Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
  • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

• This invention relates to a process for the preparation of alpha-6-deoxytetracyclines and to the use of a heterogeneous rhodium catalyst therein, and more particularly to such a process useful in the production of the antibiotic doxycycline, viz., alpha-6-deoxy-5-oxytetracycline.
• doxycycline and other alpha-6-deoxytetracyclines were first described in Blac wood et al. U.S. Patent No. 3,200,149 granted August 10, 1965. That patent described their preparation by the catalytic hydrogenation of a corresponding 6-methylene intermediate, e.g., in the case of doxycycline, lla-chloro-6-deoxy-6-demethyl- 6-methylene-5-oxytetracycline (lla-chloro methacycline) or 6-deoxy-6-demethyl-6-methylene- 5-oxytetracycline (methacycline) , in the presence of a heterogeneous noble metal catalyst, e.g. palladium on carbon.
• a heterogeneous noble metal catalyst e.g. palladium on carbon.
• the Blackwood patent disclosed the production, in yields of up to about 50%, of equimolar proportions of the diastereoisomers (epimers) of the 6-deoxytetracyclines.
• the patent disclosed the co-production of the corresponding beta epimer, beta-6-deoxy-5-oxytetracycline.
• SUBSTITUTESHEET greater stereoselectivity of formation of the desired alpha epimers, e.g., doxycycline.
• Korst U.S. Patent No. 3,444,198 granted May 13, 1969 disclosed that the stereoselectivity of formation of the alpha epimers may be increased when the noble metal hydrogenation catalyst is poisoned.
• the Korst patent described the formation of epimeric mixtures of the 6-deoxytetracyclines in total yields of up to about 60%, with the stereoselective production of the alpha epimers in amounts of up to about 90% of the epimeric product mixtures.
• Faubl et al. in U.S. Patent No. 3,962,131 describes a heterogeneous catalyst for use in hydrogenating methacycline.
• the Faubl catalyst is produced by reacting rhodium trichloride and sodium acetate in methanol at temperatures in excess of 50°C, and reacting this system with triphenylphosphine.
• the Faubl catalyst is reported to exhibit stereoselectivity for the alpha epimers by a factor of at least 9:1 versus the beta epimer with a yield of 98.8% reported in the sole Faubl example.
• SUBSTITUTESHEET Catalytic hydrogenation of methacycline using a catalytic amount of rhodium metal together with a phosphine, preferably triphenylphosphine, and a promoter, e.g., excess acid (over that required to form an acid addition salt with methacycline) , is disclosed by Morris, Jr. in U.S. Patent No. 3,954,862.
• the heterogeneous rhodium metal catalyst may be of the non-supported or supported type, e.g., supported by carbon, silica, alumina or barium sulfate.
• Page Another process for the heterogeneous hydrogenation of methacycline is disclosed by Page in U.S. Patent No. 4,597,904.
• Page employs a rhodium salt catalyst wherein the rhodium is bonded to a polysiloxane carrier, generally an aminopoly- siloxane.
• the methacycline hydrogenation is accomplished in the presence of a tertiary phosphine, e.g., triphenylphosphine.
• the Page hydrogenation process is reported to be sterospecific, typically yielding less than 0.2% beta epimer.
• polysiloxane materials are known to be sensitive to elevated temperatures, e.g., greater than 90°C, and any breakdown of the polysiloxane carrier would adversely impact the functionality and the recylability of the Page rhodium salt catalyst.
• the present invention is directed to an improved process for the production of doxycycline and other alpha-6-deoxytetracyclines, wherein the desired alpha epimer is produced in both high yield and stereospecificity, and the noble metal constituent of the hydrogenation catalyst may be utilized in smaller proportions than heretofore required and is readily recoverable from the
• This invention comprises an improved process for the preparation of alpha-6-deoxy- tetracyclines by the hydrogenation of the corresponding 6-methyl-enetetracyclines in the presence of a heterogeneous rhodium catalyst wherein the rhodium is complexed and bound to a silica gel support.
• the supported heterogeneous rhodium catalyst has the formula:
• R and R' are each selected from hydrogen and C,-C 4 alkyl; x is an integer from 1 to 6;
• Ph is phenyl
• y is an integer from 1 to 3;
• L is a ligand selected from alkoxysilyl-substituted alkyl diphenylphosphines of general formula:
• Ph is phenyl.
• Silica-supported rhodium complex catalysts of this type have been disclosed for the halogenation of alkenes. Czakova et al., J. Mo1. Catal. II. 313-322 (1981). See also Hartley, Supported Metal Complexes. D. Reidel Publishing Co., pages 150 et seq. (1985); Kochloefl et al., J.C.S. Chem. Co ⁇ tm.. 1977, 510-11; Conan et al., J. Mol. Catal. I. 375-382 (1976).
• the above heterogeneous rhodium catalyst may be used to stereospeciflcally hydrogenate methacycline to form the alpha epimer doxycycline at significantly lower rhodium metal levels as compared to prior art heterogeneous catalyst systems.
• stereospecific formation of doxycycline is achieved at rhodium metal levels of as low as 0.15 mg per gram 11-a chloro methacycline, without sacrificing product yield. Indeed, yields well above 90% and as high as 99.3% are achieved at
• the method of the present invention thus stereospeciflcally produces the alpha epimer at significantly higher yields than those reported for prior art processes with the exception of Page example 4.
• Page example 4 the ratio of rhodium to methacycline HC1 was more than twice that employed according to the present invention. Accordingly, the present invention is more efficient than prior art processes for preparing alpha-6-deoxycyclines.
• the catalysts useful in the hydrogenation process of the invention are preferably prepared by reacting silica gel with a compound having one or T A B L E
• alkoxysilyl- substituted alkyldiphenyl phosphines such as the following:
• EtO EtO
• Ph phenyl
• ligands may be formed in situ with the silica gel, e.g., by reacting chloromethyl ether and diphenylphosphine lithium.
• the silica gel used in preparing the catalyst generally has a particle size of 0.063 to 0.2 mm and a pore diameter of 20 to 100 Angstroms, e.g., Kieselgel 100 (Merck).
• the silica gel has a particle size of 0.063 to 0.090 mm and a pore size of 40 to 60 Angstroms.
• the silica gel is generally dried, e.g., in a vacuum oven at 180°C, before being reacted with an alkoxysilyl-substituted alkyldiphenyl phosphine.
• the reaction of the silica gel with the alkyldiphenyl phosphines is generally accomplished in an aromatic solvent, e.g., benzene, xylene or
• the dried silica gel may be added to the aromatic solvent under an inert gas blanket, e.g., nitrogen, together with 2-diphenyl phosphine- ethyltriethoxysilane to attach suitable ligands to the silica gel.
• the reaction mixture is generally refluxed for about one to six hours to allow the ligands to attach to the silica gel.
• reaction mixture is then azeotropically distilled to remove ethanol formed by interaction between the alkoxysilane group of the ligand compound and the surface hydroxyl groups of the gel support. Distillation conditions depend on the solvent employed and whether the reaction is done under ambient pressures or under vacuum, as will be readily apparent to one of ordinary skill in the art.
• the filter cake comprises silica gel with a plurality of ligands attached thereto, the free ends of the ligands being suitable for attachment to a rhodium complex.
• Suitable rhodium complexes include complexes having general formula
• Rh HmCln(CO) ' o(RhP)'pR wherein m, n, o and p range from 0 to 3, and R is a C C Constant.
• ⁇ --CCo 0 - ccyyccllooaallkkeennee... FFoorr eexxaammppllee suitable rhodium complexes include Rh reputationCl 2 (C 2 H.).
• Rh 2 Cl 2 (cyclooctene)., RhClAPPh.,), Wilkinson's Catalyst [Rh(PPh 3 ) 3 Cl] or any rhodium compound of formula Rh 2 Cl 2 L, wherein L is an alkoxysilyl-substituted alkyldiphenyl phosphine.
• the rhodium complex-containing system is lightly refluxed under an inert atmosphere to allow the rhodium complex to react with the free ends of the ligand groups, e.g., for 12 to 16 hours.
• the reaction mixture is then cooled to 20-40°C and filtered to recover the heterogeneous rhodium catalyst of the invention.
• the catalyst generally has from 0.3 to 0.6% rhodium metal per gram of catalyst.
• the heterogeneous rhodium catalyst is utilized in the production of any of the known alpha-6-deoxytetracyclines, preferably those having the formula:
• R and R ? are each hydrogen or chloro and R, is hydrogen or hydroxyl.
• R, R, and R 2 are as defined above.
• 6-methylenetetracyclines which are thus reacted may be prepared in the manner known in the art, e.g., as described in Blackwood U.S. Patent No. 2,984,986 granted May 16, 1961 or Villax U.S. Patent No. 3,848,491 granted November 19, 1974.
• the catalytic hydrogenation is utilized to prepare doxycycline (wherein R is hydrogen and R, is hydroxyl) from methacyline (wherein R is hydrogen, R 1 is hydroxyl and R 2 is hydrogen) or from lla-chloro methacycline (wherein R is hydrogen, R, is hydroxyl, and 2 is chloro).
• methacyline wherein R is hydrogen, R 1 is hydroxyl and R 2 is hydrogen
• lla-chloro methacycline wherein R is hydrogen, R, is hydroxyl, and 2 is chloro.
• lla-chloro methacycline is utilized as the starting material
• an equimolar quantity of triphenyl phosphine is also typically included in the hydrogenation system.
• the hydrogenation reaction is carried out in one of the manners known in the art, with the stereospecific formation of the desired alpha epimer in yields in excess of 94%. HPLC analyses of the hydrogenation products generally indicate negligible beta-epimer contents.
• the hydrogenation is effected in the presence of from about 0.05 to 0.2 grams of catalyst per gram of 6-methylenetetracycline reacted, which corresponds, for example in the production of doxycline, to a rhodium metal to methacycline ratio of 0.15 to 1.2 mg per gram.
• the amount of rhodium required for reduction of methacycline to doxycline may thus be significantly reduced as compared to prior art hydrogenation processes.
• the catalytic hydrogenation of the present invention therefore provides superior yields and purities of the desired alpha-6-deoxytetra- cyclines, with substantially improved efficiencies in the operation.
• the reaction is suitably carried out in a lower alkanolic solvent.
• a lower alkanolic solvent Preferably methanol or ethanol is employed.
• the solvents are typically degassed with nitrogen prior to use.
• reaction time depends on the amount of catalyst and the type of autoclave used for hydrogenation. Normally, to obtain high yields and purities, reaction times of from about 6 to 12 hours are utilized. It is preferred, but not critical, to carry out the reaction under pressures ranging from about 60 to 130 psig, and at temperatures of from about 90° to 100°C. At temperatures lower than about 85°C the reaction may be unacceptably slow, and at higher temperatures decomposition can occur.
• triphenylphosphine e.g., from about 4 to 8 mg per gram of the 6-methylenetetracycline substrate
• the optimum quantity of triphenylphosphine for a given catalyst is determined empirically.
• a small amount of acid, e.g., hydrochloric acid, may also be added to promote the hydrogenation reaction.
• the doxycycline or other alpha-epimer is typically crystallized as an acid addition salt from the reaction mixture, e.g., in the form of the
• SUBSTITUTESHEET p-toluene sulfonate, sulfosalicylate, or hydrochloride salt The purity is more than 99.5% by HPLC.
• the doxycycline acid addition salt is thereafter converted directly to doxycycline hyclate (the hemiethanolate hemihydrate) in stoichiometric yield by procedures known in the art.
• the catalytic hydrogenation may be utilized in a single step to effect both the reductive dehalogenation and reduction of the 6-methylene group of an lla-halo-6-deoxy-6-demethyl-6- methylenetetracycline, e.g., lla-chloro methacycline.
• the corresponding alpha-6-deoxytetra- cycline, e.g., doxycycline is directly produced in improved yield and purity, and with decreased rhodium consumption.
• a methanolic mixture containing a 6-deoxy-6-demethyl-6- methylenetetracycline, preferably the hydrochloric acid addition salt thereof, triphenylphosphine, hydrochloric acid, and a heterogeneous rhodium catalyst of the invention is subjected to agitation in a stainless steel autoclave, and hydrogenated at about 90°C under a hydrogen pressure of about 100 psig.
• the reaction mixture is cooled to about 60°C and pumped through a filter to recover the catalyst.
• To the filtrate is added p-tolune sulfonic acid and the system is stirred at 50°-60°C for one hour. Thereafter, the system is cooled to 5°C for at least two hours.
• the alpha-6-deoxy-5- oxytetracyline p-toluene sulfonate thus obtained is filtered, washed with methanol and then with acetone.
• the reductive dehalogenation and hydrogenation can be carried out with a two-step process initially effecting lla-dehalogenation with a conventional catalyst, e.g., 5% Rh/C or 5% Pd/C in methanol. The initial catalyst is then removed by filtration, and the solution is again subjected to hydrogenation in the presence of a heterogeneous rhodium catalyst of the invention.
• Silica gel (20.0 kg) was dried in a vacuum oven at 180°C for 5 to 6 hours. While stirring, the dried silica gel was added to toluene (100 liters) under a nitrogen blanket. In a separate 15 gallon polypropylene carboy vessel, ethyltriethoxysilyl-2- diphenylphosphine (960 grams) was added to toluene (50 liters) and agitated. The contents of the carboy vessel was then added to the silica gel-containing system and agitated under nitrogen. The system was gently refluxed at 113°C for 5 hours.
• the cake was added to fresh toluene (140 liters) while agitating under a nitrogen blanket.
• the mixture was warmed to 55°-70°C and Wilkinson's Catalyst (880 grams) was added.
• the system was lightly refluxed at 113°C under nitrogen for 12 to
• Methacycline HCl 13.44 kilograms was added to methanol (63.0 liters) under a nitrogen blanket.
• Triphenylphosphine 4.2 grams
• hydrochloric acid 14 mis.
• Heterogeneous rhodium catalyst 2.1 kilograms of Example 1 was added to the system which was pressurized with hydrogen to a pressure of 100 psig.
• the system was warmed to 90°C ( + 5°C) and maintained at this temperature for 24 hours.
• the system was cooled to 60°C and pumped to a filter to recover the heterogeneous rhodium catalyst.
• p-Toluene sulfonic acid (6.16 kilgrams) was added to the system and stirred at 50°-60°C for one hour. The system was allowed to cool overnight at room temperature and was then cooled to 5°C for two hours. Doxycycline p-tolune sulfonate was recovered from the system by filtering and was washed with cold methanol (3 liters) and cold acetone (3 liters). The product was dried at about 40°C. The resulting product weighed about 16.0 kilograms (94% theoretical yield) . HPLC analysis showed the product to be 99% pure alpha-deoxycycline p-toluene sulfonate with no beta epimer present. A second crop of 0.94 kg as sulfosalicylate salt was recovered. The total yield was therefore 99%.
• Example 3 Doxycycline p-toluene sulphonate (13 grams) of Example 3 was mixed with acetone (38 mis.) and water (1.78 mis.) to obtain a solution at 35°C. Nuchar G-60 (1 gram) was added to the system and stirred for one-half hour. The slurry was then filtered through a celite pad. To the filtrate was added ethanol (28.6 mis.) and 18% HCL in ethanol
• HPLC analysis showed the product to be 99.4% pure alpha-doxycycline hyclate with no detectable beta-doxycycline hyclate.
• a second crop of doxycycline hyclate yielded an additional 2.04 grams, also essentially pure alpha-doxycycline hyclate, giving a total yield of about 95%.

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• 1990
  • 1990-01-02 EP EP19900902446 patent/EP0452412A4/en not_active Withdrawn
  • 1990-01-02 WO PCT/US1990/000044 patent/WO1990007492A1/en not_active Application Discontinuation
  • 1990-01-02 JP JP2502437A patent/JP2665395B2/ja not_active Expired - Lifetime
  • 1990-01-02 CA CA 2044612 patent/CA2044612A1/en not_active Abandoned

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