WO1993011132A1

WO1993011132A1 - Method of preparing the antibiotic cefaclor

Info

Publication number: WO1993011132A1
Application number: PCT/EP1992/002741
Authority: WO
Inventors: Gottfried Sedelmeier
Original assignee: Ciba-Geigy Ag
Priority date: 1991-12-06
Filing date: 1992-11-27
Publication date: 1993-06-10

Abstract

Described is a new method (systematic method) of preparing the antibiotic cefaclor of formula (I). Also described are new starting products and intermediates used in the method. The method is carried out as described in claim 1.

Description

Process for the preparation of the antibiotic cefaclor

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, is an oral cephalosporin antibiotic, which in 1990 had a worldwide turnover of approximately 1 billion Swiss Franconia reached. 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,

)-Configuration

or a salt or hydrate, such as in particular the monohydrate thereof, characterized in that a compound of the formula II,

wherein 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,

in which R _x and R _{2 have} the abovementioned meanings, the compound of the formula IV obtained is converted into a compound of the formula V with phosphorus pentachloride,

wherein 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,

* (D) configuration

wherein 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,

* (D) configuration

wherein the substituents have the abovementioned meanings, which is then converted into a compound of the formula VIII,

* (D) configuration

wherein the 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. That it is possible to keep the rest of the formula -O-SO ₂ -R ₂ in the compounds of the formulas IV, V and VH instead of the 3-chloro substituent is completely surprising and unpredictable in view of the reaction conditions involved in the conversion a compound of formula IV can be used in a compound of formula V by means of phosphorus pentachloride. In this conversion, a large amount of concentrated hydrochloric acid is added. Even after further conversion to a compound of formula VE, treatment is carried out with large amounts of concentrated hydrochloric acid. These findings are all the more surprising in the light of the experiment that a compound of the formula IV in methylene chloride-n-propanol conc. Hydrochloric acid in a volume ratio of 3: 1: 1 is almost completely decomposed with stirring at 20 ° C within 24 hours and half within 48 hours.

In the context of this application, the term “3-cephem” means a compound of the formula IX,

where R is hydrogen, in the case of cephem derivatives, substituents in the 7-position take the position of the radical R in steric terms.

The process according to the invention is described in more detail below:

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. These and other 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.

Compounds of the formula EL are known and are also used as an intermediate for the preparation of cephalosporin derivatives other than cefaclor. The connections of the Formula II are in the dissolved state in the enol form and in the crystalline state in the tautomeric keto form (corresponding 3-oxo-cepham compound). 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). 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 Temperature between about -60 ° C and + 20 ° C, generally between -40 ° C and -10 ° C, preferably between -30 ° C and -20 ° C in the presence of 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.

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'-dicyclohexylcarbodiimide; Carbodiimide method), or N, N-disubstituted amidino esters (which can be obtained, for example, by treating the corresponding acid with a N, N-disubstituted cyanamide can be obtained; Cyanamide method), suitable aryl esters, in particular phenyl esters suitably substituted by electron-attracting substituents (which can be obtained, for example, by treating the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, method of activated aryl esters), cyanomethyl esters (which can be obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thioesters, in particular phenylthioesters optionally substituted, for example, by nitro (which can be obtained, for example, by treating the corresponding acid with optionally , e.g. by nitro, substituted thiophenols, including with the aid of the anhydride or carbodiimide method; method of the activated thiol esters), amino or amido esters (which can be obtained, for example, from Behan the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide or 1-hydroxybenztriazole, for example can be obtained by the anhydride or carbodiimide method; Method of activated N-hydroxy esters) or silyl esters (which can be obtained, for example, by treating the corresponding acid with a silylating agent, for example hexamethyldisilazane, and which react easily with hydroxyl groups but not with amino groups).

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-lower alkoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline , method of mixed O-alkyl-carbonic anhydrides), or anhydrides with dihalogenated, especially dichlorinated phosphoric acid (which can be obtained, for example, by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), or anhydrides with organic acids, such as mixed anhydrides with organic ones Carboxylic acids (which can be obtained, for example, by treating the corresponding acid re can be obtained with an optionally substituted lower alkane or phenylalkane carboxylic acid halide, for example phenylacetic acid, pivalic acid or trifluoroacetic acid chloride; Method of mixed carboxylic anhydrides) or with organic sulfonic acids (which can be obtained, for example, by treating a salt, such as an alkali metal salt, the corresponding acid, with a suitable organic sulfonic acid halide, such as lower alkane or aryl, for example methane or p -Toluenesulfonic acid chloride, can be obtained; method of mixed sulfonic anhydrides), and symmetrical anhydrides (which can be obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropine; method of symmetrical anhydrides).

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).

Derivatives of acids of formula VI that are used as acylating agents can also be formed in situ. For example, 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. Furthermore, 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.

The 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. at -15 ° C, in an open or closed reaction vessel and / or in the atmosphere of an inert gas, e.g. Nitrogen. 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. 2-ethyl-5-phenyl-l, 2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate or a suitable acylamino compound, e.g. 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline. Common 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 conversion of a compound of formula VII into a compound of formula VHI can be carried out in various ways: in the first variant, the sulfonyloxy group R ₂ -SO ₂ -O- is first hydrolyzed to hydroxy in the starting material of formula VII. The 3-hydroxy compound of formula X thus obtained,

in which the substituents have the meanings given above, is then converted into the 3-chloro compound of the formula VIII. In the second variant, the sulfonyloxy group R ₂ -SO ₂ -O- is replaced directly by chlorine.

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. Instead of the alkali metal acetate, an alkali metal formate, e.g. Sodium formate to be hydrolyzed. However, 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.

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 ). In any case 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.

The radicals -ORj and -CO-OR ₃ can be split off from a compound of the formula VIII in any order.

It is preferable to split off the group -ORj and then the group -CO-OR ₃ . If 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.

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-sulfonic acid. The compound of formula I can also form an inner salt.

For the isolation or purification of the compound of the formula I and for the compounds which are further used as an intermediate, pharmaceutically unsuitable salts can also be used. However, only the pharmaceutically usable, non-toxic salts are used therapeutically, which is why they are preferred.

Due to the close relationship between the compounds in free form and in the form of their salts, including also those acid addition salts which are used as intermediates, e.g. can be used in the purification of the compounds or for their identification are to be understood in advance and in the following under the free compounds as appropriate and appropriate, if appropriate, the corresponding salts.

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 processes described above, including the processes for deprotection and the additional process measures, are carried out in a manner known per se, e.g. in the presence or absence of preferably inert solvents and diluents, if necessary, in the presence of condensing agents or catalysts, at reduced or elevated temperature, e.g. in a temperature range from about -50 ° C to about 100 ° C, in particular from about -30 ° C to about + 70 ° C, preferably from about 0 ° C to about + 50 ° C, mainly at room temperature, in a suitable vessel and if necessary in an inert gas, eg Nitrogen atmosphere

Taking into account all the substituents in the molecule, if necessary, e.g. in the presence of easily hydrolyzable residues, particularly gentle reaction conditions, such as short reaction times, use of mild acidic or basic agents in low concentration, stoichiometric proportions, choice of suitable catalysts, solvents, temperature and or pressure conditions.

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. 0.07 g (0.06 mmol) of Pd- (0) -tetrakis-triphenylphosphine and then 0.75 ml of deionized water are added to this and the mixture is stirred at 25 ° C. overnight. After cooling to -5 ° C., the mixture is filtered and the crystals obtained are washed with 2x5 ml of cold tetrahydrofuran. It is dried in a vacuum at 25 ° C. overnight and 7- (D-2-amino-2-phenyl-acetamido) -3-chloro-3-cephem-4-carboxylic acid monohydrate is obtained; R _f = 0.22 (n-butanol: formic acid: water = 4: 1: 1).

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.

When the reaction has ended after checking the thin layer (toluene / ethyl acetate = 2: 1), 200 ml of 1N hydrochloric acid and then 200 ml of water are added at 0 ° C. and the mixture is stirred for 5 minutes. The phases are separated in a separating funnel, the organic phase is extracted 3 times with 200 ml of phosphate buffer pH 7 combined water phases extracted again with 200 ml of methylene chloride. The combined methylene chloride phases are filtered over sodium sulfate for drying and evaporated. The residue is dissolved hot in about 100-150 ml of ethyl acetate; by adding hexane (total approx. 500 ml) and seeding with a few seed crystals, the mixture is slowly cooled to room temperature with stirring, whereupon crystallization begins. The mixture is stirred for a further 2 hours at 20 ° C., then filtered through a G-3 glass filter and washed twice with 100 ml of hexane. It is dried in vacuo (approx. 20 mbar) for approx. 24 h at room temperature and 7- (2-phenyloxy-acetamido) -3-methansuuOnyIoxy-3-cephem-4-carboxylic acid benzhydric ester is obtained.

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

The aforementioned 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. For working up, another 160 ml of water and 400 ml of methylene chloride are added and the mixture is transferred to a separating funnel. The phases are separated, the aqueous phase is extracted with 300 ml of methylene chloride, the methylene chloride phases are combined and extracted again with 160 ml of water.

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. 20 mbar) at room temperature overnight, whereupon 7-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride is obtained; R _f = 0.25 (toluene: ethyl acetate = 2: 1), mp 148-149 ° C

20 (decomposition), [α] _D = -2.1 ° (c = 1; methanol).

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.

If, according to the thin-layer control (toluene: ethyl acetate = 2: 1), the 7-amino-3-methanesulfonyloxy-3-cephem is completely reacted, the reaction is immediately carried out with a mixture of 228 ml concentrated hydrochloric acid and 130 ml water at -10 ° C quenched.

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. Filtration and washing with hexane, after drying in vacuo at 20 ° C., gives 7_Q3_2-AUyloxycarbonylarmno-2-phenyl-acetamido) -3-methanesulfonyloxy-3-cephem-4-carboxylic acid benzhydric ester. Another product is obtained by concentrating the mother liquor, crystallization from ethyl acetate / hexane and recrystallization; Mp 171.5-172.5 ° C (decomposition), R _f = 0.55 (toluene: ethyl acetate = 2: 1),

20th

[α] _D = -22 ° (c = 1; dichloromethane).

Step 1.5: 10.17 g (15 mmol) of 7-φ-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. and a solution of 10.17 g of phosphorus trichloride in 70 ml of dry dimethylformamide is metered in at 30 ° C. in the course of 30 minutes. The mixture is then warmed to room temperature and stirred for a further 3-4 hours at this temperature. Then a TLC check shows complete conversion of the 3-hydroxy compound to the 3-chloro compound. The orange-brown reaction solution is poured onto 300 ml of ice and then extracted twice with 150 ml of ethyl acetate. The combined ethyl acetate phases are evaporated, the orange-brown, oily residue is taken up in toluene and filtered through silica gel. The yellow, product-containing filtrate is evaporated again and the crystalline residue is recrystallized from ethyl acetate by adding cyclohexane, whereupon 7- (D-2-allyloxycarbonylamino-2-phenyl-acetamido) -3-chloro-3-cephem-4-carboxylic acid benzhydrate ester is obtained. FAB-MS: MH + = 618, R _f = 0.68 (toluene: ethyl acetate = 2: 1), mp. 199-200 ° C (from ethyl acetate / n-hexane).

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. and 300 ml of diisopropyl ether are allowed to flow in over 30 minutes, the product crystallizing out. It is filtered, the product is washed with twice 50 ml of diisopropyl ether and dried in a high vacuum. 7-φ-2-allyloxycarbonylamino-2-phe- nyl-acetamido) -3-chloro-3-cephem-4-carboxylic acid; Mp 173-174 ° C (from a little methanol

20 and MMeetthhyylleenncchhllooriridd // DDiiiissoopprrooppyylleetthheerr)) ,, FFAABB - MMSS :: MMHH ++ == 4452, [α] _D = + 38.5 (c = 1; methanol), R _f = 0.27 (ethyl acetate / ethanol = 2 : 1).

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. When the addition is complete, the mixture is allowed to warm to 0 ° C. After conversion is complete, the pH is adjusted to 1-2 using about 6 N hydrochloric acid (about 100 ml), the organic phase is separated off, washed with 2 × 200 ml of phosphate buffer and evaporated in vacuo. The residue is crystallized from ethyl acetate. A first crystallizate and a second crystallizate, which is recrystallized again, of 7- (D-2-cinnamyloxycarbonylamino-2-phenyl-acetamido) -3-

20 mesyloxy-3-cephem-4-benzhydryl ester hydrochloride; Mp 179-180 ° C, [α] _D = -15.8 ° (c = 1; dichloromethane), R _f = 0.5 (toluene / ethyl acetate = 2: 1).

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. The residue is dissolved in 50 ml of tetrahydrofuran and added dropwise to a solution of 37.8 g of D-phenylglycine in 26 ml of 30% sodium hydroxide solution and 50 ml of water at 0-10 ° C. in the course of 30 minutes, the pH being determined by continuous addition of 1 N sodium hydroxide solution is kept at 9.5-10. A thick suspension is formed, which is kept stirrable by adding 50 ml of THF. When the reaction is complete, the mixture is diluted with water (200 ml and 300 ml of ethyl acetate and adjusted to pH 1 with concentrated hydrochloric acid. The organic phase is separated off with 100 ml of 1N NaOH and finally extracted with 100 ml of water. The ethyl acetate phase is evaporated in vacuo and the residue is crystallized from ethyl acetate hexane, whereupon φ) -N-cinnamyloxycarbonyl-phenylglycine is obtained, mp. 118-119

° C, [α] o ° = -99 ° (c = 1; ethanol), (+) FAB-MS: 311.

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. 5-10 mmol, approx. 0.5 ml) of acetonenol acetate is added. After 6-8 hours, a check by means of thin-layer chromatography shows almost complete conversion ¬ the 3-chloro compound. Small amounts of Δ-2-methanesulfonyloxy compound are present. The orange-brown DMF reaction solution is cooled to approx. 10 ° C. and, if smaller amounts (5-15%) of 3-hydroxy compound are formed, a corresponding amount of a solution of is added within 30 minutes at 0-10 ° C. Phosphorus trichloride in dry DMF too. The mixture is then warmed to room temperature and stirred for a further 3-4 hours at this temperature. Thereafter, a control by means of thin layer chromatography shows complete conversion to the 3-chloro compound. The orange-brown reaction solution is poured onto 300 g of ice and then extracted three times with 100 ml of ethyl acetate. The combined ethyl acetate phases are evaporated, the orange-brown, oily residue is dissolved in a little warm dichloromethane, filtered through silica gel and washed with dichloromethane. The yellow filtrate containing product is concentrated and crystallized after the addition of cyclohexane. 7-GD-2-allyloxycarbonylamino-2-phenyl-acetamido) -3-chloro-3-cephem-4-carboxylic acid benzhydric ester; FAB-MS: MH + = 618, R _f = 0.68 (toluene: ethyl acetate = 2: 1), mp. 199-200 ° C (from ethyl acetate / n-hexane).

Example 4: 1 g of 7- (2-phenyloxy-acetamido) -3-methanesulfonyloxy-3-cephem-4-carboxylic acid benzhydric ester (= starting material) in 6 ml of dichloromethane, 2 ml of n-propanol and 2 ml of concentrated hydrochloric acid stirred at 20 ° C. A semi-quantitative determination of the decomposition of the starting material is carried out after 24, 36 and 48 hours by thin layer chromatography. The following decomposition rates are determined by means of a series of dilutions and drops of 3, 5 or 10 μl of the reaction solution in comparison to an equally concentrated, but acid-free solution of the educt: after 24 hours 50-60% after 36 hours 75-80% after 48 hours 90-95%

Claims

Claims:

1. Process for the preparation of 7- (D-2-amino-2-phenylacetamido) -3-chloro-3-cephem-4-carboxylic acid of the formula I,

or a salt or hydrate, such as in particular the monohydrate thereof, characterized in that a compound of the formula H,

wherein R _{x is} a carboxyl protecting group, or the tautomeric 3-keto compound with a sulfonic acid chloride of the formula R ₂ -SO ₂ -Ci (III), wherein R _{2 is} methyl, trifluoromethyl, meta-nitro-phenyl, para-nitro- phenyl or para-methylphenyl is in a compound of the formula IV,

wherein R _Σ and R _{2 have} the meanings given above, converted, the compound of formula IV obtained with phosphorus pentachloride into a compound of formula V,

where R _! and R _{2 has} the meanings given above, or converts a salt thereof, which is subsequently reacted with a compound of the formula VI,

* (D) configuration

* (D) configuration

* (D) configuration

in which the 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 is converted into a salt and / or hydrate .

2. The method according to claim 1, wherein R_ ^ is diphenylmethyl, benzyl, 4-methoxy-benzyl, 4-nitro-benzyl, 2,2,2-trichloro-ethyl or tert-butyl

3. The method according to claim 1, wherein starting materials of the formulas II to VHI are used, wherein, if present in the corresponding starting material, R _{r is} diphenylmethyl, R _{2 is} methyl and R _{3 is} 2-propen-1-yl.

4. The method according to any one of claims 1-3, wherein the sulfonyloxy group R ₂ -SO ₂ -O- in the starting material of the formula VE is first hydrolyzed to hydroxy and then the compound of formula X thus obtained,

wherein the substituents have the meanings given above, chlorinated to the corresponding 3-chloro compound of the formula V-CH.

5. The method according to claim 4, wherein the hydrolysis to the compound of formula X with a mineral or sulfonic acid, sodium or potassium formate or sodium or Potassium acetate is carried out in dimethylformamide or a solvent mixture containing dimethylformamide.

6. The method according to claim 4 or 5, wherein the chlorination of the compound of formula X with phosphorus trichloride in dimethylformamide or a solvent mixture containing dimethylformamide is carried out.

7. The method according to any one of claims 1-3, wherein the conversion of a compound of formula VII into a compound of formula VIII with a quaternary phosphonium or ammonium chloride is carried out in the presence of lithium chloride.

8. The method according to any one of claims 1-7, wherein one starts from a compound of the formula IV prepared in any way and carries out the remaining process steps.

9. A process for the preparation of a compound of formula V

wherein R _{1 is} a carboxyl protecting group, and R _{2 is} methyl, trifluoromethyl, meta-nitro-phenyl, para-nitro-phenyl or para-methyl-phenyl, or an acid addition salt thereof, characterized in that a compound of formula IV ,

wherein R _j and R _{2 have} the meanings given above, dealt with phosphorus pentachloride and, if desired, an acid addition salt obtained in the free compound or converted to another acid addition salt or a free compound obtained is converted into an acid addition salt.

10. The method according to claim 9, wherein Ri is diphenylmethyl, benzyl, 4-methoxy-benzyl, 4-nitro-benzyl, 2,2,2-trichloro-ethyl or tert-butyl

11. A compound of the formula VE,

^lc (D) configuration

where R _{λ is} a carboxyl protecting group, R _{2 is} methyl, trifluoromethyl, meta-nitro-phenyl, para-nitro-phenyl or para-methyl-phenyl and R ₃ 2-propen-l-yl, 3-phenyl-2-propen-l- yl or 2-trichloromethyl-prop-2-yl mean.

12. A compound of formula VE according to claim 11, wherein R _{x is} diphenylmethyl, benzyl, 4-methoxy-benzyl, 4-nitro-benzyl, 2,2,2-trichloro-ethyl or tert-butyl

13. A compound of formula VE according to claim 11, wherein R _{x is} diphenylmethyl, R _{2 is} methyl and R _{3 is} 2-propen-l-yl.

14. A compound of the formula VTE,

* (D) configuration wherein R _{x is} a carboxyl protecting group and R _{3 is} 2-propen-l-yl, 3-phenyl-2-propen-l-yl or 2-trichloromethyl-prop-2-yl.

15. A compound according to claim 14, wherein R _{j is} diphenylmethyl, benzyl, 4-methoxy-benzyl, 4-nitro-benzyl, 2,2,2-trichloro-ethyl or tert. Butyl means.

16. A compound of formula X

wherein R _{l is} a carboxyl protecting group and R _{3 is} 2-propen-l-yl, 3-phenyl-2-propen-l-yl or 2-trichloromethyl-prop-2-yl.

17. A compound of formula X according to claim 16, wherein Rj diphenylmethyl, benzyl, 4-methoxy-benzyl, 4-nitro-benzyl, 2,2,2-trichloro-ethyl or tert. Butyl means.

18. A compound of formula VI

* (D) configuration

wherein R _{3 is} 3-phenyl-2-propen-l-yl or 2-trichloromethyl-prop-2-yl