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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • 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
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D503/02—Preparation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D505/02—Preparation
  • C07D505/06—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
  • C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
  • C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
  • C07D505/16—Nitrogen atoms

Definitions

• the present invention concerns a process for the preparation of (1-oxa- or 1- thia-) 3-cephem derivatives which are useful intermediates in the preparation of (1-oxa- or l-thia-)cephalosporins. More particularly, the invention refers to a process for the preparation of a carboxy protected 7 ⁇ -amino-7 ⁇ -methoxy-3-[l- (alkyl- or ⁇ -hydroxy .
• the above compounds flomoxef and cefinetazole are 7 ⁇ -acylamino-7 ⁇ - methoxy-cephalosporin-type antibiotics used as antibacterial drugs.
• Flomoxef is an oxacephem, described in US 4,532,233, which is prepared by a multistep process in which the key intermediate is a carboxy-protected 7 ⁇ - amino-7 ⁇ -methoxy-3-[l-(2-hydroxyethyl)-lH-tetrazol-5-yl]thiomethyl-l-dethia- l-oxa-3-cephem-4-carboxylic acid.
• This compound is converted into flomoxef by protection of the primary hydroxyl group of the hydroxyethyl radical bound to the tetrazole ring, subsequent condensation with activated 2- (difluoromethylthio)acetic acid and removal of the hydroxy- and of the carboxy- protecting groups.
• Cefinetazole is a cephem, described in GB 1449420, which is prepared by reaction of the corresponding carboxy-protected 7 ⁇ -amino-7 ⁇ -methoxy-3-(l- methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid by condensation with activated 2-(cyanomethylthio)acetic acid and removal of the the carboxy- protecting groups.
• Each of flomoxef and cefinetazole is a 7 ⁇ -(substituted-thio)acetamido-7 ⁇ - methoxy-3-(l -substituted-l/f-tetrazol-5-yl)thiomethyl-(l -oxa- or 1 -thia-)3- cephem-4-carboxylic acid.
• an enantiomerically pure, carboxy-protected 7 ⁇ -amino-7 ⁇ - methoxy-3-(l-substituted-lH-tetrazol-5-yl)thiotnethyl-(l-oxa- or l-thia-)3- cephem-4-carboxylic acid may be prepared by reaction of a carboxy-protected 7- benzamido-3-(l-substituted-li7-tetrazol-5-yl)thiomethyl-(l-oxa- or l-thia-)3- cephem-4-carboxylic acid with lithium methoxide in the presence of t-butyl hypochlorite (Kleemann et al.
• 7 ⁇ -methoxy-3-(l-substituted-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid may be prepared by reaction of corresponding 7-methyl- or 7-(4-tolyl)- thioimino derivatives with methanol in the presence of triphenylphosphine and mercuric acetate in dichloromethane as described by E.M. Gordon et al. in J. Am. Chem. Soc. 1977, 99(16) 5504-5 and ibid. 1980, 102(5), 1690-1702.
• the presence of a mercuric salt in the reaction mixture renders the purification of the products difficult.
• the carboxy protected 7 ⁇ -amino-7 ⁇ -methoxy-3-[l-(alkyl- or ⁇ - hydroxyalkyl-) li- 7" -tetrazol-5-yl]thiomethyl-(l-oxa- or l-thia-)3-cephem-4- carboxylic acid thus obtained represents the key intermediate in the preparation of flomoxef (formula A) and of cefmetazole (formula B), or of their analogs, which are obtained by the classical condensation of carboxy protected 7 ⁇ -amino-7 ⁇ - methoxy-3-[l-(alkyl- or ⁇ -hydroxy alkyl-)lH-tetrazol-5-yl]thiomethyl-(l-oxa- or l-thia-)3-cephem-4-caboxylic acid with the appropriately activated 2- (difluoromethylthio)acetic acid in the presence of silylating agents to obtain flomoxef after deprotection of the carb
• X represents oxygen or sulfur
• Y represents an alkyl group of from 1 to 3 carbon atoms or a ⁇ -hydroxyalkyl group of from 2 to 3 carbon atoms
• R° represents a carboxy-protecting group, or of a salt thereof, which comprises
• Y is an alkyl of from 1 to 3 carbon atoms or a ⁇ -hydroxyalkyl of from 2 to 3 carbon atoms, or with an alkaline metal salt thereof;
• step (c) sodium bicarbonate is preferably used as the base neutralizing aluminum trichloride.
• triarylphosphine or tri ⁇ -C ⁇ alkylphosphine designates phosphine wherein the three hydrogen atoms are replaced by an optionally substituted phenyl group such as phenyl or tolyl, by a monocyclic, aromatic heterocyclic group such as furyl or thienyl, or by a (C 1 -C 6 )Bl-CyI group such as rc-butyl.
• a 7-amino-3-chloromethyl-(l-oxa- or l-thia-)3-cephem-4-carboxylic acid esterified with an easily removable protecting group, especially in acidic medium, is used as starting material.
• Protective groups used according to the present invention and the methods for their removal are described, for example, by Theodora W. Greene, Peter G. V. Wuts in "Protective Groups in Organic Synthesis", III ed., John Wiley & Sons, Inc., 1999, pages 373-431.
• esters are 4-methoxybenzyl and diphenylmethyl (benzhydryl) esters which are easily removable with trifluoroacetic acid and anisole in dichloromethane or with aluminum trichloride and anisole in dichloromethane.
• step (a) the carboxy-protected 7-amino-3-chloromethyl-(l-oxa- or 1-thia- )3-cephem-4-carboxylic acid, as such or as the hydrochloride thereof, is reacted with a methyl- or aryl- sulfenyl chloride, in its turn separately prepared by reaction of the corresponding methyl- or aryl- disulfide with chlorine, in an inert organic solvent such as toluene or dichloromethane, at room temperature (20° ⁇ 30°C) and in the presence of hydrogen chloride acceptor such as, for example, 1,2-epoxypropane.
• a methyl- or aryl- sulfenyl chloride in its turn separately prepared by reaction of the corresponding methyl- or aryl- disulfide with chlorine, in an inert organic solvent such as toluene or dichloromethane, at room temperature (20° ⁇ 30°C) and in the presence of hydrogen chloride
• the 7-(alkyl- or aryl-)thioimino-3-chloromethyl-(l-oxa- or l-thia-)3- cephem of formula IV thus obtained is isolated according to conventional methods, for example by neutralization with a base such as an aqueous solution of sodium bicarbonate (NaHCO 3 ), removal of the salts and extraction using a suitable solvent such as dichloromethane.
• a base such as an aqueous solution of sodium bicarbonate (NaHCO 3 )
• step (b) the 7-(alkyl- or aryl- )thioimino-3-chloromethyl-(l-oxa- or 1- thia-)3-cephem of formula FV thus obtained is treated with a 1-alkyl- or l-( ⁇ - hydroxyalkyl)-lH-tetrazol-5-ylthiol of formula V, preferably in form of its sodium salt.
• the reaction is carried out at a temperature of 20° ⁇ 30°C in a biphasic system with an inert organic solvent, for example dichloromethane or toluene, and water in the presence of a quaternary ammonium salt such as tetra-r ⁇ - butylammonium bromide.
• 1 -Methyl- 1 H-tetrazol-5-ylthiol or 1 -(2-hydroxyethyl)- lH-tetrazol-5-ylthiol as a sodium salt thereof is preferably used as 1 -substituted- lH-tetrazol-5-ylthiol.
• Said sodium salt may be prepared according to known methods, for example by reaction of the l-substituted-lH-tetrazol-5-ylthiol with sodium 2-ethylhexanoate in acetone.
• step (c) the 7-(alkyl- or aryl-)thioimino-3-chloromethyl(l-oxa- or 1- thia)3-cephem of formula VI obtained at the end of step (b) is reacted with methanol in the presence of aluminum trichloride neutralized with a base and a triarylphosphine or ⁇ (Ci-C ⁇ alkylphosphine in an inert organic solvent such as dichloromethane or toluene.
• aluminum trichloride neutralized with a base and a triarylphosphine or ⁇ (Ci-C ⁇ alkylphosphine in an inert organic solvent such as dichloromethane or toluene.
• the methanol also contains sodium bicarbonate as the base neutralizing aluminum trichloride.
• the triarylphosphine or Ui(C 1 - C 6 )alkylphosphine is selected from the group consisting of triphenylphosphine, tri( ⁇ -tolyl)phosphine, tri(2-furyl)phosphine and tri( «-butyl)phosphine.
• a solution of aluminum trichloride in methanol previously prepared at a temperature of 10° ⁇ 15°C and neutralized with a base such as sodium bicarbonate, is added to a solution of the compound VI and of triphenylphosphine, tri(o-tolyl) phosphine, tri(2-furyl)phosphine or tri(r ⁇ -butyi) ⁇ hosphine in one of the above-mentioned solvents.
• the compound of formula I thus obtained is isolated by adding glacial acetic acid to the suspension obtained at the end of the reaction, subsequently separating of the phases, drying the organic phase and extracting the product of formula I with a solvent such as dichloromethane or toluene and optional addition of a salifying acid such as HCl in isopropanol, HBr in isopropanol, methanesulfonic acid, j?-toluene sulfonic acid or naphthalene-2- sulfonic acid to the organic solution.
• a solvent such as dichloromethane or toluene
• a salifying acid such as HCl in isopropanol, HBr in isopropanol, methanesulfonic acid, j?-toluene sulfonic acid or naphthalene-2- sulfonic acid
• alkaline metal methoxides such as lithium methoxide or sodium methoxide
• the compound of formula I is isolated as free base which may be purified according to known methods, for example by silica gel, an appropriate resin or by solution in a polar solvent such as dimethylacetamide and precipitation with an alcohol such as methanol or isopropanol.
• the compounds of formula II used as starting materials are known or may be easily prepared by treatment of the corresponding carboxy-protected 7- acylamido-3-chloromethyl-(l-oxa- or 1-thia-) 3-cephem-4-carboxylic acid by reaction with PCl 5 in the presence of pyridine, for example as described in DE
• the present invention provide a process as illustrated above, whereby, at the end of step (c), a compound of formula Y
• the present invention also provides a process as illustrated above, whereby, at the end of step (c), a compound of formula I"
• Y is ⁇ -hydroxyalkyl having from 2 to 3 carbon atoms, also in the presence of a silylating agent such as, for example, hexamethyldisilazane and/or trimethylchloro silane.
• a silylating agent such as, for example, hexamethyldisilazane and/or trimethylchloro silane.
• Y is methyl
• the diphenylmethyl or 4- methoxybenzyl ester of the 7 ⁇ -amino-7 ⁇ -methoxy-3-[l-(2-hydroxyethyl)-lH- tetrazol-5-yl]thiomethyl-l-dethia-l-oxa-3-cephem-4-carboxylic acid is treated with silylating agents, for example with hexamethyldisilazane and trimethylchlorosilane, then it is reacted with the 2-(difluoromethylthio)acetyl chloride (F 2 CH-S-CH 2 COCl) in the presence of pyridine in dichloromethane at a temperature of from -10° ⁇ - 25°C.
• silylating agents for example with hexamethyldisilazane and trimethylchlorosilane
• the product is isolated according to known techniques, for example by adding water to the reaction mixture, separating the phases, evaporating the organic one, taking up the residue, consisting of the diphenylmethyl or 4-methoxybenzyl ester of flomoxef, with dichloromethane and treating the solution thus obtained with trifluoroacetic acid and anisole.
• the flomoxef thus obtained, in a 98% purity, is isolated by adding water to the reaction mixture, separating the phases and recovering the product in acidic form by concentration of the organic phase or in form of the sodium or potassium salt thereof by treatment of the organic phase with sodium or potassium 2-ethylhexanoate.
• the sodium salt of flomoxef may be further purified by passing an aqueous solution at pH 5,8 ⁇ 6,2 through a column containing silica gel or a resin such as Amberlite ® XAD 1180, by eluting with deionized water or with a mixture of deionized water and of an alcohol, for example ethanol or isopropanol.
• the invention provides a process as illustrated above, whereby the compound of formula I" is further reacted and treated with activated 2-(cyanomethylthio)acetic acid and a compound of formula VII"
• the diphenylmethyl or 4- methoxy. benzyl 7 ⁇ -amino-7 ⁇ -methoxy-3-(l-methyl-lH " -tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylate is treated with 2-(cyanomethylthio)acetyl chloride (NCCH 2 SCH 2 COCI) in the presence of pyridine in dichloromethane at a temperature of from -10 to -25 0 C.
• NCH 2 SCH 2 COCI 2-(cyanomethylthio)acetyl chloride
• the product is isolated according to known methods, for example by adding water to the reaction mixture, separating the phases, evaporating the organic one, taking up the residue, consisting of the benzhydryl or 4-methoxybenzyl ester of cefmetazole, with dichloromethane and treating the solution thus obtained with trifluoroacetic acid and anisole or with aluminum trichloride and anisole.
• the cefmetazole thus obtained in a 99% purity is isolated by adding water to the reaction mixture, separating the phases and recovering the product in acidic form by concentration of the organic phase or as a sodium or potassium salt thereof by treatment of the organic phase with sodium or potassium 2-ethylhexanoate.
• X is oxygen
• Y is an alkyl group of from 1 to 3 carbon atoms or a ⁇ - hydroxyalkyl group of from 2 to 3 carbon atoms
• W is an alkyl having from 1 to 3 carbon atoms
• a benzyl group non-substituted or substituted with an alkyl having from 1 to 3 carbon atoms
• a phenyl group non-substituted or substituted with an alkyl having from 1 to 3 carbon atoms
• R° is a carboxy-protecting group.
• the alkyl substitution on the benzyl group is preferably in the benzene ring.
• Preferred compounds are those of formula VF wherein X' is oxygen, Y' is 2-hydroxyethyl, R° is benzhydryl or 4-methoxybenzyl and W is methyl, benzyl or j?-tolyl.
• X' is oxygen
• Y' is 2-hydroxyethyl
• R° is benzhydryl or 4-methoxybenzyl
• W is methyl, benzyl or j?-tolyl.
• step (b) To a solution of 11.5 g (0.026 m) of intermediate benzhydryl 7- methylthio imino-3 -chloromethyl- 1 -dethia- 1 -oxa-3 -cephem-4-carboxylate obtained in step (a) in 150 ml dichloromethane, a solution of 7 g (0.041 m) of sodium l-(2-hydroxyethyl)-li?-tetrazol-5-ylthiolate in 150 ml water is added at 2O 0 C. Then, 1.2 g of tetra- «-butyl ammonium bromide is added and the reaction mixture is stirred at a temperature of from 20°C to 25 0 C for 8 hours.
• step (c) To a solution of 51.4 g (0.093 m) of the intermediate benzhydryl 7- methylthio imino-3 - [ 1 -(2-hydroxyethyl)- lH-tetrazol-5 -yljthiomethyl- 1 -dethia- 1 - oxa-3 -cephem-4-carboxylate obtained in step (b) in 800 ml dichloromethane cooled to 5 0 C, 30 g of triphenylphosphine (0.1143 m) are added and the mixture is stirred 15 minutes at a temperature of from O 0 C to 5°C, then a solution of 13.12 g (0.097 m) of aluminum trichloride in 200 ml methanol, neutralized with 24.6 g (0.29 m) of sodium bicarbonate, is added thereinto.
• the mixture is stirred 30 minutes at 25°C, then it is cooled to a temperature of from 0°C to 5°C, diluted with 50 ml methanol and stirred 3 hours at 8 0 C ⁇ 1°C.
• the mixture is treated with 17 ml glacial acetic acid, stirred 15 minutes at a temperature of from 15°C to 2O 0 C, then treated with 250 ml water containing 5% sodium chloride and stirred for further 10 minutes.
• the phases are separated, the organic phase is washed with 250 ml of water containing 5% acetic acid and with 250 ml of water containing 5% of sodium chloride.
• the phases are separated, the organic phase is washed with 130 ml water containing 5% of acetic acid and with 130 ml water containing 5% of sodium chloride.
• the organic phase is dried and concentrated in vacuum to a volume of 145-155 ml.
• the residual solution is diluted with 210 ml methanol and the concentration in vacuum is started again until a volume of 210 - 230 ml.
• the mixture is let to crystallize at a temperature of from O 0 C to 5°C for 15 hours.
• the reaction mixture is stirred 30 minutes at a temperature of from — 10 0 C to -15°C, 440 ml water are added thereinto and stirring is continued for a further 15-minute period.
• the organic one is washed with 260 ml of 2N hydrochloric acid, then with a 5% aqueous solution of sodium bicarbonate and finally with 260 ml water.
• the organic phase is concentrated in vacuum to a dense oil which is taken up with methanol and left to crystallize for 15 hours.
• step (b) To a solution of 58 g (0.088 m) of the benzhydryl 7 ⁇ -[2- (difluoromethylthio) acetamido] -7 ⁇ -methoxy-3 -[I -(2-hydroxy ethyl)- lH-tetrazol- 5-yl]thiomethyl-l -dethia- 1 -oxa-3 -cephem-4-carboxylate intermediate obtained in step (a) in 250 ml of dichloromethane, cooled to a temperature of from -30 0 C to - 35 0 C 5 17.1 g (0.15 m) of trifluoroacetic acid and 32 g (0.29 m) of anisole are added.
• reaction mixture is stirred at the same temperature for 2-3 hours, then the temperature is let to rise to 20 o ⁇ 25°C.
• the mixture is washed with 45 ml of 5% HCl, then with 45 ml water.
• the separated organic phase is dried and concentrated in vacuum.
• the residue is crystallized with ethyl acetate and the solid is filtered to give 7 ⁇ -[2-(difluoromethylthio)acetamido]-7 ⁇ -methoxy-3-[l- (2-hydroxyethyl)- 1 H-tetrazol-5 -yl]thiomethyl- 1 -dethia- 1 -oxa-3 -cephem-4- carboxylic acid (flomoxef free acid).
• step (b) To 100 ml of anisole, 37.5 g (0.28 m) of aluminum trichloride are added at 20° ⁇ -25°C and the mixture is diluted with 250 ml of dichloromethane to obtain a solution. Separately, a solution of 50 g (0.078 m) of the benzhydryl 7 ⁇ -[2- (cyanomethylthio)acetamido] -7 ⁇ -methoxy-3 -(I -methyl- 1 /f-tetrazol-5 - yl)thiomethyl-3-cephem-4-carboxylate intermediate of step (a) in 800 ml of dichloromethane is prepared., cooled to -5 0 C and added with the solution obtained above.
• the obtained mixture is stirred 40 minutes at 0 0 C, then it is poured in a mixture of 500 ml water, 750 ml acetone and 25 ml of 35% HCl. After a 30-minute stirring, the phases are separated. To the aqueous phase, 28 g of NaCl and 75 ml of ethyl acetate are added. The organic phase is separated and washed with 200 ml of a 10% solution of NaCl. The collected organic phases are treated with 500 ml of 5% NaHCO 3 . The aqueous phase is collected, brought to pH 6 with 40 ml 35% HCl, then 15 g of activated alumina are added and the mixture is stirred for 30 minutes.
• Alumina is filtered and washed with water.
• the aqueous solution is added with 100 g of NaCl and 300 ml " of ethyl acetate, the pH is brought to 3.5-3.6 by addition of 50% H 3 PO 4 and 50 ml of methyl isobutyl ketone.
• the pH is slowly, in 2 hours, brought to 2.2 by addition of 50% H3PO4 and the product is left to crystallize for 15 hours in the cold.
• EXAMPLE 5 An amount of 40 g (0.742 m) of benzhydryl 7-methylthioimino-3-(l- methyl-li ⁇ ' -tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate are added to 640 ml of dichloro methane under stirring at room temperature. The mixture is cooled to 5 0 C and 24 g (0.0914 m) of triphenylphosphine are added thereto under stirring. The mixture is kept at 0° ⁇ 5°C for 15 minutes whereby a clear solution is obtained (Solution A).

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