FI58492B - HOMOGEN CATALYTIC REDUCERING AV 6-DEOXY-6-DEMETYL-6-METHYLENOXYETRACYCLIN - Google Patents

Description

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Patent- och register Article 7 Ansekan umgd och uti. 73 USA (US) 32851 ^, 368060, 1 * 28278 (71) Pfizer Inc., 235 East U2ncL Street, New York, NY, USA (US) (72) Thomas Mott Brennan, Niantic, Connecticut, Hermann Faubl, ifystic,

Connecticut, USA (US) (7U) Oy Kolster Ab (5l *) Homogeneous catalytic reduction of 6-deoxy-6-demethyl-6-methyleneoxytetracycline - Homogeneous, catalytic reduction of 6-deoxy-6-demethyl-6-methylenoxytetracycline

The invention relates to a process for the preparation of 6-deoxyoxytetracycline of the formula CH3) 2 CONH2 HO ° H 0 HO 0 and to its salts, which is characterized in that 6-deoxy-6-de-methyl-6-methyleneoxytetracycline of formula 2 58492 ch2hoh hhh ^ n (ch3) 2 conh2 HO OZ Ö »0 wherein Z is hydrogen, chlorine or bromine, or a salt thereof, is treated with hydrogen in an inert solvent at 20-100 ° C with a hydrogen pressure of at least atmospheric pressure, rhodium and the formula PiR ^ In the presence of a tertiary phosphine complex according to R 9, wherein R 4 and R 8 represent phenyl or U-chlorophenyl, and R 4 represents the same as R 4 or R 8 or is methyl.

Reaction of 6-demethyl-6-deoxy-6-methylenetetracyclines, 1H-halo-6-demethyl-6-deoxy-6-methylenetetracyclines, their acid addition salts and their polyvalent metal salt complexes with hydrogen in the presence of heterogeneous noble metal catalysts, and β-6-deoxy-tetracyclines for the preparation are described in U.S. Patent 3,200,1U9. The use of a poisoned noble metal catalyst to effect the same conversion, but with an increase in the ratio of β-6-deoxytetracycline to β-6-tetracycline, is described in U.S. Patent 3 MU 198. U.S. Patent 2,900,686 discloses performing catalytic reduction using hydrogen and a noble metal catalyst only. For 1dot halogenation of <-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 using hydrazine as a hydrogen source is disclosed in DE Patent 2,131,9UU. GB 1 296 3U0 discloses the use of Raney nickel and Raney cobalt as catalysts in such reductions.

The preparation and use of rhodium halide complexes with tertiary phosphine or arsine ligands as homogeneous hydrogenation catalysts are described in U.S. Patent 3,639 U39, published July 1, 1972. Platinum group metals, especially rhodium-soluble complexes containing halide and tertiary Whereas the preparation and use of phosphine, arsine, stibine or amine as hydrogenation catalysts are also disclosed in GB Patents 1,138,601 (published January 1, 1969); 1,219,763 (published January 20, 1971); 1,121,6U2 (issued July 31, 1968); and 1,121,6U 3 (issued July 31, 1968); and U.S. Patents 3,589,432 3,489,786 (January 13, 1970) and 3,549,700 (August 6, 1969). Such catalysts are reported to represent a better process for the hydrogenation of unsaturated organic compounds, especially olefins, than processes using heterogeneous catalysts.

DE-A-2 308 227, published August 30, 1973, describes the preparation of cV-6-deoxytetracyclines by homogeneous catalytic hydrogenation using tris (triphenylphosphine) chlorodhodium as a catalyst. The catalyst is reported to be prepared in advance or can be prepared directly in the reaction medium by dissolving rhodium trichloride in a medium containing one to three molar equivalents of triphenylphosphine.

U.S. Patent 3,692,864, issued September 19, 1972, describes the hydrogenation of unsaturated organic molecules using homogeneous iron-triple (nickel, cobalt, iron) type metal complexes with tertiary phosphines. A typical representative of the described complexes is chlorotris (triphenylphosphine) cobalt (i).

Numerous publications show that homogeneous catalysis represents promising progress in hydrogenation reactions, including regiospecific, selective, and asymmetric reductions. Knowles et al., Chem. Commun., Pp. 1445 (1968), Horner et al., Angew. Chem., Int. Ed., 7 (1968) 942 and BE Patent 766,960, issued November 10, 1971, disclose the use of monovalent rhodium and optically active tertiary phosphine ligand complexes as homogeneous catalysts to achieve asymmetric catalytic hydrogenation. Recent publications provide fairly extensive reviews in the field: Harmon et al., Chem. Rev. 73 (1973) 21-52; Knowles et al., Chem. Commun., Pp. 10 (1972); Grubbs et al., J. Am. Chem. Soc., 93 (1971) 3062, Kagan et al., J. Am. Chem. Soc., 94 (1972) 6429; and "Homogenous Catalysis, Industrial Applications and Implications," Vol. 70, Advances in Chemistry Series, published by the American Chemical Society, Washington, D.C. (1968); "Aspects of Homogenous Catalysis," Vol. I s.

5-75 (1970), ed. R. Ugo and publications Carlo Manfredi, Milan, Italy; and Vol'Pin et al., Russian Chemical Reviews, 38 (1969) 273-289 ·

Tris (triphenylphosphine) chlorodhodium is reported to be used as a catalyst in the hydrogenation of exocyclic methylene groups in methylene cyclohexanes with a homogeneous catalyst (Augustine et al., Ann. NY Schi. 158 (1969) 482-91; Coronopilin (Ruesch et al. in the context of the total stereoselective synthesis of seychelles (piers et al.) Chem. Communs 1069-70, (1969) the reaction of 6-methylenetetracyclines or their acid addition salts with hydrogen, in the presence of soluble coordination complexes of rhodium and donor-acceptor ligands, has now been found to occur readily by hydrogenation of the exocyclic methylene group.

Alternatively, instead of the 6-methylenetetracycline base and the acid to be added, the acid addition salt of the 6-methylenetetracycline reagent is used. The process of the present invention offers several advantages over previous reduction processes. For example, little or no unwanted anhydrotetracycline is formed; The overall conversion of 6-methylenetetracycline to 6-deoxytetracycline is improved; The 6-methylenetetracycline substrate is reduced almost quantitatively; the catalysts act stereoselectively in the reduction, i. the ratio of the desired 6β epimer to the 6β epimer increases (less than 1% of the β epimer is formed).

The structures of the complexes involved in the hydrogenation process are uncertain. In fact, several complex compounds are quite likely to be involved in the process as catalysts or precursors of catalysts. For this reason, the complexes are most conveniently defined as rhodium-containing halogen-containing complexes prepared from a metal halide and a ligand formed by tertiary phosphines of the formula PiR (R 2, R 2), wherein R 1, R 2 and are as defined above.

According to the present invention, a 6-deoxy-6-demethyl-6-methylene oxytetracycline of the above formula I, or a corresponding 11β-chloro derivative, is dissolved in a suitable solvent medium and allowed to come into contact with hydrogen over a homogeneous catalyst, i. in the presence of a catalyst soluble in the solvent medium at a suitable temperature and pressure and, when Z is hydrogen, preferably in the presence of at least about a molar equivalent of acid per mole of 6-deoxy-6-demethyl-6-methyleneoxytetracycline until the desired reaction, i. When Z is halogen, dehalogenation of the 11-halo group with hydrogenation or non-hydrogenation of the methylene group; or when Z is hydrogen, hydrogenation of the methylene group occurs. Alternatively, and especially when Z is hydrogen, the acid addition salt of 6-deoxy-6-demethyl-6-methyleneoxytetracycline is used as the reagent.

A variety of solvents can be used in this method. The solvents or solvent mixtures selected must be such that, in order to obtain a homogeneous system, the 6-deoxy-6-demethyl-6-methyleneoxytetracycline substrate and the catalyst are dissolved in them at the temperature at which the reaction is carried out. Examples of suitable solvents include the following solvents, and mixtures thereof: ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, N, N-dimethylformamide, Ν, Ν-dimethylacetamide, and alcohols such as methanol, ethanol, propanol, isopropanol.

In addition to these solvent systems, mixtures of water and water-miscible solvents listed above are also suitable. An ethanol-water mixture (90-10) is a preferred solvent when 6-demethyl-6-deoxy-6-methylecin-5-hydroxytetracycline hydrochloride is used as a substrate because the substrate and catalyst are sufficiently soluble therein, and the reaction rate and yield are satisfactory. In addition, if desired, mixtures of the solvents listed above and solvents in which the substrate and the catalyst are poorly soluble can also be used. For example, benzene-dimethylformamide mixtures can be used. The only criterion is that the catalyst and substrate are sufficiently soluble in the system for the reaction to take place.

In addition to the solubility of the catalyst and the substrate, the choice of solvent depends on several factors. Solvent Stability under reaction conditions, especially at higher temperatures, and reaction rate are important in selecting a solvent that maximizes the conversion of the substrate to the desired product. Dimethylformamide appears to decompose to carbon monoxide and dimethylamine, which inactivates the catalyst. The rate of decomposition of such solvents accelerates as the reaction temperature increases. Thus, in order to completely convert the substrate to the desired product, temperatures below 100 ° C and / or higher amounts of catalyst must be used. Dimethylacetamide is much more stable under the reaction conditions used and is the preferred solvent.

Dimethyl sulfoxide, acetone, acetonitrile and hexamethylphosphoric triamide can also be used as solvents. However, their use is not recommended because the reaction rates are lower than those achieved with the solvents listed above.

Alcohol solvents are, in general, the preferred solvents because the solubility of the substrate and catalyst in them is satisfactory, and the reaction rates and yields of the desired products become satisfactory.

The stereoselectivity of the reaction appears to be somewhat dependent on the solvent. It has been found that when dimethylformamide is used, the ratio of oi-epimer to β-epimer is higher than with alcohol solvents under certain conditions.

6 58492

The suitability of a particular solvent or solvent mixture for use in the process of this invention is determined, first roughly, by examining the solubility of the substrate and catalyst therein at the temperature at which the reaction is to be performed. Once the solubility has been found to be suitable, the suitability of a particular solvent system is evaluated by actual experiments, mainly on a small scale, by continuously monitoring the reaction mixture to assess the degree of conversion of the substrate, the nature of the products and the reaction rate. A convenient method is assay by plate chromatography on silica gel plates buffered to pH 6 using a tetrahydrofuran-water solvent system (95-5). The plates are developed with ammonia and made visible to the eye by irradiation with ultraviolet light (366 sec).

Of course, it is not necessary that the 6-methylene oxytetracycline substrate be completely soluble in the solvent medium. All that matters is that it is so soluble in the solvent that the reaction can take place and that the insoluble substrate acts as a reservoir or source of fresh substrate to maintain the concentration of the substrate in the solvent. However, it is preferred to use a solvent in which the substrate and catalyst are completely or almost completely soluble.

The hydrogen pressure used in the process is not critical, but can range from atmospheric pressure to about 27,600 kN / m. Generally, pressures between about atmospheric pressure and about 13,800 kN / m are preferred. The most preferred pressures are about 1-50 atmospheres.

The temperature used in the process is not critical, but can range from about 20 ° C to about 100 ° C. The preferred temperature range is from about 1 ° C to about 85 ° C, and the most preferred range is from about 60 ° C to about 85 ° C. At low temperatures i.e. below about 20 ° C, the reaction rate is low compared to the reaction rate in the recommended temperature range. Low temperatures are therefore not recommended when operating this method on a large scale. The catalyst is deactivated at temperatures above 100 ° C, usually so rapidly that incomplete hydrogenation of the substrate results unless the catalyst is present in large amounts. The reaction temperature range is thus determined not only by the increase in reaction rate normally expected with increasing temperature, but also by the stability of the solvent and catalyst and the quantity of the reaction directly dependent on them.

58492

The effect of the substrate concentration on the reaction, apart from its effect on the reaction rate, seems to be small even in those solvents in which the 6-methyleneoxytetracycline substrate is only partially soluble. Concentration does not appear to have a detectable effect on the stereoselectivity of the reaction; i. the ratio of oi- and /? epimers formed.

The amount of catalyst is not a critical factor either, although for economic reasons it is considered to be between about 0.01 and about 10 moles by weight of the 6-methylene oxytetracycline substrate. This method is perfectly useful even for larger amounts (e.g. up to 100 molar #), but this is disadvantageous from an economic point of view. Smaller amounts of catalyst are not usually used because catalyst deactivation and reaction incompleteness can be a serious problem. Although amounts of catalyst equal to or greater than the amounts of substrate are not generally considered "catalytic" in the sense consistent with the usual use of this term, they are considered as such because in the absence of such material the reaction with hydrogen occurs only by name or does not occur at all.

The reaction takes place only with the help of a "catalyst".

The pH (11a) of the reaction mixture has a significant effect on the reaction rate and the stereoselectivity of the hydrogenation. It has been found that the hydrogenation of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline in an alcoholic solvent using tris (triphenylphosphine) chlorododium (I) as catalyst at 1% by weight of 10% substrate concentration calculated, at 75 ° C and one atmosphere of hydrogen pressure, the β-epimer was obtained in 20-25 #.

The hydrochloride salt of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline gave less than 2β-epimer under the same conditions. Similar results are obtained when hydrogen chloride, dry or aqueous, (2-50 equivalents) is added to the reaction mixture containing 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline. The free base appears to hydrate more slowly than the hydrochloride salt. The 6-methyleneoxytetracycline substrate is preferably used as its acid addition salt, or alternatively, the acid is added to a solution of the base form of the substrate so that the reaction can take place in an acidic medium. Examples of the preferred acid components to be used in such cases are para-toluenesulfonic acid and inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid), in particular hydrochloric acid. The preferred molar ratio of acid to 6-methyleneoxytetracycline reagent 8 58492 is from about 1 to about 5. The preferred molar ratio is from about 2 to about 3 moles of acid per mole of 6-methylene oxytetracycline reagent, since these ratios have the most preferred reaction rate and stereoselectivity. Other acids may also be useful, e.g. citric acid, tartaric acid, maleic acid, fumaric acid, benzoic acid; The acids described in U.S. Patents 3,200 1,199 and 2,900,686, which may form salts with 6-methylenetetracyclines.

The valuable catalysts of this invention are present in the absence of a solvent having a solvating effect on them by means of formula II.

(L) Hh (X ·) II

a c L is a ligand, especially a ligand that can form a donor-acceptor bond, which is more fully described below; X 'is a halide or other anion that maintains electrical neutrality; a is an integer from 1 to 6 and is usually 2-U; and c is an integer from 1 to 3, provided that the sum of a and c is the sum of U when Ph is monovalent; and the sum of a and c is 6 with a different degree of oxidation of Rh.

In solution, the catalysts are believed to follow the formula

(L) Rh (S) (X'L III

m n p wherein L and X 'have the meanings given above; S 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 1 ~ 3, provided that the sum m + n + p = 6.

The exact nature of the complex or complexes involved in the hydrogenation process is not known; based on capable data, it is assumed that the complex acts as a carrier for hydrogen in the formation of dihydride complexes. The exact valence of the metal of the complex is not known because it is likely that during the hydrogenation process, the metal of the complex, if initially present in a form corresponding to higher degrees of oxidation, will be reduced to a lower oxidation state. Thus, rhodium (III) complexes are believed to be converted to rhodium (I) complexes.

Solvent molecules that may be bound to the center metal by coordination bonds can, of course, be considered as ligands. However, it is most convenient to think of them separately from the ligands (L), as it is possible that they may or may not be present in the coordination complex. Their presence in the complex depends on whether the ligands (L) present satisfy the coordination number of the metal and on the ability of the solvent to form coordination bonds not only on its own but also on the ability to form coordination bonds of the ligands already on the metal coordination ring, i.e. the solvent (3) may replace one or more ligands (L).

X ', the anion required to maintain electron neutrality, can be selected from a wide variety of anions and is not critical to this invention. Examples of anions are anions selected from the group consisting of chloride, bromide, iodide, perchlorate, fluoroborate, hydroxide and acetate. The primary anion is chloride.

Suitable ligands' (L) are phosphines corresponding to the general formula

^ 1R2R3) IV

wherein R 1, R 2 and R 2 are as defined above.

Particularly valuable for this process are rhodium complexes with triarylphosphines, due to their stereoselectivity in the reduction, which makes the ratio of pir and β epimers very advantageous. From an economic point of view, triphenylphosphine is a particularly valuable ligand because it is available as a technical product. Preferred catalysts are rhodium complexes with triarylphosphines, and in particular chloro-tris- (triphenylphosphine) rhodium (I), which is available as a technical product and gives, in good yields, mainly β-cepimers.

The catalysts are prepared by methods known to those skilled in the art.

Many of them have, in fact, been described in the above-mentioned publications in the field.

They may be preformed or, for convenience, may be made in 3itu. From a practical point of view, it is recommended to use preformed catalysts, especially in cases where the catalyst is obtained as a technical product, such as, for example, chlorine tris (triphenylphosphine) rhodium (I).

The general process for preparing the catalysts for use in this invention involves reacting a suitable metal halide, especially a chloride (e.g., RhCl 3) corresponding to the usual oxidation state of the metal, with a suitable phosphine in a suitable solvent such as ethanol. A sufficient excess of phosphine is used to reduce the metal. In the case of RhCl 2, the molar ratio of phosphine to RhCl 2 used to form the monovalent rhodium complex is 6: 1. The reaction is usually carried out in a neutral atmosphere.

An alternative process for the preparation of monovalent rhodium complexes involves the reaction of a monovalent rhodium complex with displaceable neutral ligands with the appropriate phosphine. Suitable monovalent rhodium complexes used as reagents in this process include rhodium (I) olefin complexes. Of particular value in this process are the chloro-bis- (ethylene) rhodium (I) dimer and the chloro (1,5-cyclooctadiene) rhodium (I) dimer.

10 58492

The structure of the resulting complex is determined by the ratio of phosphine to rhodium (I) olefin complex used. The molar ratio of phosphine to rhodium (I) olefin complex is 6: 1

complexes of the formula L.Bh 2 Cl are obtained, while a molar ratio of U: 1 is obtained. ^ I

complexes corresponding to the formula LgRh Cl. This method is commonly used to synthesize catalysts in situ. About 2 to about 3 equivalents of phosphine are used per mole of metal.

In the case of in situ preparation of a catalyst with chlorobis (ethylene) rhodium (I), the reaction is carried out in the absence of air and from degassed solvents, for example in a treatment vessel under nitrogen protection, in order to prevent the catalyst from decomposing by oxidation. .

As mentioned above, metal complexes are obtained from a metal halide and a suitable ligand. To maintain electronutrality, the anion usually attached to the complexes is the chloride ion because metal chlorides are generally more readily available than the corresponding bromides or iodides. Of course, the use of bromides or iodides as reagents in the preparation of complexes gives complexes in which the anion is bromide or iodide.

The relatively cumbersome acquisition of metal bromides and iodides can be avoided by adding bromide or iodide ion-producing substances to solutions of chloride complexes, e.g. KBr or KJ. From the viewpoint of accelerating the reaction, it seems preferable that the amounts of potassium bromide or iodide, based on the metal complex, are from about 0.25% to about 1% by weight. Lower or higher amounts do not appear to be an advantage and may even be detrimental to the reaction.

The rate of hydrogenation is affected by the anion of the complex. In the series Rh / P (phenyl) ^ / X, where X is a halide ion, the order appears to be I> Br> Cl. The presence of fluoride appears to be detrimental to the hydrogenation reaction.

Also included as catalysts in the scope of this invention are complexes with optically rotating phosphine, where the rotational site may be at phosphorus or at phosphorus-associated groups. Such catalysts are often even more stereoselective as hydrogenation catalysts in the process of this invention.

The 6-deoxytetracycline products prepared by this method are recovered by any method known to those skilled in the art. For example, 6-deoxytetracycline products can be isolated as amphoteric compounds or acid addition salts, especially by doping the 6-deoxy compound as an insoluble acid addition salt, e.g., by doping as a sulfosalicylate in the case of 58492 6cAdeoxy-5-hydroxytetracycline. Alternatively, the catalyst complex can be removed from the reaction mixture by extraction into a suitable solvent.

In a further process, a metal ion is added, usually in excess, to chelate with 6-deoxytetracycline and thus compete with the catalyst metal for the tetracycline compound. Typical metals include calcium, barium, magnesium, strontium, aluminum, zinc, as well as other metals known to chelate with tetracyclines.

The 6-deoxytetracycline can then be isolated by doping, e.g., the amine-alkaline earth metal complex according to the method of U.S. Patent 2,873,276, or by extraction.

A large amount of catalyst, i.e. at an amount greater than 10 moles, the presence in the reaction mixture may cause difficulties in the isolation step because the catalyst may oxidize.

It has been found that the isolation of 6-deoxytetracyclines from reaction mixtures with large amounts of rhodium complexes is preferably carried out in the absence of air.

It is most convenient to observe and sample the reaction mixtures in order to determine the approximate progress of the reaction and to evaluate the yields of the approximate <and? Isomers by plate chromatography using silica gel plates as described above. A more accurate determination of the reaction course and yields is performed using high pressure liquid chromatography. This is performed using Chromatronix 3100 chromatography (Chromatronix Inc., Berkeley, Calif.). The column used is 2 ra x 2.1 mm, packed with Dypont SAX, a quaternary ammonium-substituted methacrylate polymer coated with 1 weight percent of "Zipax" (registered trademark, EIDupont DeHemours & Co, Inc.). , Wilmington, Delaware). The solvent system is water with 0.001 m of ethylenediaminetetraacetic acid and 0.005 m of sodium acetate, the pH of which has been adjusted to 6.0 with acetic acid. The flow rate used is 0.5 ml / min. The device has 20 m ^ u of infection spindle. In this system, 6-demethyl-6-deoxy-6-methylene-5 'hydroxytetracycline has a K value of 3.6; 6-Odedeoxy-5-hydroxy-tetracycline has a K value of 3.0; and the K-value of 6β-deoxy i-5-hydroxy is a tracycline of 1.8.

As will be appreciated by those skilled in the art, ligands other than those listed above may be used to prepare the valuable catalysts of this invention. Examples of such ligands are phosphiteR 1 R 8 R 8 R 2 wherein R 1 and R 2 are as defined above; R 1 is R 2 or OR 2 (as defined above); RO, sulfides, sulfones, sulfoxides, SOg, HSO4 and SO2®.

In addition to complexes of the type described above; namely, in addition to coordination complexes that are at least moderately soluble in the solvent medium 12 5 8492, homogeneous and heterogeneous catalysis can be accomplished using a rhodium coordination complex, which may be insoluble or only sparingly soluble in the reaction medium.

It is clear, of course, that the classification of coordination complexes on the basis of their solubility is only relative and depends on the solvent system used. Therefore, simply by selecting the solvent correctly, the complex can be reclassified from a soluble complex to an insoluble complex. On the other hand, there are complexes of the type described above which have limited solubility in several solvents and are in the reaction mixture as a separate phase. Such contexts operate by a mechanism not yet known, but based on the binding of the ligand to the metal by coordination solutions.

Limited to this! the scope of solubility coordination complexes also includes a rhodium coordination complex bound to an insoluble polymer.

Of particular interest are rhodium complexes bound to a phosphine group-containing polymer by coordination bonds. Interesting polymer-supported rhodium catalysts are obtained by treating a chloromethylated styrene-divinylbenzene copolymer with lithium phosphines (LiPR 2 R 2 R 2), whereby phosphine replaces chlorine. The styrene-divinyl-benzene copolymer may have varying amounts of crosslinks. Such phosphine-containing polymers have been described by Grubbs et al., J. Am. Chem.

Soc., 93, (1971) 3062 and Capka et al., Tetrahedron Letters, no. 50, (1971) 4787.

A further class of phosphine-containing polymers are the polystyrene polymers crosslinked with the divinylbenzene polymer described by Heitz et al., Angev. Chem., Internat. Ed. 11, (1972) 298. Such polymers are prepared by bromination of a polystyrene-divinyl-benzene polymer and subsequent reaction of the brominated polymer with the sodium salt of the appropriate phosphine. The products differ from the product obtained from chloromethylated styrene-divinylbenzene in that the phosphine moiety is directly attached to the benzene ring.

The manufacturing methods described can be applied to a wide variety of such polymers. The phosphine polymer is treated with RhCl 2 .BH 2 O or another suitable salt in ethanol solution to form a polymer bound to the coordination complex.

Alternatively, the chloromethylated copolymer is treated with a suitable 5,849 13 ioaffin-rouium co-polymer for several days to form a polymer-bound complex.

In addition to the above-mentioned advantages, the limited solubility coordinate polymers and polymer-bound complexes are pleasing in that they are easily removed from the reaction mixtures in which they are present. Furthermore, the recovery of the desired products is usually simplified and the complex can be used in the largest excess without complicating the recovery methods.

In addition to this, vigorous substrates in this method also include silyl ethers of 6-methylenetetracyclines. Such ethers are prepared in a manner not described in J.Chem.Soc. (C), 636 (1970) or variations thereof. In a variation of the methods of this paper, trimethylsilylation with 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline-hydrochloride di a trimethylchlorosilane in a molar ratio of 1: 5 in tetrahydrofuran in the presence of less than 30% triethylamine) for ^5 minutes, O-trimethylsilylated hydro groups 5, 10, 12 and 12a. The product was isolated by filtration of the triethylamine hydrochloride and the enamel solvent evaporated in vacuo to an off-white solid.

Silyl groups, unless removed during the reaction, are readily removed from the reduced products by treatment with dilute acid or hydroxyl-containing solvents.

Further, the enol hydroxy group at the 11- or 12-position can be blocked by esterification, followed by conversion to the enamine as described in U.S. Patent 3,239,499.

In addition to the 6-deoxy-6-demethyl-6-ethyleneate tetraeycline of formula I, which is used as a substrate in this cocaine, the corresponding 6-netylene tetraacyclines corresponding to formulas IA and IB: X Cl (γχ KCCH3) r Jl. jj— C0NH- 1 *. 2 CR .. 0 OH * 0 0 '0 Ό. ° CR2: 21 0R2

IA T-B

111 582 and their acid addition salts, wherein Y 1 is selected from the group consisting of hydrogen and OR 2, wherein R 2 is selected from the group consisting of hydrogen, alkanoyl, phenoxyalkanoyl, lower alkoxyalkanoyl, mono- and dichloroalkanoyl, and mono- and dibromoalkanoyl, having 1 to 6 carbon atoms in the alkanoyl group; X is selected from the group consisting of hydrogen, chlorine, bromine and iodine; X 1 is selected from the group consisting of hydrogen, amino and lower alkanoylamino; X 1 is selected from the group consisting of hydrogen and nitro; R 9 and R 6 are each selected from the group consisting of hydrogen, alkanoyl, phenoxyalkanoyl, lower alkoxyalkanoyl, mono- and dichloroalkanoyl, and mono- and dibromoalkanoyl having 2-6 carbon atoms in the alkanoyl group; and is selected from the group consisting of hydrogen, chlorine and bromine; provided that if X, X 1, X 2, R 8 and R 2 are each hydrogen and Z is hydrogen or chlorine, Y 1 is other than hydrogen or hydroxy.

Example I

6 N, V-hydroxy-5-hydroxytetracycline (Rhodium-triphenylphosphine complex) Catalyst preparation

A solution of chlorobis (ethylene) rhodium (I) dimer (0.100 g, 0.515 mm) dissolved in benzene-free gas (10 mL) is passed through a pump under protection into a 100 mL 3-neck flask connected to an atmospheric hydrogenator. A solution of triphenylphosphine (0.300 g, 1.1 U mm) in degassed benzene (10 mL) is then added, the nitrogen layer is replaced with hydrogen and the mixture is stirred for twenty minutes at room temperature.

The reduction is

A solution of 6-demethyl-6-deoxy-6-methylene-5'-hydroxytetracycline (0.001 g, 0.91 mm) in ethylene glycol monomethyl ether (10 ml) is then added and the mixture is stirred vigorously under a hydrogen pressure of 1.1 atmospheres. hours. Plate chromatography of the reaction mixture (silica plates buffered with phosphate-citrate buffer, pH 6; eluting with 95 # tetrahydrofuran-water) indicated that the reaction was complete. In this TLC system, 6-demethyl-6-deoxy-6-methylene-5 'hydroxytetracycline has an Rf of 0.31, 6-deoxy-5-hydroxytetracycline has an Rf of 0.50, and 6-deoxy-5-hydroxytetracycline has an Rf of hydroxytetracycline Rf 0.2. High pressure liquid chromatography of the reaction mixture (using the system described above) showed a crude yield of 92: 8 and 6% de 6-deoxytetracyclines for the 6 <k and 6 ^ epimers of 85% ·

The authenticity of the product is checked as follows. The reaction mixture is evaporated. . . O. .....

dry at 50 ° C and 1 mm * and the residue is dissolved in a mixture of 58,492 methanol (10 ml), 1N hydrochloric acid (10 ml) and chloroform (10 ml). The aqueous phase is separated, washed with chloroform (10 ml) and then treated with aqueous sulfosalicylic acid (2 ml / 10 #). The separated resinous solid is recrystallized from aqueous methanol to give 0.01 g of 6-deoxy-5-hydroxytetracycline sulfosalicylate. The substance was identical to an authentic O, trdeoxy-5-hydroxytetracycline sulfosalicylate sample when comparing their UV, IR and chromatographic values.

Example II

The procedure of Example 1 is repeated, but replacing the triphenylphosphine with an equivalent amount of diphenylmethylphosphine. After a reaction time of 60 hours, plate chromatographic analysis showed that the crude alloy of the 6de and 6β-5 epimers was 71:29 · 6-deoxy-5 “hydroxytetracyclines by comparing the UV value with the UV value of a known concentrated mixture, 70%.

By repeating this procedure but using the hydrochloride salt of 6-methylene-5 'hydroxytetracycline, a crude product is obtained in which the β-epimer is the predominant product.

Example III

6-oxy-5 "hydroxy tetracycline (Rhodium-triphenylphosphine complex)

Triphenylphosphine (0.272 g, 1.0 U mm) and chlorobis (ethylene) rhodium dimer (0.100 g, 0.52 mm) are added in a nitrogen-filled treatment box to a 100 mL 3-neck round bottom flask equipped with a magnetic stirrer. attached partitioned reflux condenser with three-way valve and plug. The bottle is closed and removed from the bag. Add benzene (20 mL) to the flask using a hand pump and stir the mixture for ten minutes. The flask is connected to an atmospheric pressure hydrogenator, purged with nitrogen and filled with hydrogen. Using a hand pump, a solution of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (2.1 * 9 g, 5.2 mm) in degassed 1,1'-dimethylformamide is added and the mixture is added. stirred and heated at 75 ° C under one atmosphere of hydrogen for seven hours. (High performance liquid chromatographic analysis after 6.5 hours of reaction on a sample of 0.05 ml of the reaction mixture, diluted to 5 ml with methanol and run as described above, showed that the mixture contained about 95% & tk and about 0.7 % 6y9 epimer).

The mixture is then cooled to room temperature and the reaction mixture is transferred to a separatory funnel under nitrogen. Chloroform (20 ml) and water (ho ml) are added, the mixture is shaken and the aqueous phase is removed. Additional chloroform (20 ml) is added to the organic layer, followed by extraction with water (3 x 10 ml). The aqueous extracts were combined, extracted with chloroform (10 mL) and then heated under nitrogen to remove residual chloroform. An aqueous solution of sulfosalicylic acid (50 ml of a 100% solution) is added to the solution (under nitrogen protection). The mixture is stirred and then cooled to room temperature and the sulfosalicylate salt of the product is filtered off and dried in vacuo (3.12 g).

Example IV

6o (-deoxy-5-hydroxytetracycline) Rhodium-tris (k-chlorophenyl) phosphine complex In a 500 ml Parr flask containing a nitrogen-filled bag equipped with a stainless steel sampling tap, place bis (ethylene) rhodium chloride (0 .05 g, 0.26 mm) and tris (k-chlorophenyl) phosphine (0.19 g, 0.52 mm) .The flask is then connected to a hydrogenator and purged with nitrogen. Ethanol (20 ml) is added to the flask with a hand pump and the resulting mixture is shaken. 15 minutes under nitrogen, then a slurry of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (12.1 + 5 g, 26 mm) dissolved in ethanol (JO mL) and water ( 10 ml) and the flask is rinsed three times with hydrogen, pressurized to 3 * + 5 kN / m 2 and heated at 75 ° C (heating time to said temperature for one and a half hours) for 18 hours (samples taken after 1, 2 and h hours showed , as described above, by plate chromatography to determine that reactive had changed by 30%, 55% and 85% respectively). Plate chromatography and high performance liquid chromatography indicated that the reaction was complete after 18 hours.

The reaction mixture is cooled and acidified by saturation with hydrogen chloride gas. After stirring for half an hour, the solid is filtered off, washed with ethanolic hydrochloric acid and dried in vacuo at 60 ° C to give 10.5 g (82%) of 6α-deoxy-5-hydroxytetracycline hydrochloride as the hemihydrate hemialcoholate. Concentration of the filtrate gave an additional 1.1+ g (μl%) of product, with a total yield of 11.9 g (93%). Examination of the product sample by high pressure liquid chromatography showed the presence of about 0.6% β-epimer and no starting material at all.

Example V

6β-Deoxy-5-hydroxytetracycline 11α (-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline p-toluenesulfonate (1.951 + 5 g, 3.0 mm) and chlorotris (triphenylphosphine) rhodium - (1) (280.9 mg, 0.30k mm) is added under nitrogen to degassed methanol (50 ml) at room temperature in a flask connected to a hydrogenator.

u 58492

The flask is purged with nitrogen and then filled with hydrogen so that the pressure 2 o is 310 kN / m. The reaction mixture, slurry, is warmed to 30 ° C and shaken for 68 hours. High performance liquid chromatography showed that the mixture contained 1.5 * 2% (3-epimer.

The reaction mixture, the solution is removed from the hydrogenator under nitrogen, is treated with 10 ml of 1 mol of sulfosalicylic acid (in methanol). Water is then added until the solution is cloudy and the solution is stirred under nitrogen for two hours. The yellow solid was collected by filtration (1.5713 g) and washed with a small volume of methanol. Methanol is removed from the combined washings and filtrate and the solid is collected by filtration. yield of o <epimer = 89% ·

Example VI

6ofc-deoxy-5-hydroxytetracycline hydrochloride

The following reagents are placed in the hydrogenation flask under a nitrogen atmosphere: 6-demethyl-6-deoxy-6-methylene-5 * hydroxytetracycline hydrochloride (5.00 g, 10.1+ mm), chlorotris (triphenylphosphine) rhodium (1) (25 mg, 0.027 mm), potassium bromide (12.5 mg) and 50 ml of a gas-free ethanol-water mixture (9: 1). The flask is purged with nitrogen and hydrogen is added until the pressure is 1 + 1 + 0 kN / m at room temperature. The reaction mixture is heated at 70 ° C for 15-5 hours and then cooled to room temperature. High performance liquid chromatography (HPLC) analysis as described above showed that the mixture contained about 2.5% β-epimer and 97-5% oi-epimer.

Dry hydrogen chloride is bubbled into the reaction mixture and the solution is stirred until a precipitate forms. After standing for three hours, the solid product is filtered off and dried (3.65 g, 73%). HPLC analysis showed 81.7 * +% oi and 0.81% β-epimer and 5.77% starting material.

On standing, a record amount of product (551 mg) separated from the filtrate. HPLC showed 56.57% oi- and 0.52% β-epimer, as well as 1.73% starting material.

When this treatment is repeated, but using potassium iodide instead of potassium bromide, essentially the same results are obtained.

Example VII

6α4-Deoxy-5-hydroxytetracycline sulfosalicylate salt To gas-free methanol (18 mL) and water (2 mL) in an autoclave bomb is added 11α-chloro-6-demethyl-6-1818492 deoxy-6-methylene-5-hydroxytetracycline-hydroxyl (5 ml) at room temperature under nitrogen. 1.0 g, 19-9 mm) and chlorotris (triphenylphosphine) rhodium (I); a (18 mg, 0.019½ mm), potassium iodide (10 mg). The vessel is purged with nitrogen and then filled with hydrogen until the pressure is 11,700 kN / m. The reaction mixture is stirred and heated at 70 ° C for 1.5 hours and then cooled. The contents are removed and diluted with methanol (50 mL) under nitrogen.

A solution of sulfosalicylic acid (20 ml of a 10 # methanol solution) and water (10 ml) is added to the diluted reaction mixture under nitrogen. The mixture is mixed thoroughly and then filtered. The sulfosalicylate thus obtained is washed with cold aqueous methanolic solution (50-30 ml) and dried (1.0½ g).

Determination of the intensity of the UV absorption spectrum of a sample taken from the product at 3½ m | i in 0.01 N hydrochloric acid in methanol and comparison with the corresponding value of a standard sample shows a yield of 6,2-deoxy-5-hydroxytetracycline sulfosalicylate salt of 88.29%. dehalogenation

A mixture of chlorotris (triphenylphosphine) rhodium (1) (20 mg, 0.0216 mm), 11α-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxy-tetracycline hydrochloride ( 2.0 g, 3.9 mm) and degassed methanol (30 mL) are placed in a hydrogenation flask and the flask is connected to a Parr shaker. The flask is purged with hydrogen and then hydrogen is introduced until the pressure is 310 kN / m at room temperature.

The mixture is shaken and heated at 70 ° C for 15 hours. It is then cooled to room temperature and the contents of the flask are removed and examined using high pressure liquid chromatography. The main product is 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline. The mixture contains traces of 6α- and 6β-deoxy-5-hydroxytetracyclines, but not the starting material.

The same results are obtained using chlorotris / tri- (i + -chlorophenyl) phosphine-7-rhodium (I) instead of chlorotris (triphenyl) phosphine-rhodium (I).

Claims (1)

19 58492 Claim; Process for the preparation of 6-deoxyoxytetracycline of formula) 2 conh2 HO O ^ 0 H ° O and its salts, characterized in that 6-deoxy-6-demethyl-6-methyleneoxytetracycline of formula H 2 HN (CH 3) 2 v CONH 2 hT o z6e6 o wherein Z is hydrogen, chlorine or bromine, or a salt thereof, is treated with hydrogen in an inert solvent at 20-100 ° C under a hydrogen pressure of at least atmospheric pressure in the presence of a complex of rhodium and a tertiary phosphine of formula PiR (RgR ^), wherein R 1 and R 2 are phenyl or k-chlorophenyl, and R 2 is the same as or R 2 or is methyl.