CS200465B2 - Process for preparing 6-deoxotetracycline - Google Patents

Description

The present invention relates to a novel process for the preparation of 6-deoxytetracycline by hydrogenation of the 6-methylenetetracycline exocyclic methylene group. In particular, it relates to the hydrogenation of 6-methylenetetracycline, its 11α-halogeno derivative or a salt of any of the above compounds with acids by contacting the compound with hydrogen and a rhodium complex compound with ligands that form donor acceptor bonds, such as tertiary phosphines, in a solvent in which the complex is soluble.

Reaction of 6-demethyl-6-deoxy-6-methylenetetracyclines, 11α-halogen-6-demethyl-6-deoxy-6-methylenetetracyclines, their acid salts and complexes with polyvalent metal salts of hydrogen in the presence of heterogeneous noble metal catalysts to form the corresponding epimeric alpha and beta-6-deoxytetracyclines are described in U.S. Patent 3,200,140. The use of poisoned noble metal catalysts to achieve the same reaction but to increase the beta-6-deoxytetracycline alpha ratio is described in U.S. Patent 3,444,198 U.S. Patent 2,984,668 discloses the use of catalytic reduction with hydrogen and a noble metal catalyst only for 11α-dehalogenation of 11α-halogen-6-demethyl-6-deoxy-6-methylenetetracyclines. In addition, the reduction of 11α-halo-6-demethyl-6-deoxy-6-methylenetetracyclines, their salts and complexes in the presence of noble metal catalysts and hydrazine as a hydrogen source is described in German patent S. 2,131,944. British patent, g. 1 296,340 discloses the use of Raney nickel and Raney cobalt as catalysts for this reduction.

Rhodium halide complexes containing tertiary phosphine or arsine, their preparation and use as homogeneous hydrogenation catalysts are described in U.S. Patent No. 3,639,439.

Soluble platinum group metal complexes, in particular rhodium containing a halogen atom and a tertiary phosphine, arsine, stibine or amine, their preparation and use as a hydrogenation catalyst are also described in British Patents 1 138 600, 1 219 763, 1 121 642 and 1 121 643 and U.S. Pat. Nos. 3,489,786 and 3,549,780. These catalysts provide better conditions for the hydrogenation of unsaturated organic compounds, especially olefins, as compared to the heterogeneous catalysts used.

German DOS 2 308 227 describes the preparation of alpha-6-deoxytetracyclines by homogeneous catalytic hydrogenation using tris (triphenylphosphine) chlorodhodium as a catalyst. The catalyst may be prepared in advance or may be prepared directly in the reaction medium by dissolving rhodium chloride in the reaction medium in the presence of one to three molar equivalents of triphenylphosphine.

U.S. Pat. No. 3,692,864 describes the hydrogenation of unsaturated organic molecules using homogeneous complexes of an iron group metal (nickel, cobalt, iron) with tertiary phosphines. A typical complex described is chlorine tris (triphenylphosphine) cobalt.

Many publications disclose homogeneous catalysis as advantageous in hydrogenations, including positional, selective and asymmetric reductions. Knowles et al., Chem. Commun., 1445 (1968), Horner et al., Angew. Chem. Int. Ed., 2, 942 (1968) and Belgian Patent 766,960 disclose the use of monovalent rhodium complexes with optically active tertiary phosphine ligands as homogeneous catalysts, with asymmetric catalytic hydrogenation. Recent publications provide reviews in this field: Harmon et al., Chem. Roar. 73, 21-52 (1973); Kjánowles et. al., Chem. Commun., 10 (1972); Grubbs et al., J. Am. Chem. Soc., 93, 3062 (1971); Kagan et al., J. Am. Chem. Soc., 94, No. 429 (1972) and Homogeneous Catalysis, Industrial Applications and Implications, vol. 70, Advances in Chemistry Series, published by the American Chemical Society, Washington, D. C. (1968); Aspects of Homogeneous Catalysis Vol. I, pp. 5-75 (1970), published by R. Ugo and published by Carlo Manfredi, Milan, Italy; and Vol * Pin et al., Russian Chemical Reviews, 38, 273-289 (1969).

The homogeneous catalytic hydrogenation of exocyclic methylene groups using tris (triphenylphosphine) chlorrhodium as a catalyst is described for methylene cyclohexanes (Augustine et al., Ann. NY Sci. 158: 482-491 (1969); coronopilin (Ruesch et al., Tetrahedron 25). 807-811, 1969) and the intermediate in the stereoselective total synthesis of Seychellen (Piers et al., Chem. Gommuns, 1,069-1,070, 1969).

The reaction of the 6-methylenetetracyclines or their salts with hydrogen acids in the presence of soluble rhodium coordination complexes with the donor acceptor ligands as catalysts proceeds very smoothly, as is now found, by hydrogenation of the exocyclic methylene group.

Alternatively, the 6-methylenetetracycline salt may be used as the reactant instead of the 6-methylenetetracycline base and the acid. The process according to the invention has several advantages over the known reduction methods. For example, undesirable anhydrotetracycline is little or no formation; the overall conversion of 6-methylenetetracycline to 6-deoxytetracycline is better; an almost quantitative reduction of the 6-methylenetetracycline substrate is achieved; the catalyst provides stereoselective reduction; that is, the ratio of the desired .alpha.-epimer to the .beta.-epimer is higher (less than 1% of the .beta.-epimer is formed.

The process is applicable to the hydrogenation of 6-deoxymethylenetetracyclines of formula II

O

CONH ₂

OH

(II) and their acid salts, wherein Y is hydrogen or hydroxyl and wherein Z is hydrogen or chlorine.

The structures of the complexes used in the hydrogenation are not known with certainty. Without a doubt, a number of complexes will participate in the process as catalysts or as catalyst precursors. Thus, it is desirable to define the complexes as halogen containing rhodium complexes that are derived from a metal halide and the ligands are selected from the group consisting of tertiary phosphines of the formula PR 1 R 1 R 1, wherein each of R 1 and R 2 is selected from phenyl and substituted phenyl; is selected from the group consisting of halogen, alkyl, alkoxy and dialkylamino of 1 to 10 carbon atoms and R 3 is R 1, alkyl of 1 to 10 carbon atoms or benzyl.

As used herein, alkyl and alkoxy are alkyl or alkoxy containing from 1 to 10 carbon atoms. Particularly preferred are those tertiary phosphines wherein alkyl and alkoxy, if present, contains 1 to 4 carbon atoms.

According to the process of the invention, the 6-deoxymethylenetetracycline of the above formula or the corresponding 11α-chloro derivative is dissolved in an inert solvent and contacted with hydrogen in the presence of a halogen-containing rhodium-tertiary phosphine complex at 20 to 100 ° C and atmospheric pressure to 28 MPa and when Z is a hydrogen atom, in the presence of at least a molar equivalent of acid per mole of 6-methylenetetracycline until the desired reaction proceeds, that is, when Z is a halogen atom, dehalogenation of 11a halogen with or without hydrogenation of the 6-methylene group hydrogen atom, hydrogenation of methylene group. Alternatively and especially when Z is a halogen atom, the 6-methylenetetracycline acid salt is used as the reaction component.

A wide variety of solvents can be used in the process of the invention. Solvents or solvent mixtures are selected to allow the solubility of the 6-methylenetetracycline and catalyst at the temperature at which the reaction proceeds to provide a homogeneous system. Representative suitable solvents are: ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, N, N-dimethylformamide, amid, Ν-dimethylacetamide, alcohols such as methanol, ethanol, propanol, isopropanol and butanol, and mixtures of these solvents.

In addition to these solvent systems, the water-miscible solvent mixtures mentioned above may be used. When 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride is used as the substrate, ethanol-water (9: 1) is the most suitable solvent, since the solubility of the substrate and the catalyst is appropriate, the rate and yield are appropriate. Furthermore, mixtures of the above solvents with solvents in which the substrate and catalyst are poorly soluble may be used if desired. For example, a mixture of benzene-dimethylformamide may be used. The only criterion is that the catalyst and substrate are sufficiently soluble in the system to allow the reaction to proceed.

In addition to the solubility of the catalyst and the substrate, the choice of solvent depends on several factors. These factors are, for example, the stability of the solvent under the reaction conditions, especially at elevated temperatures, and the choice of the solvent is also important for the reaction rate, which then allows optimal conversion of the substrate to the desired product. Dimethylformamide degrades to carbon monoxide and dimethylamine, which deactivates the catalyst. The rate of degradation of this solvent is accelerated by increasing the temperature of the reaction. Thus, to achieve complete conversion of the substrate to the desired product, a temperature below 100 ° C must be used and / or a larger amount of catalyst must be used. Dimethylacetamide is much more stable under reaction conditions and is therefore used as the preferred solvent.

Dimethylsulfoxide, acetone, acetonitrile and hexamethylphosphoric triamide may also be used as solvents. However, their use is not the most advantageous since the reaction rate is slower than the solvents mentioned above. In general, the preferred solvents are alcohols since they allow sufficient solubility of the substrate and catalyst and yields of the desired products. The stereoselectivity of the reaction depends to some extent on the solvent. Under these conditions, it was found that dimethylformamide produces a somewhat higher ratio of alpha-epimer to beta-epimer than that provided by the use of alcohols.

The suitability of the solvent or solvent mixture for the process of the invention is determined in the first approximation by monitoring the solubility of the substrate and the catalyst at the temperature at which the reaction is to take place. Once a suitable solubility is found, the experiment is carried out in a small scale and the reaction progress and rate are monitored depending on thease. Thin layer chromatography of silica gel buffered to pH 6 using a solvent mixture of tetrahydrofuran-water (95: 5) is used as a suitable procedure. Plates are developed with ammonia and monitored in ultraviolet light at 366 nm.

Of course, it is not necessary for the 6-methylenetetracycline substrate to completely dissolve in the environment. It is only necessary that it be sufficiently soluble in the solvent to allow the reaction to proceed, and the undissolved substrate then serves as a reservoir or source of fresh substrate to maintain the substrate concentration in the solvent. Preferably, however, a solvent is used in which the substrate and catalyst are completely soluble or almost completely soluble.

The pressure of the hydrogen used in the process is not critical, a pressure not exceeding atmospheric pressure up to 28 MPa can be used. Typically, pressures from atmospheric pressure to 14 MPa are used. Preferably, a pressure of from 1 to 5 MPa is used. A hydrogen pressure lower than atmospheric pressure is suitably used by introducing an inert gas, such as nitrogen, in addition to hydrogen into the reaction vessel. Thus, a partial hydrogen pressure lower than atmospheric pressure is easily achieved.

The process temperature is not critical and may range from about 20 ° C to about 100 ° C. A preferred temperature range is from 40 to 85 ° C, and most preferably from 60 to about 85 ° C. At lower temperatures, i.e. below about 20 ° C, the reaction rate is relatively slow over the preferred temperature range. Low temperatures are therefore undesirable for carrying out the process of the invention on a larger scale. At temperatures above 100 ° C, the catalyst is deactivated, usually at a rate that results in incomplete hydrogenation of the substrate, unless a significant amount of catalyst is used. The temperature range of the reaction is therefore determined not only by determining the reaction rate normally expected at a higher temperature, but also by the stability of the solvent and the catalyst and also by the completeness of the reaction.

The concentration of the substrate has little effect on the reaction, except for the reaction rate, in solvents in which the 6-methylenetetracycline substrate is only partially soluble. Concentration does not affect the stereoselectivity of the reaction, i.e. the ratio of alpha to beta-epimer.

The concentration of the catalyst is also not a decisive factor in terms of economics, usually an amount ranging from 0.01 mol. to about 10 mol. percent by weight based on the concentration of the 6-methylenetetracycline substrate. The use of higher amounts (e.g., above 100 mole percent) is fully feasible according to the procedure, but is economically inappropriate. Lower amounts of catalyst are not commonly used, as catalyst deactivation and incomplete reaction processes cause serious problems. Although the catalyst fraction is equal to or greater than the substrate fraction, the reaction is not considered to be catalytic, but the term is used here because in the absence of this material the reaction proceeds slowly or not at all. Only in the presence of this catalyst does the reaction proceed.

The pH of the reaction mixture is a significant factor in the reaction rate and the stereoselectivity of the hydrogenation. It was found that by hydrogenating 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline in an alcoholic solution using tris (triphenylphosphine) chlorodhodium (I) as a catalyst in an amount of 1% based on 10% substrate concentration at 75 ° C and 1 t of hydrogen gave 20-25% of the beta-epimer. Under similar conditions, 6-demethyl-6-deoxy-6-methylene-5-hydroxytetra-cyclin hydrochloride provides less than 2% of the beta-epimer. Similar results were obtained when hydrogen chloride, anhydrous or aqueous (2 to 50 equivalents) was added to the reaction mixture containing 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline. The free compound is hydrogenated more slowly than the hydrochloride. The 6-methylenetetracycline substrate is therefore preferably used as an acid salt or an acid is added to the base solution to effect the reaction in an acidic medium. The acids used for this purpose are p-toluenesulfonic acid and mineral acids (hydrochloric, hydrobromic, sulfuric, nitric), in particular hydrochloric acid. The molar ratio of the acid to the 6-methylenetetracycline reaction component is used from about 1 to about 5. The preferred ratio is from about 2 to about 3 moles of acid per mole of the 6-methylenetetracycline reaction component because optimum reaction rate and stereoselectivity are formed. minimal side reactions. Other acids such as citric, tartaric, malonic, fumaric and benzoic acids and salts capable of forming the 6-methylenetetracyclines described in U.S. Patent Nos. 3,200,149 and 2,984,686 may also be used.

Catalysts used in the process of the present invention can be represented by the following formula (L) _and Rh (X ') _c without a solvent having a solvating effect, wherein L is a ligand, particularly a ligand capable of forming a donor-acceptor bond, described below, X * is a halide or other anion to maintain electroneutrality, and is an integer from 1 to 6, usually 2 to 4, c is an integer from 1 to 3, wherein the sum of aac is 4 if Rh is present in monovalent form and the sum of aac is 6 for other oxidation stages Rh.

It is believed that the catalysts in solution have the formula (L) _m Rh (S) _n (X ') _p , where L and X * are as defined above, 3 is a solvent molecule, m is an integer from 1 to 6, n is 0 or an integer from 1 to 2, p is an integer from 1 to 3, where the sum of m, n and p is 6.

The exact structure of the complex or complexes involved in the hydrogenation process is unknown. The prior art suggests that the complex functions as a hydrogen carrier to form dihydride complexes. The exact valence degree of the metal in the complex is unknown as it is likely that during the hydrogenation process the metal of the complex is initially present in one of the higher oxidation stages and is reduced to a lower oxidation stage. Thus, it is believed that rhodium complexes. (III) are converted to rhodium I complexes

Of course, solvent molecules that can coordinate to the central metal atom can be considered ligands. However, it is preferred to distinguish them from the ligand (L) as they may or may not be present in the coordination complex. Their presence in the complex is dependent on whether the metal coordination number is sufficiently filled with the present ligands (L) and the coordination ability of the solvent not only of itself but also relative to the ligands already present in the metal coordination sphere, i.e. more ligand (L) with solvent (S).

is an anion necessary to maintain electroneutrality and can be selected from a considerable number of anions, and is not critical to the invention.

Examples of anions are anions such as chloride, bromide, iodide, perchlorate, fluoroborate, hydroxide and acetate. The preferred anion is chloride.

Suitable ligands (L) are phosphines of the general formula

PR, R 2 R 3 wherein Η, R 8 and R 3 are as defined above. Of particular value for the process of the invention are rhodium-triarylphosphine complexes, since the stereoselectivity of the reduction is advantageous and a suitable ratio of alpha and beta-epimers is obtained. From an economic standpoint, the use of triphenylphosphine as a ligand is commercially available. Preferred catalysts are rhodium-triarylphosphine complexes, and in particular, chlorodis (triphenylphosphine) rhodium complex, which is commercially available and provides a high yield of the desired 6α-epimer.

Catalysts are prepared by known methods. Many of these are listed in the above literature. The catalysts may be prepared in advance or may be prepared in situ. From a practical point of view, preformed catalysts are more preferred, especially when the catalyst is commercially available, e.g., the chlor-tris (triphenylphosphine) catalyst.

The general method for preparing the catalysts used in the process of the present invention involves reacting the corresponding metal halides, especially chloride, in a conventional oxidation step of the metal (i.e., RhCl 3) in a suitable solvent such as ethanol with the appropriate phosphine. A suitable excess of phosphine is used to reduce the metal. In the case of RhCl3, the molar ratio of phosphine to RhCl3 is used. 3H2O from 6 to 1 to form a rhodium complex. The reaction is usually carried out under an inert atmosphere.

. An alternative process for preparing rhodium complexes involves reacting rhodium complexes containing neutral ligands with the appropriate phosphine. Suitable monovalent rhodium complexes serving as reaction components for this process are rhodium complexes with olefins. Particularly preferred for this process are the chloro-bis (ethylene) rhodium dimer and the chloro- (1,5-cyclooctadiene) rhodium dimer. The structure of the resulting complexes is determined by the ratio of phosphine to rhodium complexes with olefins. The molar ratio of phosphine to rhodium complex of 6: 1 olefin provides complexes of formula I-Rl, while a 4: 1 mole ratio provides complexes of LgRl-1. This procedure is commonly used for in situ synthesis of catalysts. About 2 to 3 equivalents of phosphine are used per mole of metal.

In the case of in situ formation from the chloro-bis (ethylene) rhodium complex, the reaction is carried out in the absence of air and in a solvent-free gas, such as a nitrogen atmosphere, to avoid oxidation of the catalyst.

As mentioned above, the metal complexes are derived from metal halides and respective ligands. The anion that is normally associated with the complex to maintain electroneutrality is the chloride ion, since metal chlorides are generally more readily available than the corresponding bromides and iodides. By using bromides or iodides as reaction components, of course, complexes with the anion of bromine or iodine are obtained.

The relative unavailability of metal bromides or iodides is easily circumvented by the addition of a bromine or iodine ion source such as KBr, KJ to chlorine complexes solutions. Preferably, from 0.25% to about 1% by weight, based on the metal complex, potassium bromide or potassium iodide, is used in this reaction. Lower or higher amounts do not have any advantages or may adversely affect the reaction.

The rate of hydrogenation is affected by the anion present in the complex. In many Rh (P / phenyl / 3) X compounds, where X is a halogen ion, the rate is affected in the order of J > Br > Cl. The presence of fluorine has an adverse effect on the hydrogenation reaction.

The invention also encompasses the use of complex catalysts comprising a chiral phosphine, wherein the chirality may be on phosphorus or on a group attached to phosphorus. These catalysts are often more stereoselective when hydrogenated according to the invention.

The 6-deoxytetracycline products prepared according to this process are isolated by any known method. For example, 6-deoxytetracycline products can be isolated as amphoteric compounds or as acid salts, in particular) by precipitation of the 6-deoxy compound as an insoluble acid salt, for example in the case of precipitation of 6α-deoxy-5-hydroxytetracycline as sulfosallcylate. Alternatively, the complex catalyst can be isolated from the reaction mixture by extraction into a suitable solvent.

Another method involves adding a metal ion, typically an excess, which forms a chelate with 6-deoxytetracycline and which displaces the catalyst metal of the tetracycline compound. Typical metals here are calcium, barium, magnesium, strontium, aluminum, zinc and other known chelating metals with tetracyclines. The 6-deoxytetracycline can be isolated by precipitation, for example, as an amine-alkaline earth metal complex according to the procedure of U.S. Patent 2,873,276 or by extraction.

The presence of a larger amount, i.e., above 10 mole percent of the catalyst in the reaction mixture causes isolation difficulties, since the catalyst is oxidized.

It has been found that 6-deoxytetracyclines are preferably isolated from the reaction mixture containing a higher amount of rhodium complexes in the absence of air.

Preferably, the reaction mixture is monitored and analyzed for reaction progress and yield of alpha and beta isomers by silica gel thin layer chromatography as described above. A more precise determination of the course of the reaction and the yield is obtained by high pressure liquid chromatography. This is done using a Chromatronix 3100 chromatograph. A 2 m x 2.1 mm column is packed with Dupont SAX, a quaternary ammonium substituted methacrylate polymer coated with 1 wt. Zipax.

Water containing 0.001 M ethylenediaminetetraacetic acid and 0.005 M sodium acetate adjusted to pH 6.0 with acetic acid was used as the dissolution system. A flow rate of 0.5 ml per minute is used. The device has a 20 nm injection valve. In this system, 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline K has a value of 3.6; 6alpha-deoxy-5-hydroxy-tetracycline K value 3.0 and 6beta-deoxy-5-dihydroxytetracycline K value 1.8.

Those skilled in the art will appreciate that ligand-containing catalysts other than those mentioned above may also be used in the present invention. Examples of such ligands are phosphites (R ^RgRRP, where R; and Rg are as defined above, R ^# is R nebo or ORj, as defined above); NO, sulfides, sulfones, sulfoxides, SOg, HSO3 and SO3.

In addition to complexes of the above type, namely coordination complexes that are at least partially soluble in the environment, the benefits of homogeneous or heterogeneous catalysis can be realized using irhodium coordination complexes, which may be insoluble or sparingly soluble in the reaction medium.

It goes without saying that the classification of the coordination complexes based on their solubility is purely relative and depends on the solvent system used. It is possible by simple solvent selection to shift the complex from soluble complexes to insoluble complexes. Otherwise, there are also such complexes of this type which have limited solubility in the bulk of the solvents and which are present in the reaction mixture as a separate phase. These insoluble complexes function in a not yet clear manner, but is derived from a coordinated ligand to the metal.

The invention also includes coordination complexes with limited solubility in which the rhodium coordination complex is bound to an insoluble polymer.

Of particular interest are rhodium complexes which contain a coordinated bonded polymer containing phosphine groups. The polymer used as the carrier for the rhodium catalyst is obtained by chloromethylation of a styrene-vinylbenzene copolymer and by reaction with lithiophosphines (L1PRJR2R3) ^the chlorine atom is replaced by a phosphine. The styrene-divinylbenzene copolymer may contain varying amounts of crosslinking. These phosphine-containing polymers are described in Grubbs et al., J. Am. Chem. Soc. 23 3062 (1971) and Capka and J. Tetrahedron Letters No. 50 4787 (1971).

Another class of phosphine-containing polymers is the polystyrene polymer cross-linked with divinylbenzene described by Heitz et al., Angew. Chem. Dormitory. Ed. 11,298 (1972). These polymers are prepared by bromination of the polystyrene-divinylbenzene polymer and then by reaction of the thickened product with the sodium salt of the appropriate phosphine. These products differ from the products formed by the chloromethylation of styrene-divinylbenzene in that the phosphine moiety is attached directly to the benzene ring.

The methods described are applicable to various polymers. The phosphine polymer is reacted with RhCl 2. 3H ₂ O, or other salts in ethanol to form a polymer that binds a coordination complex.

Alternatively, the halomethylated copolymer is equilibrated with the appropriate phosphine-rhodium complex for several days to form a polymer-bound complex.

In addition to the above advantages, coordination complexes of limited solubility and polymer bound complexes also have the advantage of being readily separated from the reaction medium. Further, the isolation of the desired products is usually simplified and a large excess of the complex can be removed without the complications arising from the isolation process.

Silyl ethers of 6-methylenetetracyclines can also be used as substrates in the process of the invention. These ethers are prepared as described in J. Chem. Soc. (C) 636 (1970) or a modification thereof. In another modification of the procedure, trimethylsilylao 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride is carried out with trimethylohlorosilane 1: 5 in tetrahydrofuran in the presence of triethylamine (20% excess) or at a temperature below 30 ° C for 45 minutes . O-trimethylsilylation of the hydroxy groups in the 5, 10, 12 and 12a positions takes place. The product as a white solid was isolated by filtration of triethylamine hydrochloride and evaporation of the solvent in vacuo.

Silyl groups, if not removed during the reaction, are readily removed from the reduced products by treatment with dilute acid or a solvent containing hydroxyl groups.

Further, the enolic hydroxyl groups at the 1 or 12 position can be protected by esterification and subsequent conversion to enamines as described in U.S. Pat. 3,239 499.

In addition to the 6-deoxymethylenetetracyclines of formula II, which serve as substrates in the process of the invention, 6-methylenetetracyclines of formulas II-A and II-B may also be used.

COMH ₂ (XI-B) '3 and their salts and acids, wherein Ti is hydrogen or OH, wherein S, is hydrogen, alkanoyl, phenoxyalkanoyl, lower alkoxyalkanoyl, mono- and dichloralkanoyl, and mono- and dibromalkanoyl, wherein alkanoyl contains from 1 to 6 carbon atoms, X is hydrogen, chlorine, bromine or iodine,

X is hydrogen, amino, lower alkanoylamino, X ₂ is hydrogen or nitro and _R2 and R3 are independently hydrogen, alkanoyl, fenoxyalkanoyl lower alkoxyalkanoyl dichloralkanoyl mono- and mono and dibromalkanoyl, wherein the alkanoyl contains from 2 to 6 carbon atoms and Z 1 is hydrogen, chlorine or bromine, wherein when each of X, Χ, X ₂ , R ₂ and R 3 are hydrogen and Z is hydrogen or chlorine, Y is hydrogen or hydroxyl.

He did

6alpha-deoxy-5-hydroxytetracycline (rhodium-triphenylphosphine complex)

Preparation of the catalyst

A solution of chloro-bis (ethylene) rhodium dimer (0.100 g, 0.515 mM) in degassed benzene (10 mL) was transferred under nitrogen to a 100 mL three-necked flask connected to a hydrogenation apparatus. Then a solution of triphenylphosphine (0.300 g, 1.14 mM) (in degassed benzene (10 mL)) was added and the nitrogen atmosphere was changed to hydrogen, followed by stirring at room temperature for 20 minutes.

Reduction

A solution of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (0.400 g, 0.91 mM) in ethylene glycol monomethyl ether (10 mL) was then added and the mixture was stirred vigorously for 18 hours under 1 atm of hydrogen. (Thin layer chromatography / silica gel plates buffered to pH 6.0 with phosphate citrate buffer and eluted with 95% tetrahydrofuran with 5% water) showed the reaction to be complete. In this chromatography system, 6-demethyl-6-deoxy- 6-methylene-5-hydroxytetracycline Rf = 0.31, 6alpha-deoxy-5-hydroxytetracycline Rf = 0.50 and 6beta-deoxy-5-hydroxytetracycline Rf = 0.25). High pressure liquid chromatography of the reaction mixture (the system described above) shows that the ratio of 6alpha: 6beta epimers is 92: 8 and the crude yield of 6-deoxytetracyclines is 85%.

The identity of the product was demonstrated as follows. The reaction mixture was evaporated to dryness at 50 ° C and 1 mm Hg, the residue was redissolved in a mixture of methanol (10 mL), 1 N hydrochloric acid (10 mL) and chloroform (10 mL). ¹ The aqueous phase was separated, washed with chloroform (10 mL) and then treated with an aqueous solution of sulfosalicylic acid (2 mL, 10%). The precipitated gum was recrystallized from aqueous methanol to give 0.01 g of 6α-deoxy-5-hydroxytetracycline sulfosalicylate. The material obtained is identical to an authentic sample of 6α-deoxy-5-hydroxytetracycline-sulfosalicylate according to ultraviolet and infrared spectra and chromatography.

Example 2

The procedure of Example 1 was repeated and replaced with triphenylphosphine with an equivalent amount of diphenylmethylphosphine. After a reaction time of 60 hours, according to thin layer chromatography, the ratio of epimers 6alpha: 6beta is 71:29. Crude yield of 6-deoxy-5-hydroxytetracyclines 70% (by ultraviolet spectrum) by comparison with known concentrations.

By repeating this procedure but using 6-methylene-5-hydroxytetracycline hydrochloride, a crude product is obtained in which the alpha-epimer is the main product.

\

Example 3

6alpha-deoxy-5-hydroxytetracycline (rhodium-triphenylphosphine complex)

In an inert nitrogen atmosphere, triphenylphosphine (0.272 g, 1.04 ml) and chlorobis (ethylene) rhodium dimer (0.100 g, 0.52 mM) were added to a 100 ml three-necked round flask equipped with a magnetic stirrer, three way condenser. tap and stopper. Close the flask and remove from the nitrogen atmosphere. Degassed benzene (20 mL) was added and the mixture was stirred for 0 min. Attach the flask to the hydrogenation apparatus, remove the nitrogen and fill with hydrogen. A solution of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (2.49 g, 5.2 mM) in degassed N, N-dimethylformamide was added and the mixture was stirred and heated to 75 ° C under O 1 MPa of hydrogen for seven hours. (After 6.5 hours of reaction, a 0.05 ml sample of the reaction mixture, diluted to 5 ml with methanol and chromatographed as described above, contained about 95% by HPLC.

6alpha and about 0.7% of the 6beta-epimer.

The mixture was then cooled to room temperature and the reaction mixture transferred to a separatory funnel under nitrogen. Chloroform (20 ml) and water (40 ml) were added, the mixture was shaken and the aqueous phases were separated. An additional 20 mL of chloroform was added and the organic layer was then extracted with water (3 x 40 mL). The aqueous extracts were combined, extracted with chloroform (10 mL) and then removed by heating under a nitrogen atmosphere to remove traces of chloroform. To the solution was added aqueous sulfosalivylic acid (50 mL of 10% solution) under nitrogen. The mixture was stirred, cooled to room temperature and the sulfosalicylate salt of the product was filtered off and dried in vacuo (3.12 g).

Example4

The procedure of Example 3 was repeated using the following ligands of the formula PR ₁ R ₂ R ₃ instead of triphenylphosphine:

R, ⁺ r ₂ ^r 3 4-CH ₃ C ₆ H ₄ 4-CH ₃ C ₆ H ₄ 4-CH ₃ C ₆ H ₄ 4-CH ₃ OC ₆ H ₄ 4-CH ₃ OC ₆ H ₄ 4-CH ₃ OC ₆ H ₄ 4-ClC ₆ H ₄ 4-ClC ₆ H ₄ 4-ClC ₆ H ₄ 3-ClC ₆ H ₄ 4-ClC ₆ H ₄ 3-ClC ₆ H ₄ 2-ClC ₆ H _{4 2-4} ClC6H _2-4 ClCgH 2-CH ₃ OC ₉ H _{4 2-4} CH3OC6H _2-4 CH3OC6H 3-CH 3 OC ₆ H ₄ 3-CH ₃ OC ₆ H _{4 3-4} CH3OCéH 2-CH ₃ C ₆ H ₄ 2-CH ₃ C ₆ H ₄ 2-CH ₃ C ₆ H ₄ 3-CC ₃ C ₆ H ₄ 3-CH ₃ C ₆ H ₄ 3-CH ₃ C ₆ H ₄ 4-Me ₂ NC ₆ H ₄ 4-Me ₂ W ₆ H ₄ 4-Me ₂ NC ₆ H ₄ 4-Et ₂ NC ₆ H ₄ 4-Et ₂ NG ₆ H ₄ 4-Et ₂ -C ₆ H ₄ c ₆ h ₅ c ₆ h ₅ 4-Me ₂ NC6 H ₄ c ₆ h ₅ ^c 6 ^h 5 4-ClC ₆ H ₄ ^c 6 ^h 5 ^c 6 ^h 5 4-BrC ₆ H ₄ C6 «5 c ₆ h ₅ 4-CH ₃ OC ₉ H ₄ ° 6 ^η 5 c ₆ h ₅ 4-CH ₃ C ₆ H ₄ c ₆ h ₅ c ₆ h ₅ 4-Me ₂ NC ₈ H ₄ 4-H ₂ MC ₆ H ₅ 4-H ₂ NC6H5 c ₆ h ₅ 4-CH ₃ C ₆ H _{4 4-4} CH3CgH _4-4 CH3OC6H 4-CH ₃ C ₆ H ₄ 4-CH ₃ C ₆ H ₄ 4-C1C _d h ₄ c ₆ h ₅ 4-BrC ₆ H ₄ 4-CH ₃ OC ₆ H ₄ C6 ^h 5 4-BrC ₆ H ₄ 4-Me ₂ NC ₆ H ₄ ^c 6 ^h 5 .. 4-CH ₃ OCeH ₄ 4-CH ₃ C ₈ H ₄ 4-Me ₂ NC ₆ H ₄ 4-Me ₂ NCeH ₄ c ₆ h ₅

R, + r ₂ R3 4 ΡΘ ₆ Η ₄ 4-FC6H4 4-FC6H4 c ₆ h ₅ c ₆ h ₅ ch ₃ c ₆ h ₅ c ₆ h ₅ C2H5 c ₆ h ₅ 4-CH3OC6H4 ch ₃ C6H5 4-CH 3 C 6 H 4 ch ₃ c ₆ h ₅ 4-ΟγΟ ₆ Η ₅ c ₂ h ₅ c ₆ h ₅ 4-CH 3 C 6 H 4 c ₂ h ₅ c ₆ h ₅ 4-CH3OC6H4 c ₂ h ₅ c ₆ h ₅ 4-CH3OC6H4 η-0 ₃ Ηγ c ₆ h ₅ 4-CH3OC6H4. nC ₄ Hg 4-CH 3 C 6 H 4 4-CH 3 C 6 H 4 CH3 4-CH 3 C 6 H 4 4-CH 3 C 6 H 4 C7H7 c ₆ h ₅ ΟγΗγ C2H5

Note: ⁺ Me = methyl;

Et = ethyl.

In all cases, the predominant product is 6alpha-deoxy-5-hydroxytetracycline.

Example 5

6alpha-deoxy-5-hydroxytetracycline (rhodium-tris (4-chlorophenyl) phosphine complex)

In a nitrogen atmosphere, a 500 ml Parr flask equipped with a stainless steel valve was charged with bis (ethylene) rhodium chloride (0.05 g, 0.26 mM) and tris (4-chlorophenyl) phosphine (0.19 g,

0.52 mM). The flask was then connected to the hydrogenation apparatus and purged with nitrogen. To the flask was added ethanol (20 mL), and the mixture was shaken under nitrogen for 15 minutes. A suspension of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (12.45 g, 26 mM) in ethanol (70 mL), water (10 mL) was then added and the flask was purged with hydrogen three times. The flask was charged to 50 psi with hydrogen and heated to 75 ° C for 18 hours (heating time half an hour). Aliquots were taken from the flask at intervals of 1, 2, and 4 hours, and 30%, 55% and 85% conversion of the reactant was obtained by thin layer chromatography as described above. After 18 hours, the reaction is complete according to thin layer chromatography and high pressure liquid chromatography.

The reaction mixture was cooled, acidified by saturating with a stream of hydrogen chloride gas. After stirring for half an hour, the solid was filtered off, washed with ethanolic hydrogen chloride and dried under vacuum at 60 ° C. 10.5 g (82%) of 6alpha-deoxy-5-hydroxytetracycline hydrochloride are obtained in the form of hemihydrate demi-alcoholate. Concentration of the filtrate gave an additional 1.4 g (11%) of the product in a total yield of 11.9 g (95%). Analysis of the product by high pressure liquid chromatography showed the presence of 0.6% beta-epimer and no starting material.

Example 6

By repeating the procedure of Example 3, but using the 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (6-MOTc) salt and the phosphines (PRjRgRj) below, mixtures of 6-deoxy-5-hydroxytetracycline epimers are obtained, wherein alpha -epimer prevails:

6-MOTc salt Ri P (R, R ₂ R ₃ ) ₃ r ₂ * 3 HBr ₍ c ₆ h ₅ c ₆ h ₅ c ₆ h ₅ HBr 4-CIC 6 H 4 4-ClC ₆ H ₄ 4-C1C6H4 citrate c ₆ h ₅ c ₆ h ₅ C6H5 tosylate 4-MeCO6H4 4-MeOC6H4 4-MeOCgH4 tosylate 2-CH 3 C 6 H 4 2-CH ₃ C ₆ H 4 2-CH ₃ C ₆ H ₄ H2SO4 C6H5 c ₆ h ₅ c ₆ h ₅ tartrate C6H5 c ₆ h _{5 4-4} BrC6H malate C ₆ H ₅ C6H5 4-Me ₂ NC6H4 tosylate 2-CIC 6 H 4 2-CIC 6 H 4 2-CIC 6 H 4 tosylate 4-Me ₂ NC6 H ₄ 4-Me ₂ NC6H4 4-Me ₂ NC ₈ H 4

Note: ⁺ tosylate = p-toluenesulfonate; Me = methyl.

Example 7

Reduction of 11α-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline

Under a nitrogen atmosphere, 11α-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline-p-toluenesulfonate (1.9545 g, 3.04 mmol) and chlorotris (triphenylphosphine) rhodium (280.9 mg,

0.304 mmol) was added to degassed methanol (50 mL) at room temperature in a flask connected to the hydrogenation of the apparatus. Nitrogen was removed from the flask and then filled with hydrogen to a pressure of 50 psi. The reaction mixture, the suspension, was heated to 30 ° C and shaken for 68 hours. According to HPLC, 1.5-2% of the beta-epimer is present in the mixture.

The reaction mixture, solution, was removed from the hydrogenation of the apparatus under nitrogen and 10 ml of a 1 M solution of sulfosalicylic acid in methanol was added. Water was then added until turbid, and the solution was stirred under nitrogen for two hours. The yellow solid was filtered off (1.5713 g) and washed with a small amount of methanol. The combined wash solution and filtrate were concentrated and the solid was filtered off. The yield of the alpha-epimer is 89%.

Example

Using the procedure of Example 7, but substituting bromo-tris (triphenylphosphine) rhodium and iodo-tris (triphenylphosphine) rhodium instead of the chloro derivative, the same results are obtained.

Example 9

6alpha-deoxy-5-hydroxytetracycline hydrochloride

The following reagents were placed in a hydrogenation flask under a nitrogen atmosphere: 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (5.00 g, 10.4 mmol), chloro-tris (triphenylphosphine) rhodium (25 mg) , 0.027 mmol), potassium bromide (12.5 mg) and 50 mL of degassed ethanol-water (9: 1). Nitrogen was removed from the vessel and the hydrogen was charged to -0.45 MPa at room temperature. The reaction mixture was then heated to 70 ° C for 15.5 hours and then cooled to room temperature. According to high pressure liquid chromatography as described above, the mixture contains 2.5% beta-epimer and 97.5% alpha-epimer.

Anhydrous hydrogen chloride was introduced into the reaction mixture and the solution stirred until a precipitate formed. After standing for 3 hours, the precipitated product was filtered off and dried (3.65 g, 73%).

It was found to contain 81.74% alpha-epimer, 0.81% beta-epimer and 5.77% starting material by HPLC.

On standing, 551 mg of product was obtained, which was separated from the filtrate. High pressure liquid chromatography was found to contain 96.57% alpha-epimer, 0.52% beta-epimer and 1.73% starting material.

By repeating this procedure with potassium iodide instead of potassium bromide, the same results are obtained.

Example 10

Following the procedure of Examples 3 and 5, 6-demethyl-6-deoxy-6-methylenetetracycline hydrochloride was converted to 6α-deoxytetracycline as the main product.

They did

By repeating the procedure of Example 7 but using 11α-chloro-6-demethyl-6-deoxy-6-methylenetetracycline instead of the corresponding 5-hydroxytetracycline, 6α-deoxytetracycline is obtained as the main product.

Example 12

11a-dehalogenation

A mixture of rhodium chloro-tris (triphenylphosphine) (20 mg, 0.016 mmol), 11α-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (2.0 g, 3.9 mmol) and degassed methanol (30 ml) was placed in the hydrogenation of the flask and the flask was connected to Pear's shaking apparatus. The flask was purged with hydrogen and then filled with hydrogen at 50 psi at room temperature. The mixture was shaken and heated to 70 ° C for 15 hours. After cooling to room temperature, the contents of the flask were removed and subjected to high pressure liquid chromatography. The main product is 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline. Furthermore, traces of 6alpha- and 6beta-deoxy-5-hydroxytetracycline are present, but no starting product is present.

Similar results are obtained when chloro-tris (tri (4-chlorophenyl) phosphine) is used instead of chloro-tris (triphenyl) phosphine-rhodium.

Example 13

The procedure of Example 9 was repeated, but using a high-pressure apparatus such that pressures of 12.6 were used; 17.5 and 28 MPa. The same results are obtained.

Example 14

11a-Chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline

Under a nitrogen atmosphere, 1α-chloro-6-demethyl-6-deoxy-6-methylen-5-hydroxytetracycline hydrochloride (1.0 g, 1.949 mmol) and chlorotris (triphenylphosphine) rhodium (18 mg, 0.01949 mmol) ), potassium iodide (10 mg) was added to degassed methanol (18 mL) and water (2 mL) at room temperature in an autoclave. Nitrogen is removed from the vessel and hydrogen is charged to a pressure of 11.9 MPa. The reaction mixture was stirred and heated at 70 ° C for 4.5 hours, then cooled. Take up the contents 4 and dilute with methanol (50 ml) under nitrogen. A solution of sulfosalicylic acid (20 mL of a 10% solution in methanol) and water (10 mL) was added to the reaction solution under nitrogen. The mixture was thoroughly mixed and then filtered. The obtained sulfosalicyl salt was washed with cold methanol-water (50-30 ml) and dried. 1.048 g of product is obtained.

By analyzing the production and measuring the intensity of the ultraviolet absorption spectrum at 349 πιμ in 0.01 N methanolic hydrochloric acid and by comparison with the standard, the yield of 6alpha-deoxy-5-hydroxytetracycline sulfosalicylate was found to be 88.29%.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 6-deoxytetracycline of the formula I or a salt thereof, wherein Y is hydrogen or hydroxyl, characterized in that 6-deoxymethylenetetracycline of the formula II or a salt thereof, wherein Y is as defined above and Z is hydrogen, chlorine or bromine , reduced by hydrogen at atmospheric pressure up to 28 MPa in an inert solvent at a temperature of from 20 to 100 ° C in the presence of a halogen-containing rhodium-tertiary phosphine complex of the formula P (R ₁ R ₂ H ₃ ), where R 1 and R ₂ is phenyl or phenyl substituted with halogen, alkyl, alkoxy or dialkylamino of from 1 to 10 carbon atoms in each alkyl and R 3 is as defined above for R 1 or R ₂ or is alkyl of 1 to 10 carbon atoms or benzyl.