NO153806B - PROCEDURE FOR THE PREPARATION OF 6-DEOXYTE TRACYCLINE. - Google Patents

Description

The invention relates to a method for hydrogenation

of the exocyclic methylene group in a 6-methylenetetracycline. More particularly, it applies to the hydrogenation of a 6-methylenetetracycline or an acid addition salt of said compound, by contacting the compound and hydrogen with a complex of rhodium and tertiary phosphines,

1 a solvent in which the complex is soluble.

The reaction between 6-demethyl-6-deoxy-6-methylenetetracyclines, acid addition salts thereof and polyvalent metal salt complexes thereof and hydrogen in the presence of a heterogeneous ede metal catalyst to produce the corresponding epimeric α- and /3-6-deoxytetracyclines is described in the U.S. patent 3,200,149. The use of a poisoned noble metal catalyst to achieve the same conversion but with an increase in the ratio between α- and 0-6-deoxytetracycline is discussed in U.S. Pat. U.S. Patent 3,444,198 patent 2,984,686 describes the use of catalytic reduction using hydrogen and a noble metal catalyst to achieve only an 11a-dehalogenation of 11a-halo-6-demethyl-6-deoxy-6-methylenetetracycline. In addition, reduction of lla-halo-6-demethyl-6-deoxy-6-methylenetetracyclines, salts and complexes thereof in the presence of a noble metal catalyst by using hydrazine as a hydrogen source is discussed in German patent 2 131 944. British patent 1 296 340 describes use of Raney nickel and Raney cobalt as catalysts for such reductions. Rhodium halide complexes containing tertiary phosphine or arsine ligands, their preparation and use as homogeneous hydrogenation catalysts are described in U.S. Pat. patent 3,639,439, issued February 1, 1972. Soluble complexes of the platinum metal group, especially of rhodium, containing a halide and a tertiary phosphine, arsine, stibine or amine, their preparation and their use as hydrogenation catalysts are also disclosed in British Patents 1,138,601 (published 1 January 1969), 1,219,763 (published 20

January 1971) 1,121,642 (issued July 31, 1968) and 1,121,643 (issued July 31, 1968) and in U.S. Pat. patents 3,489,786 (January 13, 1970) and 3,459,780 (August 5, 1969). Such catalysts are indicated to provide an improved process for the hydrogenation of unsaturated organic compounds, especially of olefins, compared to an- . the reversal of heterogeneous catalysts.

Norwegian patent 138 565 (27 August 1973) describes the preparation of α-6-deoxytetracyclines by homogeneous catalytic hydrogenation using tris(triphenylphosphine)chlororhodium as catalyst. According to the description, the catalyst can be formed in advance or can be prepared directly in the reaction medium by dissolving rhodium trichloride in the medium in the presence of between one and three molar equivalents of triphenylphosphine.

U.S. patent 3,692,864, issued September 19, 1972 teaches the hydrogenation of unsaturated organic molecules using homogeneous metal complexes of the iron triad type (nickel, cobalt, iron) with tertiary phosphines. Typical of the described complexes is chloro-tris(triphenylphosphine)cobalt(I).

Many publications state that homogeneous catalysis is a law-ending way to carry out hydrogenation reactions, including regiospecific, selective and asymmetric reductions. Knowles et al., Chem. Commun., p 1445 (1968), Horner et al., Angew. Chem., Int. Ed., 1_, 942 (1968) and Belgian Patent 766,960, published November 10, 1971 disclose the use of complexes of monovalent rhodium with optically active tertiary phosphine ligands as homogeneous catalysts to achieve asymmetric catalytic hydrogenation. Recent publications provide a very comprehensive overview of what is known: Harmon et al., Chem. Fox. 7_3, 21-52 (1973), Knowles et al., Chem. Commun., p 10 (1972), Grubbs et al., J. Am. Chem. Soc, 92, 3062 (1971), Kagan et al., J. Am. Chem. Soc, 94, 6429 (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), edited by R. Ugo and published by Carlo Manfredi, Milan, Italy and vol'Pin et al., Russian Chemical Reviews, 38, 273-289 (1969).

Homogeneous catalytic hydrogenation of exocyclic methylene groups in methylenecyclohexanes (Augustine et al., Ann. N. Y. Sei. 158, 482-91, (1969), in coronopilin (Ruesch et al., Tetrahedron, 25., 807-11, 1969) and in an intermediate in the stereoselective total synthesis of seychelle (Piers et al., Chem. Communs. 1069-70, 1969) using tris(triphenylphosphine)chlororhodium as a catalyst is discussed.

Osborn et al., J. Chem. Soc. (A), 1711-1732 (1966) describes the preparation of the bromide and iodide analogues of the Wilkinson catalyst by reacting said catalyst with an excess of lithium bromide or lithium iodide (p. 1712). Page 1715 of the article states that the bromide and iodide analogues react with molecular hydrogen in a reversible manner as does the chloride [Wilkinson catalyst, RhCl(PPh3)3]. The use of RhX(PPh3)3 where X=C1, Br, I, as a catalyst for the reduction of cyclohexane is described on page 1722 of the article. The increase in the catalyst's activity is Cl<

Br<I.

The reaction between 6-methylenetetracyclines or their acid addition salts and hydrogen in the presence of soluble coordination complexes of rhodium with donor-acceptor ligands as catalysts

is now found to proceed smoothly with hydrogenation of the exocyclic methylene group. The present method is characterized by the fact that it takes place in the presence of potassium bromide or potassium iodide. Alternatively, an acid addition salt of 6-methylenetetracycline is used instead of the 6-methylenetetracycline base and added acid. The method according to the invention has many advantages over the known reduction methods. For example, little or nothing of the undesired anhydrotetracycline is formed, the overall conversion of a 6-methylenetetracycline to a 6-deoxytetracycline is improved, an almost quantitative reduction of the 6-methylenetetracycline substrate is achieved, and the catalysts provide stereoselectivity in the reduction, i.e. the ratio between the desired 6a-epimer and 60-epimer are increased (less than 1% 0-epimer is formed).

The process is useful for the hydrogenation of 6-methylenetetracyclines of the following formula:

and acid addition salts thereof.

The structure of the complexes used in the hydrogenation process is not known with certainty. In all likelihood, in reality a number of complexes are involved in the process as catalysts or catalyst precursors. It therefore becomes appropriate to define the complexes as halogen-containing rhodium complexes which have been obtained from a halide of the metal and a tertiary phosphine ligand of the formula PR^R£R3 where each of and R2 is phenyl or 4-chlorophenyl, and R^ is R^ or methyl.

In accordance with the method according to the invention, a 6-methylenetetracycline of the above formula is dissolved in a suitable solvent and brought into contact with hydrogen in the presence of a homogeneous catalyst, i.e. a catalyst which is soluble in the solvent, at suitable pressure and temperature and in the presence of at least approx. one molar equivalent of acid per mol of 6-methylenetetracycline, until the desired reaction occurs, i.e. hydrogenation of the methylene group.

Alternatively, an acid addition salt of the 6-methylene-tetracycline compound is used as reactant.

Many different solvents can be used in the present method. The solvents or solvent mixtures chosen may be such as to allow solubilization of the 6-methylenetetracycline substrate and the catalyst at the temperature at which the reaction is carried out to obtain a homogeneous system. Representative suitable solvents are the following and mixtures thereof: ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide and alcohols such as e.g. methanol, ethanol, propanol, isopropanol and butanol.

In addition to these solvent systems, mixtures of water and the water-miscible solvents mentioned here are also suitable. Ethanol-water (90-10) is a preferred solvent when 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride is used as substrate, since it provides adequate solubility for substrate and catalyst, and satisfactory speed and yield of the reaction. Furthermore, if desired, mixtures of the above-mentioned solvents with solvents in which the substrate and the catalyst are poorly soluble can also be used. For example, mixtures of benzene and dimethylformamide can be used. The only criterion is that the catalyst and substrate are sufficiently soluble in the system for the reaction to take place.

The choice of solvent depends on several factors in addition to the solubility of the substrate and the catalyst. Factors such as the stability of the solvent under the reaction conditions, especially at higher temperatures, and the reaction rate are important when choosing a solvent that will give maximum conversion of the substrate to the desired product. Dimethylformamide appears to undergo decomposition to carbon monoxide and dimethylamine which inactivates the catalyst. The decomposition rate for such solvents accelerates with increasing reaction temperature. In order to achieve complete conversion of the substrate to the desired product, temperatures below 100°C and/or increased amounts of catalyst must therefore be used. Dimethylacetamide is much more stable under the reaction conditions used and is a preferred solvent.

Dimethyl sulfoxide, acetone, acetonitrile and hexamethylphosphotriamide can also be used as solvents. However, their use is not preferred since they cause lower reaction rates than the above-mentioned solvents.

Alcoholic solvents are generally the preferred solvents since they provide satisfactory solubility for substrate and catalyst, satisfactory reaction rates and yields of desired products.

The stereoselectivity of the reaction seems to depend to some extent on the solvent. Dimethylformamide has been observed to give a somewhat higher ratio of α- to β-epimer than alcoholic solvents under certain conditions.

Whether a given solvent or solvent mixture is suitable for the method according to the invention is determined as a first approximation by examining the solubility of the substrate and the catalyst therein at the temperature at which the reaction is to be carried out. As soon as adequate solubility has been observed, it is assessed whether the particular solvent system is suitable for the experiment in question, preferably on a small scale, with constant examination of the reaction mixture to determine the degree of conversion of the substrate, the nature of the products and the reaction rate. A suitable method is thin-layer chromatography on silica gel plates buffered to pH 6 by using the solvent system tetrahydrofuran-water (95-5). The plates are developed with ammonia and made visible under ultraviolet light at 366 mu.

It is of course not necessary for the 6-methylenetetracycline substrate to dissolve completely in the solvent. It is only decisive that it is sufficiently soluble in the solvent for the reaction to take place, and that the undissolved substrate serves as a reservoir or source of new substrate to maintain a substrate concentration in the solvent. However, it is preferred to use a solvent in which the substrate and catalyst are completely, or almost, dissolved.

The hydrogen pressure to be used in the method is

not critical but can vary from sub-atmospheric pressure to 280 kp/cm 2. Usually pressures from approx. an atmosphere to approx.

14o kp/cm 2. Pressure from one atmosphere to approx. 50 atmospheres is preferred. Subatmospheric hydrogen pressures are conveniently achieved by introducing an inert gas, e.g. nitrogen, in the reaction vessel in addition to the hydrogen. A hydrogen partial pressure of less than one atmosphere is then easily obtained.

The temperature during the process is not critical but can vary within a range from approx. 20 to approx. 100°C. The favorable temperature range is from approx. 40 to approx. 85°C and the preferred re-

advise from approx. 60 to approx. 85°C. At low temperatures, i.e. below approx. 20°C, the reaction rate is low compared to the rate at the favorable temperature range. Low temperatures are therefore not desirable for large-scale work using this method. At temperatures above 100°C, inactivation of the catalyst occurs, usually at such a rate that it results in incomplete hydrogenation of the substrate, except when large amounts of catalyst are used. The temperature range for the reaction is therefore determined not only by an increase in the reaction rate which is normally expected with a temperature increase, but also by the stability of the solvent and the catalyst, and as a direct consequence of this the complete completion of the reaction.

The concentration of the substrate appears to have little effect on the reaction except in terms of the reaction rate even in solvents in which the 6-methylenetetracycline substrate is only partially soluble. There appears to be no noticeable concentration-dependent effect on the stereoselectivity of the reaction, i.e. on the ratio of α- and β-epimers that are formed.

The catalyst concentration is likewise not a critical factor, but for economic reasons it is usually kept at a level

from approx. 0.01 mole percent to approx. 10 mole percent by weight based on the 6-methylenetetracycline concentration. Use of larger amounts (eg up to 100 mole percent) can be used in the present method, but is economically disadvantageous. Small amounts of catalyst are usually not used since inactivation of the catalyst and incomplete reaction are likely to be a serious problem. While amounts of catalyst equal to or greater than the amount of substrate are not usually considered "catalytic" in the common usage of the term, they are considered so here since in the absence of such material it will

no or only little reaction. It is only with the help of a "catalyst" that the reaction takes place.

The pH (apparent pH) of the reaction mixture is a significant factor in terms of the reaction rate and the stereoselectivity of the hydrogenation. It has been observed that 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline when hydrogenated in alcoholic solution using tris(triphenylphosphine)chlororhodium(I) as catalyst in an amount of 1% by weight based on 10% concentration of the substrate at 75°C and one atmosphere of hydrogen gave from 20-25% /3-epimer. 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride gave less than 2% P-epimer under similar conditions. Similar results are obtained when hydrogen chloride, dry or aqueous, (2-50 equivalents) is added to a reaction mixture containing 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline. The free base appears to hydrogenate more slowly than the hydrochloride. The 6-methylenetetracycline substrate is preferably used as an acid addition salt, or alternatively an acid is added to a solution of the base form of the substrate to allow the reaction to take place in an acidic medium. Para-toluenesulfonic acid and mineral acids (hydrochloric, hydrobromic, sulfuric and nitric acid), especially hydrochloric acid, represent preferred examples of the acid component in such cases. Molar ratio between acid and 6-methylenetetracycline is advantageous from approx. 1 to approx. 5. The preferred ratio is from approx. 2 to approx. 3 moles of acid per mol 6-methylenetetracycline, since optimal reaction rate and stereoselectivity with a minimum of side reactions occur at such conditions. Many other acids, e.g. citric, tartaric, maleic, fumaric, benzoic and acids described in U.S. Pat. patent 3,200,149 and 2,984,686 and is capable of salt formation with 6-methylenetetracyclines, can also be used.

Example 1.

6a- deoxy- 5- hydroxytetracycline hydrochloride.

The following reactants are placed in a hydrogenation flask under a nitrogen atmosphere: 6-demethyl-6-deoxy-6-methylene-5-hydroxy-tetracycline hydrochloride (5.00 g, 10.4 mmol), chlorotris(triphenylphosphine)rhodium(I) (25 mg, 0.027 mmol), potassium bromide (12.5 mg) and 50 ml degassed ethanol water (9:1). The flask is freed of nitrogen and filled with hydrogen at 4.5 kp/cm 2 at room temperature. The reaction mixture is heated to 70°C for 15.5 hours and then cooled to room temperature. High pressure liquid chromatography (HPLC) in the manner described above indicated that approx. 2.5% β-epimer and 97.5% α-epimer were present.

Anhydrous 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, 75%).

HPLC showed that it contained 81.74% α- and 0.81% β-epimer

and 5.77% starting material.

In case of delay, a second harvest of product was obtained

(551 mg) from the filtrate. HPLC showed that it consisted of 56.57% α- and 0.52% β-epimer and 1.73% starting material.

Repeating this procedure but using potassium iodide instead of potassium bromide gives essentially the same result.

Example 2.

The procedure from example 1 is repeated, but using high-pressure equipment, so that hydrogenation pressures of 126.5, 175.8 and 280 kp/cm<2> can be used with essentially the same results.

Claims (1)

Process for the production of 6-deoxyoxytetracycline with the formula and salts thereof, by reaction of 6-deoxy-6-demethyl-6-methylene-oxytetracycline with the formula or a salt thereof, with hydrogen in an inert solvent at 20-100°C under a hydrogen pressure of at least one atmosphere in the presence of a complex between rhodium and a tertiary phosphine of the formula P^I^F^), where R.j and R.sub.2 mean phenyl or 4-chlorophenyl , and R^ means the same as R^ or R 2 or a methyl group, characterized in that the reaction is carried out in the presence of potassium bromide or potassium iodide.