AU595319B2 - Process of preparation of novel rhodium hydrogenation catalysts and their application - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: ainc~xr~5 a(1W 5531 Complete Specification Lodged: Accepted: Published: Priority Related Art, 49 and Ls couimct I APPLICANT'S REF.: TEC-170/87-PP'P/IS a 4 Name(s) of Applicant(s): PLURIGHEMI ANSTALT :0 Address(es) of Applicant(s): FL-9490, Vaduz,

LIECHTENSTEIN

Actual Inventor(s): DYc. William Hleggie, Mr Philip Ronald Page, Mr Ivan Villax, Dir Indira Ghatak and Dr. M.B. H-ursthouse 00 00 o 000 0 00 o 0 0 o 0* 0 0000 .4 0000 0 000000 o 0 0 *0 I ~A 0 09 0 000000 .4 0 Address for Service is: PH ILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins St-eet Melbourne, Australita, 3000 Complete Specification for the invention entitled.

PROCESS OF PREPARATION OF NOVEL RIIODIUM IlYDRGENATION CATALYSTS AND THEIR APPLICATION The following statement is a full description of this invention, including the best method of performing it knowd to applicant(s): PLURICE2AE ANSTALT P19/3/84 PROCESS OF PREPARATION OF NOVEL fdHODIUM HYDROGENATION CATALYSTS AND THEIR APPLICATION 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(p-hydrazine-N 1

:N

2 bis[bis(triphenylphosphine)rhodium(I)]dinitrate and V-3-carbopentazane-

N',N':N

2 N'-bis[bis(triphenylphosphine)rhodiuni(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-tetracycline (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 a-6-epimer is doxycycline, whilst the B-6-epimer, called 6-epi-doxycycline, is devoid of clinical utility. Thus, it is important that the hydrogenation does not co-produce this B-6-epimer. In fact, the British Pharmacopoeia 1980 established a limit for the content of 6-epidoxycycline in doxycycline of 2%.

In the prior art, doxycycline was first described in 1960 in U.S. Patent No 3,200,149. Since that time many methods have been s 25 described for the preparation, in all of which the modification of the catalytic system has been described as producing improved yields or a purer product. In the field of heterogenous catalysis, U.S.

Patent Nos 3,444,198, 3,849,491, 3,954,862 and 4,597,904 and the *s report in Chemical Abstracts 86, 89476 f (1977) of Hungarian Patent 12 042 have all taught improved methods for the preparation of doxycycline and its analogues.

The first use of homogenous catalysis was described in U.S.

Patent No 4,207,258 (Italian priority 1972), ?'herein the catalyat was a complex of rhodium with tertiary phosphine, arsine and stibine 35 ligands. U.S. Patent No 3,962,331 extended the above process to the simultaneous reductive dehalogenation and hydrogenation of an llahalomethacycline. French Patent No 2,216,268 later disclosed the use of the same catalyst.

-la- Since that time, other patents have appeared such as U.S. Patent Nos 3,907,890, 4,001,321 and 3,962,131 all describing variations in the catalytic system and claiming improved yields and stereospecificity.

The first homogenous hydrogenation catalysts of the type of tertiary phosphine-hydrazino-rhodium complexes were described in U.S.

Patent No 4,550,096. These were prepared by reacting a rhodium salt, specifically 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 doxyeycline, containing less than 1% of the undesired 6-epi-doxycycline, in high yield using considerably less rhodium than had been taught in the prior art.

U.S. Patent No 3,463,830 describes the preparation of zero valent platinum and palladium catalysts, by the reduction of these 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 from those of U.S. 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, U.S. Patent No 3,956,177 describes compositions useful as hydroformylation catalysts, prepared by contacting an organorhodium halide with a hydrazine and a, phosphorous-containing adjuvant, to form an intimate mixture 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 eouble bonds, but as catalysts for hydroformylation reactions.

S t"e The copending Australian application, based on the Portuguese Application for a Patent of Addition to Portuguese Patent No 74.303, describes the preparation of several members of the group of triphenylphosphine-hydrazino-chlorohodium complexes in a pure state, having m 35 well defined formulae, and their application in the preparation of doxycycline.

When using rhodium trinitrate instead of rhodium trichloride in the process described in U.S. Patent No 4,550,096, it was found ;r i surprising that the formation of the complexes was generally different from that of the complexes obtained from rhodium trichloride. The catalytic system thus formed comprises rhodium complexes having differen-t formulae and is not analogous to the series containing chloride as the anionic ligand.

It has been found that, especially on an industrial scale, the minimum effective quantity of catalyst needed to hydrogenate a methacycline acid addition salt to prepare doxycycline could be further reduced by about one half, in relation to the quantity necessary when rhodium trichloride was used to prepare the catalytic system described in U.S. Patent No 4,550,096. 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.

'ne new catalytic system can be prepared by reacting one mole o rhodium trinitrate, as the dihydrate, with one to two moles, or evn with an excess, of a suitable tertiary phosphine, and between e and two moles, or an excess, of a suitable hydrazine, in a suib le solvent, at a temperature comprised between room temper ure and the reflux temperature of the medium, preferably under a inert atmosphere, The expression "suitable" denotes those compound which, when forming i* the complex, do not interfere with its cataly c activity, 4 2Not all tertiary phosphines are suit ale but simple experimenta- 25 tion will show which san be used satis ctorily Triphenylphosphine and its para-chloro and para-fluoro eivatives, for example, yield efficient complexes, whilst oth derivatives of triphenylphocphine, such as the ortho-methoxy or ara-dimethylamino, give iefficient complexes. Additionally,/ethyldiphenylphosphine and benzyl-diphenylphosphine give cataly cally inoperative complexes for the preparation of doxycycline.

The suit ,e hydrazines are of the formula R 1 R N.N R3R 4 wherein

SR

1 is pheny benzenesulphonyl, lower alkyl or hydrogen and R 2

R

3 and R are l er alkyl or hydrogen, with the proviso that when R is phenyl or b zenesulpionyl, R R and R are hydrogen. The preferred 2 3 4 h razine is hydrazine itself and its hydrate.

The usual solvents are aliphatic alcohols containing ons to four 4A carbon atoms, the preferred solvent being methanol.

Accordingly, the present invention provides 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, wherein the rhodium salt is rhodium trinitrate.

Further, the present invention provides an improved process for the stereoselective hydrogenation of an acid addition salt of 6-demethyl-6-deoxy-6-methylene-5hydroxytetra-cycline in the presence of a catalyst to prepare Q-6-deoxy-5-hydroxy-tetracycline with a high yield and purity, wherein the catalyst is a catalyst prepared according to any of claims 1 to 8, and the hydrogenation is carried out at a temperature between 60 0 C and 100 0 C, at a pressure of 1 to 10 kg/cm 2 and under acid conditions, until the reaction is complete, followed by isolation of the thus formed compound by known processes.

The new catalytic system can be prepared by reacting one mole of rhodium trinitrate, as the dihydrate, with one to two moles, or even with an excess, of a suitable t tertiary phosphine, and between one and two moles, or an S,4 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 Ssatisfactorily. Triphenylphosphine and its para-chloro and para-fluoro derivatives, for example, yield efficient complexes, whilst other derivatives of triphenylphosphine, S" such as the ortho-methoxy or para-dimethylamino, give inefficient complexes. Additionally, ethyldiphenylphosphine and benzyl-diphenyl-phosphine give catalytically inoperative complexes for the preparation of doxycycline.

3a r;p The suitable hydrazines are of the formula

R

1

R

2

N.NR

3

R

4 wherein R 1 is phenyl, benzenesulphonyl, lower alkyl or hydrogen and R2'

R

3 and R 4 are lower alkyl or hydrogen, with the proviso that when R1 is phenyl or benzenesulphonyl,

R

2

R

3 and R 4 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.

r t -r 3b 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/ whilst a molar proportion of 1:1:2 ensures a pronounced stereospecificity (24a/1l). A molar proportion of 1:1:3, results in an even higher stereospecificity (45a/1).

Generally, the preparation of the catalytic system of the present invention should be carried out using in total, at least three moles of ligands, 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 preparation of new rhodium complexes, which are homogeneous hydrogenation catalysts, having well-defined structures, comprising the step of reacting rhodium trinitrate dihydrate, triphenylphosphine and t xhydrazine, characterised by the fact that the reaction is carried out in degassed r.methanol under an inert atmosphere, to yield complexes of the formulile I and II:- 6

NO

3 re H 2 H2 Ph3P\e N /PPh 3 Rh Rh Ph P N PPh S3 3 i H2 H2 6

NO

S3

(I)

35 C Si CN I3 1 H NO II tl ',h 3 3 35 Kh CII Rh 2 Pit P N N i'Ph 3 "2 e S-r- (I i -I -I -4r?~ wherein Ph is phenyl, when one mole of rhodium trinitrate dihydrate is reacted 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 formula II is predominant with longer reaction times.

When the process of U.S. Patent No 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, ,s having well defined structures and a highly stereospecific and 0 regioselective catalytic activity, which can be employed in minute 4 20 amounts in the hydrogenation of methacycline to furnish hydroxytetracycline in high yields, near to stoichiometric.

a According to the present invention, by reacting, under an inert 09 6 atmosphere, one mole of rhodium trinitrate dihydrate, an excess of triphenylphosphine, preferably at least three and a half moles, and 25 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 ,ie, after longer reaction times, typically one to two days at room a temperature. Alternatively, the reaction mixture can be refluxed S6 30 overnight, followed by cooling and standing at room temperature.

rr The structures of the compounds of formulae I and II were established by X-ray crystallography.

The catalysts when prepared according to the conditions 4 described above, are fully active in the hydrogenation of metha- 03.3* 35 cycline to doxycycline. Furthermore, it is not necessary to add excess triphenylphosphine to ensure a high yield of the required a-epimer.

The conditions of preparation of the catalyss of the present invention are clearly illustrated in Examples 1 and 2. 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 monohydrate. It has been verified that the anhydrous base allows shorter reaction 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), triphenyla phosphine (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 of 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.

Alternatively, 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 t tiionth, 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 r results. Alternatively, they can be prepared immediately prior to use t and then employed without isolation, by addition to the hydrogenation a 30 reaction mixture, whereby equally good results can be achieved.

As already indicated, the hydrazino-rhodium complexes of the n t q present invention are efficient homogeneous stereospecific hydrogenai tion catalyst:s, in general. The present invention however, has been specifically directed to their application in the hydrogenation of the 35 exocyclic methylene group of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracy~line present in the hydrogenation reaction mixture as an acid additio salt, so as to yield a-6-deoxy-5-hydroxytetracycline in a near stoichiometric yield.

The starting methacycline can be prepared by any of the known processes, such as that described in U.S. Patent No 3,849,491, but should not contain impurities which may act as a catalyst inhibitor.

Although the new complexes will catalyse the hydrogenation of methacycline 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.

Temperatures from ambient to 95 C can be used, but to achieve the best yields and stereospecificity, the optimum reaction temperature range is between 85 0 C and about 90 0 C. At 95 0 C the yields are slightly lower than for instance at 88 0 C. Below 85 0 C, the catalytic system starts to be sensitive to the eventual presence of 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 85 C to about 90 0

C.

First, there is no necessity for extremely high hydrogen 2 2 pressures. It has been found that from 1 kg/cm to 10 kg/cm will ensure complete conversion of the methacycline substrate in between 6 to about 10 hours, Typically, the hydrogenation is carried out at 88-89 C at a hydrogen pressure of 7 to 9 kg/cm 2 and is complete after S6 1/2 to 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 o which the actual hydrogenation is carried out, o The transformation of the methacycline acid addition salt into doxycycline using the catalysts of the present invention, gives a purity above 95% in the reaction mixture, as analysed by high performance liquid chromatography (h.plc.) Additionally, the use of a rhodium to substrate ratio of 0,0002 by weight in laboratory scale experiments allows complete converslon 35 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 desccbed in Example 2. One of the -7- -4 crystals so obtained was used as catalyst in the hydrogenation of methacycline hydrochloride. The purity of the conversion of methacycline hydrochloride into doxycycline was 99.2% and the B-epimer was formed in 0.6% as determined by high performance liquid chromatography.

In relation to U.S. Patent No 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 tertiary phosphine, more specifically triphenylphosphine, to the hydrogenation mixture so as to achieve the best yields.

An explanation for this, is that the catalysts prepared acuording to the process of U.S. Patent No 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 No 4,550,096 oxidise slowly, but the presence l of the excess tertiary phosphine in the hydrogenation reaction 20 mixture, allowed substitution of the oxidised part of the tertiary I" phosphine, thereby regenerating the original catalytic system, e As hao hoan previously mentioned, the catalyst is most convenieniently pepared and used without isolation. Hydrazine (1 to 4 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 colcur turns to yellow. It is stirred for between a few minutes and two hours, and then transferred to the pressure YIr reaction vessel containing the methacycline aoid addition salt in S,4 30 methanol at 50SQ, under nitrogen, Subsequently, the reaction Vessel is purged again with nitrogen, 2 then with hydrogen, finally being pressurised to 8 kg/cm with 1, hydrogen. The reaction mixture is heated to 88 C under stirring, and the temperature maintained at 88 0 C 20C until th velocity of

"S

1 35 consumption of hydrogen alows down drastically which occurs after about 6 to 7 hours. At this time, the reaction mixture contains nearly exclusively -6-deoxy--hydroxytetracycline, As is known in the art, the rate of the hydrogenation of -8- *Iw. methacycline is increased under acid conditions. Therefore, addition of an acid, preferably 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, 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 counterions 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 directl~y crystallised from the reaction mixture by adding excess p-toluenesulphoaic acid, followed by cooling, yielding doxycycline p-toluenesulphonate with a purity superior to 99%.

Finally the new catalytic system can also be employed in the simultaneous~ dehalogenation of the lla-chloro-substituent and stereospecific hydrogenation of the 6-methyiene group of lla-Qhloromethacycline with good yields, The following examples servo to illustrate the present invention# Without in any way limiting the scope thereof,

EXAMPLES

1, Preparation of di(pA-hydrazine.-N 1 N 2)-bis~bis(triphenylph2sphine), rhodium Idinitrate ghodium trinitrAte dihycirate (0,26 q! 0.85, mmoles) andi tsrlPheW-s phoophine (Q..75 g; 2,e6 rmnoiles) Were placed in a two neckod rotund bottom flask, They Were stirred tinde vacuum for 30 Oqnu' dogassed methanol (50 ml) was added, followed by 15 irt stirring, to give an orange solution. The addition of hydrazine iU methanol (7 MI of a 12,8$ mg/ml solqtion; 2.81 rMMOles) produced 4 bright yellow suspension which was stirred for a further 30 minutes, Thko yellow ~:crystalline material Was filtered off and dried Under vacuum.

A number of attempts were made to select crystals tor X-ray :Orystallograpbic analysis, but almost all %amnplos sq~c'ed Ago##* 3$ twinned. Eventually a small fragment from a larger elongated paroa e- 2opiped was found. which was single. This was usecl tor ot X(-ray data on an Enraf-Nonius CAD4 difrraatomqter# foXloWIr p~.~~due~,0atil~of I:he dXystal data afld struoturo ceti are as follows:t t~ttt sq t S S

S

S

St's

*SSS

SI

5 S S

S

S

S SI.

S

54.

5

S

55 .5 S *4.

0 444.4.

S

*04.4 4 *5004.4

S

S

.5 5 S B I 54 .55444 S I Crystal data: (C 72 H 68 N 4 P ARh 2 ).(N0 3 1 2 .(CH 3 OH) 2 Mw 1507.19, monoclinic, space group C2/c with a 24.431(3)A, b 3.480(2) c =22.102(3)F. 94.27(2)', V 7258.8 R3 Z 4, Dc =1.38 g.cm 3 p (Mo-Kt) 5.6t cm Data collection: Intensity data was collected in the range 1,5 0 8 0 21,0 0and, a totail of 4220 intensities were measured, of which 3883 were unique and 2336 were observed [1 3 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 as rigid bodies, The cu.rrent R value is 0,13, with all atoms refined irn the isotropic approximation.

The structuire contains a centrosymnetric dimeric cation in which two (PUh 3 )Rh units iAre linked together by two bridging hydrazine molecules t(c, prodclce a central R.h N 4 ring. By smety 20 this therefore has a chair confor.-a.ion, The Rh-P and Rh-N distances are. normal.

2. reaation of p-3-carbopentazane-N N 4:N 2,N -_'bis(bis(triphertylphosphine) rhodium ]dinitrate Rhodium trinitrate dihbydrate (0,36 g; 1.18 mmoles) arid triphenylph~sphine (1.12 g; 4,27 mmoles) were placed in a two necked round bottom flasks They Were stirred under vacuum for 30 minutes and then under a4 atmosphere of nitrogen for 15 minutes, Dry, degassed metha.nol1 (100 ml) was added and the mixture stirred for 15 minutes.

30, Hydrazine in methanol (10 ml of a 10.77 mg/mi solution; 3.36 mmoles).

was added and the reactio.n mixture was refluxed overnight. The -orange solution was filtered and stoc., at room tempIerature for 3 days, during which time large orange crystals were deposited. These were filtered off and dried under vacuum, When the reaction Was repeated using rhodium. trinitrate dihydrate (0,20 g; 0.91 mmoles) triphenylphosphine (0.80 gi 3.05 mxnoles), hydrazine in methanol (8 Al of a 10.77 mg/mi solution: 2.69 mmoles) in methanol (60 ml) and stirring for two hours, clarification by filtration and standing for 5 days, similar orange crystals were obtained.

A ji3gle 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 an Enraf-Nonius CAD4 diffractometer, following standard procedures. Details of the experimental features are as follows:- Crystal data: [C73 H68N4P Rh2].[NO312.(CH3OH)n, n 0.5, Mw 1455.10 (excluding the methanol), monoclinic, space group P21/n, a 22.269 b 23.311(3)R, c 13.838(2) 5 100.51(2)°, V 7063.0 3 -3 -1 Z 2, Dc 1.37 g.cm (Mo Ka) 5.38 cm Data collection: Data were recovered for 1.50 8 C 230 at room temperature, 291 K and corrected for absorption empirically, 9820 intensities were measured, of which 7551 were observed [I 1.5 and used in the analysis.

The structure was solved via the heavy atom method and refined by full matrix least squares. All non-hydrogen atoms were refined with anisotropic thermal parameters, the phenyl groups being treated as rigid bodies. Hydrogen atoms on the phenyl groups were located expermentally, but for convenience were included and refined in idealised positions. Hydrogens on the bridging ligands were experimentally located and freely refined with isotropic thermal parameters.

The final R value is 0.05 with 707 parameters.

The complex is shown to contain a dimeric cation in which two P (Ph P) Rh units were linked together by a 3-carbopentazane unit, as 30 shown in II:- 2+ H H ,2 Ph PN PPh 3 -3 Rh CH Rh PhP1- N 'PPh H

H

2 T o -11i is Isr

I

Ir I e is i

S

It Si 4 #4 Su

I

The presence of the methylene bridge infers a boat conformation on the central Rh 2

N

4 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 methanol (40 ml) was added solution of rhodium trinitrate dihydrate (5.76 mg; 0.02 mmoles), triphenylphosphine 20 (70.0 mg; 0.27 mmoles) and hydrazine hydrate (0.71 ml of a 0.0814M solution of hydrazine in methanol; 0.058 mmoles) in methanol (20 ml).

2 This mixture was hydrogenated at a hydrogen pressure of 8 kg/cm for 6 1/2 hours at 88 C. Thereafter, p-toluenesulphonic acid (3.3 g) was added to precipitate the doxycycline p-toluenesulphonate, which weighed 8,64 g, and had a purity of 98.72% by h.p.l.c.

4. Hydrogenation of methacycline hydrochloride using a non-isolated catal.'- To a suspension of methacycline hydrochloride (7.38 g; 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 hydrazine hydrate (0.47 ml of a 0.0814M solution of hydrazine in methanol; 0.038 mmoles) in methanol (20 ml). This mixture was hydroqenated at a hydrogen pressure of 8 kg/cm 2 for 6 /2 hours at 89 C. Thereafter, p-toluenesulphonic acid (3.3 g) was added to precipitate the doxycycline p-toluenesulphonate, which weighed 9.08 g, and had a purity of 99.54% by h.p.l.c.

-12-

I-

1 I Hydrogenation of methacycline using p-3-carbopentazane-N, N :N ,N -bis[bis(triphenylphosphine)rhodium (I)]dinitrate 6-Demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (10.38 g; 21.7 mmoles) was suspended in methanol (84,5 ml) in a stainless steel high pressure reaction vessel and V-3-carbopentazane-N ,N :N ,N 5 bis[bis(triphenylphosphine)rhodium (I)]dinitrate 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/cm 2 with hydrogen. The reaction mixture was heated to 88 C for 6 1/2 hours with efficient stirring.

The hydrogen was then discharged and p-toluenesulphonic acid (4.65 g; 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 35 0

C.

Tne yield of a-6-deoxy-5-hydroxytetracycline p-toluenesulphonate was 12.0 g, or 89.8% of theoretical. By h.p.l.c. it was shown to be 99.2% pure.

0 o 9 90 ie 6 -13-

Claims (16)

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, ahae.ised ha the rhodium salt is rhodium trinitrate.

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

3. A process for the preparation of a new rhodium homogeneous hydrogenation catalytic system, according to claim 1, 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 orocess according to any of the previous claims, wherein the catalytic system is prepared separately, under an inert atmosphere, 20 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 an adequate solvent, such as methanol.

A process according to claims 1 to 3, wherein the catalytic system is prepared "in in the hydrogenation reaction mixture.

6. A process accr to claim 1 for the preparation of new rhodium complexes, wi~ n are homogeneous hydrogenation catalysts, having well-defined structures, comprising the step of reacting rhodium trinitrate dihydrate, triphenylphosphine and hydrazine, and she 30 i- t 'L .the reaction is carried out in degassed methanol under an inert atmosphere, to yield complexes of the formulae I and II:- NOe 3 Aor: 4, "2 2 Ph 3 P N- N /PPh 3 Rh Rh Pha 3 N \PPh3 H 2 H" e NO 3 -14- i- L 1 NOe 3 H H 2 Ph 3 P\ /PPh 3 Rh CH Rh 3 N/ \PPh 3 Ph3P N N PPh3 H H 2 e NO (II) wherein Ph is phenyl, when one mole of rhodiumtrinitrate dihydrate is reacted 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 formula II is predominant with longer reaction times.

7. A process according to claim 6, -:harar-te i -by- +1h a athe inert atmosphere is nitrogen.

8. A process according to claims 6 and 7, wherein the 4 4 r hydrazine is the anhydrous base or the monohydrate.

9. An improved process for the stereoselective "t hydrogenation of an acid addition salt of 4 1* 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline in the presence of a catalyst to prepare tetracycline with a high yield and purity, wherein the catalyst is a catalyst prepared according to any of claims 1 to 8, and the hydrogenation is carried out at a temperature between 60 C and 100 C, at a pressure of 1 2 to 10 kg/cm and under acid conditions, until the reaction is complete, followed by isolation of the thus formed compound by known processes.

Process according to claim 9, wherein the hydrogenation is carried out at a temperature between 85 C and about 90 C. C 15 c i.

11. Process according to claim 9, wherein the catalyst is prepared without isolation immediately prior to use, by reacting one mole of rhodium trinitrate dihydrate, three and a half moles of triphenylphosphine, and one to four moles of hydrazine.

12. Process according to claim 11, wherein t~eat three moles of hydrazine are used.

13. The compound di '1 -hydrazine-N :N )-bis[bis (triphenylphosphine)-rhodium (I)]dintirate.

14. The compound 1 -3-C~AT openta?,ane-N 1 N :N2 N bis[bis(triphenyl-phosphine)rhodium (I)]dinitrate.

A process according to claim 1, substantially as herein before described with reference to the examples.

16. A process according to claim 9, substantially as herein before described with reference to the examples. DATED: 8 DECEMBER 1989 PHILLIPS ORMONDE FITZPATRICK Attorneys for: PLURICHEMIE ANSTALT 0 0 19 *4 0 a 1 r IT 1 1j t