DE1543221C - Process for the preparation of tetracyclic compounds - Google Patents

Description

2. The method according to claim 1, characterized in that the process is carried out without isolation of the intermediate of the general formula IV.

3. Process according to Claims 1 and 2, characterized in that the compound of the general formula V methyl acetone dicarboxylate (N-tert-butyl) monoamide used.

4. Process according to claims 1 to 3, characterized in that the cleavage of the protective group —CXR ₆ via the associated imino ether or iminothio ether of the general formula VII

OH

CONHR,

(VII)

OH

wherein R ₃ , R ₄ , R ₆ and X have the meaning given and which can be substituted according to the general formula I, by treating a compound of the general formula VI with [(C ₂ Hs) ₃ O] -BF ₄ and subsequent hydrolysis or hydrogenolysis occurs.

with up to 5 carbon atoms, tetrahydropyranyl, benzyl or carbobenzoxy, R ₅ = alkyl with 1 to 6 carbon atoms, R ₆ = hydrogen, alkyl with 1 to 10 carbon atoms or a phenyl radical, which is optionally preferably replaced by lower alkyl , OH or intermediately protected OH, CH ₂ OH with optionally intermediately protected OH group, NO ₂ , halogen, NR ₁ R ₁₁ COOR ₃ XH ₂ COOr ₃ , phenylazo or phenylhydrazino can be mono- or disubstituted, but with at least one substituent in o-position, and X = O or S, and which can also be substituted in the 5-, 6a-, 6ß-, 7-, 8- and / or 9-position, as well as their acid addition salts, characterized in that one according to the general formula I optionally substituted aldehyde of the general formula II

R,

(I)

CONHR ₃

OH

where R ₁ = hydrogen or an alkyl, hydroxyalkyl or acyl group with up to IOC atoms, R ₂ = R ₁ , or, if R ₁ = H, also CXR ₆ , R ₃ = hydrogen or R ₅ , R ₄ = Hydrogen; Alkyl or acyl

CHO

wherein R _{4 has} the meaning given above, in the presence 'of an anhydrous, inert organic solvent and expediently in the presence of a dehydrating agent and a small or catalytic amount of an alkaline substance with an azlactone or thioazlactone of the general formula III.

(III)

in which R ₆ and X have the meaning given, condensed, the condensation product of the general formula IV thus obtained

N =

45

The invention relates to a process for the preparation of compounds having the tetracycline structure of the general formula I.

(IV)

OR ₄

wherein R ₄ , R ₆ and X have the meaning given and which is optionally substituted according to the general formula I, in the presence of an inert, anhydrous organic solvent and a basic condensing agent, advantageously with the exclusion of oxygen, with an acetone dicarboxylic acid ester monoamide of the general formula V

R.OOC

CONHR,

in which R ₃ and R _{5 have} the meaning given, and that, if appropriate, in the so obtained

ten compounds of the general formula VI

CXR ₆
NH

OH

CONHR,

(VI)

OR ₄ OH

in which R ₃ , R ₄ , R ₆ and X have the meaning given and which are optionally substituted according to the general formula I, in a manner known per se

a) the radical R ₃ ζ. B. by heating with hydrochloric, hydrobromic, sulfuric, phosphoric, an aryl or alkyl sulfonic acid in an inert organic solvent or simply by adding an acid in the absence of a solvent in hydrogen and / or

b) the OR ₄ radical is converted into a hydroxyl group and / or by the action of acids or ansolvo acids hydrolytically or by hydrogenation in the presence of a noble metal catalyst and a suitable solvent

c) if necessary in the 7-, 8- and / or 9-position Halogen by hydrogenation, especially in the presence of a palladium-carbon catalyst, eliminated and / or

d) the protective group CXR ₆ is split off hydrolytically or hydrogenolytically by treatment with acids or after conversion into an iminoether or iminothioether group,

e) optionally one or both hydrogen atoms of the amino group formed on C atom 4 replaced by alkyl, hydroxyalkyl and / or acyl radicals with 1 to IOC atoms,

f) the sulfur obtained from thioamides of the general formula VI, optionally with the aid removed from Raney-Nickel and

g) if appropriate, convert the compounds thus obtained into their acid addition salts in a customary manner convicted.

With the help of this current process it is possible for the first time to establish connections with the tetracycline skeleton to be synthesized on a larger scale from readily available starting materials. Such a reaction in a "one-step process" rings A and B with the for antibiotic effectiveness necessary substituents on the carbon atoms 2 and 4 have not yet been established known. A particularly great advantage of the new process is that the key reaction provides the desired products in high yield. The method according to the invention opens thus completely new ways of producing tetracyclic compounds.

Process for the preparation of compounds with the tetracycline skeleton are so far, for. B. in Journal of the American Chemical Society, Vol. 82, 1960, p. 1250, and in German Patent 11 29 480 has been described. However, it is not possible.

by these known processes to produce those compounds which have an amino group on the carbon atom and have the carboxamide group on C atom 2.

The method described in Journal of the American Chemical Society Vol. 84, 1962, p. 3222 fühn also to tetracyclic compounds, but the path to building up rings A and B des Tetracycline molecule through a large number of intermediate stages, as a result of which a considerable loss in yield occurs. In contrast, the process according to the invention, starting from an aldehyde, provides the Formula II, if desired in a single reaction stage, the rings A and B with the required Substituents on the carbon atoms 2 and 4 in high yield and in a smooth reaction with gentle Conditions.

In a very particularly preferred embodiment, the process according to the invention is carried out without isolating the intermediate of the general formula IV. The whole process of making the tetracyclic compounds of the general formulas VI and I can thus be used as a "one-pot process" be carried out, in a unique manner from easily accessible, simple starting materials the tetracyclic compounds arise. It is sufficient if one contains the condensation product of the general formula IV Reaction solution, the acetone dicarboxylic acid derivative of the general formula V and the basic condensing agent admits. The desired tetracyclic product is formed even at room temperature of the general formula VI in high yield. If necessary, also directly afterwards - Without isolation of the tetracyclic compound of the general formula VI - those described above Follow-up reactions are carried out.

In Angewandte Chemie, Vol. 74, p. 825 (1962) a process has already been described, according to which Compounds with the tetracycline structure, but without a caroxamide group on C-atom 2, are made can be. An aldehyde corresponding to the general formula II was ketalized with Oxo group condensed with a thioazlactone falling under the formula III. The product obtained in the process When reacted with dimethyl acetone dicarboxylate, it provided a compound with a still open Ring B. The compound could not be cyclized until the oxo group had been de-ketalized. Fully unpredictable and in contrast to the known implementation with acetodicarboxylic acid diester was continued found that the process according to the present invention only works in the desired manner and It goes well if, contrary to all previous experience, instead of the ketalized, the free oxo compound is used of the aldehyde of the general formula II is used. The implementation with the azlactone resp. Thioazlactone of the general formula III can also be combined with a ketalized compound of the general formula Formula II can be carried out, but this must be carried out at the latest before the reaction with the acetone dicarboxylic acid ester monoamide be released.

The implementation of a-tetralone-3-acetaldehyde with the azlactones or thioazlactones are carried out in inert, anhydrous organic solvents, e.g. Am Ethers or cyclic ethers, such as tetrahydrofuran or dioxane or in aromatic hydrocarbons, such as benzene, toluene or xylene or other solvents such as chloroform, methylene chloride,

Acetonitrile, nitrobenzene, ethyl acetate, dimethylformamide, dimethyl sulfoxide or mixtures of these solvents. If the compounds used in the reaction do not themselves contain basic groups, it is expedient to add small or even only catalytic amounts of an alkaline substance to the reaction mixture. For this come z. B. lead compounds such as lead acetate or lead tetraacetate, or organic bases, especially tertiary amines, e.g. B. triethylamine, pyridine, collidine or lutidine into consideration. The reaction is generally carried out at temperatures between 10 ^° C. and the boiling point of the solvent used, but usually at room temperature. The reaction time is between a few minutes and a few hours and is usually over after 1 to 2 hours.

Expediently, a dehydrating agent is also added during the condensation. Therefor There are primarily acetic anhydride or dicyclohexylcarbodiimide or inorganic compounds, like sodium or magnesium sulfate, in) question. It is not necessary to directly use the azlactone or to use thioazlactone of the general formula III in the reaction. Rather, initially just as well the corresponding open-chain compounds of the general formula III a

HN-H ₂ C

-CR.
X

(INa)

COOH

in which R ₆ and X have the meaning given, are used, which cyclize under the reaction conditions to give the corresponding azlactones or thioazlactones. Assuming an open-chain compound of the general formula IHa, 2 mol of dicyclohexylcarbodiimide should preferably be added to the reaction mixture. The dicyclohexylcarbodiimide can optionally make the addition of an alkaline condensing agent superfluous. The condensation products obtained by reacting the α-tetralone acetaldehydes with the azlactones or thioazlactones are then reacted in the presence of basic condensing agents with an acetone dicarboxylic acid ester monoamide which may be monosubstituted on the nitrogen atom. The acetone dicarboxylic acid derivative can be added to the reaction mixture either in solid or in dissolved form. This reaction is also carried out in the presence of an inert anhydrous, organic solvent, for which z. B. cyclic ethers such as tetrahydrofuran, dioxane or aromatic hydrocarbons such as benzene, toluene, xylene or anisole, hydroquinone dimethyl ether, dimethylformamide, dimethyl sulfoxide or solvent mixtures are suitable, for. B. tetrahydrofuran / ether in various mixing ratios, preferably z. B. tetrahydrofuran / diethyl ether in a ratio of 1: 1. Sodium amide, potassium amide or sodium hydride, for example, can be used as basic condensing agents. As the reaction temperature is advantageously chosen temperatures from 20 to 160 ⁰ C, preferably the reflux temperature of the solvent used or of the solvent mixture, preferably but temperatures between 25 and 45 "C.

The reaction time depends on the reaction temperature and varies between a few minutes and several hours, on average between 5 and 50 hours. It is a very special advantage of the procedure according to the invention that this reaction can surprisingly be carried out under such mild conditions is. Cyclizations at room temperature or only slightly above temperatures are in the Tetracycline series not yet known at all.

This unusual key reaction, which involves at least three different reactions (Michael addition of the acetone dicarboxylic acid ester monoamide, ring closure to ring B and ring closure to ring A. with simultaneous opening of the azlactone ring), surprisingly takes place in excellent Yield, namely over 80% of theory. The course of the reaction was not as smooth and favorable to be expected, especially since the preservation of the ketal grouping has always been considered necessary, about the possibility of fragmentation by retro-Michael reaction under the influence of basic Exclude reaction media that are used both for the aldehyde of the general formula II and for the There is condensation product of the general formula IV. After eliminating the side chain is natural a construction of the tetracyclic ring system is no longer possible.

The double ring closure in the presence of alkaline condensation agents according to the invention The method is also surprising insofar as normally compounds of type VI under suffer ring cleavage under the influence of bases (cf., for example, Journal American Chemical Society, Vol. 75, p. 5455 [1953], and vol. 76, p. 3573 [1954]).

After the reaction has ended, the reaction mixture is worked up in a manner customary per se. It is expedient to acidify to remove the alkaline constituents and to wash the solution then several times with water. After the concentration, the connection with the Isolate the tetracycline framework (e.g. VI) directly by crystallization. If so desired, however, it can also be separated by chromatography from any by-products formed. That on this Wise pre-purified tetracyclic product is also a possible desired without crystallization further processing pure enough. It can be used in amorphous form.

The two crystal forms that form during crystallization come from the two at C atom 4 epimeric compounds, which are converted in a manner known per se into the compounds with the natural configuration can be transferred (see. Angewandte Chemie, Vol. 74, p. 944 [1962], and South African Patent 63/4791). A separation into the epimers does not normally have to be carried out.

The compounds of general formula VI obtained by the process of the invention are to capable of multiple implementations and offer numerous possibilities, depending on the general ones used and in particular also the processes known in the field of tetracyclic compounds, to produce a large number of other valuable tetracyclic compounds.

So z. B. by treatment with hydrolyzing agents, an N-substituted carboxamide group on C atom 2 is converted into the CONH _{2 group}

609 609/15

will. The reaction works particularly well when R _{3 is} a bulky alkyl radical, in particular a tert-butyl radical. The hydrolysis is carried out e.g. B. carried out so that the substance to be hydrolyzed is either heated in an inert solvent, preferably in glacial acetic acid, with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or an aryl or alkyl sulfonic acid or that the substance is heated directly without using a special solvent with an acid , e.g. B. sulfuric acid, added. In each case, the reaction mixture is then mixed with water and the reaction product with an organic solvent, for. B. acetoacetate, n-butanol, chloroform, methylene chloride or benzene extracted and isolated from these solvents after concentration.

It was obvious that the hydrolysis of the N-substituted carboxamide group on carbon atom 2 would take place simultaneously Hydrolysis of the amide function on C atom 4 to be expected because usually amides, as they are of the type Amide function on the carbon atom 4 of the tetracycline structure correspond to, under the influence of strong acids in the corresponding amines and carboxylic acids are split. It was therefore surprising to find connections those in the 4-position represent the NH — CX — phenyl group can be treated with strong acids without significantly impairing them Group takes place.

If R ₆ denotes an alkyl radical or a phenyl radical substituted at least in the o-position, this substituent on the phenyl nucleus to facilitate hydrolysis through a "neighboring group effect", the amide function on carbon atom 4 can be hydrolyzed to an amino group by the action of acids. The hydrolysis can be carried out in accordance with the processes described above for the cleavage of the N-substituted carboxamide group at C atom 2. In many cases, however, the hydrolysis is successful even under very weakly acidic conditions (e.g. at a pH of around 6). Dilute aqueous acetic acid and a water-miscible solvent such as alcohols, dioxane or tetrahydrofuran are preferably used as the hydrolysis agent. However, hydrolysis under such mild conditions is only possible if the »neighboring group effect« described above can come into play.

The conversion of the OR ₄ substituent on the carbon atom 10 (if R _{4 is} not H) into an OH group takes place in a manner known per se by hydrolytic or hydrogenolytic means. In principle, all processes known for such reactions can be used here. The acyl and alkyl groups and the tetrahydropyranyl radical can be easily split off, for example, by the action of acids or Ansolvo acids, such as HBr, HJ and BF ₃ , in the presence of an organic solvent, preferably glacial acetic acid. In many cases it is advantageous to heat the reaction mixture up to approximately the boiling point of the solvent used. It is then diluted with water. The reaction products are washed with a suitable organic solvent, e.g. B. ethyl acetate, benzene, chloroform, methylene chloride, n-butanol and extracted from the organic phase after evaporation of the solvent in the usual way. To cleave the tetrahydropyranyl ethers, of course, dilute aqueous mineral acids, preferably sulfuric acid or hydrochloric acid, also sulfonic acids or mono-, di- and oxycarboxylic acids, eg. B. acetic acid, oxalic acid, tartaric acid, citric acid, malonic acid or succinic acid can be used.

If R _{4 is} a benzyl or carbobenzoxy group, this radical can be removed particularly easily by hydrogenolysis. Here, too, the usual reaction conditions are used, e.g. B. hydrogenation in the presence of a noble metal catalyst in a suitable solvent, e.g. B. in alcohol. In the same way as a hydrogenolytically removable radical R ₄ , a halogen atom (preferably chlorine) present in the 7-, 8- and / or 9-position can also be eliminated. Here, too, the reaction takes place in an organic solvent, preferably in alcohols and in the presence of a hydrogenation catalyst, preferably a palladium-carbon catalyst.

The conversion of the group NHCXR ₆ on C atom 4 of the tetracyclic compounds of the general formula VI into the corresponding free amine via the associated imino ether succeeds best. This can best be produced with the help of oxonium salts (Meerwein reagent). From a practical point of view, it is most convenient to use an oxonium salt represented by the formula [(C ₂ H ₅ ) ₃ O] - BF _4. Appropriately, the procedure is so that one on the solution of a starting compound of the general formula VI in a solvent, for. B. tetrahydrofuran, dioxane, methylene chloride or chloroform, which allows the oxonium salt to act. After a few hours, the solution is worked up in such a way that the solution is diluted with methylene chloride and washed with an amount of KHCO ₃ (aqueous solution) equivalent to the oxonium salt to remove the excess oxonium salt and to set the hydrofluoric acid formed by hydrolysis in the presence of water.

In this way, the imino ethers or iminothio ethers of the general formula VII are formed

OH

CONHR,

(VII)

OR ₄ OH

in which R ₃ , R ₄ , R ₆ and X have the meaning given and which, according to the formula I, can also be substituted in the 5-, 6-, 7-, 8- and / or 9-position.

It is surprising that the production of the imino ethers or the iminothio ethers with the aid of the oxonium salts in this case proceeds so smoothly and without enol ether formation, especially since it is known that oxonium salts are generally used advantageously for the preparation of enol ethers. In addition, is It is surprising that the amide function on C atom 4 can be selectively converted into the imine ether,

11 12

while the amide function on C atom 2 has been completely absorbed. The for this

ten stays. catalytic reduction solvents used

The subsequent acidic cleavage of the imino ether should be inert under the reaction conditions,

or Iminothioäthers takes place under the action of B. primarily solvents

Acids such as HBr, HJ, BF ₃ or also HCl, H ₂ SO ₄ , 5 such as water, lower alcohols such as methanol or

Phosphoric acid, aryl or alkyl sulfonic acids, ethanol, lower alkoxy-substituted alkanols such as

but best when exposed to dilute acids, 2-methoxy-ethanol or 2-ethoxy-ethanol as well

advantageously dilute aqueous acetic acid and pre-tetrahydrofuran, dioxane or dimethylformamide in

preferably in water-miscible solvents, question.

such as higher alcohols or dioxane and tetra-ι ο As chemical reducing agents for the reductive hydrofuran, and at reaction temperatures between alkylation in the presence of a carbonyl compound about O ⁰ C and the boiling point of the used can, for example, sodium borohydride or metals in solvent, but normally with space mineral acids , e.g. zinc, tin or iron at salt temperature. The reaction time depends on the acid used. If necessary, the reaction temperature used can also be other metals such as copper / zinc, tin / mercury, preferably between a few minutes and 20 hours. Aluminum amalgam or magnesium amalgam. This results in being used in a smooth reaction. Formic acid is also suitable as reducing fertilizers of the general formula I, in which R ₁ and R _{2 are} medium. In general, the Reduk will mean hydrogen. If R ₆ denotes a phenyl radical with zinc / hydrochloric acid and formic acid or a substituted phenyl radical, 20 can be preferred. If aqueous and hydrogenolytic splitting of the imino systems are used for the reductive alkylation, it is often advantageous to use water ether or the iminothioether. In addition, to use miscible organic solvents,

i, \ can be derived from that corresponding to formula VI, especially if the starting material is limited

'Thioamide (X = S) the sulfur is soluble in the reaction mixture with the help of Raney. Come for this

Remove nickel in a manner known per se. The 25 primarily dimethylformamide, dimethoxyethane,

the benzyl residue formed on the nitrogen atom as a result, in the case of methanol, ethanol, dioxane and tetrahydrofuran

which the phenyl nucleus may be optionally substituted.

can (according to the definition of R ₆ ) can then If an acid addition salt is included in the reaction, it can also be split off hydrogenolytically. The is or at the same time a chlorine atom from the hydrogenolysis is carried out in the usual way, for example by 30 7-, 8- 'and / or 9-position is to be eliminated, treatment with hydrogen in the presence of noble works is expedient in the presence of an inorganic metal catalyst, preferably PtO ₂ or pallanic or organic base. The reaction takes place with carbon. expediently in alcoholic solution using the amino group thus obtained can then preparation of z. B. palladium-charcoal and a Uber after all the usual methods, after which one on 35 shot of the aldehyde instead. As a base, an amino nitrogen atom is often hydrogen atoms, tertiary amine, for example triethylamine, can be substituted by alkyl, hydroxyalkyl or acylde, which are expediently added in two equivalents with up to 10 carbon atoms. will. Another, very advantageous alkylation-acylation is carried out, for. B. The simplest method is to convert the amine with ants Direct conversion of the primary amine with the ent-acid and formaldehyde with heating,
Speaking acid chlorides or acid anhydrides, It is of course possible and in many cases even preferably in a basic reaction medium. very advantageous if, if desired, two or more of the contingency measures described can be introduced

_N groups can e.g. B. through implementation with the ent- combined with each other.

'; Talking halides or by reaction with 45. For example, the hydrolytic aldehyde described above in the presence of hydrogen or splitting off of the radical R _{3 can be carried out} very well with a free formic acid or with an alkylating agent or the hydroxyl group is formed from the radical OR ₄ am combine by reaction with an alcohol in the presence of carbon atoms 10. Can be carried out under suitable reaction of Raney nickel. Conditions are advantageous and, if desired, the known reductive alkylation, or even the hydrolysis of the 4-iminoethers or thioethers corresponding to the formula VI with chemical or catalytic reduction, can also be carried out in the same way in many cases. The catalytic reduction can be carried out in a timely manner. In many cases it is tion can in a solvent in the presence of an expedient, as an acidic agent HBr, HJ or BF ₃ carbonyl compound and a metal catalyst and as a solvent z. B. glacial acetic acid to be used, and hydrogen at normal or elevated pressure. It is often advisable to set the reaction temperature. In general, the reductive alkylation is increased, optionally up to the boiling point at hydrogen pressures of about 1 to 5 atm solvent used,
leads. Although slightly elevated temperatures can further promote catalytic hydrogenation, the compounds of the general formula VI are generally at temperatures between 0 and 50 ⁰ C, generally 60 hydrolytic cleavage of a radical R ₃ , one even at room temperature, preferred. The metal catalyst radical R ₄ , if this is alkyl or acyl, sator can, for. B. be nickel or copper chromium oxide. as well as the group CXR ₆ take place at the same time. However, it is also possible to use noble metals such as finely divided hydrolysis conditions corresponding to those mentioned above for platinum, palladium or rhodium. given.

Preferably, the noble metal catalysts 65 can also be, for. B. the cleavage of the group R ₃

on a carrier such as barium sulfate, aluminum oxide, with the alkylation of the 4-amino group,

Coal or kieselguhr applied. The hydrogenation provided this alkylation under suitable conditions

is canceled as soon as the desired water level, e. B. by reaction with formic acid / form

aldehyde is carried out at elevated temperatures, such as by refluxing.

If, on the other hand, the substitution of this amino group z. B. by the hydrogenating end described above Alkylation, a halogen atom in the 7-, 8- and / or 9-position can be hydrogenated off at the same time.

Of course, in all of these reactions carried out under hydrogenating conditions, any benzyl or carbobenzoxy group present on the oxygen at carbon atom 10 can also be split off in a manner known per se at the same time. As a result, any halogen atom that may be present can of course also be eliminated together with the cleavage of such a benzyl or carbobenzoxy group from the 10-position. In addition, an imino ether or iminothioether can be subjected to hydrogenolysis at the same time, provided that R _{6 is} a phenyl or substituted phenyl group. This also gives the free amine of general formula I. In addition, the sulfur can be removed from the thioamide PC = S) corresponding to general formula VI with the aid of Raney nickel, and the benzyl radical formed can then also be split off by hydrogenolysis. In principle, all hydrogenolytically removable groups present in the molecule can be split off together by a hydrogenation reaction. When formaldehyde is added to such a reaction solution, methylation of the amino group on carbon atom 4 can also take place at the same time under these hydrogenating conditions. Such an alkylation is particularly gentle.

The compounds obtained by the process of the invention, provided they have a basic nitrogen atom contain, are converted into acid addition salts in a manner known per se. Come for this both organic and inorganic acids in question, e.g. B. aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic or sulfonic acids, such as formic acid, Acetic acid, propionic acid, diethyl acetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, Fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, benzoic acid, salicylic acid, Phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, cinnamic acid or hydrohalic acids, such as hydrochloric acid, sulfuric acid and phosphoric acid. These acid addition salts possess generally better solubility than the corresponding bases.

The a-tetralone-3-acetaldehyde to be used as starting material are easily accessible, e.g. B. from the optionally substituted 2-bromomethyl-4-hydroxy-benzenes or the corresponding 4-alkoxy or 4-acyloxy derivatives. The possibly in the tetracyclic end products at the carbon atoms 7, 8 and / or 9 desired substituents must be in These starting materials can be present in positions 1, 2 and / or 3, which correspond here. One The desired hydroxyl group in the 5-position of the tetracyclic compound must be used as the starting material provided aldehyde be arranged in α-position to the aldehyde function.

The 2-bromomethyl compounds can be z. B. condense with dimethylcarbomethoxysuccinate in the presence of sodium methylate. The condensation product obtained in this way can be used without further purification, e.g. B. with sodium hydroxide, saponified to the corresponding tricarboxylic acid and then, for. B. by heating to about 160 ⁰ C, to be decarboxylated to the corresponding dicarboxylic acid. The following cyclization with polyphosphoric acid, known per se, gives the corresponding 1-oxo-3-carboxy-1,2,3,4-tetrahydronaphthalene. This can be converted into the aldehydes of the general formula II in accordance with the processes given in Chemischeberichte, Vol. 95, p. 2901, 1962.

Particularly suitable starting materials of the general formula II are, for. B. the following connections: 8-hydroxy, 8-methoxy or 8-ethoxy-1-oxo-tetrahydronaphthyl- (3) -acetaldehyde or the Acyl derivatives such as the acetyl, propionyl or butyryl derivatives of 8-hydroxy-1-oxo-tetrahydronaphthyl- (3) -acetaldehyde as well as the 5-halogen derivatives, in particular the 5-chloro derivatives and / or the 4-methyl derivatives, for example 4 - methyl - 5 - chloro-8 - hydroxy - 1 - oxo - tetrahydronaphthyl - (3) - acetaldehyde. The corresponding 8-benzyloxy derivatives and the 8-tetrahydropyranyl ethers are also important the 1 - oxo - tetrahydronaphthyl - (3) - acetaldehyde. The 6-hydroxy, 6-methoxy or 6-ethoxy derivatives, especially 6-methoxy-8-methoxy-1-oxo-tetrahydronaphthyI- (3) -acetaldehyde; continue the 5-nitro derivatives or the corresponding 5-amino or the N-mono- or N-disubstituted amino derivatives, e.g. B. 5-Nitro-8 - methoxy - 1 - oxo - tetrahydronaphthyl - (3) - acetaldehyde, 5 - dimethylamino - 8 - acetoxy -1 - oxo - tetrahydronaphthyl - (3) - acetaldehyde, 5 - N - acetylamino-8 - benzyloxy -1 - oxo - tetrahydronaphthyl - (3) - acetaldehyde; also 4-hydroxy-4-methyl-8-hydroxy-1 - oxo - tetrahydronaphthyl - (3) - (α - hydroxy) - acetaldehyde and its derivatives with protected OH groups, where the OH groups (apart from the 8-position OH group) also together as a ketal, preferably as acetonide, can be protected.

For the preparation of those substituted in the 5- and / or 6-position Tetracyclic compounds of the general formula I or VI are used as starting materials best aldehydes, as they are according to the chemical reports, vol. 95, p. 2581 (1962), Chemische Reports, Vol. 95, p. 2901 (1962) and Angewandte Chemie, Vol. 74, p. 825 (1962) are accessible.

Also 4-ethylmercaptomethyl-8-methoxy-1-oxotetrahydronaphthyl - (3) - acetaldehyde, 4 - benzylmercaptomethyl - 8 - benzyloxy - 1 - oxo - tetrahydronaphthyl - (3) - acetaldehyde, 4 - benzoyl mercaptomethyl - 8 - acetoxy -1 - oxo - tetrahydronaphthyl - (3) acetaldehyde and the derivatives of these compounds substituted in the phenyl nucleus of the C-4 side chain can be used as starting materials of the general formula II.

The azlactones or thioazlactones can both as such (formula III) and in the form of the associated open-chain compounds (formula III a) are used. In addition to the aliphatic acylaminoacetic acids, such as formyl, acetyl, propionyl and butyrylaminoacetic acid, and the higher homologues with up to 11 carbon atoms in the acyl chain and the corresponding acylaminothioacetic acid derivatives In particular, there are hippuric acid and benzoylaminoacetic acids and benzoylaminothioacetic acids substituted in the phenyl nucleus in question. With regard to the further implementation of the connections of the general

Common formula VI, in which the nitrogen atom with the radical CXR ₆ is on the C atom 4, to compounds of the general formula I in which there is an NRjR ₂ group on the C atom 4, it is particularly advantageous if R _{6 has} a represents phenyl radical substituted in the o-position. Substitutions in the o-position of the phenyl nucleus are particularly favorable because they support the acidic hydrolysis of the amide function on C atom 4 through the »neighboring group effect« and thus allow milder conditions for the cleavage of this group into the carboxylic acid and the amine. The influence of halogen substituents in the phenyl nucleus is mainly of importance in this connection when the halogen atom occurs in addition to another o-position substituent.

Of the numerous possible azlactones, thioazlactones or the corresponding compounds capable of azlactone formation, in addition to hippuric acid and benzoylaminothioacetic acid for benzoylaminoacetic or thioacetic acids mono- or disubstituted in the phenyl nucleus, for example, the following possibilities for R ₆ are mentioned: 2-nitrophenyl , 2-hydroxyphenyl, 2-ethoxyphenyl, 2,4-dicarbethoxyphenyl, 2-aminophenyl, 2-N-acetylaminophenyl, 2-dimethyl- or 2-diethylaminophenyl-2-methyl-6-hydroxyphenyl, 2 - (phenylhydrazino) -phenyl , 2 - (phenylazo) - phenyl, 2 - hydroxymethyl or 22-hydroxyethylphenyl and the corresponding derivatives of these compounds with a protected hydroxyl group, e.g. B. in the form of methoxy, ethoxy, benzyl, carbobenzoxy or o-tetrahydropyranyl.

The compounds of general formula V are acetone dicarboxylic acid ester monoamides that are in the carboxamide group can also be substituted. The following may be mentioned in particular in this connection: methyl acetone dicarboxylate - N - tert. - butyl - monoamide, acetone dicarboxylic acid ethyl ester - N - tert. - butyl - monoamide, Acetondicarboxylic acid methyl ester-N-tert.-amylmonoamide, Ethyl acetone dicarboxylate - N - tert.-amyl - monoamide, isopropyl acetone dicarboxylate - N - tert. - butyl - monoamide, acetone dicarboxylic acid - tert. - butyl ester - N - tert. - butyl - monoamide, i \ Acetondicarboxylic acid isopropyl ester - N - η - hexylmonoamide, Acetondicarboxylic acid methyl ester-N-ethylmonoamide, acetone-dicarboxylic acid methyl ester - N-methyl - monoamide, acetone dicarboxylic acid methyl ester-N - propyl - monoamide, acetone dicarboxylic acid methyl ester - N - η - butyl - monoamide, ethyl acetone dicarboxylate - N - methyl monoamide, ethyl acetone dicarboxylate - N - ethyl - monoamide, acetone dicarboxylic acid ethyl ester - N - (n or i) - propyl - monoamide, Ethyl acetone dicarboxylate - N - η - butylmonoamide ^ methyl cetone dicarboxylate N-n-hexyl - monoamide, acetone dicarboxylic acid ethyl ester-N-n-hexyl-monoamide.

The process according to the invention opens up a completely new possibility of building up the tetracyclic system with the particularly valuable substituents —NR ₁ R ₂ in the 4-position and —CONHR ₃ in the 2-position. The new synthesis is generally applicable. Since the aldehydes of the general formula II are readily accessible, numerous tetracyclic compounds which are additionally substituted in the positions 5a, 5β, 6a, 6β, 7, 8 and / or 9 can also be prepared by the new process. A whole series of such substituted tetracyclines are known from the literature, for which a particularly advantageous new synthetic route is available through the present process.

The tetracyclic compounds of the general formulas VI or I can, for. B. be substituted in the 5-position by an OH group. As substituents (in u- and / or / Ϊ-position) for the carbon atom 6, in addition to hydrogen, in particular: OH, CH ₃ , CH ₂ or CH ₂ SR ₉ , in which R _{9 is} H, alkyl with up to 12 C atoms or COR ₁₀ , R ₁₀ alkyl with up to 3 C atoms, phenyl, mono- or disubstituted phenyl, benzoyl, trifluoromethyl or CH ₂ R ₁₁ , R ₁₁ mono- or disubstituted lower alkyl, carboxy, lower carbalkoxy, halogen , Phenyl or mono- and disubstituted phenyl, where possible substituents for the lower alkyl are OH, lower alkoxy, carboxy, lower carbalkoxy, halogen and amino and suitable substituents for the mono- or disubstituted phenyl radical are lower alkyl, hydroxy, lower alkoxy, Are carboxy, lower carbalkoxy, nitro and -NR ₁ R ₂ .

If there are hydroxyl groups in the 5- and 6-positions, both can also be present together as a ketal, in particular as an acetonide.
Compounds in which the substituent on the carbon atom 6 is -CH ₂ SR ₉ are, for. B. in the USA patent • 31 65 531 has been described.

In addition to hydrogen, carbon atoms 7, 8 and / or 9 can preferably have the following substituents: halogen, in particular chlorine, nitro, hydroxy, lower alkoxy or the radical —NR ₁ R ₁ , preferably the amino group or an amino group substituted by lower alkyl .

The tetracyclic compounds obtained by the process of the invention are valuable new products, some of which have antibiotic activity themselves and some of which are valuable intermediates for the preparation of further tetracyclic compounds.
The values for the UV absorption given in the following examples are measured in 0.1 M methanolic Na ₂ H ₄ O ₇ solution after equilibration for 2 hours.

example 1

a) 9.0 g of 5-chloro-8-methoxy -1-oxo-tetrahydronaphthyl- (3) -acetaldehyde are in 200 ml tetra

■ dissolved hydrofuran. 6.3 g of hippuric acid, 6.9 g of lead acetate and 11 ml of acetic anhydride are added and the mixture is refluxed for 2.5 hours. The cooled solution is mixed with chloroform and the organic phase is washed three times with water. After drying over sodium sulfate, the solvent is completely distilled off under reduced pressure. An oily residue remains, which is dissolved in a little benzene. When ether is added, the condensation product (formula IV, in which R ₄ = CH ₃ , X = O, R ₆ = phenyl and a chlorine substituent is present in the p-position to the methoxy group) begins to crystallize. It is stored in the refrigerator overnight and then filtered off with suction from the crystals. This is washed with benzene / ether and finally with pure ether and dried. Yield: 6.9 g (49% of theory). After the mother liquor has been purified by chromatography, a further 2.3 g of condensation product are obtained, so that the total yield

609 609/15

9.2 g (65.3% of theory) increased. Mp. 155 to 158 ^° C. (benzene / ether).

Analysis door C ₂₂ H ₁₈ O ₄ NCI:

Calculated ... C 66.75, H 4.58, N 3.54, Cl 8.96%; found .... C 66.72, H 4.71, N 3.48, Cl 8.95%.

; " _Mx = 222 (33 300), 242 (15 600), 255 (10 300) and 299 (26 100) τημ in CH ₃ CN.

b) To a suspension of 6.0 g of the condensation product of the formula IV obtained according to Example 1 a) in 90 ml of tetrahydrofuran is added 3.5 g of methyl acetone dicarboxylate - N - tert. - butyl monoamide and 780 mg of an approximately 50% sodium hydride in oil. The oil is advantageously removed with the aid of a solvent which dissolves the oil by slurrying the sodium hydride dispersion. The condensation product goes into solution within one minute. Then 50 ml of ether are added to the mixture and the clear, very pale yellowish solution is stirred for 30 minutes at room temperature. A further 740 mg of sodium hydride in oil are then added and the solution is refluxed for 2 days. 3 ml of glacial acetic acid are added to the cooled solution, the dark brown reaction mixture immediately lightening and showing a deep fluorescence. The solution is diluted with chloroform, the organic phase is washed three times with water and dried over sodium sulfate and the solvent is completely distilled off under reduced pressure. A solid, yellow, foamy residue of a tetracyclic compound of the formula VI, in which R ₃ = tert-butyl, R ₄ = CH ₃ , X = O, R ₆ = phenyl, which is also in the 7-position, remains in quantitative yield Chlorine is substituted.

Determination of the total yield

To purify the reaction product and to determine the total yield, 1.1 g of des foamy product was added in a little of a mixture of chloroform / acetone (500: 1) and the Solution adsorbed on silica gel. When eluting with the above mixed solvent, two migrated yellow-brown zones through the column. The eluate from these zones was completely evaporated under reduced pressure.

1st zone: Yield 252 mg (23.0% of theory)

The yellow, foamy residue was dissolved in acetone, filtered and the tetracyclic compound was precipitated with ether / petroleum ether. The substance was washed with ether / petroleum ether and dried. F. 177 to 19O ⁰ C.

2nd zone: yield 641 mg (58.5% of theory)

A middle fraction was removed from the second zone and the solvent was completely distilled off. The residue was dissolved in acetone and petroleum ether was added until the substance began to precipitate. It was stored in the refrigerator overnight and then the solvent was suctioned off from the precipitated microcrystallizate. F. 179 to 205 ⁰ C.

The connections between the two zones are the two tetracyclic compounds epimeric on the carbon atom 4 assign.

Analysis for C ₃₁ H ₃₁ 0 ₇ N ₂ Cl (579.06):

Calculated ... C 64.30, H 5.39, N 4.84, CI 6.12%; found .... C 64.21, H 5.45, N 4.72, Cl 6.17%

(M.p. 177 to 190 ° C); found .... C 64.33, H 5.45, N 4.80, CI 6.23%

(F. 179 to 205 ⁰ C).

This gives a total yield of 892 mg (81.5% of theory) after the chromatography the tetracyclic compound of the general formula VI.

The mixture of amorphous substances can, if desired, be caused to crystallize by dissolving it in acetone and adding ether / petroleum ether. The crystalline product (F. 193 to 245 ⁰ C, with decomposition) consists of two different crystal forms: almost colorless, very fine needles and yellow-orange colored plates.

Analysis for C ₃₁ H ₃₁ 0 ₇ N ₂ CI (579.06):

Calculated ... C 64.30, H 5.39, N 4.84, Cl 6.12%; found .... C 64.30, H 5.46, N 4.73, Cl 6.18%.

). _max 220 (30 800), 303 (9300), 463 (47 500) and 487 (38 500) πΐμ.

c) 500 mg of the tetracyclic compound obtained according to Example 1 b) are dissolved in 20 ml of concentrated sulfuric acid, and the mixture is left to stand for 1.5 hours at room temperature. The solution is then poured onto ice, diluted with water and extracted three times with ethyl acetate. The combined extracts are washed neutral with water, dried over sodium sulfate, and the solvent is completely distilled off. The product of the general formula VI crystallizes from acetone / ether, in which R ₃ = H, R ₄ = CH ₃ , X = O and R ₆ = benzyl and a chlorine atom is present in the 7-position (yield: 290 mg (74.2 % of theory).

After concentrating the mother liquor, a second crystalline fraction of 54 mg can be obtained, so that the total yield is 344 mg (76.3% of theory). F. 192 to 210 ⁰ C (with decomposition).

Analysis for C ₂₇ H ₂₃ O ₇ N ₂ Cl (522.96): Calculated:

C 62.01, H 4.43, N 5.36, Cl 6.78, OCH ₃ 5.93%; found:

C 61.90, H 4.58, N 5.21, Cl 6.78, OCH ₃ 6.16%.

?. _mttX 487 (34 800), 463 (45 300) and 220 (29 300) πΐμ.

d) A solution of 500 mg of the tetracyclic compound obtained according to Example 1 b) in 20 ml of glacial acetic acid 15 ml of hydrobromic acid (48%) are added and the mixture is left on for 70 minutes Steam bath heated. The cooled solution is then treated with chloroform and the organic phase washed neutral with water. The solvent of the organic dried over sodium sulfate Phase is completely distilled off under reduced pressure. A brown residue remains, which is in Acetone is dissolved and begins to crystallize when the solution is concentrated. Yield: 80 mg.

The crystallizate consists of two different crystal forms: light yellow fine needles and brown tabular crystals. F. 195 to 251 ⁰ C (with decomposition).

After chromatography of the mother liquor on silica gel with chloroform as the solvent

A further 135 mg of the tetracyclic compound of the general formula VI can be obtained from acetone / ether, in which R ₃ and R ₄ = H, X = O and R ₆ = phenyl and a chlorine atom is present in the 7-position. F. 243 to 247 ° C (with decomposition).

A total of 215 mg of the tetracyclic compound was thus isolated.

_{e) 3.8 g of oxonium salt [(C 2} H ₅ ) ₃ O] - BF _{4 are} added to a suspension of 5.8 g of the tetracyclic compound obtained according to Example 1 b) in 80 ml of methylene chloride, and within a short time a clear Solution emerges. It is stirred for 10 hours under nitrogen at room temperature, the solution is then diluted with 150 ml of methylene chloride, the organic phase is washed twice with a solution of 1 g of potassium bicarbonate in 100 ml of water and then twice with pure water. The solution, dried over sodium sulfate, is completely freed from the solvent by evaporation under reduced pressure. The imino ether of the general formula VII, in which R ₃ = tert-butyl, R ₄ = CH ₃ , X = O and R ₆ = phenyl, and a chlorine atom is present in the 7-position, is obtained without further purification used in the hydrolysis. For this purpose, the residue is dissolved in 150 ml of dioxane, and 60 ml of a 5% strength aqueous acetic acid solution are added. The mixture is stirred for 15 hours at room temperature and the solvent mixture is completely distilled off under reduced pressure. The residue is taken up in tetrahydrofuran and slowly crystallized with ether. The amine thus obtained (formula I, in which R ₁ and R ₂ = H, R ₃ = tert-butyl, R ₄ = CH ₃ ) and a chlorine atom is present in the 7-position, crystallizes with 0.5 mol of B (OH ) ₃ and melts at 185 to 206 ° C (decomp.).

}. _max 240 (12 500), 272 (10 800), 300 (11200), 464 (44 800), 490 (34 900) Γημ.

f) 700 mg of the tetracyclic compound obtained according to Example 1 e) are dissolved in 20 ml of glacial acetic acid, 15 ml of hydrobromic acid (about 48%) are added and heated to 100 ° C on the steam bath for 100 minutes. The solution is then diluted with 120 ml of ice water, washed three times with chloroform, which aqueous phase nitrated and then completely freed from water by evaporation under reduced pressure.

A solid residue remains, which is crystallized as a hydrobromide from methanol / ether. The compound of formula I wherein R _1, R _2, R ₃ and R ₄ = H and in the 7-position is a chlorine atom is present, melts above 255 ⁰ C (dec.).

λ, _ηαχ 272 (8600), 287 (7500), 471 (47 000), 497 (34 100) ηΐμ.

g) 400 mg of hydrobromide of the tetracyclic compound obtained according to Example 1 f) are dissolved in 50 ml of methanol, 2 ml of formaldehyde, 220 mg of triethylamine and 400 mg of palladium-carbon catalyst (about 5%) are added and hydrogenated at room temperature and normal pressure until no more hydrogen is absorbed. Then the catalyst is sucked off, this several times with it. Washed methanol, and the combined solvent fractions dried over sodium sulfate and the solvent are distilled off under reduced pressure totally ⁶ S. The residue is taken up in dimethyl sulfoxide and crystallized by slowly adding acetone. The compound of the general formula I, in which R ₁ and R ₂ = CH ₃ , R ₃ and R ₄ = H, melts at 216 to 223 ° C. (decomp.).

/. “,312(6100),470(46800),496(36400) ΐημ.

h) 500 mg of the compound obtained according to Example 1 e) are converted into the associated amine analogously to Example 1 c) (general formula; R ₁ , R ₂ , R ₃ = H, R ₄ = CH ₃ , in the 7-position Cl) . The compound melts with decomposition above 260 ^° C.

i) 200 mg of the compound isolated according to Example 1 d) are dissolved in 100 ml of methanol with the aid of a palladium-carbon catalyst and triethylamine hydrogenated until hydrogen is no longer absorbed. Then it will be the catalyst is filtered off, the methanolic solution acidified with HCl and concentrated. From methanol / Ether crystallizes the corresponding 7-Deschlor compound. Yield: 123 mg. M.p. 201 to 209 ° C.

j) Analogously to Example 1 i), the product from Example 1 f) is converted into the 7-Deschlor compound. F. 270 ⁰ C.

Example 2

a) 9.0 g of 5-chloro-8-methoxy-1-oxo-tetrahydronaphthyl- (3) -acetaldehyde are dissolved in 200 ml of tetrahydrofuran. After adding 4.06 g of N-acetylglycine, 14.0 g of dicyclohexylcarbodiimide and 0.2 ml of triethylamine, the mixture is stirred for 3 hours at room temperature. Then 150 ml of absolute ether, 7.53 g of acetone dicarboxylic acid methyl ester-N-tert-butyl-monoamide and 3.28 g of sodium hydride dispersion in oil (about 50%) are added to the solution and the mixture is added for 20 hours under nitrogen and under Refluxed. 6 ml of glacial acetic acid are then added to the cooled solution, the dark brown reaction product immediately lightening and showing a deep fluorescence. The solution is diluted with chloroform and worked up as indicated in Example 1. After purification by chromatography, the tetracyclic compound of the general formula VI is obtained, in which R ₃ = tert-butyl, R ₄ = CH ₃ , X = O and R ₆ = CH ₃ . The UV spectra of this compound agree with those of the compound obtained according to Example 1 b).

b) To a solution of 200 mg of the tetracyclic compound obtained according to Example 2 a) in 15 ml of glacial acetic acid, 12 ml of hydrobromic acid (48%) are added, and the mixture is heated on the steam bath for 100 minutes. 100 ml of ice water are then added to the solution and the aqueous phase is washed three times with chloroform. The aqueous solution is filtered and the solvent is completely distilled off under reduced pressure. The solid residue is taken up in methanol and ether is slowly added, the tetracyclic compound (formula I, R ₁ , R ₂ , R ₃ , R ₄ = H, and a chlorine atom in the 7-position) beginning to crystallize as the hydrobromide . F. with decomposition above 255 ° C. The compound is completely identical in all its data to the compound obtained according to Example 1 f).

Example 3

a) 9 g of 5-chloro-3-benzyloxy-1-oxo-tetrahydronaphthyl- (3) -acetaldehyde are converted analogously to Example 1 a) to the condensation product IV, in which R ₄ = benzyl, X = oxygen, R ₆ = phenyl and a chlorine atom is present in the 7-position.

b) To a suspension of 7.1 g of the condensation product IV obtained according to Example 3 a) in a solvent mixture consisting of 100 ml of tetrahydrofuran and 50 ml of absolute ether, 3.5 g of methyl acetone dicarboxylate N-tert-butyl monoamide and 1 52 g of sodium hydride dispersion in oil (about 50%) are added, the condensation product going completely into solution at the beginning of the sodium hydride addition. The clear solution is then refluxed under nitrogen for 24 hours. Then 3 ml of glacial acetic acid are added to the cooled solution and the reaction product is worked up as described under Example 1 b). After chromatographic purification on silica gel, the tetracyclic compound of the general formula VI is obtained in 80.3% yield, in which R ₃ = tert-butyl, R ₄ = benzyl, X = O and R ₆ = phenyl and in 7- Position a chlorine atom is present. The UV spectra of this compound between 220 and 550 m μ are in agreement with those of the compound obtained according to Example 1 b).

c) 500 ml of the tetracyclic compound obtained according to Example 3 b) are dissolved in 10 ml of concentrated sulfuric acid, and the mixture is left to stand for 1 hour at room temperature. The solution is then poured onto ice, diluted with water and extracted three times with ethyl acetate. The combined extracts are washed neutral with water, dried over sodium sulfate and the solvent is completely distilled off under reduced pressure. From acetone / ether, 302 mg of the tetracyclic compound of the general formula I are obtained, in which R ₁ = H, R ₂ = benzoyl, R ₃ = H, R ₄ = benzyl and a chlorine atom is present in the 7-position.

_{d) 400 mg of oxonium salt [(C 2} H _S ) ₃ O] - BF _{4 are} added to a suspension of 500 mg of the tetracyclic compound obtained according to Example 3 c) in 10 ml of absolute methylene chloride, a clear solution being formed within a short time. It is stirred for 10 hours under nitrogen at room temperature and then worked up as described under Example Ie). The imino ether obtained in this way (general formula VII, R ₃ = H, R ₄ = benzyl, X = O, R ₆ = phenyl) is used in the catalytic hydrogenation without further purification. To do this, the residue is dissolved in 15 ml of methanol, 200 mg of triethylamine and 500 mg of palladium-carbon catalyst are added and the mixture is hydrogenated at room temperature and 5 atmospheres until no more hydrogen is absorbed. The catalyst is then filtered off with suction, washed several times with methanol and the solvent is concentrated under reduced pressure. The reaction product (general formula I, R ₁ , R ₂ , R ₃ and R ₄ = H, and a chlorine atom is present in the 7-position) is crystallized as the hydrobromide from methanol / ether. F. with decomposition above 255''C. The UV absorption spectrum is completely identical to that of the compound obtained according to Example 1 f).

Example 4

a) A solution of 5.3 g of 5-chloro-8-methoxy-1-oxotetrahydronaphthyI- (3) -acetaldehyde in 30 ml of benzene gives 3.3 g of thioazlactone (general formula III, where X = S and R ₆ = phenyl ), 0.01 ml of triethylamine and 1 g of magnesium sulfate were added. The mixture is stirred for 2 hours at room temperature, the magnesium sulfate is then separated off, this is washed well with benzene and the solvent is completely distilled off under reduced pressure. What remains is an oily crude product that crystallizes from benzene / ether / petroleum ether.

In this way, 4.84 g (56%) of the condensation product of the general formula IV are obtained, in which R ₄ = CH ₃ , X = S and R ₆ = phenyl and a chlorine atom is present in the 5-position.

b) To a suspension of 3.1 g of the condensation product of the general formula IV obtained according to Example 4a) in 50 ml of tetrahydrofuran are added 1.75 g of methyl acetone dicarboxylate N-tert-butyl monoamide and 390 mg of an approximately 50% sodium hydride in oil , the condensation product going into solution. Then 25 ml of absolute ether and a further 370 mg of sodium hydride are added and the solution is refluxed for 20 hours. The reaction mixture is then worked up as described under Example 1 b). Yield: 3.58 g (80% of theory) of the tetracyclic compound of the general formula VI, in which R ₃ = tert-butyl, R ₄ = CH ₃ , X = S and R ₆ = phenyl, which are also in the 7-position is substituted by chlorine. The UV absorption maxima are identical to those of the compound obtained according to Example 1 b).

c) The following reactions of the tetracyclic compound of the general formula VI obtained according to Example 4 b) to the imino ether, hydrolysis of the imino ether and the subsequent hydrolysis of the groups R ₃ and R ₄ are carried out in such a way that the respective reaction product can be transferred to the next without further purification Stage is used.

To a suspension of 2.9 g of the tetracyclic compound obtained according to Example 4 b) in 50 ml of methylene chloride is added 2.0 g of oxonium salt of the formula [(C ₂ H ₅ J ₃ O] - BF ₄ , which within a short time a clear The mixture is stirred for 15 hours under nitrogen at room temperature and the reaction mixture is worked up as described under Example 1 c). The imino ether of the general formula VII thus obtained, in which R ₃ = tert-butyl, R ₄ = CH ₃ , X = S and R ₆ = phenyl and a chlorine atom is present in the 7-position, is hydrolysed without further purification used.

To do this, the residue is dissolved in 100 ml of dioxane and 30 ml of a 5% aqueous acetic acid solution offset. The mixture is stirred for 15 hours at room temperature and the solvent mixture completely distilled off under reduced pressure.

The amine of the general formula I obtained in this way, in which R ₁ and R ₂ = H, R ₃ = tert-butyl and R ₄ = CH ₃ and a chlorine atom is present in the 7-position, is used in the next without further treatment Reaction used.

To do this, the tetracyclic compound is dissolved in 60 ml of glacial acetic acid, 45 ml of hydrobromic acid (about 48%) are added to the solution and the mixture is heated to 100 ° C. on the steam bath for 100 minutes. The cooled solution is then diluted with water, three times with chloroform washed, the aqueous phase filtered and the water completely distilled off under reduced pressure. A residue remains which is crystallized from methanol / ether as the hydrobromide. The tetracyclic compound of the general formula I in which R ₁ , R ₂ , R ₃ and R ₄ = H and a chlorine atom is present in the 7-position. melts with decomposition above 255 ° C.

The compound is identical in all of its data to the compound obtained according to Example 10. ■

d) 500 mg of the reaction product from Example 4 b) are converted analogously to Example 1 c) in sulfuric acid into the corresponding tetracyclic compound which contains _{a CONH 2 group at C atom 2.} F. 198 to 203 ⁰ C,

Eg pi eI '5
a) A solution of 3.0 g of an aldehyde of the formula

H ₃ C, CH ₃

CHO

HO O

H, C CH

Phenyl

HO O

IO

20th

1.6 g of azlactone of the general formula III, in which X = O and R ₆ = phenyl, and 0.01 ml of triethylamine in 20 ml of absolute benzene are stirred for 3 hours at room temperature in the presence of 1 g of magnesium sulfate. The magnesium sulfate is then filtered off, this is washed with benzene and the solvent is completely distilled off under reduced pressure. After chromatographic purification on silica gel, 1.83 g (41% of theory) of the condensation product of the general formula IV, in which R ₄ = H, X = O, R ₆ = phenyl, one methyl and one in the 4-position, could be isolated Hydroxy and in α-position to the double bond a hydroxyl group is present and both hydroxyl groups are present as acetonide. Formula: ■

40

45

b) To a suspension of 1.1 g of the condensation product obtained according to Example 5 a) in 20 ml absolute tetrahydrofuran, 530 mg of methyl acetone dicarboxylate - N - tert. - butyl monoamide and 244 mg NaH dispersion in oil (about 50%). Then add 10 ml of absolute ether and reflux the solution under nitrogen for 20 hours. Then you work the cooled solution as described under Example 1 b). - -. te

After purification by chromatography, the tetracyclic compound of the general formula VI is obtained, in which R ₃ = tert-butyl, R ₄ = H, X = O, and R ₆ = phenyl, a hydroxyl in the 3-position and a 6-position one hydroxy and one methyl group is present, and both hydroxy groups are present as acetonide. The compound has the characteristic absorption maximum at 470 ητίμ.

Example 1 6

a) 4.35 g of 6,8-dimethoxy-1-oxo-tetrahydronaphthyl- (3) -acetaldehyde are dissolved in 100 ml of tetrahydrofuran. 3.15 g of hippuric acid, 3.45 g of lead acetate and 5.5 ml of acetic anhydride are added and the mixture is refluxed for 2.5 hours. The cooled solution is worked up as described under Example 1 a). In this way it was possible to isolate a total of 3.91 g (57% of theory) of the condensation product of the general formula IV in which R ₄ = CH ₃ , X = O, R ₆ = phenyl and a methoxy group is present in the 6-position.

b) 1.7 g of methyl acetone dicarboxylate N-tert-butyl monoamide, 760 mg of sodium hydride in oil (about 50% strength) are added to a suspension of 2.98 g of the condensation product of the general formula IV obtained according to Example 6a) in 50 ml of tetrahydrofuran ) and 20 ml of absolute ether and boil the mixture for 30 hours under nitrogen and under reflux. The reaction mixture is then worked up analogously to Example 1 b). In this way, the tetracyclic compound of the general formula VI is obtained, in which R ₃ = tert-butyl, R ₄ = CH ₃ , X = O, R ₆ = phenyl and a methoxy group is present in the 8-position.

The UV absorption spectra are in good agreement with those obtained according to Example 1 b) tetracyclic compound.

c) The product obtained according to Example 6 b) is converted into 4-desdimethylamino-6-desmethyl-6,12a-dideoxy-4-benzamido-8-hydroxytetracycline by heating for 6 hours in HBr / glacial acetic acid, F. 243 to 247 ⁰ C.

Example 7

a) Analogously to Example 1 a), the condensation product of the general formula IV is prepared from 5,8-dimethoxyl-oxotetrahydronaphthyl- (3) -acetaldehyde (melting point 93 to 94 ° C.) and hippuric acid, in which R ₄ = CH ₃ , X = O, R ₆ = phenyl and a methoxy group is present in the 5-position. Crystallization from ethyl acetate gives the compound in 42% yield with a temperature of 142 to 143 ° C.

_{b) Analogously to Example 1 b), a tetracyclic compound of the general formula VI in which R 3} = H, R ₄ = CH ₃ , X = O and R is obtained from the product of the general formula IV from Example 7 a) by reaction with acetone dicarboxylic acid methyl ester monoamide ₆ = phenyl and which is substituted in the 7-position by a methoxy group. The two isomers are obtained: 4 / f-epimers: mp 238 to 240 ° C., 4a-epimers: mp 245 to 247 ° C.

The 4β-epimer can be converted to the α-isomer in 80% yield by standing in pyridine.

Examples

a) A condensation product obtained analogously to Example 1 a), which additionally has a methyl group in the 4-position, is converted analogously to Example 1 b) into the corresponding tetracyclic product of the general formula VI, in which R ₃ = tert-butyl, R ₄ = CH ₃ , X = O, Rf, = phenyl and which also contains a methyl group in the 6-position and a chlorine atom in the 7-position. F. 212 to 221 C.

609 609/15

b) 300 mg of the product obtained according to Example 8 a) are dissolved in 20 ml of methanol and in the presence a Pd-carbon catalyst and triethylamine Hydrogenated until no more hydrogen is absorbed. The solvent becomes completely distilled off, the residue taken up in chloroform, the solution washed with water and dried and narrowed. The product obtained (without the Cl substituent in the 7-position) crystallizes from acetone / ether. Yield: 210 mg. 167-173 ° G. ·

c) 200 mg of the reaction product from Example 8 b) are converted into the corresponding tetracyclic as in Example 1 e) Amin transferred. Yield: 91 mg. F.> 300 ° C (decomposition).

: ■ d) The ether cleavage of the compound obtained according to example 8c) takes place analogously to example if). One gets hurt t the corresponding compound with a 10-position OH group of melting point 328-357 ⁰ C. (decomposition) ..., ·. ■■ '.. ·

Example 9

a) The condensation product used in Example 8 a) is reacted analogously to Example 1 b) with acetone dicarboxylic acid methyl ester monoamide. After epimerization in pyridine there is obtained 4-dedimethylamino-6,10,12a - trideoxy - 4 - benzamido - 7 - chloro -10 - methoxy-tetracycline with F. 242-245 ⁰ C.

b) The tetracyclic product obtained according to Example 9 a) is an ether cleavage analogous to Example 1 0 subject. The corresponding product is obtained with an OH group in the 10-position, mp 238 to 240 ° C.

c) By splitting off the protective group with the help of an oxonium salt analogously to Example 1 e), the product from Example 9 b) gives 4-desdimethylamino-6,12 a-bis-deoxy-4-amino-7-chlorotetracycline, mp 301 to 306 ⁰ C.

^; Example 10

Analogously to Example 4a), 4-methyl-5-chloro-8-methoxy-1-oxo-tetrahydronaphthyl- (3) -acetaldehyde is reacted with the thioazlactone (general formula III; X = S, R ₆ = phenyl). The product obtained in this way is converted into 4-desdimethylamino-6,10,12a-trideoxy-4-thiobenzamido-7-chloro-10-methoxy-tetracycline by reaction with acetone-dicarboxylic acid methyl ester monoamide analogously to Example 4 b). F. 208 to 214 "C.

Example 11

, a) Analogously to Example 4a), S-chloro-o-nitro-S-methoxy is used - 1 - oxotetrahydronaphthyl - 3 - acetaldehyde reacted with thiohippuric acid. The product is obtained of the general formula IV- with a temperature of 131 to 134 ° C in a yield of 48%. .

b) Analogously to Example 4b), the product from Example! 11 a) with acetone dicarboxylic acid monomethyl ester amide implemented. 4-Desdimethylamino-6-desmethyl-6,10,12a-trideoxy-4-thiobenzamido-7-chloro-8-nitro-10-methoxytetracycline is obtained from a temperature of 218 to 228 C in a yield of 66%.

Example 12

Analogously to Example 4a), 5-chloro-6,8-dimethoxy-1-oxotetrahydronaphthyl- (3) -acetaldehyde is reacted with the thioazlactone (general formula III; X = S and R ₆ = phenyl) and this condensation product is obtained analogously Example 4 b) with acetone dicarboxylic acid methyl ester monoamide in a yield of 48% 4-desdimethylamino-6,10,12a-trideoxy-6-desmethyl-7-chloro-4-thiobenzamido-8,10-dimethoxy-tetracycline with a melting point of 173 to 181 ⁰ C.

Example 13

a) As in Example 4a), 6,8-dimethoxy-1-oxotetrahydronaphthyl- (3) -acetaldehyde is reacted with thioazlactone (general formula III, X = S, R ₆ = phenyl). The condensation product is obtained in a yield of 55%. M.p. 147 to 148 ° C. .

b) The product obtained according to Example 13 a) is analogously to Example 4b) with methyl acetone dicarboxylate (N-tert-butyl) monoamide to give 4-desdimethylamino - 6,10,12 a - trideoxy - 2 - descarboxamido - 6-desmethyl - 2 - N -1. - butylcarboxamido - 4 - thiobenzamido-8,10-dimethoxytetracycline implemented. M.p. 185 to 193 ° C, yield 65%.

c) The product obtained according to Example 13 b) is converted into the associated amine (4-thio-

25. benzamido - ■ »4-amino) transferred. F. 263 to 265 ° C.

d) The product obtained according to Example 13 c) analogous to Example 1 f) subjected to an ether cleavage. 4-Desdimethylamino-6,12a-dideoxyo-desmethyM-amino-S-hydroxytetracycline is obtained. M.p. 249-253 ° C.

Example 14

a) Analogously to Example 1 a), the condensation product of the general formula IV is prepared from 5-chloro-S-methoxy-1-oxotetrahydronaphthyl-3-acetaldehyde and 2'-acetamidohippuric acid, in which R ₄ = CH ₃ , X = O ₁ R ₆ = 2-acetamidophenyl. Yield: 51%. M.p. 159 to 162 ° C.

b) The product obtained according to Example 14a) is reacted analogously to Example 1b) with acetone dicarboxylic acid methyl ester monoamide. This gives 4-desdimethylamino-6-desmethyl-6,10,12a-trideoxy-4 - (T -acetamidobenzamido) -7-chloro-10-methoxytetracycline. F. 203 to 207 ⁰ C.

Example 15

a) Analogously to Example 1 a), the condensation product of the general formula IV is prepared from 5-chloro-S-methoxy-1-oxotetrahydronaphthyl-3-acetaldehyde and 2'-nitro-4'-methoxy-hippuric acid, in which R ₄ = CH ₃ , X = O and R ₆ = 2-nitro-4-methoxyphenyl. Yield: 64%. M.p. 165 to 167 ° C.
b) The product obtained according to Example 15a) is reacted analogously to Example 1b) with acetone dicarboxylic acid methyl ester monoamide. In this reaction 4 - desdimethylamino - 6 - desmethyl - 6,10,12a - trideoxy - 4 - (2 '- nitro - 4' - methoxybenzamido) - 7 - chlorlO-methoxy-tetracycline in a yield of 78% with an F. obtained from 198 to 205 ^° C.

Example 6

a) Analogously to Example 1 a) is obtained from 5-chloro-8-methoxy-1 - oxotetrahydronaphthyl - 3 - acetaldehyde and the tetrahydropyranyl ether of 2 '- hydroxymethylhippuric acid the condensation product of the general

27 28

NEN formula IV prepared, wherein R ₄ = CH ₃ , X = O ester monoamide reacted. The result of the reaction

and R ₆ = 2 - (tetrahydropyranyloxymethyl) - phenyl tating 4 - desdimethylamino - 6 - desmethyl-

means. Yield: 48%. 147 to 151 ° C. 6,10,12a - trideoxy - 4 - [2 - (tetrahydropyranyloxy-

b) The product obtained according to Example 16a) is methyl) - phenyl - benzamido] - 7-chloro-10-methoxy-

analogous to example 1 b) with acetone dicarboxylic acid methyl 5 tetracycline has a temperature of 187 to 193 ° C.

Claims (1)

Patent claims: 1. Process for the preparation of compounds having the tetracycline structure of the general formula I. R, product of the general formula IV OH CONHR ₃ (D OR ₄ . OH CHO (H) wherein R _{4 has} the meaning given above, in the presence of an anhydrous, inert organic solvent and expediently in the presence of a dehydrating agent and a small or catalytic amount of an alkaline substance with an azlactone or thioazlactone of the general formula III IO WOHnR ₁ = hydrogen or an alkyl, hydroxyalkyl or acyl group with up to IOC atoms, R ₂ = R ₁ , or, if R ₁ = H, also CXR ₆ , R ₃ = hydrogen _{or R 5} , R ₄ = hydrogen, alkyl or acyl with up to 5 carbon atoms, tetrahydropyranyl, benzyl or carbobenzoxy, R ₅ = alkyl with 1 to 6 carbon atoms, R ₆ = hydrogen, alkyl with 1 to 10 carbon atoms or a phenyl radical, which is optionally preferably through Lower alkyl, OH or intermediately protected OH, CH ₂ OH with optionally intermediately protected OH group, NO ₂ , halogen, NR ₁ R ₁ , COOR ₃ , CH ₂ COOR ₃ , phenylazo or phenylhydrazino can be mono- or disubstituted, however at least one substituent is in the o-position, and X = O or S, and which can also be substituted in the 5-, 6a-, 6β-, 7-, 8- and / or 9-position, as well as their acid addition salts, characterized in that one according to the general formula I optionally substituted aldehyde of the general formula II 45 55 60 (HI) wherein R ₆ and X have the meaning given, condenses the condensation thus obtained (IV) wherein R ₄ , R ₆ and X have the meaning given and which is optionally substituted according to the general formula I, in the presence of an inert, anhydrous organic solvent and a basic condensing agent, advantageously with the exclusion of oxygen, with an acetone dicarboxylic acid ester monoamide of the general formula V R, O OC CONHR, (V) in which R ₃ and R _{5 have} the meaning given, reacted and that, if appropriate, in the compounds of the general formula VI thus obtained OH CONHR ₃ (VI) OH in which R ₃ , R ₄ , R ₆ and X have the meaning given and which are optionally substituted according to the general formula I, in a manner known per se a) the radical R ₃ z. B. by heating with hydrochloric, hydrobromic, sulfuric, phosphoric, an aryl or alkylsulfonic acid in an inert organic solvent or simply by adding an acid in the absence of a solvent to hydrogen and / or b) the OR ₄ radical is converted into a hydroxyl group and / or by the action of acids or ansolvo acids hydrolytically or by hydrogenation in the presence of a noble metal catalyst and a suitable solvent c) any halogen present in the 7-, 8- and / or 9-position by hydrogenation, especially in the presence of a palladium-carbon catalyst, eliminated and / or d) the protective group CXR ₆ is split off hydrolytically or drugolytically by treatment with acids or after conversion into an iminoether or iminothioether group, e) optionally one or both hydrogen atoms of the hydrogen atoms formed on carbon atom4 Amino group through alkyl, hydroxyalkyl and / or acyl radicals with 1 to IOC atoms replaced, 0 from thioamides of the general formula VI obtained, optionally with the sulfur Removed the help of Raney Nickel and g) if appropriate, convert the compounds thus obtained into their acid addition salts in a customary manner convicted.