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.
• beta-6-deoxy-5-oxytetracycline co-production of the corresponding beta epimer, beta-6-deoxy-5-oxytetracycline.
• 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.
• 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 aminopolysiloxane.
• the methacycline hydrogenation is
• phosphine e.g., triphenylphosphine.
• the Page hydrogenation process is reported to be
• 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
• This invention comprises an improved process for the preparation of alpha-6-deoxytetracyclines by the hydrogenation of the
• the supported heterogeneous rhodium catalyst has the formula:
• R and R' are each selected from hydrogen and C 1 -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
• Et is ethyl
• n is an integer from 1 to 3;
• n is an integer from 1 to 6;
• Ph is phenyl.
• Silica-supported rhodium complex catalysts of this type have been disclosed for the
• alpha-6-deoxytetracycline is produced in greater than about 95% yield and with the co-production of negligible amounts of the corresponding
• the heterogeneous rhodium catalyst is also easily recovered from the reaction system, e.g., by filtration, thereby allowing for the efficient reuse of catalyst in subsequent hydrogenation reactions, and for the elimination of expensive purification operations generally required for separation of the undesired beta epimers.
• 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 rhodium metal levels no higher than 0.2 mg/g
• Example 1 With a yield of only 87.4%.
• Example 6 At a rhodium metal 11-a chloro methacycline ratio of 0.19 mg/gram (Example 6) a yield of only 89.9% was achieved using a Page heterogeneous catalyst. Still higher rhodium metal levels are reported for the Morris, Jr. heterogeneous catalyst system (2.3 and 23 mg/gram). Thus, dramatic reductions in the amount of rhodium metal required to selectively form alpha-6-deoxytetracyclines may be achieved at high yields with the attendant cost advantages.
• Patent No. 4,597,904 to Page Table I).
• 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 HCl was more than twice that employed according to the present invention. Accordingly, the present invention is more efficient than prior art processes for
• 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:
• 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.
• alkyldiphenyl phosphines is generally accomplished in an aromatic solvent, e.g., benzene, xylene or toluene, at a temperature of from 60 to 115°C.
• 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
• 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.
• the filter cake is reslurried in an aromatic solvent and a rhodium complex is added thereto.
• Suitable rhodium complexes include
• rhodium complexes include Rh 2 Cl 2 (C 2 H 4 ) 4 , Rh 2 Cl 2 (cyclooctene) 4 , RhCl 2 (PPh 3 ),
• 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
• 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 2 are each hydrogen or chloro and R 1 , is hydrogen or hydroxyl.
• R, R 1 , 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
• R is hydrogen, R 1 is hydroxyl and R 2 is hydrogen
• lla-chloro methacycline wherein R is hydrogen, R 1 is hydroxyl, and R 2 is chloro
• 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
• 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.
• the reaction time depends on the amount of catalyst and the type of autoclave used for
• 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, to the reaction mixture prior to hydrogenation
• triphenylphosphine for a given catalyst is
• 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 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.
• alpha-6-deoxytetra- cycline e.g., doxycycline
• doxycycline is directly produced in improved yield and purity, and with decreased
• 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
• the reductive dehalogenation and hydrogenation can be carried out with a two-step process initially effecting 11a-dehalogenation witt a conventional catalyst, e.g., 5% Rh/C or 5% Pd/C in methanol.
• 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
• 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
• Example 1 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.
• 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.
• 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 CA CA 2044612 patent/CA2044612A1/en not_active Abandoned
  • 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

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