IMPROVED PROCESS FOR THE PREPARATION OF TETRACYCLINE DERIVATIVES

Abstract: The invention relates to a process for the preparation of tetracycline derivatives of formula (I), and acid addition salts thereof, wherein R stands for -CH₃ or = CH₂, by dehalogen­ ating and hy drating chloromethacycline or acid addition salt thereof of formula (II), or by hydrating methacycline or acid addition salts thereof of formula (III), by a treatment with hydrogen gas in the presence of a noble metal alloy catalyst on carrier and organic solvent which comprises perform­ ing hydrating under pressure of 0.1-1.0 MPa with an alloy catalyst consisting of the alloy palladium or platinum and sele­ nium and/or tellurium used at a ratio of 1:0.01-0.5 related to the amount of the starting tetracycline and carrying out, if de­ sired dehalogenation and hydration in one step.

Description: The present invention relates to an improved process for the preparation of doxycycline and methacycline and acid addition salts thereof by catalytic dehalogenation and hydrogenation by using a tellurium and/or selenium containing alloy catalyst. The following abbreviations are used throughout the specification: "methacycline": 4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methylene-1,11-dioxo-2-naphthacene-carboxamide of the formula "chloro-methacycline": 4-dimethylamino-1,4,4a,5,5a,6,11,12-12a-nonahydro-3,5,10,12a-tetrahydroxy-11a-chloro-6-methylene-1,11,12-trioxo-2-naphthacene-carboxamide of the formula "doxycycline": α-6-desoxy-5-hydroxy-tetracycline, i.e. 4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12-12a-pentahydroxy-6α-methyl-1,11-dioxo-2-naphthacene-carboxamide of the formula "β-Doxycycline" is the β-isomer of doxycycline. It is known that methacycline and doxycycline are very effective representatives of the tetracycline type antibiotics. Several processes are known for the preparation thereof using oxytetracycline as starting material to prepare chloromethacycline, followed by dehalogenation and if desired by hydrogenating the obtained methacycline to doxycycline. Dehalogenation has been performed with hydrogen gas in the presence of a catalyst, see e.g. Example 9 of HU-PS 150909, where rhodium precipitated on active coal was used. This process, however, was not satisfactory as reaction products were produced which were difficult to separate from side-products, and the conversion was not complete. Therefore the use of secondary or tertiary phosphines has been recommended in HU-PS 169 605. This process was accompanied by the disadvantage that an equimolar amount of tertiary or secondary phosphines was needed, resulting in a great amount of toxic waste, and the formed phosphine oxide could be converted again to phosphine only by a multi-step reaction. The introduction of hydrogen gas in the presence of a catalyst was also used for the saturation of the double bond of the methylene group at the 6-position on methacycline in order to produce doxycycline. In the course of hydrogenation, 6-desoxy-5-hydroxytetracycline of the formula (IV) can occur in the form of α- and β-isomers. Only the α-isomer is valuable as medicine, i.e. doxycycline. The amount of the α-isomer during hydrogenation determines if the hydrogenation process is successful, i.e. if hydrogenation can be carried out selectively, to produce mainly α-isomer in good yield and pure quality. It is known that 6-desoxy-5-hydroxy-tetracycline can be prepared in a yield of 60 % by using a 5 % palladium or rhodium catalyst on a carrier, but the product is a 1:1 mixture of α- and β-isomers and the separation of the α-isomer is accompanied by further losses (US-PS 3 200 149). The ratio of the formation of the α-isomer can considerably be improved, if the noble metal catalyst on a carrier is poisoned by carbon monoxide, quinoline, sulphur or other sulphur compounds. Thus the yield of the α-isomer can be increased to 40-50 %, but even so the product has to be further purified due to the remaining 10 % β-isomer impurities (HU-PS 156 925). In order to improve the stereoselectivity of hydrogenation an alloy catalyst of metals of platinum group, copper, silver or gold has been used and a doxycycline yield of about 70 % has been disclosed with 1 to 10 % β-isomer impurities (HU-PS 167 250). A 92 % α-isomer content has been achieved by using a catalyst containing palladium atoms located on ultramicroporous active coal, without poisoning, with a yield of 76 % (HU-PS 169 667). Hydrogenation can be performed by using Raney nickel and Raney cobalt as a catalyst according to GB-PS 1 296 340, but the formation of α-isomer in the reaction mixtures amounts only to about 40 %. According to Finnish PS 67210, a complex of bis(diphenylselenide) palladium(II)chloride is added to a palladium/carbon catalyst, resulting in a yield of 75 %, wherein the α-isomer content was about 95 %. According to the disclosure this effect cannot be achieved if diphenylselenide is not used in a complex form. In order to give a complete review of the known processes, we mention other hydrogenation processes performed by using triphenyl phosphine rhodium complexes, which are soluble in the reaction mixture (DE-OS 2 403 714), or by using further additives with the complexes (HU-PS 169 753, 169 508, 175 508 and 187 465). Doxycycline could thus be prepared with a good yield and selectivity. Inspite of the significant development the known processes show many drawbacks. As already mentioned the use of the known heterogeneous catalysts only partially solves the problem of stereoselectivity. A considerable amount of these catalysts have to be used, and so the ratio substrate-catalyst is not favourable. The relatively great amount of solvent is also unfavourable. Although the catalysts can be removed from the reaction mixture by filtration, the solvent has to be recovered before use by a costly and inefficient procedure. In case of homogeneous catalysis the catalyst is in solution and its isolation is not easy. Rhodium is very expensive, it is difficult to obtain, its recovery is complicated, expensive and it can contaminate the product. US-A 3 962 139 and US-A 4 384 986 generally disclose alloys of palladium or platinum with tellurium as catalysts. According to the present invention methacycline and doxycycline are prepared in a heterogeneous system, wherein dehalogenation can be performed with good yield and reduction takes place stereoselectively, the side reactions can be eliminated to such extent that no extra purification of the product is needed, and the catalyst can be prepared simply and at low cost. The dehalogenation and hydrogenation can be performed without any extra equipment by using the same type of catalyst. The present invention is directed to a process for the preparation of tetracycline derivatives and acid addition salts thereof of the general formula (I). by dehalogenating and hydrogenating chloromethacycline or an acid addition salt thereof of the formula II or by hydrogenating methacycline or an acid addition salt thereof of the formula III by a treatment with hydrogen gas in the presence of a noble metal alloy catalyst on a carrier in the presence of an organic solvent. The hydrogenation is carried out at a pressure of 0.1-1.0 MPa with an alloy catalyst used at a ratio of 1:0.01-0.5 relative to the starting tetracycline derivative and consisting of an alloy of palladium or platinum and selenium and/or tellurium. If desired the dehalogenation and hydrogenation can be performed in one step. As a carrier e.g. active charcoal, silica or aluminium oxide can be used. In order to prepare the noble metal-containing catalyst one may proceed by treating an aqueous suspension of palladium or platinum on a carrier with a solution or suspension of an organic or inorganic selenium or tellurium compound and optionally by reducing the obtained compound. Such compounds can be selected from salts, oxides and other derivatives, such as selenious acid, diphenyl selenide etc. Alternatively, palladium or platinum salts and selenium or tellurium compounds may be dissolved in acidic water and added to a carrier, preferably active charcoal, followed by reduction. The noble metal content of the catalyst may vary between 1 to 30 % by weight, preferably 5 to 10 % by weight, and the amount of the alloying components may vary between 1 to 70 % by weight relative to the amount of the noble metal content. As a solvent, lower alcohols, ketones, N,N-dialkyl amides, water and mixtures thereof may preferably be used. It is not necessary to dissolve the starting material completely. According to a preferred method methacycline may be prepared by saturating chloromethacycline with equimolar hydrogen gas at a pressure of 0.1-0.3 MPa in the presence of an alloy catalyst selected from palladium-selenium, palladium-tellurium, platinium-selenium and platinium-tellurium, by using the catalyst in an amount of 1:0.01-0.2 relative to the weight of chloromethacycline, wherein the amount of the alloying components is 20-70 % by weight relative to the noble metal content. Methacycline may be recovered from the reaction mixture by any known method in the form of a base, acid addition salt or complex. The main advantages of the dehalogenation according to the present invention: dehalogenation can be performed without side reactions, the conversion of methacyclines to 5-12a lactones can be suppressed, and the reaction takes place at atmospheric pressure and room temperature within a short time. The catalyst can be prepared simply, it is not pyrophoric and its activity does not decline with storing or in the course of the reaction, and thus it can be used several times without regeneration. Thus the catalyst costs are minimal, and almost negligible. In order to obtain doxycycline, methacycline or chloromethacycline or a salt thereof can be treated with hydrogen gas in the presence of an alloy catalyst consisting of palladium-selenium, palladium-tellurium, platinum-selenium or platinum-tellurium at a pressure of 0.1-1.0 MPa with a catalyst ratio of 1:0.05-0.5, preferably 0.15-0.25, relative to the weight of methacycline, wherein the amount of the alloying components is 1 to 40 % by weight. If chloromethacycline or a salt thereof are used as starting material, then dehalogenation and the selective saturation of the double bond can be performed in a single step. As a solvent lower alcohol, ketones, dimethylformamide, water and mixtures thereof are used. When the reaction is terminated the catalyst is filtered and may be used for further reactions. The product may be isolated from the filtrate by any known method, such as in the form of a salt of hydrogen halogenic acid, 5-sulfosalicylic acid or in the form of hyclates. The main advantages of the process for the preparation of doxycycline are as follows: the saturation of the exocyclic methylene bond in methacycline takes place substantially stereoselectively, i.e. the β-isomer content is reduced to below 1 % by weight (according to HPLC), in the reactions starting with chloromethacycline, dehalogenation and hydrogenation can be carried out in a single step, and the reaction can be performed at atmospheric pressure and room temperature in a short time, the catalyst can be rapidly prepared simply, it is not pyrophoric, and its activity does not decrease under storing or in the course of the hydrogenation reaction, and thus the catalyst costs of the process are minimal, almost negligible, the process may be continual, the isomerisation side reaction occurring in heterogeneous catalytical reactions, causing intensive decomposition, is suppressed and therefor doxycycline can be obtained in good yield. This experience is highly suprising as selenium is known to act as a catalyst in oxidation and isomerisation reactions. Further details of the invention can be found in the following Examples: Example 1 10 g 10 % by weight palladium/charcoal catalyst are suspended in 100 ml of water and 0.1 to 0.7 g of selenious acid are added as desired and the mixture is subjected to hydrogenation at room temperature under stirring. The mixture is then filtered, washed with water and acetone and dried. The activity of the catalyst is measured. Example 2 1.33 g of palladium(II)chloride and 0.2-0.7 g of tellurium(IV)oxide are dissolved in 100 ml of 6N hydrochloric acid, whereafter 10 g of charcoal are added and the mixture is stirred for 3 hours and hydrogenated with hydrogen gas. The catalyst is filtered, washed to neutral and dried. Its activity is measured. Example 3 5 g of 10 % by weight palladium/charcoal catalyst are suspended in 50 ml of ethanol, and as desired 0.15-1 g of diphenyl selenide are added, the suspension is boiled for 30 minutes, and the catalyst is filtered and dried. Its activity is measured. Example 4 10 g of 5 % by weight palladium/silica catalyst are suspended in 100 ml of water and as desired 0.1-0.4 g of selenious acid are added and we further proceed as given in Example 1. The activity is measured. Example 5 10 g of 5 % by weight platinum/active charcoal catalyst are suspended in 100 ml of water and as desired 0.05 g to 0.4 g of selenious acid are added and we further proceed as disclosed in Example 1. Example 6 1.77 g of palladium(II)chloride and as desired 0.1-0.75 g of selenium dioxide are dissolved in 80 ml of 12 N hydrochloric acid and 5 g of silica gel are added, the mixture is hydrogenated, filtered and dried. Its activity is measured. The activity of the catalysts prepared according to the above Examples are estimated by a method known per se, by hydrogenating a cyclohexene model compound. Preparation of methacycline Examples 7 to 12 20 g of 11a-chloro-methacycline-p-toluene-sulfonate are reacted with hydrogen gas in 200 ml of solvent by using 1-3 g alloy on carrier catalyst at room temperature at a pressure of 0.1-0.3 MPa. When the equimolar amount of hydrogen is taken up, the catalyst is filtered off, and working up may be performed as desired as follows: a) 20 g of 5-sulfosalicylic acid are added, the product is crystallized and methacycline sulfosalicylate is isolated, or b) the filtrate is evaporated in vacuo, and 75 ml of methanol and 7.5 g of p-toluene sulfonic acid are added to the residue. The mixture is crystallized and methacycline tosylate is isolated, or c) the filtrate is evaporated in vacuo and 50 ml concentrated hydrochloric acid are added and methacycline hydrochloride is isolated. Yield: 85-95 %. The quality of the products is homogenous according to thin layer chromatography (developing agent: a 95:5 mixture of tetrahydrofuran and water) on a silicagel carrier plate impregnated with a buffer of pH 6. Active ingredient content by biological value testing: 100 %. The details are shown in Table I. Preparation of doxycycline Examples 13 to 20 47.3 g of methacycline hydrochloride or 63.6 g of methacycline p-toluene sulfonate are hydrogenated in 500-580 ml of solvent by using 3.5 to 10 g of an alloy catalyst on carrier at room temperature and a pressure of 0.1 to 1.0 MPa until the hydrogen uptake is completed. After filtering off the catalyst the filtrate can be worked up as follows: a) 50 g of 5-sulfosalicylic acid are added to the filtrate and the product is crystallized, filtered and dried. Doxycycline sulfosalicylate is obtained as a product, or b) the filtrate is evaporated in vacuo, 250 ml methanol and 25 g of p-toluene sulfonic acid are added to the residue, the mixture is crystallized and doxycycline tosylate is isolated, or c) the filtrate is evaporated in vacuo, 180 ml of ethanol and 30 ml of hydrochloric acid are added to the residue and, after dissolving and clarification, 50 ml of hydrochloric acid and ethanol in hydrochloric acid are added to the filtrate. The mixture is crystallized and doxycycline hyclate is isolated, or d) the filtrate is evaporated to dryness in vacuo, 250 ml of acetone are added to the residue and by introducing hydrochloric acid gas the doxycycline hydrochloride is recovered. Yield: 80-90 %. Quality of the product is homogeneous according to thin layer chromatography. Active ingredient content by biological value testing: 100 %. Ratio of α-isomer: 99 %, ratio of β-isomer: 0-0.6 %. The details are shown in Table II. Examples 21-28 66.7 g of 11a-chloro-methacycline-p-toluene-sulfonate are subjected to hydrogenation in 500-580 ml of solvent by using 3.5 to 10 g of an alloy catalyst on carrier at room temperature and a pressure of 0.1 to 1.0 MPa until the hydrogen uptake is completed. After filtering off the catalyst the filtrate can be worked up as follows: a) 50 g of 5-sulfosalicylic acid are added to the filtrate and the product is crystallized and filtered, dried. Doxycycline sulfosalicylate is obtained as a product, or b) the filtrate is evaporated in vacuo, 250 ml methanol and 25 g of p-toluene sulfonic acid are added to the residue, the mixture is crystallized and doxycycline tosylate is isolated, or c) the filtrate is evaporated in vacuo, 180 ml of ethanol and 30 ml of hydrochloric acid are added to the residue and, after dissolving and clarification, 50 ml of hydrochloric acid and ethanol in hydrochloric acid are added to the filtrate. The mixture is crystallized and doxycycline hyclate is isolated, or d) the filtrate is evaporated to dryness in vacuo, 250 ml of acetone are added to the residue and by introducing hydrochloric acid gas the doxycycline hydrochloride is recovered. Yield: 80-90 %. Quality of the product is homogeneous according to thin layer chromatography. Active ingredient content by biological value testing: 100 %. Ratio of α-isomer: 99 %, ratio of β-isomer: 0-0.6 %. The details are shown in Table III.

Claims: Process for the preparation of a tetracycline derivative of the formula and acid addition salts thereof, wherein R stands for -CH₃ or = CH₂, by dehalogenating and hydrogenating chloromethacycline or an acid addition salt thereof of the formula or by hydrogenating methacycline or an acid addition salt thereof of the formula by a treatment with hydrogen gas in the presence of a noble metal alloy catalyst on a carrier and an organic solvent, which comprises performing the hydrogenation under a pressure of 0.1-1.0 MPa with an alloy catalyst consisting of (i) palladium or platinum and (ii) selenium and/or tellurium used at a ratio of 1:0.01-0.5 relative to the amount of the starting tetracycline, and carrying out, if desired, the dehalogenation and hydrogenation in one step. Process as claimed in claim 1 which comprises preparing methacycline by saturating chloromethacycline with equimolar hydrogen gas in the presence of an alloy catalyst on a carrier (the alloy being palladium-selenium, palladium-tellurium or platinum-selenium or platinum-tellurium) under a pressure of 0.1-0.3 MPa at a ratio of 1:0.01-0.2 catalyst relative to the amount of chloromethacycline, wherein the amount of selenium and/or tellurium is 20-70 % by weight relative to the amount of palladium and/or platinum. Process as claimed in claim 1 which comprises preparing doxycycline by treating methacycline or a salt thereof with hydrogen gas in the presence of alloy on carrier catalyst (the alloy being palladium-selenium, palladium-tellurium, platinum-selenium or platinum-tellurium) at a pressure of 0.1-1 MPa at a ratio of 1:0.05-5 catalyst relative to the weight of methacycline, wherein the amount of the alloying components is to 1-40 % by weight. Process as claimed in claim 1 which comprises preparing doxycycline by treating chloromethacycline or a salt thereof with hydrogen gas in the presence of alloy on carrier catalyst (the alloy being palladium-selenium, palladium-tellurium, platinum-selenium or platinum-tellurium) at a pressure of 0.1-1 MPa at a ratio of 1:0.05-5 catalyst relative to the weight of methacycline, wherein the amount of the alloying components is 1-40 % by weight. Process as claimed in any of claims 2 to 4 which comprises using water, an alcohol or a ketone, preferably methanol, propanol, dimethylformamide, acetone, methyl ethyl ketone or mixtures thereof, as the solvent. Process as claimed in any of claims 1 to 4 which comprises using as alloys which contain 1-70 % by weight of selenium or tellurium and 99-30 % by weight of palladium or platinum.

Inventors: BESENYI, GABOR, GYORI, PETER, JELINEK, ISTVAN, KALLAY, U., TAMAS, LUGOSI, GYOERGY, LUGOSI, MARTA, NAD, ZSUZSANNA, NAGY, LAJOS, SANTANE SINGOLA, ILONA, SIMANDI, LASZLO, SIMONIDESZ, VILMOS, SZALAY, ERZSEBET, BESENYI, Gábor, GYORI, Péter, JELINEK, István, KALLAY, U., Tamás, Lugosi, György, LUGOSI, Márta, SIMANDI, Lászlo, SZALAY, Erzsébet
Applicants: CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1988
Main classification: C07C237
IPC codes: C07C237, B01J27, C07C231, C07B61, C07D237, C07C233