WO1993011132A1 - Procede de fabrication de l'antibiotique cefaclor - Google Patents

Procede de fabrication de l'antibiotique cefaclor Download PDF

Info

Publication number
WO1993011132A1
WO1993011132A1 PCT/EP1992/002741 EP9202741W WO9311132A1 WO 1993011132 A1 WO1993011132 A1 WO 1993011132A1 EP 9202741 W EP9202741 W EP 9202741W WO 9311132 A1 WO9311132 A1 WO 9311132A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
benzyl
phenyl
acid
Prior art date
Application number
PCT/EP1992/002741
Other languages
German (de)
English (en)
Inventor
Gottfried Sedelmeier
Original Assignee
Ciba-Geigy Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba-Geigy Ag filed Critical Ciba-Geigy Ag
Publication of WO1993011132A1 publication Critical patent/WO1993011132A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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

  • the invention relates to a novel method (methodological method) for producing the antibiotic cefaclor and to the new starting materials and intermediates used.
  • Cefaclor i.e. 7- (D-2-amino-2-phenylacetamido) -3-chloro-3-cephem-4-carboxylic acid monohydrate
  • the present invention is based on the object of finding a novel process for the production of cefaclor which is suitable for large-scale industrial production and is based on starting materials which are readily available to the manufacturer and as little as possible toxic. If, as in the case of cefaclor, the end product contains numerous different functional groups, asymmetry centers and sensitive substructures, the development of a production process which satisfactorily fulfills the above requirements is an extremely demanding and lengthy task. It turns out again and again that reactions which, according to general specialist knowledge, should actually lead to the goal, can only be carried out on paper and in practice cannot be transferred to the very special case of the molecule to be produced.
  • the invention relates to a process for the preparation of 7- (D-2-amino-2-phenylacetamido) -3-chloro-3-cephem-4-carboxylic acid of the formula I,
  • R 2 is a carboxyl protecting group, or the tautomeric 3-keto compound with a sulfonic acid chloride of the formula R 2 -SO 2 -Cl (HI), wherein R 2 is methyl, trifluoromethyl, meta-nitro-phenyl, para- Nitro-phenyl or para-methyl-phenyl, in a compound of the formula IV,
  • R 1 and R 2 have the meanings given above, or converts a salt thereof, which is then reacted with a compound of the formula VI,
  • R 3 is 2-propen-l-yl, 3-phenyl-2-propen-l-yl or 2-trichloromethyl-prop-2-yl, or with a reactive acid derivative thereof to give a compound of the formula VII,
  • substituents have the abovementioned meanings, from which the radicals -OR x and -CO-OR 3 are then split off in any order, and, if desired, the compound of formula I obtained in a salt and / or hydrate or a salt obtained is converted into another salt or into the free compound. It is characteristic of the process according to the invention that the introduction of the 3-chloro substituent takes place very late in the reaction sequence.
  • R is hydrogen
  • substituents in the 7-position take the position of the radical R in steric terms.
  • a carboxyl protecting group R ! is preferably a suitable unsubstituted or substituted CC ⁇ alkyl group, such as especially diphenylmethyl, benzyl, 4-methoxy-benzyl, 4-nitro-benzyl, 2,2,2-trichloro-ethyl or tert-butyl.
  • suitable carboxyl protecting groups and their introduction and cleavage are described, for example, in “Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, in “Methods of Organic Chemistry", Houben-Weyl, 4th edition, Volume 15/1, Georg-Thieme-Verlag, Stuttgart 1974, and in Th. W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981.
  • the sulfonylation is carried out in an inert aprotic solvent, for example methylene chloride, N, N-dimethylformamide, N, N-dimethyl-acetamide, tetrahydrofuran or dioxane, at a temperature between about -15 ° C and + 50 ° C, generally between 0 ° C and room temperature in the presence of an acid scavenger (acid-binding agent).
  • an acid scavenger acid-binding agent
  • Tertiary amines such as triethylamine or in particular pyridine, or alkylene oxides, such as propylene oxide, are used as acid scavengers.
  • the reaction of a compound of formula IV with phosphorus pentachloride is carried out with exclusion of moisture in an inert aprotic solvent, preferably a halogenated hydrocarbon, such as methylene chloride, or in N, N-dimethylformamide, N, N-dimethyl-acetamide, tetrahydrofuran or dioxane
  • an inert aprotic solvent preferably a halogenated hydrocarbon, such as methylene chloride
  • an acid scavenger carried out as acid scavengers are tertiary amines , such as pyridine, triethylamine or in particular N, N-dimethyl-aniline, or alkylene oxides, such as propylene oxide.
  • An imine chloride is initially formed as an intermediate, which is then mixed with an alcohol, preferably a lower alkanol such as methanol, isobutanol or preferably n-propanol, at a temperature between about -40 ° C. and 0 ° C., for example at about -20 ° C. in a further intermediate stage, namely the corresponding imino ether.
  • This imino ether is then hydrolyzed to the 7-amino compound of the formula V, preferably in the form of an acid addition salt.
  • the hydrolysis is preferably carried out in a strongly acidic medium, for example in the presence of large amounts of a mineral acid, such as hydrochloric acid, in a suitable solvent, such as in particular the aforementioned lower alkanol, at a temperature between approximately -40 ° C. and + 20 ° C., preferably between approximately -40 ° C. and +5 ° C., in particular between -15 ° C. and 0 ° C. It is completely surprising and unpredictable that the O-SO-R 2 group will survive intact under these strongly acidic conditions.
  • a strongly acidic medium for example in the presence of large amounts of a mineral acid, such as hydrochloric acid, in a suitable solvent, such as in particular the aforementioned lower alkanol, at a temperature between approximately -40 ° C. and + 20 ° C., preferably between approximately -40 ° C. and +5 ° C., in particular between -15 ° C. and 0 ° C.
  • the acylation of a compound of formula V with a compound of formula VI is preferably carried out with a reactive acid derivative of a compound of formula VI, which can also be formed in situ.
  • a reactive acid derivative of a compound of the formula VI is in particular a reactive (activated) ester, a reactive anhydride or a reactive cyclic amide.
  • Reactive (activated) esters of an acid of the formula VI are unsaturated esters, for example of the vinyl ester type, in particular on the linking carbon atom of the esterifying radical, such as actual vinyl esters (which can be obtained, for example, by transesterification of a corresponding ester with vinyl acetate; method of the activated vinyl ester), Carbamoyl vinyl esters (which can be obtained, for example, by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxy vinyl esters (which can be obtained, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene Method), or amidino type esters, such as N, N'-disubstituted amidino esters (which can be obtained, for example, by treating the corresponding acid with a suitable N, N'-disubstituted carbodiimide, for example N, N'-
  • Anhydrides of an acid of the formula VI can be symmetrical or preferably mixed anhydrides of this acid, for example anhydrides with inorganic acids, such as acid halides, in particular acid chlorides (which can be obtained, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride can get; Acid chloride method), azides (which can be obtained, for example, from a corresponding acid ester via the corresponding hydrazide and its treatment with nitrous acid; azide method), anhydrides with carbonic acid semi-derivatives, such as with corresponding esters, for example carbonic acid lower alkyl semesters (which can be obtained, for example, by treating the corresponding acid with halogen -, Like chloroformic acid lower alkyl esters, for example isobutyl chloroformate, or with an l-lower alkoxycarbonyl-2-lower alkoxy-1, 2-dihydroquinoline, for example 1-low
  • Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, e.g. Imidazole (which can be obtained e.g. by treating the corresponding acid with N, N'-carbonyldiimidazole; imidazolide method), or pyrazoles, e.g. 3,5-dimethyl-pyrazole (which can be obtained, for example, from the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • imidazoles e.g. Imidazole (which can be obtained e.g. by treating the corresponding acid with N, N'-carbonyldiimidazole; imidazolide method)
  • pyrazoles e.g. 3,5-dimethyl-pyrazole (which can be obtained, for example, from the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • N, N'-di-substituted amidino esters can be formed in situ by mixing the mixture of the starting material of the formula V and the acid used as acylating agent in the presence of a suitable N, N-disubstituted carbodiimide, for example N, N ' -Dicyclohexylcarbodiimid, brings to reaction.
  • a suitable N, N-disubstituted carbodiimide for example N, N ' -Dicyclohexylcarbodiimid
  • amino or amido esters of the acids used as acylating agents can be formed in the presence of the starting material of formula V to be acylated by mixing the mixture of corresponding acid and amino starting materials in the presence of an N, N'-disubstituted carbodiimide, for example N, N'-dicyclohexyl-carbodiimide, and an N-hydroxyamine or N-hydroxyamide, for example N-hydroxysuccinimide, if appropriate in the presence of a suitable base, for example 4-dimethylamino-pyridine
  • the compound of the formula VI is preferably used in the form of a mixed anhydride which is obtained from the acid of the formula VI by reaction with isobutyl chloroformate in an inert organic solvent, preferably methylene chloride, at a temperature between about -40 ° C. and room temperature, e.g. at -15 ° C, and then adding N-methyl-morpholine in the same temperature range.
  • an inert organic solvent preferably methylene chloride
  • reaction conditions in the acylation of a compound of formula V depend primarily on whether and how the carboxyl group of the acylating agent of formula VI is activated.
  • the reaction is carried out in the presence of a suitable solvent or diluent, e.g. Methylene chloride, or a mixture thereof, and, if necessary, in the presence of a condensing agent which, for example, when the carboxyl group participating in the reaction is present as an anhydride, also contains an acid binding agent, e.g. N-methyl-morpholine, with cooling or heating, e.g. in a temperature range from about -30 ° C to about + 70 ° C, in particular from about -15 ° C to room temperature (about + 20 ° C), e.g.
  • Common condensing agents are e.g. Carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N'-dicyclohexyl or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, suitable carbonyl compounds, for example carbonyl - Diimidazole, or 1,2-oxazolium compounds, e.g.
  • acylamino compound e.g. 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline.
  • acid-binding condensing agents are e.g. Alkali metal carbonates or hydrogen carbonates, e.g. Sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate), or organic bases such as usually sterically hindered tri-lower alkylamines, e.g. N, N-diisopropyl-N-ethyl-amine.
  • the starting compounds of the formula VI in which R 3 is 3-phenyl-2-propen-1-yl or 2-trichloromethyl-prop-2-yl are new.
  • the starting compound in which R 3 is 3-phenyl-2-propen-l-yl can be prepared, for example, from cinnamon alcohol, phosgene and D-phenylglycine. as described in detail in the example section.
  • the hydrolysis of the sulfonyloxy group according to the first variant is carried out in a suitable solvent, preferably dimethylformamide, which has a low content, preferably about 0.1% water, by means of a salt from a strong base, e.g. Alkali metal hydroxide and a weak acid e.g. Acetic acid or formic acid, e.g. by means of alkali metal acetate, such as sodium or preferably potassium acetate, which also has a low water content, e.g. B. about 0.1, has at a temperature between about 10 ° C and 70 ° C, preferably at about 40-45 ° C.
  • a suitable solvent preferably dimethylformamide, which has a low content, preferably about 0.1% water
  • a salt from a strong base e.g. Alkali metal hydroxide and a weak acid e.g. Acetic acid or formic acid
  • alkali metal acetate such as sodium or preferably potassium acetate
  • the sulfonyloxy group can also be acidic, e.g. with a mineral acid, such as sulfuric acid, or a sulfonic acid, such as p-toluenesulfonic acid, or a strongly acidic ion exchanger, preferably at 40 ° C to 60 ° C.
  • a mineral acid such as sulfuric acid
  • a sulfonic acid such as p-toluenesulfonic acid
  • a strongly acidic ion exchanger preferably at 40 ° C to 60 ° C.
  • the conversion of the compound of the formula X into a compound of the formula VII can be carried out in the same reaction vessel as the hydrolysis without prior work-up of the hydrolysis product if the solvent for the precursor, ie the above-mentioned hydrolysis, dimethylformamide is selected (one-pot reaction ).
  • dimethylformamide is selected (one-pot reaction ).
  • the substitution of the hydroxyl group by chlorine in dimethylformamide must be carried out, although in addition to dimethylformamide, additional solvents such as tetrahydrofuran, dioxane, methylene chloride, dimethylacetamide or dimethyl sulfoxide may be present.
  • Chlorinating agents such as phosgene, oxalyl chloride, thionyl chloride, phosphorus oxychloride or preferably phosphorus trichloride, but not phosphorus pentachloride, can be used.
  • the chlorination is carried out by adding the chlorinating agent in dry dimethylformamide to a solution of the 3-hydroxy compound of the formula X in dimethylformamide at a temperature between about 0 ° C. and 20 ° C., preferably at 0 ° C. to 15 ° C. , after which the reaction solution is stirred for several hours at a slightly higher temperature, preferably room temperature.
  • the direct substitution of the sulfonyloxy group R 2 -SO 2 -O- by chlorine according to the second variant mentioned above is possible under conditions which are as anhydrous as possible in the presence of a suitable quaternary phosphonium or, in particular, ammonium salt, for example an optionally substituted tetraalkylammonium chloride, preferably tetraethylammonium chloride, in In the presence of ithium chloride and boron trifluoride etherate in a suitable solvent, such as a suitable ether, for example diethylene glycol dimethyl ether, or in a chlorinated hydrocarbon, such as dichloromethane or 1,2-dichloroethane, in the temperature range between about 10 ° C. and 70 ° C, preferably between approximately 40 ° C and 60 ° C.
  • a suitable quaternary phosphonium or, in particular, ammonium salt for example an optionally substituted tetraalkylammonium chloride,
  • radicals -ORj and -CO-OR 3 can be split off from a compound of the formula VIII in any order.
  • Rj is diphenylmethyl
  • the cleavage is preferably carried out with anisole trifluoroacetic acid.
  • Benzyl, 4-methoxy-benzyl or 4-nitro-benzyl R x is split off by catalytic hydrogenation in the presence of a palladium / carbon catalyst.
  • 2,2,2-trichloroethyl R r is cleaved with zinc in a suitable acid, such as acetic acid or formic acid.
  • Tert butyl R 2 is split in an acidic medium, preferably with trifluoroacetic acid.
  • Allyloxycarbonyl and 3-phenyl-2-propen-l-yl R 3 are cleaved with dimedone / triphenylphosphine in the presence of catalytic amounts of a suitable palladium (0) compound, for example palladium tetrakis triphenylphosphine, in which palladium has the oxidation state 0 has, in a suitable solvent, such as a suitable ester, for example acetic acid ethyl ester, a suitable chlorinated hydrocarbon, for example methylene chloride, or preferably a suitable ether, such as dioxane, tert. Butyl methyl ether or preferably tetrahydrofuran, at room temperature. 2-Trichloromethyl-prop-2-yl R 3 is split with zinc in a suitable acid, such as acetic acid or formic acid.
  • a suitable solvent such as a suitable ester, for example acetic acid ethyl ester
  • Salts of compounds of formulas I and V are especially acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g.
  • aliphatic mono- or dicarboxylic acids such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, oxalic acid or amino acids, such as arginine or lysine, such as aromatic benzoic acids, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane, ethane or 2-hydroxy -ethane sulfonic acid, or aromatic sulfonic acids, for example Benzene, p-toluene or naphthalene-2-s
  • Acid addition salts of compounds of formulas I and V are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchange reagent. Acid addition salts can be converted into the free compounds in a conventional manner, e.g. by treating with a suitable basic agent.
  • a hydrate of the compound of formula I is in particular the monohydrate, the hydrate is obtained, for example, by adding sufficient amounts of water when the protective groups are split off from a compound of the formula VTI, for example as described in Example 1.
  • the invention also relates to those embodiments of the method in which a compound which is obtainable as an intermediate product at any stage of the method, in particular a compound of the formula IV, is used and the missing method steps are carried out or the method is terminated at any stage or forms a starting material under the reaction conditions or is used in the form of a reactive derivative or salt.
  • the starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.
  • the invention also relates to the process for the preparation of a compound of the formula V from a compound of the formula IV, which is carried out analogously to the corresponding step in the preparation process for cefaclor described above.
  • New starting materials and / or intermediates such as in particular the above-mentioned compounds of the formula VI, in which R 3 is 3-phenyl-2-propen-l-yl or 2-trichloromethylprop-2-yl and the formulas VE, VIII and X, and processes for their manufacture tion are also the subject of the present invention.
  • Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed as particularly preferred in this application are obtained.
  • the following examples illustrate the invention without restricting it in any way.
  • the R values are determined on thin-layer silica gel sheets (Merck, Darmstadt Germany).
  • the ratio of the solvents in the solvent mixtures used to each other is in volume fractions (V / V), temperatures are given in degrees Celsius.
  • the concentration, c, of the substance in the solvent (mixture) is given in percent (weight / volume) in the case of optical rotation.
  • Example 1 1.36 g (3.0 mmol) of 7- (D-2-allyloxycarbonylamino-2-phenyl-acetamido) -3-chloro-3-cephem-4-carboxylic acid are dissolved in 15 in a 100 ml sulfonation flask ml of tetrahydrofuran dissolved at 20 ° C. and mixed with 0.28 g (2.0 mmol) of dimedone and 0.15 g (0.57 mmol) of triphenylphosphine. A clear, light yellow solution results.
  • the starting product is obtained as follows:
  • Stage 1.1 206.6 g of 7- (2-phenyloxyacetamido) -3-oxo-3-cepham-4-carboxylic acid benzhydryl ester (0.4 mol) are placed in a 2.5 liter sulfonation flask and by adding 500 ml of methylene chloride dissolved at room temperature. The mixture is then cooled to 0 ° C. and 149 g (1.3 mol) of methanesulfonic acid chloride are quickly added. A light yellow reaction solution results with slight exotherm. Then 83 g (1.5 mol) of dry pyridine are added dropwise at 0 ° C. in the course of 15 minutes. The dropping funnel is rinsed with a little methylene chloride and stirred at 0 ° C. for a further 1.5-2 hours.
  • Stage 1.2 89.2 g (0.150 mol) of 7- (2-phenyloxyacetamido) -3-methanesulfonyloxy-3-cephem-4-carboxylic acid benzhydryl ester are dissolved in 375 ml of dry methylene chloride at room temperature in a 2.5 liter sulfonation flask a clear, light yellow solution. The mixture is cooled to -30.degree. C. and 33.2 g (0.274 mol) of N, N-dimethylaniline and then a PCIs suspension cooled to -30.degree. C. are added in one portion, heating to approx. -20.degree
  • PCIs suspension is previously prepared as follows: 52.5 g (0.252 mol) of phosphorus pentachloride are dissolved in 250 ml of methylene chloride under reflux in a 1 liter round-bottom flask. The mixture is then cooled to -30 ° C. with stirring using a magnetic stirrer, resulting in a fine Suspension arises. All operations are carried out with the exclusion of moisture.
  • the mixture is left to stir for about 1 hour at -20 ° C and then 105 ml of n-propanol are added to the brown reaction solution at -20 ° C. The addition takes place in such a way that the temperature can be kept at approx. -20 to -15 ° C.
  • the mixture is then stirred at -15 ° C for one hour. Then you give a mixture of 80 ml of n-propanol and 80 ml of conc. Hydrochloric acid at -15 ° C within 30 minutes. The result is a cloudy, viscous reaction solution.
  • the mixture is stirred for another hour and allowed to warm to 0 ° C.
  • the methylene chloride phase is concentrated on a rotary vaporizer, with product already precipitating.
  • To complete the crystallization after three-quarters of the methylene chloride has been distilled off, about 300 ml of n-hexane are added. Then further solution medium mixture (methylene chloride, hexane) distilled off (approx. 300 ml) and supplemented with approx. 300 ml hexane.
  • the resulting crystal suspension is stirred for a further 1 hour using a magnetic stirrer, then filtered through a glass suction filter and washed with hexane.
  • the product is dried in vacuo (approx.
  • Step 1.3 97.4 g (0.414 mol) of (D) -allyloxycarbonylphenylglycine are suspended in 450 ml of methylene chloride at room temperature in a 2500 ml sulfonation flask. The mixture is cooled to -15 ° C. and 56.5 g (0.414 mol) of isobutyl chloroformate are added dropwise in the course of 10 minutes and the mixture is rinsed with 10 ml of methylene chloride. Then 41.9 g of N-methylmorpholine are added dropwise at -15.degree. C. and stirring is continued at -15.degree. C. for a further 15 minutes. The solution obtained, containing the mixed anhydride, is processed further in stage 1.4.
  • Stage 1.4 178.9 g (0.360 mol) of 7-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid benzhydrate ester hydrochloride are suspended in 500 ml of methylene chloride in a 1 liter sulfonation flask and cooled to 0.degree. 32.9 g of N-methylmorpholine are then added dropwise at 0 ° C. in the course of 10 minutes and the mixture is stirred at 0 ° C. for 15 minutes. This solution is transferred together with 7.2 g of N-methylmorpholine and 100 ml of methylene chloride into a 1 liter dropping funnel and added dropwise at -15 ° C. to the solution of the mixed anhydride prepared in step 1.3 within 30 minutes. When the addition is complete, the mixture is allowed to warm to 0 ° C. and is stirred at this temperature for a further 45 minutes.
  • the two phases are filtered through a little filter aid in a separating funnel.
  • the methylene chloride phase is washed three times with 300 ml of phosphate buffer pH 7 each, then filtered through a little sodium sulfate and concentrated on a rotary evaporator.
  • the oily residue is dissolved in approx. 250 ml of ethyl acetate, then hexane is metered in with stirring up to the cloud point, then inoculated with a little product, after which the rest of the hexane (total approx. 300 ml) is slowly metered in with stirring to.
  • Step 1.5 10.17 g (15 mmol) of 7- ⁇ -2-allyloxycarbonylammo-2-phenyl-acetamido) - 3-methanesulfonyloxy-3-cephem-4-carboxylic acid benzhydryl ester are mixed in a 750 ml sulfonation flask together with 2.94 g ( 30 mmol) of potassium acetate (water content approx. 0.1%) in 100 ml of dimethylformamide (water content approx. 0.1%) at a temperature of 40 - 45 ° C to react. After 12-15 hours, a TLC check shows complete conversion to the corresponding 3-hydroxy compound. The dimethylformamide reaction solution is cooled to 0 ° C.
  • Stage 1.6 12.36 g (20 mmol) of 7- (D-2-allyloxycarbonylamino-2-phenyl-acetamido) -3-chloro-3-cephem-4-carboxylic acid benzhydryl ester are dissolved in 100 ml of methylene chloride at room temperature and mixed with 4. 33 g (40 mmol) of anisole added. The mixture is then cooled to 0 ° C. and 16 g of trifluoroacetic acid are added dropwise at 0 ° C. in the course of 15 minutes. Then allowed to warm to 20 ° C and stirred for a further 2 hours at this temperature. When complete conversion is reached after this time after TLC control, the mixture is cooled again to 0 ° C.
  • Example 2 In a dry flask, 59.64 g (120 mmol) of 7-amino-3-mesyloxy-3-cephem-4-benzhydryl ester hydrochloride are suspended in 150 ml of methylene chloride and cooled to 0 ° C. At this temperature, 11.4 g of N-methylmorpholine are added dropwise within 30 minutes, a thin, brown suspension being formed, which is transferred to a dropping funnel. The flask is rinsed with a mixture of 2.56 g of N-methylmorpholine in 15 ml of methylene chloride. This solution is then added dropwise at -15 ° C. to the solution of the mixed anhydride prepared according to step 2.2 within 15 minutes.
  • the starting material is obtained as follows:
  • Stage 2.1 69.2 g (0.5 mol) of cinnamon alcohol are dissolved in 60 ml of toluene at room temperature and, after cooling to 0 ° C., added dropwise to 250 ml of 20% phosgene solution in toluene within 30 minutes. After stirring for 1 hour at 20 ° C., during which a small amount of a red-brown oil separates, the toluene product solution is separated from this by decanting and evaporated in vacuo at a temperature of approx. 40 ° C. until the oil.
  • Step 2.2 43.0 g (138 mmol) of (D) -N-cinnamyloxycarbonyl-phenylglycine are suspended in 120 ml of methylene chloride at 20 ° C. in a dry sulfonation flask. After cooling to -15 ° C., 18.48 g (138 mmol) of isobutyl chloroformate in 15 ml of methylene chloride are added to the suspension within 5 minutes and then a mixture of 13.96 g of N-methylmorpholine and 15 ml of methylene chloride. After 15 minutes at -15 ° C, a clear yellow solution of the mixed anhydride is formed, which is used directly.
  • Example 3 21.7 g (32 mmol) of 7- (D-2-allyloxycarbonylamino-2-phenyl-acetamido) -3-methanesulfonyloxy-3-cephem-4-carboxylic acid benzhydrate are mixed in a 250 ml sulfonation flask together with 8.14 g (192 mmol) lithium chloride (water content ⁇ 0.1%) and 0.53 g of tetraethylammonium chloride (water content 0.05%) in 50 ml of dimethylformamide (DMF; water content ⁇ 0.05) at a temperature of 60 ° C. for the reaction In order to chemically bind small amounts of water, a smaller amount (approx.
  • DMF dimethylformamide

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

Il est décrit un nouveau procédé (procédé systèmatique) de fabrication de l'antibiotique cefaclor de formule (I), ainsi que les nouveaux produits de départ et produits intermédiaires utilisés dans ce procédé. Le procédé s'effectue comme spécifié à la revendication 1.
PCT/EP1992/002741 1991-12-06 1992-11-27 Procede de fabrication de l'antibiotique cefaclor WO1993011132A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH3593/91-5 1991-12-06
CH359391 1991-12-06

Publications (1)

Publication Number Publication Date
WO1993011132A1 true WO1993011132A1 (fr) 1993-06-10

Family

ID=4259338

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/002741 WO1993011132A1 (fr) 1991-12-06 1992-11-27 Procede de fabrication de l'antibiotique cefaclor

Country Status (1)

Country Link
WO (1) WO1993011132A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104086573A (zh) * 2014-07-24 2014-10-08 孙巧玲 头孢克洛的一锅法制备方法
CN115372498A (zh) * 2022-07-14 2022-11-22 石家庄四药有限公司 一种头孢克洛中残留杂质的检测方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925372A (en) * 1973-02-23 1975-12-09 Lilly Co Eli Alpha-aminoacyl-3-halo cephalosporins
US3926978A (en) * 1974-02-06 1975-12-16 Lilly Co Eli Process for preparing 3-fluorocephalosporins

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925372A (en) * 1973-02-23 1975-12-09 Lilly Co Eli Alpha-aminoacyl-3-halo cephalosporins
US3926978A (en) * 1974-02-06 1975-12-16 Lilly Co Eli Process for preparing 3-fluorocephalosporins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 107, no. 13, 28. September 1987, Columbus, Ohio, US; abstract no. 115430k, Seite 612 ;Spalte L ; *
JOURNAL OF MEDICINAL CHEMISTRY Bd. 18, Nr. 4, April 1975, WASHINGTON Seiten 403 - 408 ROBERT R. CHAUVETTE 'Chemistry of Cephalosporin Antibiotics. 3_Methoxy- and 3-Halo-3-cephems.' *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104086573A (zh) * 2014-07-24 2014-10-08 孙巧玲 头孢克洛的一锅法制备方法
CN115372498A (zh) * 2022-07-14 2022-11-22 石家庄四药有限公司 一种头孢克洛中残留杂质的检测方法
CN115372498B (zh) * 2022-07-14 2023-05-05 石家庄四药有限公司 一种头孢克洛中残留杂质的检测方法

Similar Documents

Publication Publication Date Title
DE2432415A1 (de) Antibiotica
DE3444046C2 (fr)
EP0137441A2 (fr) Dérivés de céphalosporine et procédé pour leur préparation
CH618175A5 (en) Process for the preparation of penicillins
DE2514020A1 (de) Acylureidocephalosporine
WO1993011132A1 (fr) Procede de fabrication de l'antibiotique cefaclor
EP0624590A1 (fr) Dérivés nacyles de staurosporine, procédé et intermédiaires pour leur préparation et leur utilisation comme medicaments
AT328085B (de) Verfahren zur herstellung neuer penicilline
DE2446254A1 (de) 5-substituierte niedrigalkyl-1,3,4thiadiazol-2-thiolverbindungen, ihre salze und ein verfahren zu ihrer herstellung
DD279887A1 (de) Verfahren zur herstellung von d-alpha-(4(1h)-1,5-naphthyridon-3-carboxamido)-benzylpenicillin und anderen beta-lactamantibiotika
AT403048B (de) Verfahren zur herstellung von cephem-derivaten
DE2333256A1 (de) Halogenpenam- und halogencephamderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
EP1607090A1 (fr) Asimadoline pour le traitement du syndrome du colon irritabile
DE2700271A1 (de) Thienopyridinderivate
DE2442702C2 (de) Cephalosporinverbindungen, Verfahren zu ihrer Herstellung und antibakterielle Mittel, die diese Verbindungen enthalten
EP0064256B1 (fr) Dérivés de céphalosporine et procédé pour leur préparation
CH644865A5 (de) Cephalosporinderivate, verfahren zu ihrer herstellung und ihre verwendung als zwischenprodukte.
DE2944086A1 (de) Peptidderivate
DE3901405A1 (de) Cephalosporinderivate und verfahren zu ihrer herstellung
DE2841706C2 (de) N,N-Dimethylacetamid-Addukt der 7-[D(-)-α-(4-Äthyl-2,3-dioxo-1-piperazincarboxamido)-α-(4-hydroxyphenyl)-acetamido]-3-[5-(1-methyl-1,2,3,4-tetrazolyl)-thiomethyl]-Δ↑3↑-cephem--4-carbonsäure, Verfahren zu seiner Herstellung und seine Verwendung
EP0539330B1 (fr) Procédé pour la préparation d'indoles substituées
EP0427161B1 (fr) Picolylsélénobenzamides d'aminopyridines, d'anilines et de picolylamines
CH618161A5 (en) Process for the preparation of azetidinone derivatives
DE2202274C2 (de) 3-Triazolylthiomethyl-cephalosporine und Verfahren zu ihrer Herstellung
DE2649545A1 (de) Cephalosporinderivate, deren salze, verfahren zu ihrer herstellung und arzneipraeparate

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA CS HU JP KR PL US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA