CA1338107C - Process of preparation of new catalysts containing rhodium and their application - Google Patents
Process of preparation of new catalysts containing rhodium and their applicationInfo
- Publication number
- CA1338107C CA1338107C CA000539015A CA539015A CA1338107C CA 1338107 C CA1338107 C CA 1338107C CA 000539015 A CA000539015 A CA 000539015A CA 539015 A CA539015 A CA 539015A CA 1338107 C CA1338107 C CA 1338107C
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- Prior art keywords
- hydrazine
- hydrogenation
- mole
- triphenylphosphine
- process according
- Prior art date
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
Abstract
The present invention refers to the compounds (µ-hydrazine-N1:N2)-bis[bis(triphenylphosphine)-chlororhodium (I)] and di(µ-hydrazine-N1:N2)-bis[bis(triphenylphosphine)rhodium (I)] dichloride, 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 .alpha.-6-deoxy-5-hydroxytetracycline (doxycycline).
Description
~ I3~8107 PROCESS OF PREPARATION OF NEW CATALYSTS
CONTAINING RHODIUM AND THEIR APPLICATION
The present invention refer~ to the compound~ hydrazine-NI:N2)-bi~[bis(triphenylphosphine)-chlororhodium (I)] and di(~-hydrazine-N~:N2)-bis[bis(triphenylphosphine)rhodium (I)]dichloride, which are h- -gen-ous hydrogenation catalyst~ and their application in the hydrogenation of the exocyclic methylene group of acid addition ~alts of 6 ~ hyl-6-deoxy-6-methylene-5-hydroxytetracycline (methacycline) to prepare a-6-deoxy-5-hydroxytetracycline (doxy~-ycline).
Doxy~ycline is a wide-spectrum antibacterial agent, with widespread application 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 i8 doxycycline, whilst the B-6-epimer, called 6-epi-doxycycline, is devoid of clinical utility. Thus, it is important that the hydrogenation doe~ not co-produce this B-6-epimer. In fact, the British phA -copoeia 1980 established a limit for the content of 6-epi-doxy~ycline in doxycycline of 2%.
In the prior art, doxy~ycline was first described in 1960 in Blackwood 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 ; p,oved yields or a purer product. In the field of heterogeneous catalysis, U.S. Patent Ns 3,444,198 (Korst, 1969), 3,849,491 (Villax, 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 ; _oved methods for the preparation of doxy~ycline and its analogues.
The first use of h- -ge-ecus 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 lla-halomethacycline. Brennen et al French Patent N 2,216,268 (1978) later disclosed the use of the same cataly~t.
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 syetem and claiming ; oved yields and stereospecificity.
The first h~ -ganeous hydrogenation catalysts of the type of tertiary phosphine-hydrazine-rhodium complexes were described in Page et al. U.S.
Patent N 4,550,096 (1985). These were prepared either by reacting a rhodium salt, specifically i'''' rhodium trlchloride, with a tertiary phosphine and a hydraz,ne~ 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 had been taught in the prior art.
These complexes have proved to be very satisfactory catalysts for the hydrogenation of methacycline especially if an excess of a tertiary phos-phine is included in the hydrogenation mixture as a promoter.
The exact chemical formulae and structures of the catalysts of this U.S. Patent were not disclosed in the patent, ~ut reported elemental analyses showed some significant variability in elemental composition indicating variations in constitution.
It has now been found that, by changing the process conditions used in the U.S. Patent, very satisfactory new catalysts can be made which have well defined structures. It is advantageous, from general considerations, to be able to use catalysts of precisely known formula and structure, and further-more the new catalysts are very effective for the hydrogenation of metha-cycline without the need to add any excess tertiary phosphine.
According to the present invertion, there is provided a process for the preparation of a complex of rhodium and hydrazine, containing triphenyl-phosphine and chlorine, useful as a homogeneous hydrogenation catalyst, which comprises reacting tris(triphenylphosphine)chlororhodium with hydrazine or hydrazine hydrate in methanol under an inert atmosphere, stirring the reaction mixture at room temperature, or refluxing it and then recovering the solid complex from the mixture, characterised in that the reaction is conducted in the absence of oxygen using degassed methanol, and wherein either (a) a complex of formula I:-PPh3 ~PPh3 Cl - Rh - NH2 - NH2 - Rh - Cl PPh3 PPh3 ( I ) wherein Ph his phenyl, is obtained when each mole of tris(triphenyl-phosphine)chorJ~ ~ um ~ qeacted with at least one half of a mole of ~_ 1338107 hydrazine with stlrring at room temperature until precipitation thereof from ~he mixture, or (b) a complex of formula II:-Ph3P \ ~ / N N \ ~ / PPh3 Rh Rh Ph3P \ N ,~ / ~ PPh H2 H2 Cl ( II ) wherein Ph is phenyl, is obtained when for each mole of tris(triphenyl-phosphine)ch10rorhodium at least one mole of hydrazine is used, and the reaction mixture is stirred at room temperature for a prolonged period or refluxed, followed by standing at room temperature for at least 12 hours in order to form crystals of the complex.
The invention includes the new catalyst compounds of formu1a I and formula II per se, and also a process for the catalytic stereospecific hy-drogenation of an acid addition salt of 6-demethyl-5-deoxy-6-methylene-5-hydroxytetracycline to prepare -6-deoxy-5-hydroxytetracycline, wherein the hydrogenation is carried out at a temperature between 60C and 100CC, at a pressure of 1 to 10 kg/cm2 until the reaction is complete, followed by isolation of the thus formed compound by known processes, characterised by using a catalyst prepared by the process of the invention.
In the process of the invention for making the ne~ catalysts, the tris(triphenylphos?hine)chlororhodium must be freshly prepared, and stored and manipulated under an inert atmosphere. The preparation and isolation of the complexes must be carried out 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 a uniform composition and well defined formulae, being novel compounds, never previously described.
According to the present invention, a catalyst of the formu~a I is obtained by reacting, under an inert atmosphere at room temperature for up to four hours, one mole of tris(triphenylphosphine)chlororhodium with at least half a mole of hydrazine in degassed methanol, followed by isolation and drying under an inert a; -2~h_re or vacuum.
The same reaction can be carried out, with the same precautions as to the exclusion of air, at room temperature for a prolonged period or at reflux, followed by st~n~ing at room temperature for at least 12 hours, for example one to two day~, with at lea~t one mole of hydrazine, giving crystals of the catalyst of the formula II.
Both fc l~e have been unequivocally established by elemental analysis, as well as by infra-red and nuclear magnetic resonance spectrQsccpy~ and in the seccnd case by X-ray cryatallography.
It i~ to be noted that both of these structures fall within the general structure given in said U.S. Patent N 4,550,096.
The catalysts when prepared according to the conditions de~cribed above, are fully active in the hyd~o~nation of methacycline to doxycycline. Furthermore, it is not nece~sary to add excess triphenylphosphine to ensure a near ~toichiometric yield of the required a-epimer.
The complex bis(triphenylphosphine)hydrazinomethoxyrhodium Ph3P ~~~~~ OCH3 ~ Rh Ph3P ~ ~ NH2NH2 ( III ) has been disclosed in Hovione Inter Ltd's European Patent Application N 85 305 045.8 (Publ. N 0 187 436, 1986). Thi~ compound is the result of a side-reaction of the hydrazine and the tris(triphenylpho~phine)chlo~o.hodium, with the methanol solvent taking direct part in the reaction.
Thus, the preparation of any one of these three c~ ~_nds is solely dependent on the physical parameter~ of the reaction. On thi~
basis, the _ _ -'~ of structure~ I and II are in equilibrium in the reaction mixture obtained from the tris(triphenylphosphine)chlororhodium and hydrazine. The precise proportion of each _ ~nd is substantially controlled by the physical parameters existing in the mixture.
It is believed that the -~ ic structure:-Ph3P \ / Cl Rh Ph 3 p \ NH2NH2 ( IV ) is also in equilibrium in the reaction mixture, although this has not been isolated so far.
The conditions of preparation of the catalysts of the present inven-tion are illustrated in ~xamples 1 and 2. The tris(triphenylphos-1~ phine)chlororhodium and hydrazine can be reacted in the molecular proportioncorresponding 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 complex.
The hydrazine can be used as either the anhydrous base or as the mono-hydrate. It has been verified that the anhydrous base allows shorter re-ac~ion times.
To achieve the best results in prepa-ing the compound of formula I, tris(triphenylphosphine)chlororhodium (1 mole) and hydrazine hydrate (3 moles) are mixed in degassed methanol under a nitrogen atmosphere. After stirring for a few hours, the yellow solid precipitates and is filtered and dried under vacuum.
When tris(triphenylphosphine)chlororhodium (1 mole) and hydrazine hydrate (3 moles) are refluxed in degassed methanol under a nitrogen atmos-phere, in adequate equipment, followed by standing at room temperature, filtration and drying under vacuum, yellow crystals of the compound of formula II are formed, In contrast, cooling, preferably after concentra-tion, favours the isolation of a yellow solid of formula III.
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 ob-tain the best hydrogenation results. Al~ernatively, they can be prepared immedlate,ly prior to use and then employe~ without isolation by addition to roq ~ 0~
the h~rogcffltion reaction mixture, whereby equally good results can be achieved.
As already indicated, the hydrazino-rhodium complexes of the present S h om~gen~o~
nventlon are efficient homog~,eous stereos?ecific hydrogenation catalysts, in general. The present invention, however, has specifically been directed to their application in the hydrogenation of the exocyclic methylene group of 6-demethyl 6 deo~y-6-methylene-s-hydLu~y~etracycline present in the hydrogenation reaction mixture as an acid addition 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 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 80 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 60C to 100C can be used, but to achieve the best yields and stereospecificity, the optimum reaction temperature range should be between 85C and about 90C. At 95C the yields are slightly lower than for instance at 88C. Below 85C, 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 85C to about 90C.
First, there is no necessity for extremely high hydrogen pressures. It has been found that from 1 kgtcm2 to 10 kg/cm2 will ensure complete conve,sion of the methacycline substrate in between 6 to about 10 hours. Typically, the hydrogenation is carried out at 88-89C at a hydrogen pressure of 7 to 9 kg/cm2 and is complete after 6 1/2 to 7 hours.
Second, the amount of rhodium necessary to obtain complete conversion is of 'he order of 0.003 part by weight of rhodium in relation to the methacycline acid addition salt substrate.
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 methycycline acid addition salt into doxycycline using the catalysts of the present invention gives a purity above ~r 13~81o7 95% in the reaction mixture, as analysed by high performance liquid chromatGgLaphy (h.p.l.c.).
In contrast to the catalysts of U.S. Patent N 4,550,096, the cat-alysts of the prasent invention when prepared, dried, and stored under a strictly inert al -_~hera, 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 explar.ation for thi~ is tha. the catalysts prepared according to the proce~s of U.S. Patent N 4,550,096 were believe to be stable and, in fact, they exert a very high catalytic activity, even when stored for long periods, becau~e they were subsequently employed in presence of a controlled excess of tertiary phosphine. It is now believed that the catalysts prepared according to the process described in U.S.
Patent 4,550,096 oxidise slowly, but the presence of the excess tertiary phosphine in the hydrogenation reaction mixture allowed substitution of the oYi~;~ed part of the tertiary phosphine, thereby regenerating the original catalytic eystem.
As has been previously mentioned, the catalyst is most conveniently prepared i -~ia~tely prior to use. Thus, hydrazine hydrate (0.5 to 4 mole~) is added with stirring to tris(triphenylphosphine)chlo,orllodium (1 mole) in degassed methanol in a glass vessel, under a nitrogen at ~~phare. Upon addition of the hydrazine, the initial red colour turns to yellow. The reaction mixture is stirred for between a few minutes and two hours, and then transferred to the hydrogenator containing the methacycline acid addition salt in methanol at 50C, under nitrogen.
Subsequently, the reaction vessel is purged again with nitrogen, then with hydrogen, finally being pressurised to 8 kg/cm2 with hydLogen. The reaction mixture is heated to 88C under stirring, and the tF -_ature maintained at 88C ~ 2C until the velocity of consumption of hydrogen slow~ down dra~tically, which occurs after about 6 to 7 hours. At this time, the reaction mixture contains nearly exclusively a-6-deoxy-5-I.yd-o~Letracycline.
The purity of the reaction mixture thus obtained is such that the do~y~ycline can be directly crystallised from the reaction mixture by adding exces~ p-toluenesulphonic acid, followed by cooling, yielding do~y~ycline p-toluenesulphonate with a purity about 99%.
The new catalyst~ have been shown to be effectively superior to the W~ n~~- catalytic system.
1338l 07 So as to elucidate the behaviour of the triphenylphosphine-hydrazino-chlororhodium catalysts, as well as the actual role of the hydrazine present in the complex, an extensive study on this catalytic system was carried out.
According to U.S. Patent No. 4,550,096, triphenylphosphine-hydrazino-chlororhodium catalysts can be prepared "in situ" by the addition of rhodium trichloride, triphenylphosphine and hydrazine hydrate to the cold hydrogenation reaction mixture, followed by heating, after which the actual hydrogenation is carried out.
Therefore, a 6eries of parallel hydrogenations was carried out, using methacycline (MOT) hydrochloride in presence of the "in situ"
prepared catalyst, in the molar proportion of one mole of rhodium trichloride trihydrate and one mole of triphenylphosphine, without addition of hydrazine hydrate, and with the addition of one and two moles of hydrazine hydrate. Whilst in the absence of hydrazine hydrate, only 60.87%
of the a-epimer was formed, together with 12.44% of ~-epimer and 14.95% of degradation products, it was verified that in the presence of hydrazine hydrate, the formation of the a-epimer increased drastically:
RhCl3.3H20 Ph3PNH2NH2-H2O a-epimer % ~-epimer ~o MOT % D~.~ldtio~
products 70 Expt. 1 1 mole1 mole 0 6087 12.44 1174 1495 Expt.21 mole 1 mole1 mole 82.86593 575 546 Expt. 3 1 mole1 mole 2 moles 92.91 2.2 456 033 As can be ascertained from these values, the triphenylphosphine-hydrazino-chlororhodlum catalytic system contains an active species of only one mole of triphenylphosphine and two moles of hydrazine for each mole-atom of rhodium, which is in contrast with the 30 Wil ki n~on catalytic system, which must contain at least two moles of triphenylphosphine for each mole-atom of rhodium in order to be efficient.
, , -In parallel hydrogenation experiment, with the rnodium-hydrazine cata-lytic system and the well-known Wilkinson catalyst, using deuterium instead of hydrogen, the products were analysed by mass spectrometry. It has been found that the doxycycline obtained ~ith the hydrazine-containing system contains significantly less deuterium than the doxycycline obtained using the Wilkinson catalyst. This difference indic~tes that the hydrazine takes an active part in the catalytic hydrogenation.
These resul's show the positive e~fect of the hydrazine ligand in the catalytic system of the present invention.
The following examples serve to illustrate the present invention, without in any way limiting the scope thereof.
EXAMPLES
1) Preparation of (~-hydrazine-N1:N2)-~is~bis(triphenylphosphine)-chloro-rhodium (I)~
Tris(triphenylphosphine)chlororhodium (Q.50 9; 0.54 mmoles) was placed in a two necked round bottom flas~. The solid was s~irred under vacuum for 20 30 minutes and tnen under an atmosphere of nitrogen. Dry, degassed methanol (50 ml) was added and the mixture was stirred for 15 minutes. A methanolic solution of hydrazine hydrate (15 ml of a methanolic solution of hydra~ine hydrate containing 5.91 mg/ml; 1~77 mmoles) was added, and the mixture stirred for 3 hours at room temperature. A yellow precipitate formed, which 25 was filtered off and dried under vacuum.
The proton nmr spectrum showed a complex signal centred on ~ 7~5~
(phenyl ring protons) and a broad peak at ~ 1.8 (hydrazine protons). The infra-red spectrum shows a doublet at 3130 cm 1 (N - H stretching), a band at 305 cm~1 (Rh - Cl stretching), as well as bands indicative of triphenyl-30 phosphine.
Elemental analysis: C: 63~31~o H: 4.81% N: 2~73% P 9~15%
C72H64Cl2N2P4Rh2 requires: C: 63~68% H: 4~75% N: 2~06~ P 9.1~do 35 A repeat preparation using hydrazine hydrate (1 ml; 20~57 mmoles) gave the same product after stirring at room temperature for 1 hour.
CONTAINING RHODIUM AND THEIR APPLICATION
The present invention refer~ to the compound~ hydrazine-NI:N2)-bi~[bis(triphenylphosphine)-chlororhodium (I)] and di(~-hydrazine-N~:N2)-bis[bis(triphenylphosphine)rhodium (I)]dichloride, which are h- -gen-ous hydrogenation catalyst~ and their application in the hydrogenation of the exocyclic methylene group of acid addition ~alts of 6 ~ hyl-6-deoxy-6-methylene-5-hydroxytetracycline (methacycline) to prepare a-6-deoxy-5-hydroxytetracycline (doxy~-ycline).
Doxy~ycline is a wide-spectrum antibacterial agent, with widespread application 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 i8 doxycycline, whilst the B-6-epimer, called 6-epi-doxycycline, is devoid of clinical utility. Thus, it is important that the hydrogenation doe~ not co-produce this B-6-epimer. In fact, the British phA -copoeia 1980 established a limit for the content of 6-epi-doxy~ycline in doxycycline of 2%.
In the prior art, doxy~ycline was first described in 1960 in Blackwood 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 ; p,oved yields or a purer product. In the field of heterogeneous catalysis, U.S. Patent Ns 3,444,198 (Korst, 1969), 3,849,491 (Villax, 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 ; _oved methods for the preparation of doxy~ycline and its analogues.
The first use of h- -ge-ecus 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 lla-halomethacycline. Brennen et al French Patent N 2,216,268 (1978) later disclosed the use of the same cataly~t.
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 syetem and claiming ; oved yields and stereospecificity.
The first h~ -ganeous hydrogenation catalysts of the type of tertiary phosphine-hydrazine-rhodium complexes were described in Page et al. U.S.
Patent N 4,550,096 (1985). These were prepared either by reacting a rhodium salt, specifically i'''' rhodium trlchloride, with a tertiary phosphine and a hydraz,ne~ 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 had been taught in the prior art.
These complexes have proved to be very satisfactory catalysts for the hydrogenation of methacycline especially if an excess of a tertiary phos-phine is included in the hydrogenation mixture as a promoter.
The exact chemical formulae and structures of the catalysts of this U.S. Patent were not disclosed in the patent, ~ut reported elemental analyses showed some significant variability in elemental composition indicating variations in constitution.
It has now been found that, by changing the process conditions used in the U.S. Patent, very satisfactory new catalysts can be made which have well defined structures. It is advantageous, from general considerations, to be able to use catalysts of precisely known formula and structure, and further-more the new catalysts are very effective for the hydrogenation of metha-cycline without the need to add any excess tertiary phosphine.
According to the present invertion, there is provided a process for the preparation of a complex of rhodium and hydrazine, containing triphenyl-phosphine and chlorine, useful as a homogeneous hydrogenation catalyst, which comprises reacting tris(triphenylphosphine)chlororhodium with hydrazine or hydrazine hydrate in methanol under an inert atmosphere, stirring the reaction mixture at room temperature, or refluxing it and then recovering the solid complex from the mixture, characterised in that the reaction is conducted in the absence of oxygen using degassed methanol, and wherein either (a) a complex of formula I:-PPh3 ~PPh3 Cl - Rh - NH2 - NH2 - Rh - Cl PPh3 PPh3 ( I ) wherein Ph his phenyl, is obtained when each mole of tris(triphenyl-phosphine)chorJ~ ~ um ~ qeacted with at least one half of a mole of ~_ 1338107 hydrazine with stlrring at room temperature until precipitation thereof from ~he mixture, or (b) a complex of formula II:-Ph3P \ ~ / N N \ ~ / PPh3 Rh Rh Ph3P \ N ,~ / ~ PPh H2 H2 Cl ( II ) wherein Ph is phenyl, is obtained when for each mole of tris(triphenyl-phosphine)ch10rorhodium at least one mole of hydrazine is used, and the reaction mixture is stirred at room temperature for a prolonged period or refluxed, followed by standing at room temperature for at least 12 hours in order to form crystals of the complex.
The invention includes the new catalyst compounds of formu1a I and formula II per se, and also a process for the catalytic stereospecific hy-drogenation of an acid addition salt of 6-demethyl-5-deoxy-6-methylene-5-hydroxytetracycline to prepare -6-deoxy-5-hydroxytetracycline, wherein the hydrogenation is carried out at a temperature between 60C and 100CC, at a pressure of 1 to 10 kg/cm2 until the reaction is complete, followed by isolation of the thus formed compound by known processes, characterised by using a catalyst prepared by the process of the invention.
In the process of the invention for making the ne~ catalysts, the tris(triphenylphos?hine)chlororhodium must be freshly prepared, and stored and manipulated under an inert atmosphere. The preparation and isolation of the complexes must be carried out 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 a uniform composition and well defined formulae, being novel compounds, never previously described.
According to the present invention, a catalyst of the formu~a I is obtained by reacting, under an inert atmosphere at room temperature for up to four hours, one mole of tris(triphenylphosphine)chlororhodium with at least half a mole of hydrazine in degassed methanol, followed by isolation and drying under an inert a; -2~h_re or vacuum.
The same reaction can be carried out, with the same precautions as to the exclusion of air, at room temperature for a prolonged period or at reflux, followed by st~n~ing at room temperature for at least 12 hours, for example one to two day~, with at lea~t one mole of hydrazine, giving crystals of the catalyst of the formula II.
Both fc l~e have been unequivocally established by elemental analysis, as well as by infra-red and nuclear magnetic resonance spectrQsccpy~ and in the seccnd case by X-ray cryatallography.
It i~ to be noted that both of these structures fall within the general structure given in said U.S. Patent N 4,550,096.
The catalysts when prepared according to the conditions de~cribed above, are fully active in the hyd~o~nation of methacycline to doxycycline. Furthermore, it is not nece~sary to add excess triphenylphosphine to ensure a near ~toichiometric yield of the required a-epimer.
The complex bis(triphenylphosphine)hydrazinomethoxyrhodium Ph3P ~~~~~ OCH3 ~ Rh Ph3P ~ ~ NH2NH2 ( III ) has been disclosed in Hovione Inter Ltd's European Patent Application N 85 305 045.8 (Publ. N 0 187 436, 1986). Thi~ compound is the result of a side-reaction of the hydrazine and the tris(triphenylpho~phine)chlo~o.hodium, with the methanol solvent taking direct part in the reaction.
Thus, the preparation of any one of these three c~ ~_nds is solely dependent on the physical parameter~ of the reaction. On thi~
basis, the _ _ -'~ of structure~ I and II are in equilibrium in the reaction mixture obtained from the tris(triphenylphosphine)chlororhodium and hydrazine. The precise proportion of each _ ~nd is substantially controlled by the physical parameters existing in the mixture.
It is believed that the -~ ic structure:-Ph3P \ / Cl Rh Ph 3 p \ NH2NH2 ( IV ) is also in equilibrium in the reaction mixture, although this has not been isolated so far.
The conditions of preparation of the catalysts of the present inven-tion are illustrated in ~xamples 1 and 2. The tris(triphenylphos-1~ phine)chlororhodium and hydrazine can be reacted in the molecular proportioncorresponding 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 complex.
The hydrazine can be used as either the anhydrous base or as the mono-hydrate. It has been verified that the anhydrous base allows shorter re-ac~ion times.
To achieve the best results in prepa-ing the compound of formula I, tris(triphenylphosphine)chlororhodium (1 mole) and hydrazine hydrate (3 moles) are mixed in degassed methanol under a nitrogen atmosphere. After stirring for a few hours, the yellow solid precipitates and is filtered and dried under vacuum.
When tris(triphenylphosphine)chlororhodium (1 mole) and hydrazine hydrate (3 moles) are refluxed in degassed methanol under a nitrogen atmos-phere, in adequate equipment, followed by standing at room temperature, filtration and drying under vacuum, yellow crystals of the compound of formula II are formed, In contrast, cooling, preferably after concentra-tion, favours the isolation of a yellow solid of formula III.
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 ob-tain the best hydrogenation results. Al~ernatively, they can be prepared immedlate,ly prior to use and then employe~ without isolation by addition to roq ~ 0~
the h~rogcffltion reaction mixture, whereby equally good results can be achieved.
As already indicated, the hydrazino-rhodium complexes of the present S h om~gen~o~
nventlon are efficient homog~,eous stereos?ecific hydrogenation catalysts, in general. The present invention, however, has specifically been directed to their application in the hydrogenation of the exocyclic methylene group of 6-demethyl 6 deo~y-6-methylene-s-hydLu~y~etracycline present in the hydrogenation reaction mixture as an acid addition 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 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 80 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 60C to 100C can be used, but to achieve the best yields and stereospecificity, the optimum reaction temperature range should be between 85C and about 90C. At 95C the yields are slightly lower than for instance at 88C. Below 85C, 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 85C to about 90C.
First, there is no necessity for extremely high hydrogen pressures. It has been found that from 1 kgtcm2 to 10 kg/cm2 will ensure complete conve,sion of the methacycline substrate in between 6 to about 10 hours. Typically, the hydrogenation is carried out at 88-89C at a hydrogen pressure of 7 to 9 kg/cm2 and is complete after 6 1/2 to 7 hours.
Second, the amount of rhodium necessary to obtain complete conversion is of 'he order of 0.003 part by weight of rhodium in relation to the methacycline acid addition salt substrate.
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 methycycline acid addition salt into doxycycline using the catalysts of the present invention gives a purity above ~r 13~81o7 95% in the reaction mixture, as analysed by high performance liquid chromatGgLaphy (h.p.l.c.).
In contrast to the catalysts of U.S. Patent N 4,550,096, the cat-alysts of the prasent invention when prepared, dried, and stored under a strictly inert al -_~hera, 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 explar.ation for thi~ is tha. the catalysts prepared according to the proce~s of U.S. Patent N 4,550,096 were believe to be stable and, in fact, they exert a very high catalytic activity, even when stored for long periods, becau~e they were subsequently employed in presence of a controlled excess of tertiary phosphine. It is now believed that the catalysts prepared according to the process described in U.S.
Patent 4,550,096 oxidise slowly, but the presence of the excess tertiary phosphine in the hydrogenation reaction mixture allowed substitution of the oYi~;~ed part of the tertiary phosphine, thereby regenerating the original catalytic eystem.
As has been previously mentioned, the catalyst is most conveniently prepared i -~ia~tely prior to use. Thus, hydrazine hydrate (0.5 to 4 mole~) is added with stirring to tris(triphenylphosphine)chlo,orllodium (1 mole) in degassed methanol in a glass vessel, under a nitrogen at ~~phare. Upon addition of the hydrazine, the initial red colour turns to yellow. The reaction mixture is stirred for between a few minutes and two hours, and then transferred to the hydrogenator containing the methacycline acid addition salt in methanol at 50C, under nitrogen.
Subsequently, the reaction vessel is purged again with nitrogen, then with hydrogen, finally being pressurised to 8 kg/cm2 with hydLogen. The reaction mixture is heated to 88C under stirring, and the tF -_ature maintained at 88C ~ 2C until the velocity of consumption of hydrogen slow~ down dra~tically, which occurs after about 6 to 7 hours. At this time, the reaction mixture contains nearly exclusively a-6-deoxy-5-I.yd-o~Letracycline.
The purity of the reaction mixture thus obtained is such that the do~y~ycline can be directly crystallised from the reaction mixture by adding exces~ p-toluenesulphonic acid, followed by cooling, yielding do~y~ycline p-toluenesulphonate with a purity about 99%.
The new catalyst~ have been shown to be effectively superior to the W~ n~~- catalytic system.
1338l 07 So as to elucidate the behaviour of the triphenylphosphine-hydrazino-chlororhodium catalysts, as well as the actual role of the hydrazine present in the complex, an extensive study on this catalytic system was carried out.
According to U.S. Patent No. 4,550,096, triphenylphosphine-hydrazino-chlororhodium catalysts can be prepared "in situ" by the addition of rhodium trichloride, triphenylphosphine and hydrazine hydrate to the cold hydrogenation reaction mixture, followed by heating, after which the actual hydrogenation is carried out.
Therefore, a 6eries of parallel hydrogenations was carried out, using methacycline (MOT) hydrochloride in presence of the "in situ"
prepared catalyst, in the molar proportion of one mole of rhodium trichloride trihydrate and one mole of triphenylphosphine, without addition of hydrazine hydrate, and with the addition of one and two moles of hydrazine hydrate. Whilst in the absence of hydrazine hydrate, only 60.87%
of the a-epimer was formed, together with 12.44% of ~-epimer and 14.95% of degradation products, it was verified that in the presence of hydrazine hydrate, the formation of the a-epimer increased drastically:
RhCl3.3H20 Ph3PNH2NH2-H2O a-epimer % ~-epimer ~o MOT % D~.~ldtio~
products 70 Expt. 1 1 mole1 mole 0 6087 12.44 1174 1495 Expt.21 mole 1 mole1 mole 82.86593 575 546 Expt. 3 1 mole1 mole 2 moles 92.91 2.2 456 033 As can be ascertained from these values, the triphenylphosphine-hydrazino-chlororhodlum catalytic system contains an active species of only one mole of triphenylphosphine and two moles of hydrazine for each mole-atom of rhodium, which is in contrast with the 30 Wil ki n~on catalytic system, which must contain at least two moles of triphenylphosphine for each mole-atom of rhodium in order to be efficient.
, , -In parallel hydrogenation experiment, with the rnodium-hydrazine cata-lytic system and the well-known Wilkinson catalyst, using deuterium instead of hydrogen, the products were analysed by mass spectrometry. It has been found that the doxycycline obtained ~ith the hydrazine-containing system contains significantly less deuterium than the doxycycline obtained using the Wilkinson catalyst. This difference indic~tes that the hydrazine takes an active part in the catalytic hydrogenation.
These resul's show the positive e~fect of the hydrazine ligand in the catalytic system of the present invention.
The following examples serve to illustrate the present invention, without in any way limiting the scope thereof.
EXAMPLES
1) Preparation of (~-hydrazine-N1:N2)-~is~bis(triphenylphosphine)-chloro-rhodium (I)~
Tris(triphenylphosphine)chlororhodium (Q.50 9; 0.54 mmoles) was placed in a two necked round bottom flas~. The solid was s~irred under vacuum for 20 30 minutes and tnen under an atmosphere of nitrogen. Dry, degassed methanol (50 ml) was added and the mixture was stirred for 15 minutes. A methanolic solution of hydrazine hydrate (15 ml of a methanolic solution of hydra~ine hydrate containing 5.91 mg/ml; 1~77 mmoles) was added, and the mixture stirred for 3 hours at room temperature. A yellow precipitate formed, which 25 was filtered off and dried under vacuum.
The proton nmr spectrum showed a complex signal centred on ~ 7~5~
(phenyl ring protons) and a broad peak at ~ 1.8 (hydrazine protons). The infra-red spectrum shows a doublet at 3130 cm 1 (N - H stretching), a band at 305 cm~1 (Rh - Cl stretching), as well as bands indicative of triphenyl-30 phosphine.
Elemental analysis: C: 63~31~o H: 4.81% N: 2~73% P 9~15%
C72H64Cl2N2P4Rh2 requires: C: 63~68% H: 4~75% N: 2~06~ P 9.1~do 35 A repeat preparation using hydrazine hydrate (1 ml; 20~57 mmoles) gave the same product after stirring at room temperature for 1 hour.
2) P~epa,alion of di(~-hydrazine-N':N2)-bis rbis (triphenylphosphine)rhodium(I)~dichloride Tris(l~ henylphosphine)chlororhodium (1.05 g; 1.13 mmoles) was placed in a tw s necked round bottom flask. The solid was stirred under vacuum for 30 minutes and then under an atmosphere of nillogen. Dry, deg~sed methanol (170 ml) was added and the IlliAIUl~ was stirred for 15 minutes. A methanolic solution of hydrazine hydrate (30 ml of a lu~ olic solution co~ inil-g 5.91 mg/ml; 3.54 mmoles) was added. The reaction IniA~ure was refluxed for 2 hours. Upon st~n-ling overnight, yellow crystals were 10 deposited, which were filtered and dried under vacuum.
A single crystal of apploAimate ~imPnSions 0.3 mm x 0.15 mm x 0.1 mm was sealed under argon in a thin walled glass capillary. Unit cell and intensity data were obtained using a four circle X-ray diffractometer, following standard procedures. Details of the e,.~lill,enlal fe&lul~s are as follows:-Crystal data: [C72H68N4P4Rh2].[Cl]2.CH3OH, Mw = 1422.02, monoclinic, space groupP2l/n, a = 15.009(3)A, b = 13.294(2)A, c = 18.391(4)A"B = 108.9(1), V = 3471.9 A3, z = 2, Dc = 1.36 g.cm~3, ~(Mo - K~x) = 6.14 cm~l.
Data collection: Data were recovered for 1.5 < ~ < 21 at room te---~l~ture, 291K
and coll~;led for absorption empirically. 3716 intensities were measured, of which 1805 20 were considered observed [I ~ 1.5 ~(I)] and used in the analysis."
The structure was solved via the heavy atom method and refined by full matrix least squa~es. In view of the sm.~Jl number of observeid data, the structure was refined in the anisotropic approximation, but with the phenyl groups defined as rigid bodies. No hydrogens were confidently located on the hydrazine nitrogen atoms and none were25 included. The final R value is 0.06.
The complex was found to contain a dimeric cation in which two (Ph3P)2Rh units were linked together by two bridging hydrazine molecules, as shown in II:-_ 2+
,H2 H2 Ph~P \ / N N \ / PPh3 Rh Rh Ph3P \ N - N/ \ PPh3 The rhodium centres have the expected s~uare planar configuration, with the Rh-P and Rh-N dis~ances being normal. The central Rh2N4 ring has a chalr conforma+ion, compatible with its centrosymmetric nature.
A single crystal of apploAimate ~imPnSions 0.3 mm x 0.15 mm x 0.1 mm was sealed under argon in a thin walled glass capillary. Unit cell and intensity data were obtained using a four circle X-ray diffractometer, following standard procedures. Details of the e,.~lill,enlal fe&lul~s are as follows:-Crystal data: [C72H68N4P4Rh2].[Cl]2.CH3OH, Mw = 1422.02, monoclinic, space groupP2l/n, a = 15.009(3)A, b = 13.294(2)A, c = 18.391(4)A"B = 108.9(1), V = 3471.9 A3, z = 2, Dc = 1.36 g.cm~3, ~(Mo - K~x) = 6.14 cm~l.
Data collection: Data were recovered for 1.5 < ~ < 21 at room te---~l~ture, 291K
and coll~;led for absorption empirically. 3716 intensities were measured, of which 1805 20 were considered observed [I ~ 1.5 ~(I)] and used in the analysis."
The structure was solved via the heavy atom method and refined by full matrix least squa~es. In view of the sm.~Jl number of observeid data, the structure was refined in the anisotropic approximation, but with the phenyl groups defined as rigid bodies. No hydrogens were confidently located on the hydrazine nitrogen atoms and none were25 included. The final R value is 0.06.
The complex was found to contain a dimeric cation in which two (Ph3P)2Rh units were linked together by two bridging hydrazine molecules, as shown in II:-_ 2+
,H2 H2 Ph~P \ / N N \ / PPh3 Rh Rh Ph3P \ N - N/ \ PPh3 The rhodium centres have the expected s~uare planar configuration, with the Rh-P and Rh-N dis~ances being normal. The central Rh2N4 ring has a chalr conforma+ion, compatible with its centrosymmetric nature.
3. Comparative hydrogenations in presence and absence of hydrazine A. Molar ratio - Rh:PPh3 = 1:1 Methacycline hydrochloride (4.0 g; 8.35 mmoles) was suspended in methanol (60 m1) and rhodium trich7Oride trihydrate (200 mg; 0.75 mmoles) and triphenylphosphine (196.5 mg; 0.75 mmoles) added. The mix+!~re was then hydrogenated for 6 hours at a hydrogen pressure of 8 kg/cm2 and a tempera-ture of 80C in a convent~onal stainless steel high pressure reactor. At the end of the reaction, a sample of the reaction mixture was analysed by h.p.l.c. and gave:-a-epimer = 60.87%
~-epimer = 12.44%
methacycline = 11.74%
others = 14.95 B. Molar ratio - Rh:PPh3:NH~NH2 = 1:1:1 The experiment as described in A above was repeated but wi'h the ad-dition of 0.95 ml of a 0.814 M solution of hydrazine hydrate in methanol (0.77 mmoles NH2NH2). H.p.l.c. of the crude reaction mixture ~ave:-a-epimer = 82.86~
~-epimer = 5.93%
methacycline = 5.75%
others = 5.46%
~~ - 12 - 1 3381 0 7 C. Molar ratio - Rh:PPh3:NH2NH2 = 1:1:2 The experiment as described in A above was repeated but with the ad-dition of 1.9 ml of 0.814 M solution of~hydrazine hydrate in methanol (1.55 mmoles NH2NH2). H.p.l.c. of the crude reaction mixture gave:-a-epimer = 92.91%
Q-epimer = 2.2 %
methacycline = 4.56%
others = 0.33%
~-epimer = 12.44%
methacycline = 11.74%
others = 14.95 B. Molar ratio - Rh:PPh3:NH~NH2 = 1:1:1 The experiment as described in A above was repeated but wi'h the ad-dition of 0.95 ml of a 0.814 M solution of hydrazine hydrate in methanol (0.77 mmoles NH2NH2). H.p.l.c. of the crude reaction mixture ~ave:-a-epimer = 82.86~
~-epimer = 5.93%
methacycline = 5.75%
others = 5.46%
~~ - 12 - 1 3381 0 7 C. Molar ratio - Rh:PPh3:NH2NH2 = 1:1:2 The experiment as described in A above was repeated but with the ad-dition of 1.9 ml of 0.814 M solution of~hydrazine hydrate in methanol (1.55 mmoles NH2NH2). H.p.l.c. of the crude reaction mixture gave:-a-epimer = 92.91%
Q-epimer = 2.2 %
methacycline = 4.56%
others = 0.33%
4. Hydrogenation of methacycline using a non-isolated catalyst Tris(triphenylphos?hine)chlororhodium (15.0 mg; 0.016 mmoles) and a methanolic solution of hydrazine (124 ~l of a 0.4M solution; 0.050 mmoles) were added to methanol (60 ml) in a nitrogen atmosphere with stirring.
lS Methacycline hydrochloride (7.38 g; 15.41 mmoles) was added, and the mixturetransferred to a conventional stainless steel high pressure reactor, which was charged to a pressure of 8 kg/cm2 with hydrogen, and then reacted at 88C for 6 1/2 hours.
p-Toluenesulphonic acid (3.3 g) was then added and the mixture stirred at 0C for 2 hours. The doxycycline p-toluenesulphonate obtained by fil-tration and drying at 35C weighed 8.84 9 and had a puri~y of 98.9%.
lS Methacycline hydrochloride (7.38 g; 15.41 mmoles) was added, and the mixturetransferred to a conventional stainless steel high pressure reactor, which was charged to a pressure of 8 kg/cm2 with hydrogen, and then reacted at 88C for 6 1/2 hours.
p-Toluenesulphonic acid (3.3 g) was then added and the mixture stirred at 0C for 2 hours. The doxycycline p-toluenesulphonate obtained by fil-tration and drying at 35C weighed 8.84 9 and had a puri~y of 98.9%.
5. Hydrogenation of methacycline using (~-hydrazine-~l:NZ)-bis[bis (triphenylphosphine)chlororhodium (I)]
(~-Hydrazine-Nl:N2)-bis[bis(triphenylphosphine)chlororhodium (I)] (11 mg; 0.0081 mmoles; 0.0162 mmoles of rhodium), as prepared in Example 1, was added to a suspension of methacycline hydrochloride (7.25 g; 15.14 mmoles) in methanol (59 ml) and the mixture hydrogenated at a pressure of 8 kg/cm2 for 6 1/2 hours at 88aC. Thereafter, p-toluenesulphonic acid (3.3 g) was added and the mixture stirred at 0C for several hours. The yield of doxy-cycline p-toluenesulphonate was 8.45 g, 90.5%, which had a purity of 99.0q.
(~-Hydrazine-Nl:N2)-bis[bis(triphenylphosphine)chlororhodium (I)] (11 mg; 0.0081 mmoles; 0.0162 mmoles of rhodium), as prepared in Example 1, was added to a suspension of methacycline hydrochloride (7.25 g; 15.14 mmoles) in methanol (59 ml) and the mixture hydrogenated at a pressure of 8 kg/cm2 for 6 1/2 hours at 88aC. Thereafter, p-toluenesulphonic acid (3.3 g) was added and the mixture stirred at 0C for several hours. The yield of doxy-cycline p-toluenesulphonate was 8.45 g, 90.5%, which had a purity of 99.0q.
Claims (16)
1. A process for the preparation of a complex of rhodium and hydrazine, containing triphenylphosphine and chlorine, useful as a homogeneous hydrogenation catalyst, which comprises reacting tris(triphenylphosphine)chlororhodium with hydrazine or hydrazine hydrate in methanol under an inert atmosphere, stirring the reaction mixture at room temperature, or refluxing it, and then recovering the solid complex from the mixture, characterised in that the reaction is conducted in the absence of oxygen using degassed methanol, and wherein either (a) a complex of formula (I):- (I) wherein Ph is phenyl, is obtained when each mole of tris-(triphenylphosphine)chlororhodium is reacted with at least one half of a mole of hydrazine with stirring at room temperature until precipitation thereof from the mixture, or (b) a complex of formula (II):- (II) wherein Ph is phenyl, is obtained when for each mole of tris(triphenylphosphine)chlororhodium at least one mole of hydrazine is used, and the reaction mixture is stirred at room temperature or refluxed until the reaction is substantially complete, followed by standing at room temperature for at least 12 hours in order to form crystals of the complex.
2. A process according to claim 1, characterised by the fact that the hydrazine is the anhydrous base or the monohydrate.
3. A process according to claim 1, characterized by the fact that the inert atmosphere is nitrogen.
4. A process according to claim 3, characterized by the fact that the hydrazine is the anhydrous base or the monohydrate.
5. A process according to claim 4, wherein the catalyst is prepared from one half to four moles of hydrazine per one mole of tris(triphenylphosphine)chlororhodium.
6. A process according to claim 5, wherein three moles of hydrazine are used per mole of tris(triphenyl-phosphine)chlororhodium.
7. A process for the catalytic stereospecific hydrogenation of an acid addition salt of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline to prepare .alpha.-6-deoxy-5-hydroxytetracycline, wherein the hydrogenation is carried out at a temperature between 60°C and 100°C, at a pressure of 1 to 10 kg/cm2 until the reaction is complete, followed by isolation of the thus formed compound, characterized by using a catalyst of the formula or or a mixture thereof wherein Ph is phenyl.
8. A process according to claim 7, wherein the amount of rhodium contained in the catalyst is less than 0.0003 part by weight per part of the 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline acid addition salt to be hydrogenated, with the hydrogenation being substantially complete within 10 hours, and the hydrogenation reaction medium is methanol.
9. Process according to claim 7, characterized by the fact that hydrogenation is carried out at a temperature between 85°C and about 90°C.
10. A process according to claim 9, wherein the amount of rhodium contained in the catalyst is less than 0.0003 part by weight per part of the 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline acid addition salt to be hydrogenated, with the hydrogenation being substantially complete within 10 hours, and the hydrogenation reaction medium is methanol.
11. A process according to claim 10, wherein the catalyst is prepared from at least 1/2 of a mole of hydrazine per mole of tris(triphenylphosphine)chlororhodium, and the catalyst is then added without isolation to the hydrogenation reaction mixture.
12. A process according to claim 11, wherein three moles of hydrazine are used per mole of tris(triphenyl-phosphine)chlororhodium.
13. A process according to claim 7, wherein the catalyst is prepared from at least 1/2 of a mole of hydrazine per mole of tris(triphenylyphosphine)chlororhodium, and the catalyst is then added without isolation to the hydrogenation reaction mixture.
14. A process according to claim 13, wherein three moles of hydrazine are used per mole of tris(triphenyl-phosphine)chlororhodium.
15. The compound (µ-hydrazine-N1:N2)-bis[bis(triphenylphosphine)-rhodium (I)].
16. The compound di(µ-hydrazine-N1:N2)-bis[bis(triphenylphosphine)-rhodium (I)]dichloride.
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| DE3771705D1 (en) * | 1987-03-25 | 1991-08-29 | Plurichemie Anstalt | RHODIUM HYDRATION CATALYSTS. |
| ATE68476T1 (en) * | 1989-04-03 | 1991-11-15 | Ranbaxy Lab Ltd | PROCESS FOR THE PRODUCTION OF ALPHA-6DEOXYTETRACYCLINES. |
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| US4550096A (en) * | 1982-01-19 | 1985-10-29 | Plurichemie Anstalt | Homogeneous catalytic system comprising rhodium, hydrazine and phosphine and a process for the preparation of same |
| PT79774A (en) * | 1984-12-28 | 1985-01-01 | Joao Emerico Villax | Process to prepare rhodium catalysts and applications thereof |
| ATE63312T1 (en) * | 1987-03-25 | 1991-05-15 | Plurichemie Anstalt | RHODIUM CONTAINING HYDROGENATION CATALYSTS. |
-
1987
- 1987-05-14 AT AT87304278T patent/ATE63312T1/en not_active IP Right Cessation
- 1987-05-14 DE DE8787304278T patent/DE3769977D1/en not_active Expired - Fee Related
- 1987-05-18 ZA ZA873543A patent/ZA873543B/en unknown
- 1987-05-27 AU AU73432/87A patent/AU595606B2/en not_active Ceased
- 1987-05-29 NZ NZ220506A patent/NZ220506A/en unknown
- 1987-06-05 CA CA000539015A patent/CA1338107C/en not_active Expired - Lifetime
- 1987-06-18 IE IE161087A patent/IE60598B1/en not_active IP Right Cessation
-
1991
- 1991-10-17 HK HK811/91A patent/HK81191A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE871610L (en) | 1988-09-25 |
| AU595606B2 (en) | 1990-04-05 |
| ZA873543B (en) | 1988-11-30 |
| NZ220506A (en) | 1989-09-27 |
| IE60598B1 (en) | 1994-07-27 |
| ATE63312T1 (en) | 1991-05-15 |
| AU7343287A (en) | 1988-09-29 |
| HK81191A (en) | 1991-10-25 |
| DE3769977D1 (en) | 1991-06-13 |
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