CA1296327C - Process of preparation of novel rhodium hydrogenation catalysts and theirapplication - Google Patents

Abstract

ABSTRACT

The present invention refers to complexes prepared by reacting rhodium trinitrate with a suitable hydrazine and a suitable tertiary phosphine, more specifically to the compounds di(µ-hydrazine-N1:N2)-bis[bis( riphenylpnos-phine)rhodium (I) ]dinitrate and µ-3-carbopentazane-N1,N4:N2,N5-bis[bis(tri-phenylphosphine)rhodium (I) ]dinitrate, which are homogenous hydrogenation catalysts and their application in the hydrogenation of the exocyclic methylene group of acid addition salts of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (methacycline) to prepare a-6-deoxy-5-hydroxy-tetra-cycline (doxycycline).

Description

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~OCESS OF PR~PARATION OF NDVEL R~ODIUM
HrDRO6ENATION CATALYSTS AND THEI~ APPLIC~TIDN

S The present invention refers to complexes prepared by reacting rhodium trinitrate with a suitable hydraz;ne and a suitable2tertiary phosphine, m9re specifically to the compounds di(~-hydrazine-N :N )1bi4[b2s(5riphenylphos-phine)rhodium (I)~ dinitrate and ~-3-carbopentazane-N ,N :N ,N -bis[bis(tri-phenylphospnine)rhodium (I)] dinitrate, which are homogeneous hydrogenation catalysts and their application in the hydrogenation of the exocyclic methylene group of acid addition salts of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (methacycline) to prepare a-6-deoxy-5-hydroxytetra cycline (doxycycline).
Doxycycline is a wide-spectrum antibacterial agent, with widespread application in the treatment of numerous infections in humans and in animals. The hydrogenation of the exocyclic methylene group of methacycline can produce two epimers. The ~-6-epimer is doxycycline, whilst the ~-6-epimer, called 6-epi-doxycycline, is devoid of clinical utility. Thus, it is important that the hydrogenation does not co-produce this ~-6-epimer. In fact, the British Pharmacopoeia 1980 established a limit for the content of 6-epi-doxycycline in doxycycline of 2%.
In the prior art, doxycycline was first described in 1960 in Blackwood et al. U.S. Patent N 3,200,149 (1965). Since that time many methods have been described for its preparation, in all of which modification of the catalytic system has been described as producing improved yields or a purer product. In the field of heterogeneous catalysis, U.S. Patent Ns 3,444,198 (Korst, 1969), 3,849,491 (Yillax, 1974), 3,954,862 (Morris Jr., 1976) and 4,597,904 (Page, 1986) and the report in Chemical Abstracts 86, 89476 f (1977) of Bodnar et al. Hungarian Patent 12 042 (1976) have all taught improved methods -For the preparation of doxycycline and its analogues.
The first use of homogeneous catalysis was described in Broggi et al.
U.S. Patent N 4,207,258 (1980 based on Italian priority 1972), wherein the catalyst was a complex of rhodium with tertiary phosphine, arsine and stibine ligands. Cotti U.S. Patent N 3,962,331 (1976) extended the above process to the simultaneous reductive dehalogenation and hydrogenation oF an 11a-halomethacycline. Brennan et al. French Patent N 2,216,268 (1978) later disclosed the use of the same catalyst.
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3~i3 2~7 Since that time, other patents have appeared such as U.S. Patent Ns 3,907,890 (Scanio, 1975), 4,001,321 (Faubl, 1977) and 3,962,131 (Faubl et al., 1976) all describing variations in the catalytic system and claim;ng improved yields and stereospecificity.
The first homogeneous hydrogenation catalysts of the type of tertiary \\

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phosphine-hydrazino-rhodium complexes were described in Page et al. U.S.
Patent N 4,550,096 (1985). These were prepared either by reac-ting a rhodium salt, specifically rhodium trichloride, with a tertiary phosphine and a hydrazine, or by reacting a rhodium complex, such as tris(triphenyl-phosphine)chlororhodium, with a hydrazine. These complexes allowed thepreparation of doxycycline, containing less than 1~ o~ the undesired 6-epi-doxycycline, in high yield using considerably less rhodium than had been taught in the prior art.
Dunning et al. U.S. Patent N 3,463,830 (1969) describes the prepara-tion of zero valent platinum and palladium catalysts, by the reduction ofthese metals from oxidation state II by the use of the reducing agent, hydrazine. The function of the hydrazine is merely as a reducing agent, and it is not incorporated into the catalyst so prepared. As will be described herein-below, the compounds of the present invention differ ~rom those of U.S. Patent N 3,463,~30 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.
Zuech U.S. Patent N 3,956,177 (1976) describes compositions useful as hydroformylation catalysts, prepared by contacting an organorhodium halide 2~ with a hydrazine and a phosphorus-containing adjuvant, to form an intimatemixture thereof. It is stated in the specification that these catalysts are not compounds formed by the components of the mixture, and they are not described as useful for the hydrogenation of carbon/carbon double bonds, but as catalysts for hydroformylation reactions.
The copending application N 539.015, based on the Portuguese Applica-tion for a Patent of Addition to Portuguese Patent N 74.303, describes the preparation of several members of the group of triphenylphosphine-hydrazino-chlororhodium complexes in a pure state, having well def;ned formulae, and their application in the preparation of doxycycline.
When using rhodium trinitrate instead of rhodium trichloride ;n the process described in U.S. Patent N 4,550,096, it was found surprising that the formation of the complexes was generally different from that of the complexes obtained from rhodium trichloride. The catalyt;c system thus formed comprises rhodium complexes having different formulae and is not analogous to the series containing chloride as the anionic ligand.
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~` ~L2 ~ 7 - 2a -It has been found that, especially on an industrial scale, the minimum effective quantity of catalys~. needed to hydrogenate a methacycline acid addition salt to prepare doxycycline can be further reduced by about one _ . . \
. .

:- .

~ 3~ 2 ~

half, in relation to the quantity necessary when rhodium trichloride was used to prepare the catalytic system described in U.S. Patent N 4,5~0,096.
This is an extremely important advantage because of the very high cost of rhodium.
Therefore, the present invention comprises a new rhodium homogeneous hydrogenation catalytic system with high stereospecificity, as well as new isolated complexes of fully elucidated formulae.
The new catalytic system can be prepared by reacting one mole of rho-dium trinitrate, as the dihydrate, with one to two moles, or even with an excess, of a suitable tertiary phosphine, and between one and two moles, or an excess, of a suitable hydrazine, in a suitable solvent, at a temperature comprised between room temperature and the reflux temperature of the medium, preferably under an inert atmosphere. The expression "suitable" denotes those compounds which, when forming the complex, do not interfere with its catalytic activity.
Not all tertiary phosphines are suitable but simple experimentation will show which can be used satisfactorily. Triphenylphosphine and its para-chloro and para~fluoro derivatives, for example, yield efficient complexes, whilst other derivatives of triphenylphosphine, such as the ortho-methoxy or para-dimethylamino, give inefficient complexes.
The suitable hydrazines are of the formula R1R2N.N R3R4, wherein R1 is phenyl, benzenesulphonyl, lower alkyl or hydrogen and R2, R3 and R4 are lower alkyl or hydrogen, with the proviso that when R1 is phenyl or benzenesulphonyl, R2, R3 and R4 are hydrogen. The preferred hydrazine is hydrazine itself and its hydrate.
The usual solvents are aliphatic alcohols containing one to four carbon atoms, the preferred solvent being methanol.
It has been found that the catalyst prepared "in situ" in the molar proportion of one mole of rhodium trinitrate dihydrate, one mole of triphenylphosphine and one mole of hydrazine does not have a satisfactory activity in the hydrogenation of methacycline p-toluenesulphonate to prepare doxycycline (a-epimer), in that the stereospecificity is reduced (7a/1~), whilst a molar proportion of 1:1:2 ensures a pronounced stereospecificity (24/1~). A molar proportion of 1:1:3, results in an even higher stereospecificity (45a/1~).

3~7 Generally, the preparation of the catalytic system o~ the present in-vention should be carried out using in total at least ~hree moles of li-gands, of which the tertiary phosphine must be present in one to two moles, for each mole of rhodium nitrate.
After extensive studies, it has been possible to isolate certain catalysts of the invention, and to elucidate their structural formulae.
Thus, in particular, the invention provides a process for the prepa-ration of new rhodium complexes, which are homogeneous hydrogenation catalysts, having well-defined structures, comprising-the step of reacting rhodium trinitrate dihydrate, triphenylphosphine and hydrazine, characterised by the fact that the reaction is carried out in degassed methanol under an inert atmosphere, to yield complexes of the formulae I and II:-H H
Ph p ~ / N2 N2 ~? / PPh Ph P / \ N N / \ PPh ( I ) ~ ,.

~5H2 H
3 \ / N / N \ ~ / PPh3 Rh CH Rh Ph P / \ N~ 2 N / \ PPh H H

~ II ) wherein Ph is phenyl, when one mole of rhodium trinitrate dihydrate isreacted with an excess of triphenylphosphine, preferably at least three and a half moles, and at least one mole of hydrazine, wherein the complex of formula I is predominant with short reaction times and the complex of for-mula II is predominant with longer reaction times.

~ ~2~32~7 When the process of U.S. Patent N 4,550~096 is carried out in accordance with the present invention, that is using rhodium trinitrate, a mixture of products can be obtained. However individual complexes can in general be obtained by carrying out the process under an inert atmosphere with complete exclusion of air and in degassed reaction media, followed by drying under an inert atmosphere or in vacuum. After eventual purification, the complexes obtained are of uniform composition and well defined formulae, being novel compounds, never previously described.
Thus, the present invention includes within its scope the preparation of novel homogeneous catalysts, that is, complexes of rhodium with triphenylphosphine and hydrazine in their pure states, having well defined structures and a highly stereospecific and regioselective catalytic activity, which can be employed in minute amounts in the hydrogenation of methacycline to furnish ~-6-deoxy-5-hydroxytetracycline in high yields, near to stoichiometric.
According to the present invention, by reacting, under an inert atmos-phere, one mole of rhodium trinitrate dihydrate, an excess of triphenylphosphine, preferably at least three and a half moles, and at least one mole of hydrazine in degassed methanol, a complex of formula I can be isolated after a short reaction time, typically of the order of one hour, and a complex of formula II can be isolated after longer reaction times, typically one to two days at room temperature. Alternatively, the reaction mixture can be refluxed overnight, followed by cooling and standing at room temperature.
~5 The structures of the compounds of formulae I and II were established by X-ray crystallography.
The catalysts when prepared according to the conditions described above, are fully active in the hydrogenatior of methacycline to doxycycline.
Furthermore, it is not necessary to add excess triphenylphosphine to ensure a high yield of the required ~-epimer.
The conditions of preparation of the catalysts of the present invention are clearly illustrated in Examples 1 and 20 The rhodium trinitrate dihydrate and hydrazine can be reacted in the molecular proportion corresponding to their respective formulae, but it is advantageous to use hydrazine in excess so as to obtain the maximum yield in relation to the expensive rhodium salt.
The hydrazine can be used as either the anhydrous base or as the mono-~9~- 6 -hydrate. It has been verified that the anhydrous base allows shorter reac-tion times.
The triphenylphosphine is present in excess, preferably in a molar ratio of 3.5 in comparison with the rhodium present. This excess can be increased without any noticeable change in the products formed.
To achieve the best results in preparing the compounds of formulae I
and II, rhodium trinitrate dihydrate (1 mole), triphenylphosphine (3.5 moles) and hydrazine (3 moles) are mixed in degassed methanol under a nitrogen atmosphere. After stirring for 1 hour, a yellow crystalline solid 1~ ~f formula I is isolated by filtration and dried under vacuum. If the reaction mixture is stirred for a longer period, that is one to two days, an orange crystalline solid of formula II can be isolated by filtration and dried under vacuum. Aiternatively, the reaction mixture can be refluxed overnight, followed by cooling and standing at room temperature.
The complexes of formulae I and II are stable for at least one month, providing they are stored under nitrogen at reduced temperatures. After this period, slightly diminished catalytic activity is sometimes observed.
Therefore, these complexes should be in preference freshly prepared to obtain the best hydrogenation results. Alternatively, they can be prepared ~0 immediately prior to use and then employed without isolation, by addition to the hydrogenation reaction mixture, whereby equally good results can be achieved.
As already indicated, the hydrazino-rhodium complexes of the present invention are efficient homogeneous stereospecific hydrogena~ion catalysts, ~5 in general. The present invention however, has been specifically directed to their application in the hydrogenation of the exocyclic methylene group of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline present in the hydrogenation reaction mixture as an acid addition salt, so as to yield ~-6-deoxy-5-hydroxytetracycline in a near stoichiometric yield.
The starting methacycline can be prepared by any of the known process-es, such as that described in U.S. Patent N 3,849,491, but should not contain impurities which may act as a catalyst inhibitor, Although the new complexes will catalyse the hydrogenation of metha-cycline base, the rate is so slow that the time of hydrogenation does not permit the yields obtained when using an acid addition salt.
The rate of hydrogenation increases with the temperature. Temperatu-res from ambient to 95C can be used, but to achieve the best yields and ~.

stereospecificity, the optimum re~ction temperature range is bet~een 85C
and about 90C. At 95C the yields are sligh~ly lower than ~or instance at 88C. Below 85C, the catalytic system starts to be sensitive to the eventual presence o-f certain trace impurities which may interfere with the rate of hydrogenation.
In the context of the hydrogenation of methacycline acid addition salts for the preparation of doxycycline, the present invention has several advantages when the temperature range during hydrogenation is 85C to about 90C.
First, there is no necessity for extremely high hydrogen pressures.
It has been found that from 1 kg/c~ to 10 ky/cm2 will ensure complete con-version of the methacycline substrate in from 6 to about 10 hours.
Typically, the hydrogenation is carried out at 88-89C at a hydrogen press-ure of 7 to 9 kg/cm2 and is complete after 6 1/2 ~o 7 hours.
The painstaking preparation of the catalysts under strictly inert conditions can be alleviated by their preparation in degassed methanol under a nitrogen atmosphere immediately prior to use, followed by addition to the hydrogenation reaction mixture, after which the actual hydrogenation is carried out.
The transformation of the methacycline acid addition salt into doxy-cycline using the catalysts of the present invention, gives a purity above 95~ in the reaction mixture, as analysed by high performance liquid chroma-tography (h.p.l.c.).
Additionally, the use of a rhodium to substrate ratio of 0.0002 by weight in laboratory scale experiments allows complete convers;on within about 6 1/2 to 7 hours. On an industrial scale, a rhodium to substrate ratio of 0.00015 by weight is sufficient to permit complete conversion of the substrate within about 7 to 8 hours.
To ascertain the efficiency of the catalyst of formula II, large sized crystals were prepared, as described in Example 2. One of the crystals so obta;ned was used as catalyst in the hydrogenation of methacycline hydro-chloride. The purity of the conversion of methacycline hydrochlor;de into doxycycline was 99.2~ and the ~-epimer was formed in 0.6% as determined by high performance li~uid chromatography.
In relation to U.S. Patent N 4,550,096, the most striking observation concerning the present invention lies in the fact that when the catalysts are prepared, dried, and stored under a strictly inert atmosphere, the catalysts exert full activity without the necessity of adding an excess of ~L~3~i3~'7 tertiary phosphine, more specifically triphenylphosphine, to the hydrogen-ation mixture so as to achieve the best yields.
An explanation for this is that the catalysts prepared according to the process of U.S. Patent N 4,550,096 were believed to be stable and, in fact, they exerted a very high catalytic activity even when stored for long periods because they were subsequently employed in presence of a controlled excess of a tertiary phosphine. It is now believed that the catalysts prepared according to the process described in U.S. Patent N 4,550,096 oxid;se slowly, but the presence of the excess tertiary phosphine in the hydrogenation reaction mixture, allowed substitution of the oxidised part of the tertiary phosphine, thereby regenerating the original catalytic system.
As has been previously mentioned, the catalyst is most conveniently prepared and used without isolation. Hydrazine (1 to 4 moles) is added with stirring to rhodium trinitrate dihydrate (1 mole) and triphenylphosphine (3.5 moles) in degassed methanol in a glass vessel, under a nitrogen atmosphere. Upon addition of the hydrazine, the initial red colour turns to yellow. It is stirred for between a few minutes and two hours, and then transferred to the pressure reaction vessel containing the methacycline acid addition salt in methanol at 50C, under nitrogen.
Subsequently, the reaction vessel is purged again with nitrogen, ~hen with hydrogen, finally being pressurised to 8 kg/c~ with hydrogen. The reaction mixture is heated to 88C under stirring, and the temperature maintained at 88C ~ 2C until the velocity of consumption of hydrogen slows down drast;cally, which occurs after about 6 to 7 hours. At this time, the react~ion mixture contains nearly exclusively ~-6-deoxy-5-hydroxytetracy-cl lne.
As is known in the art, the rate of the hydrogenation of methacycline ;s increased under acid conditions. Therefore, addition of an acid, prefer-ably the same acid present in the acid addition salt of the substrate, will assure high yields and purity. The amount of extraneous acid is not critical. It can be between one mole per mole of rhodium present, and up to about one mole per mole of the substrate to be hydrogenated. When the extraneous acid is not nitric acid, it is possible that the nitrate counter-ions of the compounds of formulae I and II, could be exchanged by the anion of the added acid.
The purity of the reaction mixture thus obtained is such that the ; doxycycline can be directly crystallised from the reaction mixture by adding ~ excess p-toluenesulphonic acid, followed by cooling, yielding doxycycline p-~ i3 2 ~

toluenesulphonate with a purity superior to 99%.
Finally the new catalytic system can also be employed in the simul-taneous dehalogenation of the 11a-chloro-subs~ituent and stereospeci~ic hydrogenation of the 6-methylene group of 11a-chloromethacycline with good yields.
The following examples serve to illustrate the present invention, without in any way limiting the scope thereof.

EXAMPLES
1. Prepara~ion of di(u-hvdrazine-Nl:N2)-bisrbi~ phenYlphosPhine) rhodium (I)l dinitrate Rhodium trinitrate dihydrate (0.26 9; 0.85 mmoles) and triphenylphos-phine (0.75 9; 2.86 mmoles) were placed in a two necked round bottom flask.
They were stirred under vacuum for 30 minutes. Dry, degassed methanol (50 ml) was added, followed by 15 minutes stirring, to give an orange solution.
The addition of hydrazine in methanol (7 ml of a 12.85 mg/ml solution; 2.81 mmoles) produced a bright yellow suspension which was stirred for a further minutes. This yellow crystalline material was filtered off and dried under vacuum.
A number o~ attempts were made to select crystals for X-ray crystal-lographic analysis, but almost all samples selected were twinned. Eventual-ly a small fragment from a larger elongated parallelopiped was -found which was single. This was used for collection of X-ray data on a 4-circle X-ray 2~ diffractometer, following standard procedures. Details of the crystal data and structure determination are as follows:-72 68 4 4Rh2] [N3]2 (CH30H)2, Mw = 1507 19 mon li ispace group C2/c with a = 24.431(3)~, b = 13.480(2)R, c = 22.102(3)R, ~ =
94.27(2), V = 7258.8R3, Z = 4, Dc = 1.38 g.cm 3, ~(MO-Ka) = 5.8 cm Data collection: Intensity data were collected in the range 1.5 ~ ~ ~ 21.0 and a total of 4220 intensities were measured, of which 3883 were unique and 2336 were observed [I > 3~ (I)], and used in the analysis.
The structure was solved via the heavy-atom method, and refined by full matrix least squares. The phenyl groups in the phosphines were treated D
..

as rigid bodies. The current R value is 0.13, with all atoms refined in the isotropic approximationO
The s~ructure contains a centrosymmetric dimeric cation in which two (PPh3)2Rh units are linked to~ether by two bridging hydrazine molecules to 5 produce a central Rh2N4 ring. By symmetry, this therefore has a chair conformation. The Rh-P and Rh-N distances are normal.

2. Preparation of u-3-carbopentazane-Nl.N4:N2 N5-bis~bis(triDhenvlPhos-phine ~ dinitrate Rhodium trinitrate dihydrate (0.36 g; 1.18 mmoles) and triphenylphos-phine (1.12 g; 4.27 mmoles) were placed in a two necked round bottom flask.
They were stirred under vacuum for 30 minutes and then under an atmosphere of nitrogen for 15 minutes. Dry, degassed methanol (100 ml) was added and the mixture stirred for 15 minutes. Hydrazine in methanol (10 ml of a 10.77 1~ mg/ml solution; 3.36 mmoles) was added and the reaction mixture was refluxedovernight. The orange solution was ~iltered and stood at room temperature for 3 da~s, during which time lar~e orange crystals were deposited. These were filtered off and dried under vacuum.
When the reaction was repeated using rhodium trinitrate dihydrate (0.28 9; 0.91 mmoles), triphenylphosphine ~0.80 9; 3.05 mmoles), hydrazine in methanol (8 mi of a 10.77 mg/ml solution; 2.69 mmoles) in methanol (60 ml) and stirring for two hours, clarification by filtration and stand;ng for 5 days, similar orange crystals were obtained.

A single crystal of average diameter 0.4 mm was sealed under argon in a thin walled glass capillary. Unit cell and intensity data were obtained using a 4-circle X-ray diffractometer, following standard procedures.
~etails of the experimental features are as follows:-30 Crystal data: [C H N P Rh ].~NO ] .(CH OH) , n ~ 0.5, Mw = 1455.10 (ex-cluding the meth 73l~8 4 4 2lj j 3 2 3 n 21/ ( )~
23.311(3)R, c = 13.838(2)R, ~ = 100.51(2), V = 7063.0R3, z = 2, Dc =
1.37 g.cm 3, ~(Mo - K~) = 5.38 cm 1.

Data collection: Data were recovered for 1.5 ~ ~ ~ 23 at room tempera-ture, 291K and corrected for absorption empirically. 9820 intensities were measured, of which 7551 were observed [I > 1.5a(I)], and used in the analy-sis .

3;~ ~

The structure was solved via the heavy atom method and refined by full matrix least squares. All non-hydrogen atoms were refined ~,lith anisotropic thermal parameters, the phenyl groups being treated as rigid bodies. Hydro-gen atoms on the phenyl groups were located experimentally, but for conve-nience were included and refined in idealised positions. Hydrogens on thebridging ligands were experimentally located and freely refined with iso-tropic thermal parameters. The final R value is 0.05 with 707 parameters.
The complex is shown to contain a dimeric cation in which two (Ph3P)2Rh units were linked together by a 3-carbopentazane unit, as shown in 10 II:-_ _ 2+

Ph3P \ / N ~ N \ / PPh3 Rh \ / CH2 / Rh (II~

The presence of the methylene bridge infers a boat conformation on the20 central Rh2N4 ring, with the bridge linking the "prow and stern" positions.
The nitrate ions are well separated from the cation and do not appear to be forming any unusually close contacts. Indeed, one of them seems to occupy a cavity of such size that some positional disorder can occur, and it is also possible that a further cavity in the structure may be partially occupied by methanol of crystallisation.
In a repeat experiment, orange crystals of very similar morphology were obtained, but which appeared to suffer loss of crystallinity on removal from the methanol. On crystallographic examination, these were found to contain considerably more methanol of crystallisation, but the structure of the cation was found to be analogous to that in the first complex.

3. Hydrogenation of methacycline p-toluenesulphonate using a non-isolated catalyst To a suspension of methacycline p-toluenesulphonate (9.50 g; 15.46 mmoles) in methanal (40 ml) was added a solution of rhodium trinitrate di-hydrate (5.76 mg; 0.02 mmoles), triphenylphosphine (70.0 mg; 0.27 mmoles) D and hydrazine hydrate (0.71 ml of a 0.0814M solution of hydrazine in . . .

~2~6~'7 methanol; 0.058 mmoles) in methanol (20 ml). This mixture was hydrogenated at a hydrogen pressure of 8 kg/cm2 for 6 1/2 hours at 88C. Thereafter, p-toluenesulphonic acid (3.3 9) was added to precipitate the doxycycline p-toluenesulphonate~ which weighed 8.64 9, and had a purity of 98.72% by h.p.l.c.

4. Hydrogen_tion of methacycline hydrochloride using a non-isolated catalyst To a suspension of methacycline hydrochloride (7.38 9; 15.41 mmoles) in methanol (40 ml) was added a solution of rhodium trinitrate dihydrate ~5.90 mg; 0.02 mmoles), triphenylphosphine (19.1 mg; 0.07 mmoles) and hydra~ine hydrate (0.47 ml of a 0.0814M s`olution of hydrazine in methanol; 0.038 mmoles) in methanol (20 ml). This mixture was hydrogenated at a hydrogen pressure of 8 kg/cm2 for 6 1/2 hours at 89C. Thereafter, p-toluenesulphonic acid (3.3 9) was added to precipitate the doxycycline p-toluenesulphonate, which weighed 9.08 9, and had a purity of 99.54% by h.p.l.c.

5. Hydrogenation of methacycline using ~-3-carbopentazane-N1,N~:N2,N5-bis [bis(tri~henylphosphine)rhodium (I)] dinitrate 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (10.38 9; 21.7 mmoles) was suspended in methanol (84.5 ml) in a stainless steel high pressure reaction vessel and ~-3-carbopentazane-N1,N4:N ,N -bis ~bis(triphenylphosphine)rhodium (I)] dinitrate (25 mg; 0.017 mmoles; 0.034 mmoles of rhodium) was added under an atmosphere of nitrogen. The vessel was purged with nitrogen, then with hydrogen and pressurised to 8 kg/cm2 with hydrogen. The reaction mixture was heated to 88C for 6 1/2 hours with efficient stirring. The hydrogen was then discharged and p-toluenesulphonic acid (4.65 9; 24.2 mmoles) added under efficient stirring. The stirring was continued for 2 hours whereafter the resulting precipitate was filtered, washed with a small quantity of methanol and dried at 35C.
The yield of ~-6-deoxy-5-hydroxytetracycline p-toluenesulphonate was 12.0 9, or 89.8% of theoretical. By h.p.l.c. it was shown to be 99.2% pure.

D~ .

Claims (17)

1. A process for the preparation of a rhodium-containing homogeneous hydrogenation catalytic system, which comprises reacting a rhodium salt, a hydrazine and a tertiary phosphine in a solvent under otherwise inert conditions, characterized in that the rhodium salt is rhodium trinitrate.

2. A process for the preparation of a new rhodium homogeneous hydrogen-ation catalytic system, according to claim 1, wherein the tertiary phosphine is triphenylphosphine, the hydrazine is hydrazine itself or its hydrate, and the solvent is an aliphatic alcohol containing one to four carbon atoms.

3. A process for the preparation of a new rhodium homogeneous hydrogen-ation catalytic system, according to claim 2, wherein the molar proportion of the reagents calculated for each mole of rhodium trinitrate dihydrate is from one to four moles of triphenylphosphine, one to four moles of hydrazine hydrate, and the solvent is degassed methanol.

4. A process according to claim 1, characterized by the fact that the hydrazine is the anhydrous base or the monohydrate.

5. A process according to claim 1, wherein the catalytic system is prepared separately, under an inert atmosphere, by reacting the reagents at a temperature comprised between room temperature and the reflux temperature of the medium, and added under a nitrogen atmosphere, to the reaction mixture of the substrate to be hydrogenated in a solvent.

6. A process according to claim 5, wherein the solvent is methanol.

7. A process according to claim 1, wherein the catalytic system is prepared "in situ" in the hydrogenation reaction mixture.

8. A process according to claim 1 for the preparation of new rhodium complexes, which are homogeneous hydrogenation cataiysts, having well defined structures, comprising the step of reacting rhodium trinitrate. dihy-drate, triphenylphosphine and hydrazine, and characterized by the fact that the reaction is carried out in degassed methanol under an inert atmosphere, to yield complexes of the formulae I and II:- ( I ) ( II ) wherein Ph is phenyl, when one mole of rhodium trinitrate dihydrate is reacted with an excess of triphenylphosphine and at least one mole of hydrazine, wherein the complex of formula I is predominant with short reaction times and the complex of formula II is predominant with longer reaction times.

9. A process according to claim 8, characterized by the fact that the inert atmosphere is nitrogen.

10. A process according to claim 8, characterized by the fact that the hydrazine is the anhydrous base or the monohydrate.

11. A process according to claim 8, characterized by the fact that the rhodium trinitrate dihydrate is reacted with at least three and a half moles of triphenylphosphine.

12. The compound di(p-hydrazine-N1:N2)-bis[bis(triphenylphosphine)-rhodium (I)] dinitrate.

13. The compound µ-3-carbopentazane-N1,N4:N2,N5-bis[bis(triphenylphos-phine)rhodium (I)] dinitrate.

14. An improved process for the stereoselective hydrogenation of an acid addition salt of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline in the presence of a catalyst to prepare .alpha.-6-deoxy-5-hydroxytetracycline with a high yield and purity, characterized by the fact that the catalyst is a catalyst prepared according to any of claims 1 to 11, and the hydrogenation is carried out at a temperature between 60°C and 100°C, at a pressure of 1 to 10 kg/cm2 and under acid conditions, until the reaction is complete, followed by isolation of the thus formed compound.

15. Process according to claim 14, characterized by the fact that the hydrogenation is carried out at a temperature between 85°C and about 90°C.

16. Process according to claim 14, characterized by the fact that the catalyst is prepared without isolation immediately prior to use, by reacting one mole of rhodium trinitrate dihydrate, three and a half moles of tri-phenylphosphine, and one to four moles of hydrazine.

17. Process according to clime 16, characterized by the fact that three moles of hydrazine are used.