Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/02—Preparation
  • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
  • C07D501/06—Acylation of 7-aminocephalosporanic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

• This invention relates to a novel process for the preparation of 3-cyclic-ether-substituted cephalosporins.
• the invention also relates to novel processes for preparing zwitterions, para-nitrobenzyl esters and allyl esters useful in the preparation of the above cephalosporins.
• the invention also relates to 3-cyclic-ether-substituted cephalosporins. These compounds possess certain advantageous properties, such as crystalline form and high enantiomeric excess (e.e.).
• the 3-cyclic-ether-substituted cephalosporins prepared by the methods of the present invention have prolonged and high levels of antibacterial activity and possess good absorption parentally in humans and animals.
• the 3-cyclic-ether-substituted cephalosporins prepared by the processes of the present invention contain a cyclic ether substituent at carbon 3 of the cephalosporin nucleus.
• GB 1405758 describes alternative methods of preparation of certain 3-cyclic-ether-substituted cephalosporins.
• the present inventors have discovered a novel compound of formula I, as defined herein below.
• the present inventors have also discovered a high-yielding process for the preparation of said compounds of formula I.
• the present invention relates to a process for the preparation of a 3-cyclic-ether-substituted cephalosporin of the formula I
• the group CO 2 R 1 is a carboxylic acid or a carboxylate salt
• R 2 has a formula:
• a 1 is C 6-10 aryl, C 1-10 heteroaryl or C 1-10 heterocyclyl
• a 2 is hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-6 alkyl(CO)(C 1-6 )alkyl-O—, HO(CO)(C 1-6 )alkyl, mono-(C 6-10 aryl)(C 1-6 alkyl), di-(C 6-10 aryl)(C 1-6 alkyl) or tri-(C 6-10 aryl)(C 1-6 alkyl);
• R 2 is as defined above, and L is a leaving group, in the presence of a solvent and a base.
• the aforesaid process may be performed in the presence of a coupling agent and a catalyst.
• the group OA 2 of said compounds of formula III is cis to the amide linkage, i.e., the Z-configuration is preferred.
• Suitable solvents for the aforesaid process of conversion of compounds of formula II into compounds of formula I of the invention include water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, methylene chloride, 1,2-dichloroethane or mixtures thereof.
• the solvent is tetrahydrofuran.
• the solvent is ethyl acetate.
• the solvent is water, acetone or mixtures thereof. More preferably the solvent is a mixture of acetone and water. Most preferably the solvent is a 1.3:1 mixture of acetone and water.
• Suitable bases for the aforesaid conversion of the invention include diisopropylethylamine or sodium hydroxide.
• the base is sodium hydroxide, most preferably 15% aqueous sodium hydroxide.
• Suitable coupling agents for the aforesaid conversion of the invention include N,N′-diethylcarbodiimide, N,N′-dipropyl carbodiimide, N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide, N,N′-carbonyldiimidazole or N,N′-carbonyldithiazole.
• a preferred coupling agent is N,N′-dicyclohexylcarbodiimide.
• the aforesaid conversion is conducted in the absence of any coupling agents.
• Suitable catalysts for the aforesaid conversion of the invention include Lewis acids.
• Suitable Lewis acids are selected from the group consisting of boron trihalide, such as boron tribromide, and aluminum halide, such as aluminum chloride.
• the aforesaid conversion is conducted in the absence of any catalysts.
• the aforesaid conversion of the invention can be conducted at a temperature of about ⁇ 40° C. to about +30° C., preferably about +20° C. to about +30° C.
• the aforesaid process can be conducted for a period from about 1 hour to about 24 hours; preferably about 3 hours.
• Suitable leaving groups L of the aforesaid compound of formula III of the aforesaid conversion include hydroxy, halo, azido, mono(C 1-6 alkyl)carbonate, (C 1-6 alkyl)carboxylate, (C 6-10 aryl)carboxylate, mono-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di(C 1-6 alkyl)phosphorothioate, (C 1-6 alkyl)sulfonyl, mono-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, di-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, (C 1-6 alkyl)-(CO)—S—, cyano-C 1-6 alkoxy, C 6-10 aryloxy, 3-benzthiazolyloxy, 8-quinolin
• the leaving group L of the compound of formula III is selected from the group consisting of hydroxy, halo and azido.
• the leaving group L of the compound of formula III is selected from the group consisting of mono(C 1-6 alkyl)carbonate, (C 1-6 alkyl)carboxylate, (C 6-10 aryl)carboxylate, mono-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di-(C 6-10 aryl)(C 1-6 alkyl)carboxylate and di(C 1-6 alkyl)phosphorothioate.
• the leaving group L of the compound of formula III is selected from the group consisting of (C 1-6 alkyl)sulfonyl, mono-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, di-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl and (C 1-6 alkyl)-(CO)—S—.
• the leaving group L of the compound of formula III is selected from the group consisting of cyano-C 1-6 alkoxy, C 6-10 aryloxy, 3-benzthiazolyloxy, 8-quinolinyloxy and N-oxy-succinimidyl.
• the leaving group L of the compound of formula III is selected from the group consisting of halo, methanesulfonyl, diethylphosphorothioate and 3-benzthiazolyloxy.
• the leaving group L of the compound of formula III is di(C 1-6 alkyl)phosphorothioate, more preferably diethylphosphorothioate.
• the present invention also relates to an alternative process for the preparation of the above 3-cyclic-ether-substituted cephalosporin of the formula I, or the pharmaceutically acceptable salts thereof, comprising reacting a compound of formula V
• R 2 has the formula
• a 1 is C 6-10 aryl, C 1-10 heteroaryl or C 1-10 heterocyclyl
• a 2 is hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 1-6 alkyl(CO)(C 1-6 )alkyl-O—, HO(CO)(C 1-6 )alkyl, mono-(C 6-10 aryl)(C 1-6 alkyl), di-(C 6-10 aryl)(C 1-6 alkyl) or tri-(C 6-10 aryl)(C 1-6 alkyl); and
• R 3 is para-nitrobenzyl or allyl, preferably allyl;
• alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched moieties or combinations thereof, alkyl groups, wherever they occur, may be optionally substituted by a suitable substituent.
• cycloalkyl includes a mono or bicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined below such as fluoro, chloro, trifluoromethyl, (C 1-4 )alkoxy, (C 6-10 )aryloxy, trifluoromethoxy, difluoromethoxy or (C 1-4 )alkyl, more preferably fluoro, chloro, methyl, ethyl and
• alkoxy includes O-alkyl groups wherein “alkyl” is as defined above.
• halo as used herein, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine, preferably bromine or chlorine.
• aryl includes an organic radical derived from an aromatic hydrocarbon by removal of one or more hydrogen(s), such as phenyl or naphthyl, optionally substituted by 1 to 3 suitable substituents such as fluoro, chloro, cyano, nitro, trifluoromethyl, (C 1-6 )alkoxy, (C 6-10 )aryloxy, (C 3-8 )cycloalkyloxy, trifluoromethoxy, difluoromethoxy or (C 1-6 )alkyl.
• suitable substituents such as fluoro, chloro, cyano, nitro, trifluoromethyl, (C 1-6 )alkoxy, (C 6-10 )aryloxy, (C 3-8 )cycloalkyloxy, trifluoromethoxy, difluoromethoxy or (C 1-6 )alkyl.
• heteroaryl includes an organic radical derived from an aromatic heterocyclic compound by removal of one or more hydrogen(s), such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridiny
• a group derived from pyrrole can be C-attached or N-attached where such is possible.
• a group derived from pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
• heterocyclyl includes an organic radical derived from a non-aromatic heterocyclic compound by removal of one or more hydrogens, such as 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrol
• the foregoing groups can be C-attached or N-attached where such is possible.
• a group derived from piperidine can be piperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).
• the foregoing groups, as derived from the compounds listed above can be optionally substituted where such is possible by a suitable substituent, such as oxo, F, Cl, Br, CN, OH, (C 1-4 )alkyl, (C 1-4 )perfluoroalkyl, (C 1-4 )perfluoroalkoxy, (C 1-4 )alkoxy, or (C 3-8 )cycloalkyloxy.
• a suitable substituent is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitory activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art.
• substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, carboxy groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups and the like.
• carboxylate salt includes metal salts (such as aluminium, alkali metal salts, such as sodium or potassium, preferably sodium), alkaline earth metal salts (such as calcium or magnesium), and ammonium salts.
• the ammonium salts can be substituted with C 1-6 alkylamines (such as triethylamine), hydroxy-(C 1-6 )alkylamines (such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, or tris-(2-hydroxyethyl)amine), cycloalkylamines (such as dicyclohexylamine), procaine, dibenzylamine, N,N-dibenzylethylenediamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N′-bis-dehydro-abietylamine, ethylenediamine, or pyridine-type bases (such as pyridine, collidine or quinoline), or other amines which have been used to form salts with known penicillins and 3-cyclic-ether-substituted cephalosporins.
• active compounds refers to compounds of formula I.
• Compounds of formula I contain chiral centers and therefore exist in different enantiomeric forms.
• This invention relates to all optical isomers, enantiomers, diastereomers and stereoisomers of the compounds of formula I and mixtures thereof.
• the compounds of the invention also exist in different tautomeric forms.
• This invention relates to all tautomers of formula I.
• Those skilled in the art are well aware that the cephalosporin nucleus exists as a mixture of tautomers in solution. The various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.
• the group OA 2 of said compounds of formula III is cis to the amide linkage, i.e., the Z-configuration is preferred.
• Suitable deprotecting agents for the aforesaid process of conversion of compounds of formula V into compounds of formula I of the invention include sodium dithionite or tetrakis triphenyl phosphine palladium (0).
• Suitable solvents for the aforesaid conversion include acetone, water, tetrahydrofuran, methylene chloride or mixtures thereof.
• the solvent is methylene chloride, tetrahydrofuran or mixtures thereof.
• the solvent is tetrahydrofuran.
• the solvent is methylene chloride.
• the aforesaid conversion may be conducted at a temperature of about 0° C. to about 45° C.
• the aforesaid conversion may be conducted for a period from about 1 hour to about 24 hours.
• R 3 is para-nitrobenzyl.
• the deprotecting agent is sodium dithionite.
• the aforesaid conversion is conducted at a temperature of about 40° C.
• the aforesaid process is conducted for about 4 hours.
• R 3 is allyl.
• the preferred deprotecting agent is tetrakis triphenyl phosphine palladium (0).
• the aforesaid process is conducted at a temperature of about 20° C. to about 35° C.; preferably about 27° C. to about 30° C. Within this embodiment, preferably the aforesaid process is conducted for about 5 hours.
• the present invention also includes a process for the preparation of the above compound of formula II comprising reacting a compound of formula IV
• R 3 is para-nitrobenzyl or allyl, preferably para-nitrobenzyl; and X is halo, preferably chloro; with a suitable deprotecting agent; in the presence of a solvent.
• Suitable solvents for the process of conversion of compounds of formula IV into compounds of formula II of the invention include acetone, water, tetrahydrofuran, methylene chloride or mixtures thereof.
• the solvent is acetone, water, tetrahydrofuran or mixtures thereof.
• the solvent is a mixture of acetone and water. More preferably, the solvent is a 3:1 mixture of acetone and water.
• Suitable deprotecting agents for the aforesaid conversion include sodium dithionite, catalytic hydrogenating agent (such as hydrogen gas over 10% palladium over carbon) or tetrakis triphenyl phosphine palladium (0).
• the aforesaid conversion may be conducted at a temperature of about 0° C. to about 45° C.
• the aforesaid conversion may be conducted for a period from about 1 hour to about 24 hours.
• R 3 is para-nitrobenzyl.
• the preferred deprotecting agent is sodium dithionite.
• the aforesaid process is conducted at a temperature of about 45° C.
• the aforesaid process is conducted at a temperature of about 1 hour.
• R 3 is allyl.
• the deprotecting agent is tetrakis triphenyl phosphine palladium (0).
• Suitable solvents include methylene chloride and tetrahydrofuran. The aforesaid process can be conducted at a temperature of about 20° C. to about 35° C.
• the present invention also relates to a process for the preparation of the above compound of formula V comprising reacting the above compound of formula IV, wherein R 3 is para-nitrobenzyl or allyl; preferably allyl; and X is halo; preferably chloro; with a compound of the formula III, as defined above, in the presence of a solvent.
• the aforesaid process can be conducted in the presence of an optional coupling agent or an optional catalyst.
• Suitable solvents for the aforesaid conversion of compounds of formula IV into compounds of formula V include methylene chloride, tetrahydrofuran or mixtures thereof.
• a coupling agent is used.
• suitable coupling agents include N,N′-diethylcarbodiimide, N,N′-dipropyl carbodiimide, N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide, N,N′-carbonyldiimidazole or N,N′-carbonyldithiazole.
• a preferred coupling agent is N,N′-dicyclohexylcarbodiimide.
• the aforesaid conversion is conducted in the absence of any coupling agents.
• a catalyst is used.
• the catalyst can be a Lewis acid. Suitable Lewis acids are boron trihalide, such as boron tribromide, or aluminum halide, such as aluminum chloride.
• the aforesaid conversion is conducted in the absence of any catalysts.
• the aforesaid conversion may be conducted at a temperature of about ⁇ 40° C. to about +40° C.
• the aforesaid conversion may be conducted for a period of from about 1 hour to about24 hours.
• R 3 is para-nitrobenzyl.
• the aforesaid conversion is conducted at a temperature of about +20° C. to about +30° C.
• the aforesaid conversion is conducted for about 3 hours.
• R 3 is allyl.
• the solvent is methylene chloride.
• the aforesaid conversion is conducted at a temperature of about 20° C. to about 40° C. Within this embodiment, preferably the aforesaid conversion is conducted for about 24 hours.
• the leaving group L of the compound of formula III in the aforesaid conversion of the invention includes hydroxy, halo, azido, mono(C 1-6 alkyl)carbonate, (C 1-6 alkyl)carboxylate, (C 6-10 aryl)carboxylate, mono-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di(C 1-6 alkyl)phosphorothioate, (C 1-6 alkyl)sulfonyl, mono-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, di-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, (C 1-6 alkyl)-(CO)—S—, cyano-C 1-6 alkoxy, C 6-10 aryloxy, 3-benzthiazolyloxy, 8-quinoliny
• the leaving group L of the compound of formula III is selected from the group consisting of hydroxy, halo and azido.
• the leaving group L of the compound of formula III is selected from the group consisting of mono(C 1-6 alkyl)carbonate, (C 1-6 alkyl)carboxylate, (C 6-10 aryl)carboxylate, mono-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di-(C 6-10 aryl)(C 1-6 alkyl)carboxylate and di(C 1-6 alkyl)phosphorothioate.
• the leaving group L of the compound of formula III is selected from the group consisting of (C 1-6 alkyl)sulfonyl, mono-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, di-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl and (C 1-6 alkyl)-(CO)—S—.
• the leaving group L of the compound of formula III is selected from the group consisting of cyano-C 1-6 alkoxy, C 6-10 aryloxy, 3-benzthiazolyloxy, 8-quinolinyloxy and N-oxy-succinimidyl.
• the leaving group L of the compound of formula III is selected from the group consisting of halo, methanesulfonyl, diethylphosphorothioate and 3-benzthiazolyloxy.
• the leaving group L of the compound of formula III is mono(C 1-6 alkyl)carbonate, more preferably acetate.
• the present invention also relates to a compound of formula II
• the compound of formula II has an enantiomeric or diastereomeric purity of 96% to 100%; preferably 97%.
• the present invention also relates to a compound of formula V
• R 2 is as defined above; and R 3 is para-nitrobenzyl or allyl; preferably allyl.
• the compound of formula V has an enantiomeric or diastereomeric purity of 96% to 100%; preferably 97%.
• the A 1 moiety of said R 2 is C 6-10 aryl, such as phenyl.
• the A 1 moiety of said R 2 is C 1-10 heteroaryl selected from the group consisting of furyl, thienyl, pyridyl, aminothiazolyl and aminothiadiazolyl, in which the amino moiety of said aminothiazolyl or aminothiadiazolyl is optionally protected.
• the A 1 moiety of said R 2 is C 1-10 heterocyclyl; such as 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl,
• the A 2 moiety of said R 2 is hydrogen or C 1-6 alkyl.
• a preferred embodiment of the invention includes each of the foregoing generic and sub-generic embodiments wherein the A 2 moiety of said R 2 is C 1-6 alkyl, more preferably methyl.
• a compound of the formula III has a formula IIIa
• L is a leaving group, such as halo, methanesulfonyl, dialkylphosphorothioate, such as diethylphosphorothioate or 3-benzthiazolyloxy.
• a compound of the formula III has a formula IIIa, as defined above, wherein L is diethylphosphorothioate or acetate.
• R 2 The optional conversion of R 2 to a different R 2 and the optional formation of a pharmaceutically acceptable salt, can be carried out using methods well known in the art.
• the present invention also relates to a method of using a zwitterion intermediate for the preparation of 3-cyclic-ether-substituted cephalosporins.
• Scheme 1 refers to the preparation of compounds of formula I.
• a compound of formula I can be prepared by reacting a compound of formula II with a compound of formula III
• L is a leaving group, in the presence of a base and a solvent.
• Suitable leaving groups include hydroxy, halo, azido, mono(C 1-6 alkyl)carbonate, (C 1-6 alkyl)carboxylate, (C 6-10 aryl)carboxylate, mono-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di-(C 6-10 aryl)(C 1-6 alkyl)carboxylate, di(C 1-6 alkyl)phosphorothioate, (C 1-6 alkyl)sulfonyl, mono-(C 1-6 alkyl)( C 6-10 aryl)sulfonyl, di-(C 1-6 alkyl)(C 6-10 aryl)sulfonyl, (C 1-6 alkyl)-(CO)—S—, cyano-C 1-6 alkoxy, C 6-10 aryloxy, 3-benzthiazolyloxy, 8-quinolinyloxy or N-oxy-succinimidyl.
• the leaving groups include hydroxy,
• Suitable bases include diisopropylethylamine or sodium hydroxide, preferably sodium hydroxide, most preferably 15% aqueous sodium hydroxide.
• Suitable solvents include water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, methylene chloride, 1,2-dichloroethane, or mixtures thereof; preferably a mixture of water and acetone, most preferably a mixture of 1:1.3 of water and acetone.
• the aforesaid reaction can be conducted at a temperature of about ⁇ 40° C. to about 30° C.; preferably about 20° C. to about 30° C.
• the aforesaid reaction can be conducted for a period from about 1 hour to about 24 hours, preferably for about 3 hours.
• the aforesaid reaction can be effected in the presence of an acid binding agent, for example a tertiary amine (such as triethylamine), pyridine (such as 2,6-lutidine or 4-dimethylaminopyridine), or dimethylaniline.
• an acid binding agent for example a tertiary amine (such as triethylamine), pyridine (such as 2,6-lutidine or 4-dimethylaminopyridine), or dimethylaniline.
• the aforesaid reaction can also be carried out in the presence of molecular sieves, an inorganic base (such as calcium carbonate or sodium bicarbonate) or an oxirane, which binds the hydrogen gas liberated in the aforesaid reaction.
• the oxirane is preferably C 1-6 alkyl-1,2-alkylene oxide, such as ethylene oxide or propylene oxide.
• the aforesaid reaction can be conducted in the presence of a coupling agent.
• Suitable coupling agents include N,N′-diethylcarbodiimide, N,N′-dipropyl carbodiimide, N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide, N,N′-carbonyldiimidazole, and N,N′-carbonyldithiazole.
• the coupling agent is N,N′-diethylcarbodiimide.
• the reaction is conducted in the absence of any couplings agents.
• the aforesaid reaction can be conducted in the presence of a catalyst.
• Suitable catalysts include a Lewis acid, such as boron trihalide or aluminum halide.
• the reaction is conducted in the absence of any catalysts.
• the compound of formula III can be prepared by methods known in the art. Suitable methods include those described, for example, in U.K. Patent No. 2 107 307 B, U.K. Patent Specification No. 1,536,281 and U.K. Patent Specification No. 1,508,064.
• the compound of formula III i.e. R 2 L
• R 2 has a formula:
• a 1 is 2-aminothiazol-4-yl
• a 2 is methyl
• L is (C 1-6 alkyl)sulfonyl, such as methylsulfonyl, or di(C 1-6 alkyl)phosphorothioate, such as diethylphosphorothioate, can be prepared by reacting a compound of formula IIIb
• (C 1-6 alkyl)sulfonylhalide such as methanesulfonylchloride, or di(C 1-6 alkyl)thiophosphonic acid, such as diethylthiophoshonic acid.
• the compound of formula III is diethylthiophoshoryl-[Z]-2-aminothiazol-4-yl-methoxylamino (DAMA), which can be prepared according to the methods described in U.S. Pat. No. 5,567,813 and EP 628561.
• DAMA diethylthiophoshoryl-[Z]-2-aminothiazol-4-yl-methoxylamino
• Scheme 2 refers to the preparation of a compound of formula II.
• a compound of formula II can be prepared by reacting a compound of formula IV, wherein R 3 is preferably para-nitrobenzyl ester; and X is preferably chloro; with a suitable deprotecting agent in a solvent.
• Suitable deprotecting agents include sodium dithionite or a catalytic hydrogenating agent, such as hydrogen gas over 10% palladium on carbon.
• Suitable solvents include acetone, water, tetrahydrofuran, methylene chloride or mixtures thereof.
• the solvent is a mixture of 3:1 acetone and water.
• the aforesaid reaction can be conducted at a temperature of about 0° C. to about 45° C., preferably about 45° C.
• the aforesaid reaction can be conducted for a period from about 1 hour to about 24 hours, preferably from about 1 hour.
• a compound of formula IV can be prepared by various synthetic methods such as those described in the U.S. Non-Provisional Patent Application entitled “Process and Ester Derivatives Useful For Preparation of Cephalosporins”, filed Dec. 4, 2001. These methods are described hereinbelow in Schemes 4-6.
• Scheme 3 refers to an alternative process of preparation of a compound of formula I.
• a compound of formula I can be prepared by reacting a compound of formula V, wherein R 3 is preferably allyl; with a suitable deprotecting agent in a solvent.
• Suitable deprotecting agents include sodium dithionite or tetrakistriphenyl phosphine palladium (0).
• Suitable solvents include acetone, water, tetrahydrofuran, methylene chloride or mixtures thereof.
• the solvent is methylene chloride.
• the aforesaid reaction can be conducted at a temperature of about 0° C. to about 45° C.
• the aforesaid reaction can be conducted for a period from about 1 hour to about 24 hours.
• a compound of formula V can be prepared by reacting a compound of formula IV, wherein R 3 is preferably allyl; and X is preferably chloro; with a compound of formula III
• Suitable solvents for the aforesaid reaction include methylene chloride, tetrahydrofuran or mixtures thereof.
• the solvent is methylene chloride.
• the aforesaid reaction can be conducted in the presence of a coupling agent.
• Suitable coupling agents include N,N′-diethylcarbodiimide, N,N′-dipropyl carbodiimide, N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide, N,N′-carbonyldiimidazole, or N,N′-carbonyldithiazole.
• the coupling agent is N,N′-diethylcarbodiimide.
• the aforesaid reaction is conducted without any coupling agents.
• the aforesaid reaction can be conducted in the presence of a catalyst.
• Suitable catalysts include a Lewis acid, such as boron trihalide or aluminum halide.
• the aforesaid reaction is conducted without any catalysts.
• the aforesaid reaction can be conducted at a temperature of about ⁇ 40° C. to about +40° C., preferably about +20° C. to about +40° C.
• the aforesaid reaction can be conducted for a period from about 1 hour to about 24 hours; preferably about 24 hours.
• a compound of formula IV can be prepared as described below in the description for Schemes 4-6.
• Scheme 4 refers to the preparation of a compound of formula (IV).
• a compound of formula (IV) wherein R 1 is preferably para-nitrobenzyl can be prepared by reaction of a compound of formula (VI) wherein R 1 is preferably para-nitrobenzyl, and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl, with an acid in a solvent.
• Suitable acids include Lewis Acids, such as phosphorus pentachloride or phosphorus pentabromide, preferably phosphorus pentachloride.
• Suitable solvents include toluene, xylene, tetrahydrofuran, methylene chloride or acetonitrile; preferably methylene chloride.
• the aforesaid process can be conducted at a temperature of about ⁇ 40° C. to about +40° C.
• the aforesaid process is conducted for a period of from about 1 hour to about 24 hours.
• a compound of formula (VI) wherein R 1 is preferably para-nitrobenzyl, and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl can be prepared by cyclizing a compound of formula (VIIa), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; by heating said compound of formula (VIIa) in a solvent.
• the aforesaid process for the conversion of compounds of formula (VIIa) into compounds of formula (VI) is a so called intramolecular Wittig-type reaction and is typically conducted by heating the above compound of formula (VIIa).
• Suitable solvents include toluene, xylene, tetrahydrofuran, methylene chloride and acetonitrile, preferably methylene chloride.
• the aforesaid process is conducted at a temperature of from about 40° C. to about 160° C.
• the aforesaid process is conducted for a period of from about 1 hour to about 24 hours, preferably about 16 hours.
• the aforesaid conversion of the compound of formula (VIIa) to the compound of formula (IV) can be performed as a two step process in which the compound of formula (VI) may be isolated but is preferably carried out as a one step reaction without isolation of the phosphorus ylide.
• Scheme 5 refers to the preparation of compounds of the formula (VIIa), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; by the processes of the present invention.
• Compounds of the formula (VIIa) are intermediates useful in the preparation of compounds of formula (IV) in Scheme 4.
• the aforesaid compound of formula (VIIa) can be prepared by reacting a compound of formula (VIIb), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; and X is preferably chloro, with trimethylphoshine, in a solvent, optionally in the presence of a suitable base.
• Suitable solvents include tetrahydrofuran, acetonitrile and methylene chloride, preferably tetrahydrofuran.
• Suitable bases include imidazole, 2,6-lutidine, pyridine, N-methylmorpholine or sodium bicarbonate, preferably sodium bicarbonate.
• the reaction is conducted with the suitable base during work up.
• the aforesaid process is conducted at a temperature of from about ⁇ 40° C. to about ⁇ 20° C.
• the aforesaid process is conducted for a period of from about 30 minutes to about 1 hour.
• a compound of formula (VIIb), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; can be prepared by reacting a compound of formula (VIIc), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; with a halogenating agent in the presence of a base in a solvent.
• Suitable halogenating agents include thionyl chloride, thionyl bromide, phosphorus tribromide or phosphorus trichloride, preferably thionyl chloride.
• Suitable bases include pyridine, 2,6-lutidine, N-methylmorpholine or imidazole, preferably 2,6-lutidine.
• Suitable solvents include tetrahydrofuran or methylene chloride, preferably methylene chloride.
• the aforesaid process is conducted at a temperature of from about ⁇ 40° C. to about ⁇ 20° C., preferably about ⁇ 20° C.
• the aforesaid process is conducted for a period of from about 15 minutes to about 1 hour, preferably about 1 hour.
• a compound of formula (VIIc), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; can be prepared by reacting a compound of formula (IX), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; with a compound of formula (VIII)
• Y is a leaving group such as bromo, chloro, fluoro, iodo or tosylate, preferably bromo, in a solvent.
• Suitable solvents include alcohol, such as methanol, ethanol and propanol; methylene chloride; acetone; dimethylformamide; or mixtures thereof.
• the aforesaid process is conducted at a temperature of from about 10° C. to about 25° C.
• the aforesaid process is conducted for a period of from about 4 hours to about 24 hours.
• the compound of formula (VIII) can be prepared in situ by reacting the corresponding carboxylic acid of formula (VIIIb)
• halogenating agent in methanol or water solution; and subsequently exposing the solution to an acid, preferably para-toluene sulfonic acid.
• Suitable halogenating agents include bromine, chlorine or iodine, preferably bromine.
• Scheme 6 refers to the preparation of compounds of the formula (IX), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; by the processes of the present invention.
• Compounds of the formula (IX) are useful intermediates in the preparation of compounds of formula (IV), via compounds of the formula (VIIa).
• the conversion of compounds of formula (IX) into compounds of formula I are described in Schemes 1 and 2.
• a compound of formula (IX) can be prepared by reacting a compound of formula (Xa), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; with an acid in a solvent.
• Suitable acids include para-toluene sulfonic acid and methane sulfonic acid, preferably para-toluene sulfonic acid.
• Suitable solvents include methylene chloride, tetrahydrofuran, acetone or mixtures thereof, preferably methylene chloride.
• the aforesaid process is conducted at a temperature of from about 20° C. to about 25° C.
• the aforesaid process is conducted for a period of from about 2 hours to about 24 hours.
• a compound of formula (Xa), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; can be prepared by reacting a compound of formula (Xb), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably
• Suitable reducing agents include sodium borohydride, sodium cyanoborohydride, borane and sodium triacetoxy borohydride, preferably sodium triacetoxyborohydride or sodium borohydride.
• Suitable solvents include acetic acid, methylene chloride, tetrahydrofuran, alcohol (such as isopropanol) or mixtures thereof.
• the reducing agent is sodium triacetoxy borohydride
• the solvent is methylene chloride.
• the solvent is acetic acid.
• the aforesaid process is conducted at a temperature of from about 20° C. to about 66° C.
• the aforesaid process is conducted for a period of from about 4 hours to about 24 hours.
• the compound of formula (Xa), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; can be prepared by reacting a compound of formula (XV), wherein R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl, with a compound of formula (XIV),
• R 1 is preferably para-nitrobenzyl, in the presence of a base in a solvent.
• Suitable bases include diisopropylamine, triethylamine, pyridine and 2,6-lutidine; preferably triethylamine; more preferably the triethylamine is catalytic.
• Suitable solvents include methylene chloride, tetrahydrofuran or mixtures thereof. The aforesaid process is conducted at a temperature of from about 20° C. to about 25° C. The aforesaid process is conducted for a period of from about 30 minutes to about 2 hours, preferably about 1 hour.
• R 1 is preferably para-nitrobenzyl; in a solvent, in the presence of a base.
• Said compound of formula (XII) is prepared by reacting said compound of formula (XV) with a compound of formula (XIII)
• each of L 1 and L 2 is a leaving group, such as halo, preferably chloro, in a solvent, optionally in the presence of a base.
• Suitable solvents include methylene chloride, tetrahydrofuran, or mixtures thereof, preferably methylene chloride.
• Suitable bases include diisopropylamine, triethylamine, pyridine and 2,6-lutidine, preferably triethylamine.
• the aforesaid process is conducted at a temperature of about ⁇ 78° C. to about 25° C., preferably about ⁇ 78° C.
• the aforesaid process is conducted for a period of from about 5 minutes to about 10 minutes, preferably about 5 minutes.
• the compound of formula (XII) may be isolated, or may be carried on to the next step without isolation. Preferably the compound of formula (XII) is isolated.
• a compound of formula (Xb), wherein R 1 is preferably para-nitrobenzyl; and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; can be prepared by reacting a compound of formula (Xc), wherein R 1 is preferably para-nitrobenzyl; R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; R 3 is preferably C 1-6 alkyl, such as methyl; and R 4 is preferably C 1-6 alkyl, such as methyl; with an oxidizing agent, in a solvent. Suitable oxidizing agents include ozone.
• Suitable solvents include methylene chloride, tetrahydrofuran or mixtures thereof, preferably methylene chloride.
• the aforesaid process is conducted at a temperature of about ⁇ 70° C.
• the aforesaid process is conducted for a period of from about 1 hour to about 24 hours.
• a compound of formula (Xc) is commercially available.
• a compound of formula (Xb), wherein R 1 is preferably para-nitrobenzyl, and R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; can be prepared by reacting a compound of formula (XV), wherein R 2 is preferably C 6-10 arylC 1-6 alkyl, such as benzyl; with a compound of formula (XVI)
• R 1 is preferably para-nitrobenzyl
• L 3 is a leaving group, such as halo, preferably chloro, in a solvent in the presence of a base.
• Suitable solvents include methylene chloride, tetrahydrofuran or mixtures thereof.
• Suitable bases include diisopropylamine, triethylamine, pyridine or 2,6-lutidine.
• the aforesaid process is conducted at a temperature of from about ⁇ 40° C. to about 25° C.
• the aforesaid process is conducted for a period of about 5 minutes to 15 minutes.
• Compounds of this invention can be crystallized or recrystallized from solvents such as organic solvents. In such cases solvates can be formed.
• This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that can be produced by processes such as lyophilization.
• the compounds of formula (I) are useful for the preparation of a 3-cyclic-ether-substituted cephalosporin, i.e., the active compound.
• the active compound possesses activities against gram positive and gram negative bacteria.
• Methods for assaying the activity and methods for formulating and administering the active compounds are disclosed in U.S. Pat. No. 6,020,329, issued Feb. 1, 2000. Methods of treatments are also described in the aforesaid patent.
• the toluene was then stripped under vacuo at a maximum temperature of 60° C.
• Ethyl acetate was then added and was then stripped under vacuo at a maximum temperature of 60° C.
• To the semi solid oil was added tert-butyl methyl ether (2.5 liters) and the solution stirred overnight.
• the crystalline product was filtered off and washed with further tert-butyl methyl ether (0.3 liters).
• the mother liquors were concentrated and resubjected to silica chromatography (dissolved in 5 liters of toluene, added onto silica, eluted with 15 liters of toluene) and crystallized in the same fashion to afford a second crop.
• the product was isolated as a white crystalline solid. Yields range from 70% to 80%.
• the solution was stirred overnight, diluted with methylene chloride (10 liters) and washed twice with water (10 liters total) then once with saturated sodium chloride (10%, 10 liter). After drying over sodium sulphate, the solution was concentrated under vacuo at a maximum temperature of 40° C. to ensure dryness. The solution was redissolved in tetrahydrofuran (5 liter) for use in the next step. If storage was required, the tetrahydrofuran solution was stored and dried before use.
• N-bromosuccinimide (1340 g, 7.53 moles) was added to the solution at a maximum temperature of ⁇ 5° C. over a period of approximately 45 minutes in six portions. After a 30 minute stirring, the solution was sampled for GC and TLC analysis, which showed that the reaction was completed. The solution was then transferred to a 50-liter separating vessel, and 5% sodium bicarbonate (5 liters) was added with caution. The solution was stirred and separated. The upper aqueous phase was discarded, and the methylene chloride phase was washed with water, dried over sodium sulphate, filtered and stored in a freezer before use in the next step.

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• 2001
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