxide solution to the clockwise 18ß-oxy-11,17a-dimethoxy - 3 - oxo- 16.1-carboxy-2,3-seco-20ayohimban (V) converts this with acetic anhydride in the presence of acetic acid and lithium acetate in the corresponding levorotatory Lactone VI converted this with phosphorus oxychloride in the heat to the lactone des 18ß-oxy-11,17a - dimethoxy-16,1-carboxy-3,4-dehydro-20a-yohimbans (VII) ring closes this with zinc powder in the presence of acetic acid directly to reserp acid lactone or reduced with an alkali borohydride to Isoreserpsäurelacton and this in itself known way isomerized to reserp acid lactone and the lactone of reserp acid converted in a manner known per se into the reserp acid methyl ester and this with 3,4,5-trimethoxybenzoyl chloride esterified to reserpine.

In the known Woodward method (see Journal of the American Chemical Society, Vol. 78, 1956, pp. 2023 to 2025 and 2657) is only in the stage of the O-acetylisoreserps acid methyl ester, i.e. approximately in the twentieth stage of the Process, a cleavage into the optical isomers carried out. Such a one The procedure is more expensive because it is used for the production of the O-acetylisoreserpsic acid methyl ester in the known process about twice the amount of the starting materials and the others Reactant to the process of the invention is required in which the optical cleavage is carried out in the second stage of the process. the optical cleavage in the second stage of the process has the following additional ones Advantages.

The levorotatory lactone of 5ß-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1ß-carboxylic acid (II) has a high rotation value of 790O (c = 0.5 501 in ethanol).

This high rotation value enables extensive control of the cleaning of this intermediate compound, which helps to increase the yields obtained.

The levorotatory lactone of 6α-bromo-8β-oxy-2α-methoxy-3β, 5β-oxido-7-oxo-4aα, 8aα-decahydronaphthalene-1β-carboxylic acid is in the mixture of acetone and acetic acid that is used in the reduction with zinc powder is used, highly soluble. As a result, the reduction runs reliably and is can be carried out smoothly on a large scale, while the very low solubility of the corresponding racemic lactones carry out on a large scale because of the to be used makes large quantities impossible, taking into account the irregularities in the yield is still quite apart.

The solubility of the levorotatory methyl ester of 3ß-acetoxy-2α-methoxy-7-oxo-1,2,3,4,4aα, 7,8,8aα-octahydronaphthalene-1β-carboxylic acid is also much higher than that of the racemic methyl ester, whereby the Oxidation with ozone is facilitated.

The 1ß-carboxymethyl-2ß-methoxycarbonyl-3α-methoxy-4ß-acetoxy-6ß-formylcyclohexane, which is amorphous as a racemate, crystallizes immediately in the levorotatory form, whereby its manufacture is facilitated.

The German patent specification 933 628 can be seen that the statement whether it is advantageous to carry out the optical cleavage at the beginning of the alkaloid production, is to be checked for validity in each individual case. In the British patent 799 272 it is asserted that the cleavage into the optical antipodes also occurs in a earlier stage of reserpine production can be carried out. However, it was a Overcoming prejudice, the optical splitting as early as the second stage of the procedure carry out the invention, since the racemic "aldehydic acid", 1ß-carboxymethyl-2-methoxycarbonyl-3a-methoxy-4- acetoxy-6B-formylcyclohexane, with various for splitting into optical antipodes commonly used bases such as quinine, brucine, cinchonine, ephedrine, not can be dismantled. In the presence of these bases, epimerization of the aldehyde acid occurs, so that it cannot be used for further synthesis.

In the method of the invention is also used in the implementation of levorotatory 1,8-lactones of 5,1,8,1-dioxy-1, 4,4aa, 5,8,8aa-hexahydronaphthalene-1,1-carboxylic acid, the "oxylactone", to the dextrorotatory lactone the 8ß-oxy-2α-methoxy-3ß, 5ß-oxido-1,2,3,4,4aα, 5,8,8aα-octahydronaphthalene-1ß-carboxylic acid, the "methoxylactone", as an intermediate resulting dextrorotatory lactone of 8ß-oxy-2α-bromo-3ß, 5ß-oxido-1,2,3,4, 4aα, 5,8,8aα-octahydronaphthalene-1β-carboxylic acid (III) separated. To Woodward (see Journal of the American Chemical Society, Vol. 78, 1956, p. 2657) is obtained from the conversion of the "oxylactone" into the "methoxylactone" through treatment with bromine in methanol and then with sodium methylate without separating the than Intermediate product bromine derivative only a low yield (about 400 (0). According to the method of the invention, however, the dextrorotatory bromolactone III, which has not yet been described, obtained in yields of about 900 (0. This Bromlactone III can be converted into the "methoxylactone" with a yield of over 90% convict.

The conversion of the levorotatory methyl ester of 3ß-acetoxy-2α-methoxy-7-oxo-1,2,3,4,4aα, 7,8,8aα-octahydronaphthalene-1ß-carboxylic acid to the levorotatory 1,1-carboxymethyl-2,1-methoxycarbonyl-3a-methoxy-4ß-acetoxy-6ß-formylcyclohexane takes place in the process of the invention via the ozonide. The use of osmium tetroxide is in the known method more expensive, in addition, osmium tetroxide is more toxic and volatile, making it difficult to recover.

Another advantage of the method of the invention is that when the ozonide is decomposed with water, the levorotatory 1,1-carboxymethyl-2ß-methoxycarbonyl-3a-methoxy-4ß-acetoxy-6ß-formylcyclohexane is obtained immediately receives. From the reference H o ub e n Weyl, Methods of Organic Chemistry, Vol. 7, Part 1, 1954, 4th edition, p. 336, although it can be seen that carbon-carbon double bonds, which are in an aromatic ring, via the ozonide and through subsequent Treating with water can break down, creating aldehyde carboxylic acids. in the In the present case, however, it is not a question of reactions in the aromatic Series, but the compound that is subjected to ozone splitting is an octahydronaphthalene derivative, that contains only a single double bond. It also contains a keto group alongside the double bond, and cannot be deduced from the cited reference how the ozonide obtained in the present invention decomposes will. In addition, in Chemistry for Laboratory and Operations, Vol. 8, 1957, p. 95, that it is only suspected that the reaction with ozone for some reason less has been cheap. The ozonization of a double bond with the formation of ozonide and its decomposition with water belong to the classical methods of chemistry, however, the production of ozonide is the 3,1-acetoxy-2a-methoxy-7-oxo-1,2,3,4,4 aa, 7,8,8aa-octahydronaphthalene-lß-carboxylic acid not without inventive achievement possible. In addition, this ozonide was decomposed to form a carboxymethylene group not to be expected in the 1-position and an aldehyde group in the 6-position of the cyclohexane. Decarboxylation occurs in the 1-position of the cyclohexane Chain on, d. that is, the cleavage proceeds with the loss of one carbon atom. this is especially with regard to the state of the art (compare e.g.

Karrer, 12th edition, 1954, p. 616) completely new and surprising.

The production of the lactone of the dextrorotatory 18ß-oxy-11,17a-dimethoxy-3-oxo-16ß-carboxy-2,3-seco-20a-yohimbans (V) according to the method of the invention enables several steps and to be saved expensive chemicals. Following the Woodward procedure (see Journal of the American Chemical Society, Vol. 78, 1956, pp. 2023 and 2657) is obtained upon ring closure the racemate of 18ß-acetoxy-11,17a-dimethoxy-3 is not directly in the alkaline medium -oxo-1 6,1-methoxycarbonyl-2,3-seco-20a-yohimbans, since an incomplete ring closure occurs Saponification of the acetyl group and even a saponification of the methyl ester, albeit takes place only to a small extent. It is therefore with the Woodward method required to methylate again with diazomethane and with a mixture of pyridine and re-acetylating acetic anhydride while in the process of the invention due to the formation of the lactone, these two stages are omitted. In addition, the Formation of dextrorotatory 18-oxy-11,17a-dimethoxy-3-oxo-16ß-carboxy-2,3-seco-20a-yohimbane (V) with better yields than isoreserpic acid, and the use of dicyclohexylcarbodiimide is also not required.

From Experientia, Vol. 12, 1956, pp. 249 to 251, it is known that isoreserpic acid and acetic anhydride form reserpic acid lactone, whereby also the use of dicyclohexylcarbodiimide and the subsequent isomerization superfluous. The saving of two steps in the method of the invention compared to Woodward's method, which is a considerable Progress means you could get out of it however, cannot be derived.

Also from the Journal of the American Chemical Society, Vol. 78, 1956, 5. 2021 and following, published manufacture of 16 - carbomethoxy - 18 - oxy-15 (20) -yohimben could not draw any conclusions about the method of the invention to be pulled. This synthesis leading to a substantially different from reserpine Leads to a compound which has no methoxy group in either the 11 or 17 position, has nothing in common with the method of the invention. Just the presence or absence a ll-methoxy group already causes considerable differences in the Conversions of the respective intermediates. For example, it is known that the isomerization of Isodeserpedinsäurelactons to Deserpedinsäurelacton very much is much more difficult than the isomerization of isoreserp acid lactone to reserp acid lactone (cf. Rauwolfia, Botany, Pharmacognosy, Chemystry and Pharmacology, 1957, p. 85, 2nd paragraph, line 11.

It is also known that 3-isoreserpine, 3-isoreserpic acid methyl ester and 3-Isoreserpsäuremethylester-18-acetate can oxidize with mercury acetate (cf. Journal of the American Chemical Society, Vol. 78, 1956, p. 2022).

This oxidation can only be carried out with compounds in the 3a position carry a hydrogen atom. The reduction of the 3-dehydro compounds obtained in this way with zinc and acetic acid leads to reserpine, reserp acid methyl ester or reserp acid methyl ester-1 8-acetate (the hydrogen atom in the 3ß-position). So it's just a matter of an isomerization.

The example illustrates the method of the invention.

The melting points given are those determined on the Maquenne block Melting points. The rotation values were all determined in ethanol.

Example A. Optical cleavage of the dl-5β-oxy-8-oxo-1,4,4aa, 5,8,8aa-hexahydronaphthalen1-carboxylic acid a) With quinine 1. Separation of the 1-5ß-oxy-8-oxo-1,4,4aa, 5,8,8aa-hydroxahydronapthalene-1,1-carboxylic acid 104 g according to Woodward and co-workers (cf.

Journal of the American Chemical Society, Vol. 78, 1956, p. 2023) dl-58-0xy-8-oxo-1,4,4aa, 5,8,8aa-hexahydronaphthalene-lß-carboxylic acid are with 400 cc of ethanol is heated under refluxing until it dissolves, then it is added of the boiling solution at once 162 g of quinine. The resulting quinine salt of the left-turning 5,1-Oxy-8-oxo-1, 4,4aa, 5,8,8aa-hexahydronaphthalene-1,1-carboxylic acid crystallized immediately off. The mixture is left to boil for a further 114 hours while stirring, and it is cooled 2 hours on ice, sucks off the crystals and rubs them twice with 100 ccm each iced ethanol.

The levorotatory quinine salt is sucked off and dried; M.p. 225 "C; [a] 2D -151 i 4 ". The yield is 117 g; the quinine salt obtained is in 300 cc water and 500 cc chloroform slurried. After adding 30 g of sodium carbonate The mixture is stirred for 3 hours until the evolution of carbon dioxide ceases. One lets clarify the emulsion formed, separate the chloroform layer and wash it several times Paint with an aqueous saturated sodium bicarbonate solution. The aqueous layer is extracted three times with chloroform to remove any quinine it still contains to free. After that, the one with the bicarbonate washes the Chloroform layer combined aqueous layer with 5N hydrochloric acid to a pa value = 2 acidified, saturated with sodium chloride and left to stand for 1 hour. After this Sucking off and drying the precipitate in vacuo over solid sodium hydroxide 20 ° C one receives 33 g of the levorotatory 5jB-Oxy-8- oxo - 1,4,4aa, 5,8,8aa- hexahydronaphthalene- 1,1-carboxylic acid, mp = 210 ° C; [a] i> = -781 4. The compound still contains 3 g Sodium chloride, which is obtained by recrystallization from a mixture of equal parts of alcohol and ether is removed. The pure left-handed connection has a melting point of 210 ° C; [α] D20 = -85 ° (c = 0.5% in ethanol).

C11H12O4; Molecular Weight = 208.21.

Calculated ... C 63.45, H 5.81, 0 30.74%; found . . C 63.3, H 5.8, 0 30.5 01o.

The aqueous mother liquors of the crude product are several times with extracted from a mixture of chloroform and ethanol in a ratio of 3: 1. The extract is washed with aqueous sodium chloride solution to a ps value = 4, over magnesium sulfate dried and evaporated to dryness in vacuo. You get with after rubbing a mixture of chloroform and ethanol in a ratio of 3: 1 3 g of the levorotatory Link, [a] D = -84 °. The grinding liquid results in dryness after evaporation and digesting with chloroform a third portion of the crystalline compound, whereby the overall yield in the cleavage is increased to 80%.

2. Separation of the d-5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid (I) The one used in the preparation of the quinine salt of l-5,1-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid The resulting ethanolic mother liquor is evaporated to dryness. The one from the quinine salt dextrorotatory 5-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1,1-carboxylic acid and about 10010 of the quinine salt of the left-rotating carboxylic acid The residue is, as described above, with stirring in a mixture of 300 cc water, 500 cc chloroform and 30 g sodium bicarbonate slurried. The decomposition of the quinine salt is finished in about 1 hour.

After the emulsion formed has been clarified, the chloroform layer is separated off, washed twice with an aqueous sodium bicarbonate solution and extracted the aqueous layer several times with chloroform in order to separate it from that still contained therein Free quinine. The combined bicarbonate-containing solutions are with 5N hydrochloric acid acidified to pH = 2 and left to stand. After 1 hour The crystals formed are filtered off with suction and, after drying, 21 g of the racemic mixture are obtained Mixture of compound I which still contains part of the dextrorotatory compound; [aj 2O = +22 "(c = 0.5 01o in ethanol). The filtrate obtained is treated with sodium chloride saturated and several times with a mixture of chloroform and alcohol in proportion 3: 1 extracted. The extract is mixed with aqueous saline solution up to a pH value washed from 4, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is made into a paste with chloroform and yields 16 g of crystalline pure dextrorotatory 5β-Oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1,1-carboxylic acid (I). Mp = 210 ° C; [α] D20 = +83140.

After evaporation and leaving the mother liquors to stand for several days a second crop of crystalline compound I is obtained. That described above obtained mixture of racemic and dextrorotatory Compound (21 g), [a] 2O = +220, is dissolved in the smallest possible amount, about 4 volumes, of hot water.

After cooling with ice and filtering off with suction, 11 g of the racemate are obtained from the F. = 202 °, which is again subjected to the cleavage. The mother liquors are saturated with sodium chloride and deliver according to the procedure described above another lot of right-handed connection. b) With brucine according to the described Procedures, but using 1 mole of brucine per mole of racemate, are obtained the brucine salt of the levorotatory 5ß-oxy-8-oxo-1,4,4aa, 5,8,8aa - hexahydronaphthalene - 1,1 - carboxylic acid, m.p. = 210 "C; [α] D20 = -40 ° C (c = 0.5 01o in ethanol), in a yield of 8801o of theory. The left-turning salt is obtained from this salt Carboxylic acid, [aj2oO = 850, and from the mother liquors of the brucine salt of the levorotatory Connection the clockwise connection. c) With cinchonine 1. Production of the cinchonine salt of the dextrorotatory 5β - oxy - 8 - oxo - 1,4,4aα, 5,8,8aα - hexahydronaphthalene / β-carboxylic acid 1 g of dl-5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid is dissolved in water at 95 ° C in 10 ccm of water. 1.4 g of cinchonine are then added to the solution and it is stirred 5 minutes at 90 ° C, cool it with ice, suck off the precipitate, wash it with it Water and dry it at 80 ° C. 940 mg are obtained, corresponding to 78% of the calculated values Amount of cinchonine salt of the clockwise 5,1 - Oxy - 8 - oxo - 1,4,4aa, 5,8,8aa - hexahydronaphthalene-β-carboxylic acid. This so far not described connection forms fine, colorless platelets with a temperature of about 192 ° C; [α] D20 = +146 # 6 ° (c = 0.5% in ethanol). It is soluble in ethanol, methanol and acetone, in ether and Petroleum ether insoluble and not very soluble in water.

C30H34O5N2; Molecular Weight = 502.59.

Calculated ... C 71.69, H 6.82, N 5.57%; found ... C 71.4, H 6.8, N 5.4%.

2. Production of the cinchonine salt of the clockwise 5.1 - Oxy - 8-oxo - 1,4,4aa, 5,8,8aa - hexahydronaphthalene-1,1-carboxylic acid in aqueous ethanol 1 g of dl-5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid is dissolved in 4 cc of boiling ethanol and gives 1.4 g of cinchonine and then 8 cc of water at 70 ° C. The mixture is allowed to cool while stirring, is cooled on ice and is suctioned the precipitate is washed off, washed with water and dried at 80 ° C. This gives 1 g, corresponding to 840/0 of the calculated amount of cinchonine salt of the right-handed 5β-Oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid, the corresponds to the compound produced by method c, 1.

3. Decomposition of the cinchonine salt of the dextrorotatory 5ß - Oxy - 8 - oxo - 1,4,4aα, 5,8,8aα - hexahydronaphthalene-1ß-carboxylic acid Slurry 940 mg of the cinchonine salt of the dextrorotatory 5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1,1-carboxylic acid in 4 cc of water and add 1 cc of 20% ammonia to the slurry. One stirs the mixture and sucks off the precipitated cinchonine, which is washed with water and is dried.

0.5 g is obtained corresponding to 90% of the calculated amount of cinchonine return. The filtrate is with 35 weight percent hydrochloric acid to a p-value = 1 acidified, concentrated in vacuo to 2 cc and treated with sodium chloride saturated. After the precipitate has been suctioned off, it is dissolved in 10 ccm of acetone, filter the solution, add 20 cc of ether, concentrate it to 3 cc, suck the precipitate and dries it. 330 mg are obtained, corresponding to 6601o of calculated amount of pure dextrorotatory 5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1,1-carboxylic acid (I). The compound melts at 210 ° C with decomposition, [α] D20 = +83 # 4 ° (c = 0.5% in ethanol) and it corresponds to that prepared according to method a, 2 Link. d) With ephedrine 1. Ephedrine salt of the dextrorotatory 5ß-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1ß-carboxylic acid 100 g of 5β-oxy-8-oxo-1,4,4aα-5,8,8aα-hexahydronaphthalene-1β-carboxylic acid are dissolved at the boiling point in 500 cc of anhydrous ethanol, the mixture cools to 50 ° C and quickly gives 108 ccm of an anhydrous ethanol solution containing 71.5% l-ephedrine. One cools the mixture to + 50 C, it can stand for 2 hours at this temperature, sucks the precipitate and dry it in a vacuum. 67.5 g are obtained accordingly 75% of the calculated amount of ephedrine salt of the clockwise 5ß - oxy - 8 - oxo - 1,4,4aα, 5,8,8aα - hexahydronaphthalene-1ß-carboxylic acid as fine colorless Needles, m.p. = 1530 C; [α] D20 = +30 # 1 ° (c = 5% in water).

2. Decomposition of the ephedrine salt of the clockwise 5ß - Oxy - 8 - oxo - 1,4,4aα, 5,8,8aα - hexahydronaphthalene-1ß-carboxylic acid Slurry 67.5 g ephedrine salt of the right-handed 5,1-oxy-8-oxo -1, 4,4aα, 5,8,8aα - Hexahydronaphthalene-1ß-carboxylic acid in 250 cc of acetone, stir the mixture and mixed with 16 ccm of concentrated hydrochloric acid at 20 ° C. The mixture is still stirred 15 minutes at normal temperature, the l-ephedrine hydrochloride formed sucks and the filtrate is evaporated to dryness in vacuo. The residue obtained is Made into a paste five times with 10 ccm of water and dried at 80 ° C in a vacuum. You get 34.4 g, corresponding to 9201o of the calculated amount, of pure dextrorotatory 5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid (I).

This compound melts at 210 ° C. with decomposition; [α] D20 = +83 # 4 ° (c = 0.5 ° / 0 in ethanol); it corresponds to that produced by method a, 2 Link.

B. Left-handed lactone of S, 1-oxy-8-oxo-1, 4,4aa, 5,8,8aa-hexahydronaphthalene-1,1-carboxylic acid (II) 8 g of dextrorotatory 5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid are added (I) and 4 g of powdered sodium acetate in a mixture of 200 cc of methylene chloride and 16 cc of acetic anhydride.

After refluxing for 2 hours, the mixture is cooled and then added 16 cc of pyridine and 16 cc of methanol, leave them for 1 hour at ordinary temperature stand, acidify it with 2N hydrochloric acid to a p-value of 1, allow to settle, wash the solution with water and sodium bicarbonate, dry over magnesium sulfate and evaporate in a vacuum to dryness. The residue is taken up in 30 cc of ether and heated reflux, cool on ice, suck off the precipitate and wash it with ether.

6.1 g are obtained, corresponding to 83% of the calculated amount of left-turning Lactone of 5β-oxy-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid (II), m.p. = 108 ° C, [α] D20 = -790 # 20 ° (c = 0.5% in ethanol). This so far compound not described forms colorless Crystals in acetone and chloroform are soluble and very sparingly soluble in ether.

C11H10O3; Molecular Weight = 190.19.

Calculated ... C 69.46, H 5.30,0 25.24 ° lo; found ... C 68.8, H 5.6,0 24.8%.

C. Right-handed lactone of 5β-oxy-2α-bromo-3,1,5,1-oxido-1 , 2,3,4,4aa, 5,8,8aa-octahydronaphthalene-1ß-carboxylic acid (III) a) Left-turning 1st , 8-Lactone of 5ß, 8ß-Dioxy-1, 4,4aa, 5,8,8aa-hexahydronaphthalene-1,1-carboxylic acid Man mixes 40 g of molten aluminum isopropylate and 500 ccm of anhydrous isopropanol, distilled off a few drops and added 20 g of the levorotatory lactone of 5.1 - Oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid (II) too. The mixture is concentrated to a volume of 100 ccm by distillation, cools down, adds 300 cc of methylene chloride, and washes the mixture with 1N sulfuric acid and then with water, dry over magnesium sulphate and evaporate to dryness. Of the The residue is taken up in 50 cc of ice-cold ether. After suctioning off the precipitate 17.1 g, corresponding to 85% of the calculated amount of levorotatory 1,8-lactone, are obtained the 5ß, 8ß-Dioxy-1,4, 4aa, 5,8,8aa-hexahydronaphthalene-lß - carboxylic acid from F. = 151 ° C, [α] D20 = -3 ° (c = 0.5% in ethanol). This has not yet been described Compound forms colorless crystals that are soluble in acetone and chloroform and in Ethers are very sparingly soluble.

C11H12O2; Molecular Weight = 192.21.

Calculated ... C 68.73, H 6.29.0 24.970 / ;; found ... C 68.8, H 6.1, 0.25.20 / 0. b) Right-handed lactone of 8β-oxy-2α-bromo-3β, 5β-oxido 1,2,3,4,4aα, 5,8,8aα-octahydronaphthalene-1β-carboxylic acid (III) 11.5 g of levorotatory 1,8-lactone of 5β, 8β-dioxy-1,4,4aα, 5,8,8aα - Hexahydronaphthalene - 1ß - carboxylic acid to 55 ccm of tertiary butanol, stir the Mix for 5 minutes at 25 ° C and add in small portions while stirring constantly 10.8 g of N-bromosuccinimide. Stirring is continued for a further 15 minutes, added the mixture is added dropwise with 110 ccm of water, stirs for a further 15 minutes, sucks off, washed with 20 ccm of water, dried at 70 ° C and thus obtained 13.7 g, accordingly 85 0 /, the calculated amount of dextrorotatory lactone of 8β-oxy-2α-bromo-3β, 5β-oxido-1,2,3,4,4aα, 5,8,8aα-octahydronaphthalene-1β-carboxylic acid (III) mp = 152 ° C; [α] D20 = + 93 ° (c = 0.50 /, in ethanol). This new connection forms colorless crystals that are soluble in acetone and chloroform and very soluble in ether are sparingly soluble.

C11H11O3Br; Molecular Weight = 271.12.

Calculated ... C 48.73, H 4.09, 0 17.70, Br 29.480 / 0; found ... C 48.7, H 4.3, 0 17.8, Br 29.60 / 0.

D. Right-handed 18β-oxy-11,17α-dimethoxy-3-oxo-16β-carboxy-2,3-seco-20α-yohimbane (V) a) Right-handed lactone of 8,1-oxy-2o-methoxy-3ß, 5ß-oxido-1,2,3,4,4aα, 5,8,8aα-octahydronaphthalene-1ß-carboxylic acid 11 g of dextrorotatory lactone of 8β-oxy-2α-bromo-3β, 5β-oxido-1,2,3,4,4aα, 5,8,8aα-octahydronaphthalene-1β-carboxylic acid are triturated (III) with 25 cc of methanol, add 55 cc of methanol and then 19.9 cc to the mixture one Solution of 5 g of sodium in 100 cc of methanol allows the mixture Stand for 3 hours at 200 C and add 10 drops of glacial acetic acid. After evaporation to dryness in vacuo, the residue is taken up in 1000 ccm of ether and the resulting Solution filtered and concentrated to 50 cc. By cooling the solution with ice and suction of the precipitate one receives 8.38 g, corresponding to 920/0 of the calculated amount of clockwise rotation 8ß-Oxy-2α-methoxy-3ß, 5ß-oxido-1, 2,3,4,4aa, 5,8,8aa-octahydronaphthalene-1ß- lactone carboxylic acid of m.p. = 102 ° C; [α] 20 D = +48 # 3 ° (c = 0.5% in ethanol).

This not yet described compound forms colorless crystals, which are soluble in acetone and chloroform and very sparingly soluble in ether.

C12H14O4; Molecular Weight = 222.23.

Calculated ... C64.85, H6.35, O 28.80%; found ... C 64.8, H 6.5, 0 28.3010. b) Left-handed 1,8-lactone of 6α-bromo-7β, 8β-dioxy-2a-methoxy-3p, 5β-oxido-4aa, 8aa-decahydronaphthalene-1,1-carboxylic acid 8.38 g of dextrorotatory lactone of 8β-oxy-2α-methoxy-3β, 5β-oxido-1,2,3,4,4aα, 5,8,8aα-octahydronaphthalene-1,1-carboxylic acid in 75 cc of water, add 15 cc of 1N sulfuric acid and then 7.55 g to the mixture N-bromosuccinimide and heat the mixture to 50 ° C for 30 minutes. After cooling down, The precipitate is filtered off with suction and dried in vacuo to give 9.25 g, correspondingly 790 /, the calculated amount of levorotatory 1,8-lactone of 6α-bromo-7ß, 8ß-dioxy-2α-methoxy-3ß, 5, B-oxido -4aa, 8aa-decahydronaphthalene-1β-carboxylic acid, melting point = 203 ° C; [a] 2oo = -120 # 3 ° (c = 0.50 / 0 in ethanol), This new compound forms colorless crystals which are soluble in acetone and chloroform and very sparingly soluble in ether.

C12H15O5Br; Molecular Weight = 319.16.

Calculated ... C 45.16, H 4.74.0 25.06, Br 25.040 /,; found ... C 45.0, H 4.9, 0 25.0, Br 25.0%. c) Left-rotating lactone of 6a-bromo-8ß-oxy-2a-methoxy-3ß, 5ß-oxido-7-oxo-4aα, 8aα-decahydronaphthalene-1ß-carboxylic acid 8.48 g of levorotatory 1,8-lactone of 6α-bromo-7β, 8β-dioxy-2α-methoxy-3β, 5β-oxido-4aα, 8aα-decahydronaphthalene-1β-carboxylic acid are added in 25 cc acetic acid and add 31 to the mixture drop by drop while stirring ccm of a 11.3% solution of chromic acid in acetic acid, the temperature is kept between +5 and + 10 ° C during the reaction. The mixture is left Stand with occasional stirring for 3 hours at ordinary temperature, then add 12 cc of methanol are added, the mixture is stirred for 1 hour, 50 cc of water are added, and the mixture is extracted three times with chloroform and washes the combined chloroform extracts with water, which is then dried over magnesium sulfate and evaporated to dryness in vacuo. To Taking up the residue in ether, suctioning off and drying gives 6.2 g, correspondingly 74% of the calculated amount of levorotatory lactone of 6α-bromo-8ß-oxy-2α-methoxy-3ß, 5ß-oxido-7-oxo-4aα, 8aa - decahydronaphthalene -1,1-carboxylic acid, mp = 152 ° C; [α] D20 = -231 # 3 ° (c = 0.5% in ethanol). This compound, not yet described, forms colorless ones Crystals that are soluble in acetone and chloroform and insoluble in ether.

C12H13O5Br; Molecular Weight = 317.14.

Calculated ... C 45.44, H 4.13, 0 25.22, Br 25.20%; found ... C 45.9, H 4.2, 0 25.5, Br 24.80 / 0. d) Left-handed 3p-oxy-2a-methoxy-7-oxo-1,2,3,4,4aα, 7,8,8aα-octahydronaphthalene-1β-carboxylic acid 3.88 g of levorotatory lactone of 6α-bromo-8β-oxy-2α-methoxy-3β, 5β-oxido-7-oxo-4aα, 8aα-decahydronaphthalene-1β-carboxylic acid are dissolved in a mixture of 70 cc acetone and 8 cc acetic acid. After cooling to + 5 ° C 15.5 g of zinc powder are added to the solution. The mixture is stirred for a few minutes at + 15 ° C, filtered and evaporated to dryness in vacuo.

The residue is taken up in chloroform containing 200% ethanol, mixed with 8 ccm of water, acidified to pH = 1 with 7N sulfuric acid and extracted with chloroform containing 200/0 ethanol.

The combined chloroform extracts are dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is in a mixture of acetone and ether, mixing ratio 2: 3, added. After cooling the mixture with Ice, suction and drying of the precipitate at 80 ° C are obtained in one yield of 820 /, levorotatory 3ß-oxy-2α-methoxy-7-oxo-1,2,3,4,4aa, 7,8,8aa - octahydronaphthalene-lß-carboxylic acid of mp = 197 ° C; [α] D20 = -170 # 5 ° (c = 0.5% in ethanol). This new compound forms small prismatic colorless crystals, which are soluble in water, alcohol and acetone, sparingly soluble in ether and in chloroform are insoluble.

Cl2Hl605; Molecular weight = 240.25.

Calculated ... C 59.99, H 6.71,0 33,300 ;; found . C 60.2, H 6.7, 0 33.70 / 0 e) Left-rotating methyl ester of 3ß-oxy-2α-methoxy-7-oxo-1,2,3,4,4aα, 7,8,8aα-octahydronaphthalen1β-carboxylic acid 4.2 g of levorotatory 3,1-oxy-2α - methoxy - 7 - oxo - are dissolved in the heat 1,2,3,4,4aα, 7,8,8aα - octahydronaphthalene-1β-carboxylic acid in 160 ccm Dioxane, cools the mixture to 10 ° C and adds a solution of diazomethane in methylene chloride to a permanent yellow color. After standing for 5 minutes with ordinary Temperature, the solution is evaporated to dryness in vacuo. When adding 50 ccm of ether crystallizes the residue, and is obtained after suctioning off and drying of the precipitate in a yield of 950 /, the levorotatory methyl ester of 3,1-0xy-2amethoxy-7-oxo-1 2,3,4, 4aa, 7,8, 8aa-octahydronaphthalene-1β-carboxylic acid. This compound, which has not yet been described, forms small, colorless crystals that appear in Alcohol, acetone and chloroform are soluble and almost insoluble in ether; F. = 166 ° C; [α] 20 D = -170 # 5 ° (c = 0.5% in ethanol).

C13H18O5; Molecular Weight = 254.27.

Calculated ... C61.40, H7.14, O 31.46%; found . C 61.4, H 7.1, 0 31.70 /. f) Left-handed methyl ester of 3ß-acetoxy-2α-methoxy-7-oxo-1 2,3, 4,4aa, 7,8,8aa-octahydronapbthalene-1ß-carboxylic acid 3.2 g of levorotatory are added Methyl ester of 3β-oxy-2α-methoxy-7-oxo-1,2,3,4,4aα, 7,8,8aα-octahydronaphthalene-1β-carboxylic acid to 12 cc pyridine. 10 cc of acetic anhydride are added to the mixture and left over Stand overnight at ordinary temperature. Extracted after adding 20 cc of water one with chloroform, the chloroform extracts washed with 2N hydrochloric acid, aqueous Saline solution and sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness in vacuo a. The residue is taken up in ether, and isopropyl ether is added until it remains Turbidity and sucks the levorotatory methyl ester of 3ß-acetoxy-2a-methoxy-7-oxo-1 , 2,3,4,4aa, 7,8,8aa-octahydronaphthalene-1β-carboxylic acid with a melting point of 96 ° C; [a] 2D0 = -206 15 ° (c = 0.50 /, in ethanol). The yield is 900 / ,.

This new compound forms colorless crystals, which in alcohol, acetone and chloroform are soluble and sparingly soluble in ether.

C15H2006; Molecular weight = 296.31.

Calculated ... C 60.80, H 6.80,0 32,400 / ,; found ... C 60.7, H 6.8, 0. 32.60 /. g) Left-handed lβ-carboxymethyl-2β-methoxycarbonyl-3α-methoxy-4β-acetoxy-6β-formylcyclohexane 200 mg levorotatory methyl ester of 3ß-acetoxy-2a-methoxy-7-oxo-1 in one stage , 2,3,4,4aa, 7,8,8aa-octahydronaphtha lin-1ß-carboxylic acid in 5 cc of anhydrous Ethyl acetate dissolved. After cooling, the solution is ozonated at -30 ° C, by flowing a stream of about 1% ozone-containing oxygen with a Speed of 0.21 per minute passes through the solution. Then you remove the dissolved ozone as quickly as possible by passing nitrogen through the solution for 5 minutes directs. The solution is then allowed to come to the usual temperature and 2 cc of water are added to, stir for 6 minutes and extract the acidic mixture by stirring with a saturated aqueous sodium bicarbonate solution. Acid after separating the layers the aqueous layer is adjusted to a p-value = 1, saturated with sodium chloride, and extracted with methylene chloride and the extract, dried over magnesium sulfate, is evaporated Dry up. 128 mg are obtained, corresponding to a yield of 600% levorotatory Aldehyde. After digestion of the residue with a little ether, the melting point is 165 ° C; [α] 20 D = -27 # 2 ° (c = 0.5% in ethanol).

If the left-handed methyl ester is used instead of the left-handed methyl ester Methyl ester, then the corresponding dextrorotatory is obtained in the same yield Aldehyde; [α] D20 = + 26 ° (c = 0.5% in ethanol). h) methyl ester of the levorotatory 1fl-Carboxymethyl-2β-methoxycarbonyl-3α-methoxy-4β-acetoxy-6β-formylcyclohexane 450 mg of levorotatory β-carboxymethyl-2fl-methoxycarbonyl-3a are slurried - methoxy - 4fl - acetoxy-6ß-formylcyclohexane in 15 ccm of ether at 0 ° C, adds to the slurry a solution of diazomethane in methylene chloride until the remaining Yellow color, left to stand for 5 minutes at 0 ° C. and evaporated to dryness in a vacuum. The resulting colorless greasy residue is used immediately for the next reaction used. i) Condensation product from the methyl ester of levorotatory 1ß-carboxymethyl-2ß-methoxycarbonyl-3α-methoxy-4ß-acetoxy-6ß-formylcyclohexane and 6-methoxytryptamine The colorless greasy residue obtained is in 3 ccm Benzene was added and a lukewarm solution of 284 mg of 6-methoxytryptamine added to 18 cc of benzene. The mixture is 20 minutes at a temperature of Allowed to stand at 30 ° C. and then evaporated to dryness in vacuo. You get one colorless greasy residue that is used immediately for the next implementation will. j) Right-handed 18β-acetoxy-11,17α-dimethoxy-3-oxo-16β-methoxycarbonyl-2,3-seco-20α-yohimbane The colorless, greasy residue is dissolved in 47 cc of methanol. One adds to the Solution 1.25 g of sodium borohydride, heat the mixture to the boil for about 10 minutes under reflux, concentrated to 5 cc, added 1 cc of acetic acid, taken in chloroform on, washes the chloroform extracts with 2N hydrochloric acid, water, sodium carbonate and Finally with water, dry it over magnesium sulfate and evaporate in a vacuum Dry up. The residue is in a mixture of 4 cc of pyridine and 3 cc of acetic anhydride taken up, left to stand for 10 minutes at 40 ° C and evaporated to dryness in vacuo. After taking up the residue obtained in a mixture of ethyl acetate and ether in a mixing ratio of 2: 3, cooling with ice and sucking off the precipitate 1.2 g, corresponding to 60% of the calculated amount of dextrorotatory 18β-acetoxy-11,17α-dimethoxy-3-oxo-16β, are obtained - methoxycarbonyl -2,3 - seco - 20a - yohimban of F. = 162 and 184 ° C after temporary Solidification; [a] 2D0 = +31 +20 (c = 0.50 / 0 in ethanol). This not yet described Compound forms colorless, prismatic crystals in acetone and chloroform are soluble and almost insoluble in ether.

C25 H32 O 7N2; Molecular Weight = 472.52.

Calculated ... C 63.54, H 6.83,023.70, N 5.930 /,; found ... C 63.8, H 6.7, 0.23.6, N 6.00 / ,. k) Right-handed 18β-oxy-11,17α-dimethoxy-3-oxo-16β-carboxy-2,3-seco-20a-yohimbane (V) 4 g of dextrorotatory 18β-acetoxy-11,17α-dimethoxy-3-oxo-16β-methoxycarbonyl-2,3-seco-20α-yohimbane from F. = 184 ° C, [a] 2o0 = +310 (c = 0.5% in ethanol), are in a mixture of 84 ccm of anhydrous methanol, 24 ccm of water and 12 com 10 N sodium hydroxide solution dissolved.

The mixture is refluxed for 1 hour and acidified with 10 N hydrochloric acid to a p value = 1 and concentrated in vacuo to the beginning Turbidity a. After cooling with ice, the precipitate is filtered off with suction and washed with it Water and dry it. 3.11 g of compound V are obtained, corresponding to a yield from 890 / ,. This compound is recrystallized from aqueous methanol; M.p. = 150 ° C; [a] 2o0 = + 34 ° (c = 0.5 ° / 0 in ethanol), it is very sparingly soluble in water and soluble in alkalis and aqueous methanol.

C22H18 0.6N2; Molecular Weight = 416.46.

Calculated ... C 63.44, H 6.78.023.05, N 6.730 /,; found ... C 63.3, H 6.80, 0 23.4, N 6.80 /, This compound has not yet been described.

The levorotatory 18β-acetoxy-1 1,1 can be used in the same way 7a-dimethoxy-3-oxo-1 6fl-methoxycarbonyl-2,3-seco-20a-yohimban saponify and obtain then the compound V in levorotatory form, which corresponds to the attached equation can be converted into the optical isomer of natural reserpine. The described The method can also also apply to the racemic 18β-acetoxy-11,17α-dimethoxy-3-oxo-16β-methoxycarbonyl-2,3-seco-20α-yohimbane can be applied.

E. Left-handed lactone des 18β-oxy-11,17a-dimethoxy-3-oxo-16β-carboxy-2,3-seco-20α-yohimbane (VI) 3 g of dextrorotatory compound V for 2 hours in a vessel in which 30 cc of acetic anhydride, 30 cc acetic acid and 1.5 g lithium acetate located, heated. The mixture is allowed to cool, water is added and the mixture is left crystallize. After the crystals have been filtered off with suction, they are washed with water and dried. 1.57 g of lactone VI are obtained. The mother liquors are with methylene chloride extracted. The extract is washed with sodium hydroxide solution and water over magnesium sulfate dried and evaporated to dryness. After recrystallization from aqueous Acetone, 610 mg of the lactone VI are obtained, whereby the total yield is 760 mg. The lactone VI forms colorless crystals with a melting point of 175 ° C; [a] 2o0 = 830 (c = 0.250 /, in acetone), which are soluble in chloroform, acetone and ethyl acetate and in alcohol are sparingly soluble.

C22HS605N2; Molecular weight = 398.44.

Calculated ... C 66.31, H 6.58.0 20.08, N 7.030; found ... C 66.1, H 6.7, 0 19.7, N 6.8010.

This connection has not yet been described.

The same working method can also be applied to the left-handed connection Apply V and then get the dextrorotatory lactone VI with a temperature of 175 ° C; [a] 20 - +860 (c = 0.250 /, in ethanol), which according to the equation into the optical isomer of natural reserpine can be transferred.

The method is also applicable to the racemic compound V. It can also be done in the absence of acetic acid.

F. Reserpic acid lactone (VIII) 2.6 g levorotatory lactone VI, [a] 200 = -83 ", are reacted with 90 cc of phosphorus oxychloride for 2 hours under reflux. The excess phosphorus oxychloride is by evaporating the mixture to Dry away. The residue consisting of the quaternary base VII is in 180 cc of acetic acid was added and after the addition of 15 g of zinc powder and 10 cc of water heated to boiling under reflux. The mixture is heated for a further 40 minutes Boil them, cool them down, siphon off the zinc, which is washed with acetone, combine them Wash liquids with the acetic acid filtrate, evaporate to dryness, take the Residue in chloroform, the chloroform extract washes with water and then with Ammonia, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo a. After recrystallization from acetone, 1.32 g, corresponding to 520 /, are obtained the calculated amount of reserpic acid lactone that obtained from natural reserpine Connection corresponds.

If you start from the clockwise lactone VI and under the works under the same conditions, the optical isomer of reserp acid lactone is obtained. The quaternary base can also be reduced with an alkali borohydride, but then one obtains the isoreserpsäurelacton, which by treatment with pivalic acid (Trimethyl acetic acid) isomerized to reserp acid lactone in a manner known per se must become.

The reserp acid lactone is also converted into reserpine in a manner known per se.

Claims (1)

PATENT CLAIM: Process for the production of reserpine, characterized in that that the 5β-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1β-carboxylic acid with an optically active base, e.g. B. quinine, brucine, cinchonine or l-ephedrine, splits into its optical antipodes, the dextrorotatory 5ß-oxy-8-oxo-1,4,4aα, 5,8,8aα-hexahydronaphthalene-1ß-carboxylic acid (I) with sodium acetate and acetic anhydride in methylene chloride under refluxing Heating converts the resulting levorotatory lactone of 5ß-oxy-8-oxo-1,4,4aα, 5,8,8aα - Hexahydronaphthalene-1ß-carboxylic acid (II) is separated off and treated with aluminum isopropoxide in isopropanol to the levorotatory 1,8-lactone of 5ß, 8ß - dioxy - 1,4,4aα, 5,8,8aα - Reduced hexahydronaphthalene-carboxylic acid, this after separation with the calculated amount of an N-bromimide, e.g. B. N-bromosuccinimide, an N-bromamide, or N-bromohydantoin at ordinary temperature in a bromine inert Reacts solvent, the dextrorotatory lactone of 8ß-oxy-2α-bromo-3ß, 5ß-oxido-1,2,3,4,4aα, 5,8,8aα-octahydronaphthalene-1ß-carboxylic acid (III) separated by precipitation with water and after customary work-up and with sodium methylate in methanol into the dextrorotatory lactone of 8B-oxy-2a-methoxy-318, SB-oxido-1,2,3,4,4aa, 5,8,8aa - Octahydronaphthalene- 1ß - transferred carboxylic acid, this separated and with N-bromosuccinimide converts in dilute sulfuric acid, the resulting levorotatory 1, 8-lactone the 6a-bromo-7β, 8β-dioxy-2a-methoxy-3β, 5β-oxido -4aa, 8aα-decahydronaphthalene-1β-carboxylic acid separated and oxidized with chromic acid in acetic acid, the resulting levorotatory Lactone of 6a-bromo-8ß-oxy-2a-methoxy-3ß, 5ß-oxido-7-oxo-4aa, 8aa-decahydronaphthalene-1ß-carboxylic acid separated and with zinc powder in acetone and acetic acid in the levorotatory 3ß-oxy-2α-methoxy-7-oxo-1,2,3,4,4aα, 7,8, 8aα-octahydronaphthalene-1ß-carboxylic acid transferred, from which one with diazomethane first the levorotatory methyl ester is prepared in dioxane, which is then mixed with acetic anhydride acetylated in pyridine, this levorotatory methyl ester of 3ß-acetoxy-2α-methoxy-7-oxo-1,2,3,4,4aα, 7,8,8aα-octahydronaphthalene-1β-carboxylic acid in an organic solvent, e.g. B. ethyl acetate or methylene chloride, Treated with ozone at temperatures between 0 and -600C, the resulting ozonide (IV) either with water or iodic acid or periodic acid directly into the levorotatory 1ß-carboxymethyl-2ß-methoxycarbonyl-3a-methoxy-4-acetoxy-6ß-formylcyclohexane transferred, or that from the ozonide by treatment with zinc powder in the presence of Acetic acid obtained hydrate of 1ß- (2 ', 3'-dioxopropyl) -2ß-methoxycarbonyl-3α-methoxy-4ß-acetoxy-6ß-formylcyclohexane oxidized with chromic or periodic acid, the levorotatory 1ß-carboxymethyl-2ß - methoxycarbonyl - 3a - methoxy - - acetoxy-6ß-formylcyclohexane with diazomethane methylated in methylene chloride and ether, the ester obtained with 6-methoxytryptamine condensed, the condensation product with sodium borohydride and then with alcoholic sodium hydroxide to the clockwise 18ß-oxy-11,17a-dimethoxy-3-oxo-16B-carboxy-2, 3-seco-20a-yohimban (V) converts this with acetic anhydride in the presence of Acetic acid and lithium acetate converted into the corresponding levorotatory lactone (VI), this ring closes with phosphorus oxychloride in the heat, the lactone obtained des 18β-Oxy-11,17a-dimethoxy-16β-carboxy-3,4-dehydro-20α-yohimbans (VII) with Zinc powder in the presence of acetic acid directly to or with reserp acid lactone Alkali borohydride reduced to Isoreserpsäurelacton, this in itself known Way isomerized to reserp acid lactone, the lactone of reserp acid in itself converted into the reserp acid methyl ester in a known manner and this with 3,4,5-trimethoxybenzoyl chloride esterified to reserpine. Documents considered: German Patent No. 933 628; Journal of the American Chemical Society, Vol. 78, 1956, pp. 2021-2025 and 2657 Experientia, Vol. 12, 1956, pp. 249 and 250; H o u b e n - W e y l, Methods of Organic Chemistry, Vol. 7, Part 1, 1954, 4th edition, p. 336; P. Karrer, Textbook of Organic Chemistry, 12th edition, 1954, p. 616.