NO169342B - PROCEDURE FOR THE PREPARATION OF A HYDROGENATION CATALYST, AND USE THEREOF. - Google Patents

Description

The present invention relates to the compound p-3-carbopentazan-N1,!?4 :N2 ,N5-bis[bis (triphenylphosphin) rhodium (I) ] - dinitrate, which is a homogeneous hydrogenation catalyst, method for its preparation and method for stereoselective hydrogenation of the exocyclic methylene group in the acid addition salts of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (metacycline) to prepare cx-6-deoxy-5-hydroxy-tetracycline (doxycycline).

Doxycycline is a broad-spectrum antibacterial agent, with wide-ranging application in the treatment of various infections in humans and animals. The hydrogenation of the exocyclic methylene group in methacycline can give two epimers. The cx-6-epimer is doxycycline, while the 3-6-epimer, called 6-epi-doxycycline, has no application in clinical treatment. It is therefore important that the hydrogenation does not form by-products such as the 3-6-epimer. The British Pharmacopoeia 1980 actually set a limit for the content of 6-epi-doxycycline in doxycycline at 2%.

From the state of the art, doxycycline was first described in 1960 in US Patent No. 3,200,149. Since then, many methods have been described for its preparation, in all of which the modification of the catalytic system has been described as producing improved yields or a cleaner product. In the field of heterogeneous catalysis, US Patent Nos. 3,444,198, 3,849,491, 3,954,862 and 4,597,904 and the review in Chemical Abstracts 86, 89476 f (1977) of Hungarian Patent No. 12042 all address improved methods of preparation of doxycycline and its analogues.

The first time homogeneous catalysis was described was in U.S. Patent No. 4,207,258 (Italian priority 1972), where the catalyst was a complex of rhodium with tertiary phosphine, arsine and stibine ligands. US Patent No. 3,962,331 extended the above process to the simultaneous reductive dehalogenation and hydrogenation of an 11a-halomethacycline. French Patent No. 2,216,2 68 later described the use of

the same catalyst.

Since then, other patents have also been issued, such as US Patent Nos. 3,907,890, 4,001,321 and 3,962,131, all of which describe variations in the catalytic system and demonstrate improved yields and stereospecificity.

The first homogeneous hydrogenation catalysts of the tertiary phosphine-hydrazine-rhodium complex type were described in US patent no. 4,550,096. These were prepared by reacting a rhodium salt, especially rhodium trichloride, with a tertiary phosphine and a hydrazine or by reacting a rhodium complex, such as tris(triphenylphosphine)chlororhodium, with a hydrazine. These complexes allowed the preparation of doxycycline, containing less than 1% of the undesired 6-epi-doxycycline, in high yield using considerably less rhodium than was known in the art, although addition of an excess of tertiary phosphine described to give the best dividends.

US Patent No. 3,463,830 describes the production of zero-valent platinum and palladium catalysts by reducing these metals from oxidation state II using the reducing agent hydrazine. The function of the hydrazine is mainly as a reducing agent, and it is not incorporated into the catalyst produced in this way. As will be described below, the compounds according to the present invention differ from the compounds described in US Patent No. 3,463,830 in that the hydrazine is incorporated into the rhodium complex as a ligand, and surprisingly, the rhodium is not reduced to the zero oxidation state.

US Patent No. 3,956,177 discloses compositions useful as hydroformylation catalysts prepared by contacting an organorhodium halide with a hydrazine and a phosphorus-containing excipient to form a mixture therefrom. It is explained in the description that these catalysts are not compounds formed from the components of the mixture, and they are not described as applicable for the hydrogenation of carbon/carbon double bonds, but as catalysts for hydroformylation reactions.

By using rhodium trinitrate instead of rhodium trichloride in the process described in US Patent No. 4,550,096, it was surprisingly found that the complex formed was different from the complexes obtained with rhodium trichloride. The catalytic system thus formed comprises a rhodium complex which has a completely different formula, and which is not analogous to the series containing chloride as the anionic ligand.

According to the invention, a new rhodium complex is formed. This new rhodium complex, which is a homogeneous hydrogenation catalyst, is formed when rhodium trinitrate dihydrate is reacted with triphenylphosphine and hydrazine, in degassed methanol under an inert atmosphere, so that one mole of rhodium trinitrate dihydrate is reacted with an excess of triphenylphosphine, preferably at least 3Vz mol, and at least one mole of hydrazine, for to form a complex of formula I:

wherein Ph is phenyl.

The present invention also includes the use of the complex of formula I in the hydrogenation of methacycline to produce a high yield of α-6-deoxy-5-hydroxytetracycline, almost in a stoichiometric amount.

When the method according to the invention is carried out, by reacting under an inert atmosphere, one mole of rhodium trinitrate dihydrate, an excess of triphenylphosphine, preferably at least 3 1/2 moles, and at least one mole of hydrazine in degassed methanol, a complex of the formula I can be isolated after a reaction time in usually about one to about four days at room temperature. Alternatively, the reaction mixture can be refluxed overnight, followed by cooling and standing at room temperature. If, on the other hand, short reaction times of about one hour at room temperature are used, another compound is preferably formed, which should be avoided.

The structure of the compound of formula I was elucidated by X-ray crystallography.

When the catalyst is prepared according to the conditions described above, it is fully active in the hydrogenation of methacycline to doxycycline. Moreover, it is not necessary to add triphenylphosphine in excess to ensure a high yield of the desired cx-epimer.

The manufacturing conditions for the catalyst according to the present invention are clearly illustrated in examples 1. Rhodium trinitrate dihydrate and hydrazine can be reacted in ratios calculated from their molecular formulas, but it is advantageous to use hydrazine in excess to achieve maximum yield with regard to the expensive rhodium salt.

The hydrazine can be used either as the anhydrous base or as the monohydrate. It has been confirmed that the anhydrous base allows shorter reaction times.

The triphenylphosphine is present in excess, preferably in a molar ratio of 3.5 to the rhodium present. This surplus can be increased without any noticeable change in the products formed.

To obtain the best results in the preparation of the compound of formula I, rhodium trinitrate dihydrate (1 mol), triphenylphosphine (3.5 mol) and hydrazine (3 mol) are mixed in degassed methanol under a nitrogen atmosphere. After stirring for a longer time, i.e. one to two days, an orange crystalline solid of formula I can be isolated by filtration and drying under vacuum. Alternatively, the reaction mixture can be refluxed overnight, followed by cooling and standing at room temperature.

The complex of formula I is stable for at least one month, provided they are stored under nitrogen at a lower temperature. After this period, slightly reduced catalytic activity is sometimes observed. Therefore, this complex should preferably be freshly prepared in order to obtain the best hydrogenation results.

As already indicated, the hydrazine-rhodium complex according to the present invention is an effective homogeneous stereospecific hydrogenation catalyst in general. However, the present invention is particularly directed to its use in the hydrogenation of exocyclic methylene groups of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline present in the hydrogenation reaction mixture as an acid addition salt, to give cx-6 -deoxy-5-hydroxytetracycline in an almost stoichiometric yield.

The starting methacycline can be prepared according to any of the known methods, as described in US Patent No. 3,849,491, but should not contain impurities that may act as a catalyst inhibitor.

Although the new complex will catalyze the hydrogenation of the methacycline base, the rate is so low that the hydrogenation time does not allow the yields obtained using an acid addition salt. The rate of hydrogenation increases with temperature. Temperatures from ambient to 95°C can be used, but to achieve the best yield and stereospecificity, the optimal reaction temperature range is between 85°C and approx. 90°C. At 95°C, the yield is somewhat lower than e.g. at 88°C. Below 85°C, the catalytic system begins to be sensitive to the possible presence of certain trace contaminants that can affect the hydrogenation rate.

In connection with the hydrogenation of metacycline acid addition salts for the production of doxycycline, the present invention has many advantages when the temperature range during the hydrogenation is 85°C to approx. 90°C.

First, there is no need for extremely high hydrogen pressures. It has been found that from 1 kg/cm<2> to 10 kg/cm<2> will ensure complete conversion of the methacycline substrate within between 6 to approx. 10 hours. The hydrogenation is usually carried out at 88-89°C at a hydrogen pressure of 7 - 9 kg/cm<2> and is finished after 6 1/2 - 7 hours.

The conversion of the metacycline acid addition salt to doxycycline using the catalyst according to the present invention gives a purity of over 95% in the reaction mixture, as shown by liquid chromatography (h.p.l.c).

Moreover, by using a weight ratio of rhodium to substrate of 0.0002 in laboratory-scale experiments, total conversion is achieved within approx. 6 1/2 - 7 hours. On an industrial scale, rhodium to substrate in a weight ratio of 0.00015 gives total conversion of the substrate within approx. 7-8 hours.

In order to ensure the effectiveness of the catalyst of formula I, crystals of large size were prepared, as described in Example 1. One of the crystals thus obtained was used as a catalyst in the hydrogenation of methacycline hydrochloride, as described in Example 2. The purity of the conversion of methacycline hydrochloride to doxycycline was 99.2% and the p<->epimer was formed in 0.6% as calculated by high performance liquid chromatography.

According to US Patent No. 4,550,096, the most striking observation of the present invention is that when the catalyst is prepared, dried and stored under a strictly inert atmosphere, it exhibits full activity without the need to add an excess of tertiary phosphine, more particularly triphenylphosphine, to the hydrogenation mixture to obtain the best yields.

One explanation for this is that the catalysts prepared according to the process in US Patent No. 4,550,096 were believed to be stable, and they actually exhibited a very high catalytic activity even when stored for longer periods, because they then was used in the presence of a controlled excess of a tertiary phosphine. It is now believed that the catalysts prepared according to the process described in US Patent No. 4,550,096 oxidize slowly, but the presence of the excess tertiary phosphine in the hydrogenation reaction mixture allowed replacement of the oxidizing part of the tertiary phosphine, and on this way of regenerating the original catalytic system.

The hydrogenation is advantageously carried out by adding the catalyst to the pressure reaction vessel containing the metacycline acid addition salt in methanol at 50°C under nitrogen. The reaction vessel is then purged again with nitrogen, then with hydrogen, and finally a hydrogen pressure of 8 kg/cm<2> is set. The reaction mixture is heated to 88°C with stirring, and the temperature is maintained at 88°C ± 2°C until the absorption rate of hydrogen decreases drastically, which occurs after approx. 6 to 7 hours. At this point, the reaction mixture contains almost exclusively oc-6-deoxy-5-hydroxytetracycline.

As is known in the art, the rate of hydrogenation of methacycline is increased under acidic conditions. Therefore, adding an acid, preferably the same acid that is present in the acid addition salt, to the substrate will ensure high yields and purity. The amount of foreign acid is not critical. It can be between one mole per moles of rhodium added, and up to approx. one mole per moles of the substrate to be hydrogenated. If the foreign acid is not nitric acid, it is possible that the nitrate moieties of the compounds of formula I could be exchanged for the anion of the added acid.

The purity of the reaction mixture thus obtained is such that doxycycline can be crystallized directly from the reaction mixture by adding excess p-toluenesulfonic acid, followed by cooling, to give a yield of doxycycline p-toluenesulfonate with a purity above 99%.

The new catalytic system can also be used in the simultaneous dehalogenation of the lla-chloro substituent and stereospecific hydrogenation of the 6-methylene group in lla-chloro-metacycline with good yields.

The following examples serve to illustrate the present invention.

1. Preparation<g> of u- 3-carbopentazan- N-^, N—; N—, N-5--bisfbis ( triphenylphosphin) rhodium( I) " jdinitrate

Rhodium trinitrate dihydrate (0.36 g; 1.18 mmol) and triphenylphosphine (1.12 g; 4.27 mmol) were placed in a two-necked round bottom flask. It was stirred under vacuum for 30 minutes and then under a nitrogen atmosphere for 15 minutes. Dried, degassed methanol

(100 mL) was added and the mixture stirred for 15 minutes. Hydrazine in methanol (10 mL of a 10.77 mg/mL solution; 3.36 mmol) was added and the reaction mixture was refluxed overnight. The orange solution was filtered and allowed to stand at room temperature for 3 days, i

during which time large orange colored crystals were deposited. These were filtered off and dried under vacuum.

When the reaction was repeated using rhodium trinitrate dihydrate (0.28 g; 0.91 mmol), triphenylphosphine (0.80 g; 3.05 mmol), hydrazine in methanol (8 ml of a 10.77 mg/ml solution ; 2.69 mmol) in methanol (60 ml) and stirring for two hours, clarification by filtration and standing for 5 days, the corresponding orange-colored crystals were obtained.

A single crystal with an average diameter of 0.4 mm was sealed under argon in a thin-walled glass capillary. Unit cell and intensity data were obtained using an Enraf-Nonius CAD4 diffractometer, following standard procedures. Details of the experimental features are as follows: Crystal data: [C73H68<N>4P4Rh2]•[N03]2*(CH3OH)n, n « 0.5, Mw = 1455.10 (excluding the methanol), monoclinic group P21/n, a = 22.269(3)Å, b= 23.311(3)Å, c = 13.838(2)Å, 3 = 100.51(2)°, V = 7063, OÅ3, Z = 2, Dc = 1.37 g- cm"<3>, jjfMo-Ka) = 5.38 cm"<1>.

Data Collection: Data were collected for 1.5° < 0 < 23° at room temperature, 291°K and corrected for empirical absorption. 9820 intensities were measured, of which 7551 were observed

[I > 1.5 a( I)] and used in the analyses.

The structure was found using the heavy atom method and calculated using the least squares method. All non-hydrogen atoms were fitted with anisotropic thermal parameters, and the phenyl groups were treated as locked bodies. The hydrogen atoms on the phenyl groups were located experimentally, but for convenience included and adjusted in ideal positions. Hydrogens on the bridging ligands were experimentally located and freely fitted with isotropic thermal parameters. The final R value is 0.05 with 707 parameters.

The complex is shown to contain a dimeric cation with two (Ph3P)2Rh units linked by a 3-carbopentazane unit, as shown in Ia:

The presence of the methylene bridge results in a boat conformation in the central Rb^^ ring with the bridge attached to the "bow and stern" positions. The nitrate ions are clearly separated from the cation and do not appear to form any unusually close contacts. However, one of them appears to occupy a cavity of such a size that some positional disturbances may occur, and it is also possible that other cavities in the structure may be partially occupied by crystal methanol.

In a repeated experiment, orange-colored crystals with very identical morphology were obtained, but which appeared to suffer from a lack of crystallinity when the methanol was removed. On crystallographic examination, these were found to contain considerably more crystal methanol, but the structure of the cation was found to be completely analogous to the first complex.

2. Hydrogenation of methacycline using H -- 3-carbopentazan-N-^. N^N^. N5— bis fbis ( triphenvlphos-fin) rhodium( I )] dinitrate

6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (10.38 g; 21.7 mmol) was suspended in methanol (84.5 mL) in a stainless high-pressure reaction vessel and ^-3-carbopentazane-N <1>,N<4>:N<2>,N5-bis[bis(triphenylphosphine)rhodium(I)]dinitrate

(25 mg; 0.017 mmol; 0.034 mmol rhodium) was added under a nitrogen atmosphere. The container was purged with nitrogen, then with hydrogen and pressurized to 8 kg/cm<2> with hydrogen. The reaction mixture was heated to 88°C for 6 1/2 hours with vigorous stirring. The hydrogen then flowed out and p-toluenesulfonic acid (4.65 g; 24.2 mmol) was added with vigorous stirring. Stirring was continued for 2 hours, after which the resulting precipitate was filtered, washed with a small amount of methanol and dried at 35°C.

The yield of α<->6-deoxy-5-hydroxytetracycline-p-toluenesulfonate was 12.0 g or 89.8% of the theoretical. Using h.p.l.c. was shown to be 99.2% pure and to contain only 0.6% of the 3-epimer.

Claims (3)

1. Compound characterized in that it is p-3-carbopentazan-N<1>,N<4>:N2,N5-bis[bis(triphenylphosphine)rhodium (I)]dinitrate with formula I: where Ph is phenyl. 2. Process for the preparation of the compound according to claim 1, where a rhodium salt, triphenylphosphine and hydrazine are reacted in the presence of degassed methanol under an inert atmosphere, preferably nitrogen, so that for each mole of rhodium present an excess of triphenylphosphine is used, preferably at least three and half a mole,' and at least one mole of hydrazine, preferably the anhydrous base or the monohydrate, characterized in that rhodium trinitrate dihydrate is used as the rhodium salt, and that the reaction time is from about one to about four days at room temperature. 3. Process by stereoselective hydrogenation of an acid addition salt of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline in the presence of a catalyst to prepare cx-6-deoxy-5-hydroxytetracycline with high yield and purity, characterized by that the catalyst is the compound according to claim 1, and the hydrogenation is carried out at a temperature between 60°C and 100°C, preferably 85°C and 90°C, at a pressure of 1 to 10 kg/cm<2>, under acidic conditions, until the reaction is complete, followed by isolation of the compound thus formed.