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 dehalogenating 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 performing hydrating under pressure of 0.1-1.0 MPa with an alloy catalyst consisting of the alloy palladium or platinum and selenium 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 desired dehalogenation and hydration in one step.

Description: IMPROVED PROCESS FOR THE PREPARATION OF TETRACYCLINE DERIVATIVES 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 tellurian and/or selenium containing alloy catalyst latter being prepared according to this invention as well. The following abbreviations are used throughout the specification: "methacycline": 4—dimethylamino-1, -,4a, ,5a,6,11,12a-octa- hydro-3, » 10,12,12a-pentahyd oxy-6-methylene-1,11-dioxo-2- naphtacene-carboxamide of the formula 11 chlo o-methacycline": —dimethylamino-1, , a,5,5a,6,11,12- 12a-nonahydro-3,5,10,12a-tetrahydroxy-lla-chloro-6-methylene- l,ll,12-trioxo-2-naphtacene-carboxamide of the formula "doxycycline" : OC -6-desoxy-5-hydroxy-tetracycline, i.e. -dimethylamino-l,4,4a,5 ,5a,6,ll,12a-octahydro-3 ,5 ,10, 12- 12a-pentahydroxy-60G -methyl-1 , 11-di oxo-2-naphtacene-carb ox- amide of the formula "g>-doxycycline" is the jS-isomer of doxycycline E stands for -CH, or = CH- 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 and preparing chloromethacycline followed by dehalogenation and if desired by hydrating the obtained methacycline zo doxycycline. Dehalogenation was solved - among other methods - by introducing hydrogen gas in the presence of a catalyst, see e.g. Example 9 of HU-PS 1 0909, wherein rhodium pre¬ cipitated 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 either. Therefor the use of secondary or tertiary phosphines has ' been recommended in HU-PS 169 6O5. This process was accompanied with the disadvantage that an equimolar amount of tertiary or secondary phosphines was needed, resulting in a great amount of waste, being poisonous, and the formed phosphine oxide could be con¬ verted again to phosphine only by a multi-step reaction. The introduction of hydrogen &s 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 hydration 6-desoxy-5-hydroxy- tetracycline of the formula (IV) can occur in the form of 00- and β-isomers. Only the o_-isomer is valuable as medicine, i.e. doxycycline. The amount of the oc-isomers during hydration determines if the hydration process is successful, i.e. if hydrogenation can be carried out selectively, to produce mainly c_-isomer with good yield and pure quality. It has been known that 6-desoxy-5-hydroxy- etra¬ cycline could be prepared with a yield of 60 % by using a 5 % palladium or rhodium catalyst on a carrier, but the product was a 1:1 mixture of Cc- and ^-isomers, which was followed by the separation of the CC-isomer accompanied by further losses (US-PS 3 200 149) . The ratio of the formation of the oc-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 CC-isomer could be increased to 40-50 . $, but even so the product had 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 consisting of the metals of platinum group, copper, silver or gold has been used and a doxycycline yield of about 70 % has been dis¬ closed with 1 to 10 % -isomer impurities (HU-PS 167 0) . A 92 CC—isomer content has been achieved by using a catalyst containing palladium atoms located on ultra- microporous active coal, without poisoning, with a yield of 76 (HU-PS 169 667). Hydration could be performed by using Raney nickel and Raney cobalt as a catalyst according to GB-PS 1 296 34-0, but the formation of cc-isomer in the reaction mixtures amounted only to about 40 , According to Finnish PS 67210 to palladium/charcoal catalyst a complex of bis- (diphenylselenide) palladium(II)chloride was added resulting thus in a yield of 75 #, wherein the ratio of the oc-isomer was about 95 #• According to the disclosure this effect could not be achieved if diphenylselenide was not used in a complex form. In order to give a complete review of the known processes, we mention those hydration processes, which are not close to our process, but wherein hydration was per- formed by using triphenyl phosphine rhodium complexes, being catalysts which are soluble in the reaction mixture (DE-OS 2403 714) or by using further additives next to the complexes (HU-PS 169 753, 169 508, 173 508 and 187 65). 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 does only parti- ally solve the problem of stereoselectivity. A considerable amount of these catalysts had to be used, and so the ratio substrate-catalyst was not favourable. The relative great amount of the used solvent was 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, 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. According to the present invention methacycline and doxycycline resp. are prepared by process in hetero- geneous layer, wherein dehalogenation can be performed with good yield and reduction takes place stereoselectively and the side reactions can be eliminated to such extent that no extra purification of the product is needed and the used catalyst can be prepared simply and the specific costs of the catalyst are low. It was further aimed that dehalogenati and hydration pan be prepared without any extra equipment by using the same type of catalyst. Thus the just ' needed medicine can be prepared. The present invention is directed to a process for the preparation of tetracycline derivatives and acid additio salts thereof of the general formula (I) , by dehalogenating and hydrating chloromethacycline or acid addition salt thereof of the ormula II or by hydrating methacycline or acid addition salt thereof of the formula III by a treatment of same with hydrogen gas in the pre- sence of a noble metal alloy catalyst on a carrier in the presence of an organic solvent comprising carrying out the hydrogenation at a pressure of 0.1-1.0 MPa with an alloy catalyst used at a ratio of 1:0.01-0.5 related to the starting tetracycline derivative consisting of an alloy of palladium or platinum or selenium and/or tellurium and performing, • if desired the dehalogenation and hydration 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 the aqueous suspension of palladium or platinum on a carrier with a solution or suspension organic or inorganic selenium or tellurium compounds 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. One may use a different method according to which palladium or platinum salts and selenium or tellurium compounds may be dissolved in acidic water and a carrier, preferably active charcoal can be added to the carrier, followed by reduction. The noble metal content of the catalyst may vary between 1 to 30 % by weight, preferably 5 to 10 by weight, the used noble metal can be selected from palladium and platinum and the amount of the alloying components may vary between 1 to 70 by weight related to the amount of the noble metal content. As a solvent preferably lower alcohols, ketones, N, -dialkyl amides, water and mixtures thereof may be used. It is not necessary to dissolve the starting material comp¬ letely. 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 related to the weight of chloromethacycline, wherein the amount of the alloying components amounts to 20-70 % by weight related 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. Main advantages of the dehalogenation according to the present invention: dehalogenation can be performed without side reactions, the conversion of methacyclines to 5- 2a lactones can be suppressed, the reaction takes place at atmospheric pressure and room temperature within a short time, the catalyst can be prepared simply and it is not pyrophoric or its activity does not weaken under storing or in the course of the reaction, thus- it can be used several times without regeneration, thus the catalyst costs of the process are minimal, almost negligible. In order to obtain doxycycline metacycline or chlorometacycline 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 an amount of catalyst of 1:0.05-0.5, preferably 0.15-0.25 related to the weight of methacycline, the amount of the alloying components is 1 to 40 by weight. If chloromethacycline or salts thereof are used as starting material then dehalogenation and the selective saturation of the double bond can be performed in one single step. As a solvent lower alcohol, ketones, dimethyl- formamide, 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- sulfo salicylic acid or in the form of hyclates. Main advantages of the process for the preparation of doxycycline are as follows: - the saturation of the exocyclic methylene bond in metha¬ cycline takes place substantially stereoselectively, i.e. the \)-isomer content is reduced in doxycycline below 1 % by weight (according to HPLC) , - in the reactions starting with chloromethacycline de- halogenation and hydration can be carried out in one single - technological step, the reaction can be performed at atmospheric pressure and room temperature within 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 hydration reaction and thus the catalyst costs of the process are minimal, almost negligible - the process may be continualized, - the isomerisation side reaction occurring in heterogeneous catalytical reactions, causing intensive decomposition are suppressed and therefor doxycycline can be obtained with good yield. This experience is highly suprising as the 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 hydro¬ chloric acid, whereafter 10 g of charcoal are added and the mixture is stirred for 3 hours and hydrated 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 0 ml of ethanol, and as desired 0,15-1 g of diphenyl selenide are added, the suspension is boiled ' for 30 minutes, 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 U hydrochloric acid and 5 g ' of silicagel are added, the mixture is hydrated, filtered and dried. Its activity is measured. The activity of the catalysts prepared according to the above Examples are qualified by a method known per se, by hydrating a cyclohexene model compound. Preparation of methacycline Examples 7 to 12 20 g of lla-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, it is crystallized and methacycline sulfosalicylate is isolated, b) the filtrate is evaporated in vacuo, and 75 ml of metha 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 concentra hydrochloric acid are added and methacycline hydrochloride is isolated. Yield: 85-95 • The quality of the products is thin layer chroma- tographically. homogeneous (developing agent: a 95J5 mixture of tetrahyd ofuran and water) on a silicagel carrier plate impregnated with a buffer of pH=6. Active ingredient con- tent by biological value testing: 100 #. The details are shown in Table I. The noble metal content of the catalyst related to the weight of catalyst is given in # by weight and the amount of the alloying metal is determined in by weight related to the noble metal content. ++ The composition of the solvent is given in % by volume. Preparation of doxycycline Examples 13 to 20 -7 ' 3 g of methacycline hydrochloride or 63.6 g of methacycline p-toluene sulfonate are hydrated 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 l ' .O 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. Doxy¬ cycline sulfosalicylate is obtained as a product, or b) the filtrate is evaporated in vacuo, 250 ml methanol and 25 g of p-toluene sul onic 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 hydro- chloric acid and ethanol in hydrochloric acid are added to the filtrate. The mixture is crystallized and doxy¬ cycline 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 homo ¬ geneous.according to thin 'layer chromatography. - - Active ingredient content by biological value testing: 100 % . Ratio o -isomer: 99 #, ratio of ^-isomer: 0-0.6 %. The details are shown in Table II. Example Catalyst No. pressure 13 10 g % Pd/charcoal Se 5 % . 0.3 MPa 14 g 5 Pt/charcoal Se 8 #, 0.3 MPa 15 8 g 10 % Pd/charcoal Se 20 #, 0.4 MPa 16 5 g 3«5 Pd/charcoal Te 15 #, 0. MPa 17 10 g 5 # Pd/silicagel Se 10 #, 0.3 MPa 18 4 g 10 Pd/charcoal Se 15 #, 0.3 MPa 19 6 g 10 Pd/charcoal Se 12 % , 0.2 MPa 20 ' 10 g 5 # Pd/silicagel Se 7 %, 0.3 MPa The nobel metal content of the catalyst related to the weight of catalyst is given in by weight and the amount of the alloying metal is determined in % by weight related to the noble metal content. The composition of the solvent is given in by volume. Examples 21-28 66.7 g of lla-chloro-methacycline-p-toluene-sulfonate are subjected to hydration in 500-580 ml of solvent by using 3-5 to 10 g of an alloy catalyst on carrier at room tempera- ture 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. Doxy- cycline 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 homo- • geneous according to thin layer chroma ography. Active ingredient content by biological value testing: 100 % . Ratio of oc-isomer: 99 % , ratio of β-isomer: 0-0.6 % . The details are shown in Table III. Table III Example Catalyst Solvent Pressure Working up Product Yield l!No. MPa method 21 10 g 5 % Pd/charcoal acetone- 0.2-0.4 a/ 61.5 g doxycycline 88 % Se 5 % water 4 : 1 sulfosalic late 88 % 22 5 g 5 % Pd/charcoal methyl-ethyl- 0.2-0. A a/ 59.2 g doxycycline Se 8 % ke tone /water 4: 1 sulfosalicylate 85 % 23 8 g 10 % Pd/charcoal acetone-water 0.3-0.5 b/ 53.6 g dαxycycline- Se 20 % 4 : 1 tosylate 87 % 2k 5 g 3.5 % Pd/charcoal methyl-ethyl- 0.4-0.5 b/ 50.5 g dαxycycline- Te 15 % ket one /water 4: 1 tosylate 82 % 25 10 g 5 % Pd/silicagel methyl-ethyl- 0.2-0.4 c/ 42.1 g dαxycycline- Se 10 % ket one /water 4: 1 hyclate 82 % 26 4 g 10 % Pd/charcoal acetone- 0.4-0.5 c/ 42.1 g dαxycycline- Se 15 % water 4 : 1 hyclate 82 % 27 6 g 10 % Pd/charcoal acetone- 0.2-0.3 d/ 39.2 g dαxycycline- Se 12 % water 4:1 hydrochloride 85 % 28 10 g 5 % Pd/silicagel methyl-ethyl- 0.2-0.3 d/ 38.3 g dcixycycline- Se 7 % ket one /water 4: 1 hydrochloride 83 % + The nobel metal content of the catalyst related to the weight of catalyst is given in % by weight and the amount of the alloying metal is determined in % by weight related to the nobel metal content . H" The composition of the solvent is given in % by volume.

Claims: CLAIMS: 1. Process for the preparation of tetracycline derivatives of the formula and acid addition salts thereof wherein R stands for -CH., or = CH p by dehalogenating and hydrating chloromethacycline or acid addition salt thereof of the formula or ObyHhydOrating- 0methacy0cline or acid addition salts thereof of the formula by a treatment with hydrogen gas in the presence of a noble metal alloy catalyst on carrier and organic solvent which comprises performing hydrating under pressure of 0.1-1.0 MPa with an alloy catalyst consisting of the alloy palladium or platinum and selenium and/or tellerium used at a ratio of 1:0.01-0.5 related to the amount of the starting tetracycline and carrying out, if desired dehalogenation and hydration in one step. 2. 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 carrier of palladium-selenium, palladium-telluriu ' 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 related to the amount of chloromethacycline, wherein the amount of selenium and/or tellurium amounts to 20-70 % by weight related to the amount of palladium and/or platinum. 3. Process as claimed in claim 1 which comprises preparing doxycycline by treating methacycline or salts thereof with hydrogen gas in the presence of alloy on carrier catalyst consisting of palladium-selenium, palladium-telluriu platinum-selenium or platinum-tellurium at a pressure of 0.1-1 MPa at a ratio of 1:0.05-5 catalyst related to the weight of methacycline, wherein the amount of the alloying . components amounts to 1-40 % by weight. 4. Process as claimed in claim 1 which comprises preparing doxycycline by treating chloromethacycline or salts thereof with hydrogen gas in the presence of alloy on carrier catalyst consisting of 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 related to the weight of methacycline, wherein the amount of the alloying components amounts to 1-40 % by weight. 5- Process as claimed in any of the claims 2 to 4 which comprises using water, alcohols, ketones, preferably methanol, propanol, dimethylformamide, acetone, methyl ethyl ketone or mixtures thereof as a solvent. . 6. Process as claimed in any of the claims 1 to 4 which comprises using as alloys for hydration alloys which contain 1-70 % by weight of selenium or tellurium and 99—30 % by weight of palladium or platinum. 7. Process for preparing an alloy-catalyst as claimed in claim 1 which comprises treating an aqueous suspension of palladium- or platinum catalyst on a carrier with a solution or suspension of organic or inorganic selenium or tellurium compounds and optionally reducing the obtained compounds. 8. Process for preparing an alloy catalyst as claimed in claim 1 which comprises dissolving palladium or platinum salt and selenium or tellurium compound in acidic water j adding a carrier, preferably active charcoal to the mixture and reducing the obtained compound.

Inventors: BESENYI GABOR, GYOERI PETER, JELINEK ISTVAN, KALLAY U TAMAS, LUGOSI GYOERGY, LUGOSI MARTA, NAD ZSUZSANNA, NAGY LAJOS, SANTANE SINGOLA ILONA, SIMANDI LASZLO, SIMONIDESZ VILMOS, SZALAY ERZSEBET, BESENYI, GABOR, GYOERI, PETER, JELINEK, ISTVAN, KALLAY, U., TAMAS, LUGOSI, GYOERGY, LUGOSI, MARTA, NAD, ZSUZSANNA, NAGY, LAJOS, SANTANE SINGOLA, ILONA, SIMANDI, LASZLO, SIMONIDESZ, VILMOS, SZALAY, ERZSEBET
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1988
Main classification: C07C103
IPC codes: B01J27, C07B61, C07C231, C07C233, C07C237, C07D237