IL44084A

IL44084A - Homogeneous catalytic reduction of 6-methylenetetracyclines

Info

Publication number: IL44084A
Application number: IL44084A
Authority: IL
Original assignee: Pfizer
Priority date: 1973-02-01
Filing date: 1974-01-25
Publication date: 1977-10-31
Also published as: SE435619C; JPS49102662A; DD110855A5; NO153806B; PH14446A; YU39915B; CH589605A5; NO151585C; NL7401340A; IE38797B1; NO151585B; SE7400879L; NO153806C; SE435619B; NO740320L; FR2216268A1; YU25374A; ES422758A1; JPS5912111B2; AR210453A1

Description

Homogeneous catalytic reduction of 42248 This invention relates to a novel process for h the exocyclic methylene group of a it relates to the of a an derivative or an acid addition salt of any of the aforementioned by contacting the compound and hydrogen with a complex of rhodium with ligands which form such as tertiary in a solvent medium in which the complex is The reaction of lenetetracyclines acid addition thereof and polyvalent metal complexes thereof with hydrogen presence of a heterogeneous noble metal catalyst to produce and is described in Thii of a poisoned noble metal catalyst to the same conversion t with increase in the ratio of to is reported in Israel Patent Specification describes the use of catalytic reduction using gen a noble metal catalyst to achieve of reduc of thyienetetracyclines and complexes thereof in the presence of a noble metal catalyst using hydrazine as hydrogen i reported in German specifica on British describes the use of Raney nickel and Raney cobalt as catalysts for such reduc halide complexes containing tertiary or arsine their preparation and use as described in Patent February of the platinum group of particularly of which contains a and a tertiary or their and use as hydrogenation catalysts are also reported in British Patents January January July and July and in 3 89 786 and Such catalysts are reported to provide an improved process for hydrogenation of unsaturated organic particularly of compared to the use of heterogeneous Israel Patent Specification 41600 describes the preparation of etracyclines by homogeneous catalytic tion using tris chlororhodium as The catalyst can reportedly preformed or can be prepared directly in the medium by dissolving trichloride in the medium in the presence of between one and three molar equivalents of Patent issued September genation of unsaturated organic molecules using homogeneous the iron triad type with tertiary Typical of the complexes described is chlorotris Numerous publications indicate homogeneous catalysis is a promising approach to hydrogenation including regiospecific selective and asymmetric Horner et An e 942 and Belgian Patent lished November 1971 report the use of complexes of univalent rhodium with o tertiary phosphine ligands as homogeneous catalysts asymmetric catalytic Recent publications rather a comprehensive review of the Harmon et Knowles 10 Grubbs 3062 Kagan et 6429 and Industrial Applications and in Chemistry published by the American Washington of Homogeneous edited by Ugo and published by Carlo and et Russian Chemical Homogeneous catalytic hydrogenation of exocyclic methylene in coronopilin and in an mediate in the stereoselective total of seychellene et using tris chlororhodium as catalyst is The reaction of or acid addition salts thereof with hydrogen in the presence of soluble coordination complexes of rhodium with ligands as catalysts has now been found to proceed smoothly with hydrogenation of the exocyclic methylene an acid addition salt of the reactant is used in place of the base and added The process of this invention affords several advantages over the prior art reduction For or no formation of undesired ahhydrotetracylcine the overall conversion of a cycline to a is near quantitative reduction of substrate the catalysts stereoselectivity in the that the ratio of the desired epimer to is increased of is The process is useful for hydrogenation of clines selected from the grou consisting of those having the and acid addition salts thereof wherein Y is a hydrogen atom or a hydroxy and Z is a hydrogen chloro atom or bromo The structures of the complexes involved in hydrogenation process are not known with In all a number of plexes arc actually involved in the process as catalysts or becomes convenient to define the complexes as containing complexes of rhodium which have been derived from a of the metal and a ligand selected from the group consisting of tertiary phosphines of the formula PR R R wherein each of R and R is selected from the group consisting of phenyl and substituted wherein the substituent is selected from the group consisting of and and is selected from the group consisting of alkyl and benzyl By the d as used herein is and alkoxy groups containing from 1 to 10 carbon Of special interest are those tertiary phosphines wherein the alkyl and alkox when contain from 1 to 4 carbon In accordance with the process of the present a methylcnetetracycline of the above or the corresponding chloro is dissolved in an appropriate solvent medium and with hydrogen in the presence of a homogeneous that a catalyst soluble in the solvent at an appropriate temperature and pressure when Z is in the presence of at least about a molar equivalent of acid per mole of u til the desired reaction when Z is dchalogenation of the 1 halo group with or without hydrogenation of the when Z is hydrogenation of the and especially when Z is acid addition salt of the compound is used as A wide variety of solvents can be used the present The solvents or mixture of solvents chosen may be such as to permit s bilization of the and the catalyst at the temperature the reaction run so as to afford a homogeneous Representative of solvents and tures ethylene glycol monomethyl ethylene glycol monoethy and alcohols such as ethanol isopropanol and In addition to these solvent mixtures of water with the solvents enumerated herein are also is a favored solvent when using hydrox tetracycline hydrochloride as substrate since it provides adequate sol bility of substrate and and satisfactory rate and yield of reactio mixtures of the solvents with solvents in which the substrate and catalyst are poorly soluble can also be used if For mixtures can be criterion that the catalyst and substrate be sufficiently soluble in the system to perm reaction to The choice of solvent is upon several factors in additi to solubility of the catalyst and Factors such as stability of th solvent under the conditions of the particularly of elevated tem and of the reaction rate are important in selecting a solvent which wi afford optimum conversion of substrate to the desired amide appears to undergo degradation to carbon monoxide and whi iiiactivate the The rate of degradation of such solvents is acceler ted with increase in temperature of the in order to obtain complete conversion of substrate to the desired temperatures below increased amounts of catalyst must be araide is much more stable under the reaction conditions used and is a favored acetonltrile and amide can also be used as Their is not favored they give rise to reaction rates slower than those obtained with the enumerated Alcoholic in are the preferred solvents since they permit satisfactory solubility of substrate and satisfactory reaction rates and yields of desired The stereoselectivity of the reaction does appear to some extent upon the Dimethylformamide has been observed to duce somewhat higher ratio of to than do alcoholic solvents under a given set of The suitability of a given solvent or mixture of solvents for the process of this invention is as a first by checking the solubility of the substrate and therein at the temperature which the reaction is to be Once solubility is the suitability the particular solvent evaluated by actual preferably on a small frequen monitoring of eaction mixture to assess the degree of conversion of the nature of the products and the rate of the A convenient procedure thin layer chromatography on silica gel plates buffered at pH 6 using the solvent system The plates are developed with ammonia and visualized under ultraviolet at 366 It of not necessary that the substrate dissolve completely in the solvent It is only essential that it be sufficiently soluble in the solvent so as to permit reaction to occur and that the undissolved substrate serve as a reservoir or source of fresh substrate to maintain a substrate concentration in the I is to use a solvent in which the substrate and catalyst are or almost pressure of hydrogen to be employed in the process is not critical but can range from pressure to 4000 In pressures of from about atmospheric pressure to about 2000 are Pressures of from about one atmosphere to about 50 atmospheres are pressures of hydrogen are conveniently obtained by introducing an inert into the reaction vessel in addition to the A partial pressure of hydrogen of less than one atmosphere is then readily The temperature of the process is not critical but can vary over the range of from about to about The favored range is bout to about and the preferred range about to about At low below about reaction rate is slow relative to that at the favored temperature temperatures not desirable for operation of this At temperatures above deactivation of the catalyst usually at such a rate as to in incomplete substrate except at high levels of The temperature of the reaction determined not only by the increase in reaction rate normally expected with an increase in but also b the Stability of the solvent and as a direct corollary completeness the The concentration of substrate appears to have littl on the reaction except from the standpoint of reaction rate even in solvents in which the substrate is only partially There appears to be no appreciable concentration related the stereoselectivity of reaction that upon the ratio of to The catalyst concentration is likewise not a critical factor for reasons of is generally to levels mole percent to about 10 mole percent by based the substrate The use higher levels u to 100 mole is fully operative in the present process but is levels of catalyst are normally not used since tion or the catalyst and incompleteness of the reaction are likely a serious proportions of catalyst equal to or greater than th amount of substrate are not generally considered in normal usage this they are so considered here in the absence of such little or no reaction with hydrogen would is only thr ug assistance of the that reaction The pH of the reaction mixture is a significant as reaction rate and stereoselectivity of has been observed that when alcoholic solution using tris as at by weight based upon concentration of strate and one of hydrochloride of under conditions gave less than of the Similar results are obtained when hydrogen anhydrous or is added to a reaction containing The free base appears to hydrogenate at a slower rate than does the hydvochloride The is desirably used as an acid addition an acid is added to a solution of the base form of the substrate so as to permit reaction to take place in an acidic acid and mineral acids especially hydrochloric represent preferred examples of the acid component in such Molar ratios of acid to reactant of from about 1 to about 5 are The preferred ratio is from about 2 to about 3 moles of acid per mole of reactant since optimum reaction rate and stereoselectivity with a minimum of side reactions occur such A variety of other and acids described in as capable of salt tion with can also be The catalysts of value in the process of this invention in the absence of a solvent having a solvating effect be represented by the formula a c L is a especially a ligand capable of forming a described more fully is a halide or other anion to maintain a is an integer of from 1 to 6 and is generally 2 to c is an integer of from 1 to 3 provided that the sum of a and c totals 4 when Rh is present in monovalent and the sum of a and c totals 6 for other the coordination of the present and upon the coordinating only of itsslf but relative to that ligands already in the coordinatio of one or ligands by solvent the anion necessary can be a wide of anions and is not critical to current Representative anions are those selected from the group ing of hydroxide and The preferred anion is Suitable ligands are of wherein and are as defi ed Of particular value to this process are complexes of with because of their stereoselectivity of reduction which affords highly favorable ratios of a From an economical triphenylphosphine is an especia valuable ligand since it is mercially The preferred catalysts the complexes of with and especially hodiu whic is commercially available and provides high yields of predominantl the The catalysts are by known to those in Many of them in reported art cited They ma be preformed for prepared in From a practical use of the preformed catalyst is especially i instances wherein the is rhodium A general method for preparing catalysts of use in this invention comprises reacting the etal especiall suitable solvent such as thanol with the appropriate A sufficier excess of the is used to reduce the In the case a molar ratio of phosphin to of ό to 1 is employed to produce the monovalent rhodium The reaction is generally conducted in to electroneutrality is the chloride ion since the metal chlorides are generally more readily available than are the corresponding bromides and The use of the bromides or iodides as reactants in the preparation cf complexes of complexes with bromide or iodide as The relative unavailability of bromides and iodides of the to solutions of chloride Levels of potassium or iodide of about to about by weight based upon the metal beneficial in expediting the Lower or higher appear to offer no advantage and may even be detrimental to the rate of hydrogenation is affected by the anion of the In the series where X is a halide the order appears to be The presence of fluoride appears detrimental to the hydrogenation i The present invention also includes as catalysts complexes which t in a chiral phosphine wherein can be on the phosphorous or on the groups attached to the Such catalysts are often more selective as hydrogenation catalysts in process of this The products produced in the current process are f recovered by any of several techniques known to those skilled in the For the tetracycline products can be isolated as amphoteric compounds acid addition salts especially by precipitation of the an salt e in case of precipitation as the sulfosalicylate the catalyst complex can be removed from the reaction mixture by extraction into a suitable A further method comprises addition of a metal usually in forms a chelate with the and thus competes the catalyst for the tetracycline Typical metal include as well metals known to form chelates with The can then be isolated by precipitation for as an alkaline complex according to the method of patent or by The presence of above 10 mole catalyst the reaction mixture can give to difficulties in isolation because of oxidation about by the It has been found convenient to isolate the from reaction containing high levels of rhodium in the absence The reaction mixtures are conveniently monitored and assayed to the extent of the reaction and approximate of and by thin layer chromatography on silica gel plates as describe More precise determination of the extent and yields of the reactions are achieved by hig pressure liquid chromatography This is accomplished using the atronix The column used a 2 x column a ammonium substituted r late polymer coated by on trademark of ours The solvent system is water containing ethylene diaininetetracetic plus sodium acetate adjusted to pH with acetic A flow rate of per minute is The instrument has a 20 injection In this has a value of tetracycline a K value of and a K value of those skilled in the art will ligands other than those enumerated above can also be form catalysts of in the Representatives of such ligands are phosphites herein and R2 are as defined or wherein is as defined1 and In addition to complexes of the type described coordination complexes which are of at least moderate solubility in the vent the advantages of homogeneous and heterogeneous catalysis can be realized by the us o a coordination of rhodium which may be in or of limited solubility in the reaction It is of that classification of coordination complexes on the basis of their solubility is purely relative and de upon the solvent system It simply by judicious choice of to reclassify a complex from a soluble complex to an insoluble On the other there are those complexes of the type described herein which are of limited solubility in most solvents and are present in the reaction mixture as a separate Such insoluble complexes function by a mechanism which is not yet understood but which derives from the coordinative binding of ligand to the Also embraced within this facet of coordination complexes limited solubility is that of a coordination complex of rhodium bound to insoluble Particular interest resides complexes are tively bonded to phosphine groups Polymer supported rhodium of re by treating copolymer lithio phosphines the chloro is replaced by the copolymer can contain varying amounts of cross Such polymers are Grubbs et 3062 and Capka et Tetrahedron 4787 A further class polymer is the polyme described An 11 298 Such polymers are prepared by the polymer and then reacting the with the sodio salt of the appropriate The products differ from those derived from chloromethylated in that hosphine moiety is attached directly to a benzenoid methods of preparation described are applicable to wide variety of such The phosphine is treated with or appropriate salt in solution to the polymer bound coordination the copolymer is equilibrated appropriate complex for a period of several days to produce the The complexes of solubility and the bound in addition to the that of easy removal from reaction mixtures in which they are the recovery of desirable products is generally and excess complex can be used without complications arising in recovery can be blocked y ester ol owe y trans ormat on t ereof into an as is described in In addition to the of formula I which serve as substrates in the process of this of formulae also serve as EXAMPLE I Reduction of etracycline Under a nitrogen rhodium are added ti degassed methanol at room in a flask connected to an The flask is purged nitrogen and then filled with hydrogen to a pressure of 45 The reaction a is heated to shaken for 68 High pressure liquid chromatography indicated from to of present in the shewed it to comprise and and starting a record crop of product seuarated from HPLC showed it to be and and starting Repetition of this procedure but using iodide of potassium bromide produces substantially the same IV Repetition of the procedure of Example I but in place of the corresponding j affords primarily yclin of 6a and none of startin are Similar results are achieved when used place of rhodium ris rhodium The procedure IX repeated using high pressure so as to permit pressures of and 4000 with substantially the Under a nitrogen hydrochloride and iodide ng are added to degassed methanol and water in an autoclave The vessel is purged of nitrogen and then filled with hydrogen to a pressure of 1700 The reaction mixture is agitated and heated to over a period and then he contents are removed and diluted with methanol A solution of acid of solution in and water are added to the diluted reaction mixture The mixture is thoroughly stirred and the The salicylate salt thus obtained is washed with a cold of a d dried Assay of the product measurement of the intensity of ultra absorption at 349 in M hydrochloric acid and with a standard indicates a yield of o sulfosalicylate insufficientOCRQuality

Claims

44084/2 CLAIMS:

1. An improved process for the production of a 6- -deoxytetracycline of the formula: by hydrogenation of a 6-methylenetetracycline of the formula: wherein Y is a hydrogen atom or a hydroxy group; and Z is a hydrogen atom, chloro atom or bromo atom or their salts; characterized by treating the 6-methylenetetracycline with hydrogen at sub- to supraatmospheric pressures, in an inert solvent at a temperature within the range of 20° to 100°C. in the presence of a complex of rhodium with a tertiary phosphine of the formula PtR^f^R^) wherein and R2 each represent unsubstituted phenyl or phenyl substituted by . halo, alkyl, alkoxy or dialkylamino radical containing 1 to 10 carbon atoms; and R_ is R, , alkyl containing 1 to 10 carbon atoms or benzyl; and, at least in the case where Z is hydrogen, an alkali metal bromide or iodide.

2. A process according to claim 1, characterized by the fact that the reduction is carried out in an alcohol with the molar ratio of rhodium to tertiary phosphine from 1:2 to 1:3 and at a preferred hydrogen pressure from one atmosphere to 50 atmospheres and at a preferred temperature from 40 to 85 °C.

3. A process according to either of claims 1 and 2, characterized by the fact that the alkali metal halide is potassium bromide or potassium iodide in the amount from about 0.25% to about 1% by weight based upon the catalyst.

4. A process according to claim 1, characterized by the fact that the concentration of catalyst in the reaction mixture is from about 0.01 mole per cent to about 10 mole per cent by weight based upon the 6-methylene-tetracycline .

5. A process according to any one of the preceding claims, wherein 6-methylene tetracycline is produced by hydrogenation of llOd -chloro-6-methylenetetracycline in the catalytic presence of a complex of rhodium and a tertiary phosphine.

6. A process according to any one of the preceding claims, wherein the catalyst is chloro-tris (triphenyl phosphine) rhodium [I] .

7. A process according to claim 1 substantially as 44084/2 hereinbefore described in any of the Examples.

8. A 6-methylenetetracycline or 6-methylene-5-hydroxy tetracycline whenever obtained by the process of any one of the preceding claims.