Process for preparing cephalosporin compounds

Abstract: There is described a process for the preparation of compounds of general formula (I) (wherein R¹ represents an amino or protected amino group, R² is hydrogen or a carboxyl blocking group, B is S or S → O and the dotted line indicates that the compound is a ceph-2-em or ceph-3-em compound) or a corresponding compound having at the 4-position a group of formula -COOR³ (where R³ is a carboxyl blocking group) and having an associated anion A ⊖ , and salts and esters thereof which comprises reacting a compound of formula (II)

Description: This invention relates to improvements in or relating to cephalosporins. More particularly it relates to processes for the preparation of the cephalosporin antibiotic ceftazidime. Ceftazidime ((6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-oxyimino)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboyylate) is a valuable antibiotic having broad spectrum activity, in particular, unusually high activity against gram-negative organisms, including Pseudomonas organisms, as described in UK Patent Specification No. 2025398. Semi-synthetic cephalosporins may conventionally be prepared by the acylation of an appropriate 7-aminocephalosporin with a compound serving to introduce a preformed 7-substituent, or by modification at the 3-position, for example the reaction of a 3-acyloxymethyl-or 3-halomethylcephalosporin with a nucleophile, to introduce the desired 3-substituent. These general processes are described in U.K. Patent No. 2025398 for the preparation of ceftazidime. We have now devised a process for the preparation of ceftazidime, and salts and protected derivatives thereof in which the 2-carboxyprop-2-yl moiety in the 7-substituent of ceftazidime is introduced as the last major chemical step in the synthesis, by an etherification reaction. According to one aspect of the invention, therefore, we provide a process for the preparation of compounds of general formula (I) (wherein R¹ represents an amino or protected amino group, R² is hydrogen or a carboxyl blocking group, B is S or S→O and the dotted line indicates that the compound is a ceph-2-em or ceph-3-em compound) or a corresponding compound having at the 4-position a group of formula -COOR³ (where R³ is a carboxyl blocking group) and having an associated anion A ⊖ , and salts and esters thereof which comprises reacting a compound of formula (II) (wherein R¹, B and the dotted line are as defined above) or a corresponding compound having a group of formula COOR³ at the 4-position (wherein R³ is as defined above) together with an associated anion A ⊖ , or a salt thereof, with an agent serving to introduce the etherifying group Such an agent being a compound of formula (III) (where Y is a leaving group, in particular a halogen e.g. chloro, bromo or iodo; sulphate; or a hydrocarbylsulphonyloxy, e.g. methanesulphonyloxy or p-toluenesulphonyloxy group, and R² is as defined above) in the presence of a base selected from an alkali metal carbonate (e.g. sodium, potassium or lithium carbonate), hydride (e.g. sodium, potassium or lithium t-butoxide), dialkylamide (e.g. lithium diisopropylamide) or a disilylamide. The anion A ⊖ which may be associated with a compound of formula (I) or (II) may be derived from an organic or inorganic acid, such as an alkyl-, aryl- or aralkyl- carboxylic or -sulphonic acid or a mineral acid. Examples of such acids include formic, trifluoroacetic, methanesulphonic, p-toluene-sulphonic, hydrochloric, hydrochloric, hydrobromic, phosphoric and sulphuric acids. The etherification reaction may be effected in an organic medium, conveniently at a temperature in the range -50 to +100°C, preferably 0-50°C. Examples of reaction media which may be employed include ethers, e.g. cyclic ethers such as tetrahydrofuran or dioxan or acylic ethers such as diethyl ether or diglyme; amides such as N,N-dimethylformamide, N,N-dimethylacetamide or hexamethylphosphoramide; lower ketones such as acetone; nitriles such as acetonitrile; nitroalkanes such as nitromethane; sulphoxides such as dimethylsulphoxide; sulphones such as sulpholane; hydrocarbons, such as benzene or hexane; and esters such as ethyl acetate, as well as mixtures of such solvents. The reaction medium may contain some water, but is preferably anhydrous. The etherification is carried out in the presence of an agent serving to generate an anion from the hydroxime function, and/or as an acid binding agent, i.e. a base selected from the group listed above. If the compound of formula (II) is employed in the form of an acid addition salt, the base should be present in sufficient quantity to neutralize rapidly the acid in question. The etherification reaction may be effected in a single liquid-phase or a two liquid phase reaction medium. When a two-phase system is used the reaction is generally carried out in the presence of the base e.g. an alkali metal carbonate or an alkali metal hydroxide together with a phase transfer reagent, such as a crown ether (i.e. a macrocyclic polyether). The crown ether may contain for example a number of ethyleneoxy units, which may be substituted, e.g. by phenyl or cyclohexyl groups joined to form a ring. Examples of such a reagent include 18-crown-6 (containing 6 ethyleneoxy units) e.g. dibenzo-or dicyclohexyl 18-crown-6, and 15-crown-5 (containing 5-ethyleneoxy units). A preferred two-phase medium is water/dichloromethane. The etherification reaction may be followed where necessary and/or desired by conversion of the compound of formula (I) initially obtained into a different compound of formula (I), for example by means of one or more of the following reactions:- (i) reduction of a compound wherein B is S→O to a compound wherein B is S; (ii) conversion of a Δ²-isomer into a Δ³-isomer; (iii) removal of any carboxyl-blocking or amino protecting groups; and (iv) formation of a non-toxic salt or a non-toxic metabolically labile ester. These reactions may be effected by conventional methods, and in any convenient order. Thus, if desired, a Δ²- cephalosporin obtained in accordance with the process of the invention may be converted into the corresponding Δ³- derivative by, for example, treatment of the Δ²- ester with a base, such as pyridine or triethylamine. A ceph-2-em reaction product may also be oxidised to yield the corresponding ceph-3-em 1-oxide, for example by reaction with a peracid, e.g. peracetic or m-chloroperbenzoic acid; the resulting sulphoxide may subsequently be reduced as described hereinafter to yield the corresponding ceph-3-em sulphide. Where a compound of formula (I) is obtained in which B is S→O this may, if desired, be converted into the corresponding sulphide by, for example, reduction of the corresponding acyloxysulphonium or alkoxysulphonium salt prepared in situ by reaction with e.g. acetyl chloride in the case of an acetoxysulphonium salt, reduction being effected by, for example, sodium dithionite or by iodide ion as in a solution of potassium iodide in a solvent e.g. acetic acid, acetone, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide. The reaction may be effected at a temperature of from -20° to +50°C. Carboxyl blocking groups which may be present in the compounds of general formula (I) or any of the intermediates described herein may be any of the conventional carboxyl protecting groups known in the art, a list of representative protected carboxyl groups being included in British Patent No. 1399086. The carboxyl blocking group may be for example the residue of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol preferably containing 1-20 carbon atoms. Thus, carboxyl blocking groups which may conveniently be employed include aryl lower alkyl groups, such as p-methoxybenzyl, p-nitrobenzyl and diphenylmethyl; lower alkyl groups such as t-butyl; lower haloalkyl groups such as 2,2,2-trichloroethyl; and tri(lower alkyl) silyl groups such as trimethylsilyl. An amino protecting group present in the compounds of formula (I) or intermediates therefor is conveniently a group which may be readily removed at an appropriate stage in the reaction sequence, for example an aralkyl group, such as triphenylmethyl, or an acyl group, such as formyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isoamyloxycarbonyl or chloroacetyl. Any carboxyl blocking or amino protecting group present in the compound of formula (I) may be removed, if desired, by any appropriate methods known in the art. Suitable methods for removing carboxyl protecting groups include acid or base hydrolysis and reduction. Thus, for example, diphenylmethyl and t-butyl carboxyl blocking groups may conveniently be removed by acid hydrolysis. A p-nitrobenzyl group may conveniently be cleaved by reduction, effected for example by zinc and acetic acid, or sodium dithionite or iodide ion in water conveniently in the presence of a water-miscible solvent such as acetone, tetrahydrofuran, dioxan, dimethylformamide or dimethylacetamide. Methods of removing amino protecting groups are also well known in the art. A trityl group may for example be removed using an optionally halogenated carboxylic acid e.g. acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid or using a mineral acid, e.g. hydrochloric acid or mixtures of such acids, preferably in the presence of a protic solvent such as water. Acid-labile acyl amino-protecting groups, e.g. formyl, t-butoxycarbonyl or isoamyloxycarbonyl may also be removed, where appropriate under the conditions described above for a trityl group. Other acyl amino-protecting groups e.g. 2,2,2-trichloroethoxycarbonyl may be removed, for example, by reduction. It will be appreciated that the use of amino protecting and carboxyl blocking groups is well known in the art. Relevant examples of such use are given in e.g. Theodora W. Greene "Protective Groups in Organic Synthesis" (Wiley-Interscience, New York 1981), and J.F.W. McOmie, "Protective Groups in Organic Chemistry" (Plenum Press, London 1973). Salt derivatives of the compounds of formula (I) include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium and magnesium salts); ammonium salts; amino acid salts (e.g. lysine and arginine salts); organic base salts (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglucosamine salts), and acid addition salts, e.g. formed with a mineral acid such as hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid, or with an organic acid such as formic, acetic, trifluoroacetic, methanesulphonic or p-toluenesulphonic acid. The salts may also be in the form of resinates formed with, for example, a polystyrene resin or cross-linked polystyrene divinylbenzene copolymer resin containing amino or quaternary amino groups or sulphonic acid groups, or with a resin containing carboxyl groups, e.g. a polyacrylic acid resin. It will be appreciated that when the compound of formula (I) prepared according to the invention is ceftazidime itself, salt and ester derivatives should be non-toxic and physiologically acceptable, such as are described in UK Patent Specification No. 2025398. Base salts of formula (I) may be formed by reacting an acid of formula (I) with an appropriate base. Thus, for example, sodium or potassium salts may be prepared using the respective 2-ethylhexanoate or hydrogen carbonate salt. Acid addition salts may be prepared by reacting a compound of formula (I) with the appropriate acid. The reaction product may be separated from the reaction mixture, which may contain, for example, unchanged cephalosporin starting material and other substances, by a variety of processes including solvent extraction, recrystallisation, ionophoresis, column chromatography and use of ion-exchangers (for example by chromatography on ion-exchange resins) or macroreticular resins. Where a compound of formula (I) is obtained as a mixture of isomers, the syn isomer may be obtained by, for example, conventional methods such as crystallisation or chromatography. A preferred embodiment of the invention relates to the preparation of ceftazidime or a protected derivative thereof, i.e., the compound of formula (I) in which R¹ represents an amino or protected amino group, R² represents hydrogen or an esterifying group, B represents S, and the dotted line represents a ceph-3-em compound, followed if desired by removal of the protecting and/or esterifying groups, optionally in situ . A compound of formula (II) may be prepared, for example, by acylating a compound of formula (IV) (wherein B and the dotted line are as defined above) or a corresponding compound having at the 4-position a group -COOR³, and an associated anion A ⊖ (where R³ and A ⊖ are as defined above) or a salt e.g. an acid addition salt or N-silyl derivative thereof, with an acid of formula (V) (wherein R¹ has the meaning defined for formula (I) and R⁴ represents hydrogen or a hydroxyl protecting group), or an acylating agent corresponding thereto, followed by removal of the group R⁴, when this represents a hydroxyl protecting group. The hydroxy protecting group will preferably be one which is readily removed under mild conditions and examples of such groups include acyl groups such as t-butoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl and benzyloxycarbonyl; silyl groups such as trimethylsilyl; a tetrahydropyranyl or methoxytetrahydropyranyl group; or a methoxyisopropyl group. The acylation reaction may be effected by conventional methods, for example as described in British Patent No. 2025398. Thus acylating agents corresponding to the acid of formula (V) which may be employed include acid halides, e.g. acid chlorides or bromides, activated esters, and symmetrical or mixed anhydrides. Acylation may also be effected using an acid of formula (V), in which case a condensing agent such as N,N'-dicyclohexylcarbodiimide, carbonyldiimidazole or N-ethyl-5-phenylisoxazolium perchlorate, is desirably present in the reaction mixture. Alternatively, an activated form of an acid of formula (V) for use in the acylation reaction may be formed in situ by reacting an acid of formula (V) with a solution or suspension of a halogenating agent preformed by adding a carbonyl halide, e.g. oxalyl chloride or phosgene or a phosphoryl halide, e.g. phosphorus oxychloride, to a solvent such as a halogenated hydrocarbon, e.g. methylene chloride, containing a lower acyl tertiary amide such as N,N-dimethylformamide. The acylation reaction may conveniently be effected in a suitable solvent or mixture of solvents, such as an alcohol e.g. aqueous ethanol or aqueous industrial methylated spirit at temperatures from -50 to +50°C, if desired in the presence of an acid binding agent. Compounds of formula (IV) may be prepared as described in British Patent Specification No. 2,025,398 and compounds of formula (V) may be prepared as described in British Patent Specification No. 1,587,941. The invention will now be more particularly described in the following Examples. All temperatures are in °C. Example 1 [6R,7R]-7-[(Z)-2-(2-methoxyprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate (Z)-2-Hydroxyimino-2-(2-triphenylmethylaminothiazol-4-yl)-acetic acid (2.15 g) was suspended in methylene chloride (20 ml) and 2-methoxypropene (2 ml) was added. After 25 minutes the solution was evaporated and the residue was redissolved in methylene chloride. Further 2-methoxypropene (2 ml) was added and after 20 minutes, the solution was evaporated to a gum. This gum was dissolved in methylene chloride (5 ml) and added to the Vilsmeier reagent (prepared by mixing at -20° oxalyl chloride (0.47 ml) and N,N-dimethylformamide (0.47 ml)) at -20° with stirring and under nitrogen. The solution was stirred with ice-water cooling for five minutes and then recooled to -20°. It was then added to a solution of (6R,7R)-7-amino-3-(1-pyridiniummethyl)-ceph-3-em-4-carboxylate dihydrochloride dihydrate (1.89 g) in water (3.8 ml) and industrial methylated spirits (15 ml) containing triethylamine (2.9 ml) at -10°. The resulting solution was allowed to warm to 23° over one hour and it was then partitioned between water and methylene chloride. The aqueous layer was extracted with more methylene chloride and the combined organic layers were washed with water. The organic solution was dried with magnesium sulphate and evaporated to a gum which was triturated with diethyl ether to give the title compound (2.34 g) [α] 21 / D -34.8° ( c 1.08, DMSO). Example 2 [6R,7R]-7-[(Z)-2-Hydroxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate The product of Example 1 (1.55 g) was suspended in acetone (5 ml) with stirring and concentrated hydrochloric acid (0.16 ml) in water (1.75 ml) was added. After one hour, further hydrochloric acid (0.16 ml) was added. After a further 30 minutes, the solution was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The aqueous layer was extracted with more methylene chloride and the combined organic layers were washed with water, dried with magnesium sulphate and evaporated to a foam (1.01 g), [α] 21 / D -31.8° ( c 0.75, DMSO). Example 3 (6R,7R)-7-[(Z)-2-(2-t-Butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate The product of Example 2 (100 mg) was dissolved in N,N-dimethylformamide (2 ml) with stirring and t-butyl 2-bromo-2-methylpropionate (45 mg) was added followed by potassium carbonate (50 mg). After stirring at 23° for three hours, the title compound had been formed as demonstrated by high pressure liquid chromatographic comparison with a standard sample, whose spectroscopic characteristics resembled those of the product obtained in Example 4(a) of UK Patent No. 2025398. The product of this Example may be deprotected for example by the methods described in UK Patent No. 2025398 and UK Patent No. 2063871.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, NL, SE A process for the preparation of compounds of general formula (I) (wherein R¹ represents an amino or protected amino group, R² is hydrogen or a carboxyl blocking group, B is S or S→O and the dotted line indicates that the compound is a ceph-2-em or ceph-3-em compound) or a corresponding compound having at the 4-position a group of formula -COOR³ (where R³ is a carboxyl blocking group) and having an associated anion A ⊖ , and salts and esters thereof which comprises reacting a compound of formula (II) (wherein R¹, B and the dotted line are as defined above) or a corresponding compound having a group of formula COOR³ at the 4-position (wherein R³ is as defined above) together with an associated anion A ⊖ , or a salt thereof, with a compound of formula (III) wherein Y is a leaving group and R² is as defined above in the presence of a base selected from an alkali metal carbonate, hydride, alkoxide, dialkylamide or a disilylamide. A process as claimed in claim 1 wherein reaction is carried out in an ether, amide, ketone, nitrile, nitroalkane, sulphoxide, sulphone, hydrocarbon or ester, or a mixture of two or more thereof. A process as claimed in claim 1 wherein reaction is carried out in a two liquid phase reaction medium in the presence of a phase transfer reagent. A process as claimed in any of claims 1 to 3 wherein the reaction is followed, where necessary or desired, by conversion of the compound of formula (I) initially formed into a different compound of formula (I) by means of one or more of the following reactions (i) reduction of a compound wherein B is S→O to a compound wherein B is S; (ii) conversion of a Δ²-isomer into a Δ³-isomer; (iii) removal of any carboxyl-blocking or amino protecting groups; and (iv) formation of a non-toxic salt or a non-toxic metabolically labile ester. A process as claimed in any of claims 1 to 4 wherein, in the compound of formula (I) obtained, R¹ represents an amino group, R² represents a hydrogen atom or esterifying group, the dotted line represents a ceph-3-em compound and B is S. (6R,7R)-7-[(Z)-2-(2-methoxyprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate. (6R,7R)-7-[(Z)-2-Hydroxyimino-2-(2-triphenylmethylaminothiazol-4-yl)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate. Claims for the following Contracting State : AT A process for the preparation of compounds of general formula (I) (wherein R¹ represents an amino or protected amino group, R² is hydrogen or a carboxyl blocking group, B is S or S→O and the dotted line indicates that the compound is a ceph-2-em or ceph-3-em compound) or a corresponding compound having at the 4-position a group of formula -COOR³ (where R³ is a carboxyl blocking group) and having an associated anion A ⊖ , and salts and esters thereof which comprises reacting a compound of formula (II) (wherein R¹, B and the dotted line are as defined above) or a corresponding compound having a group of formula COOR³ at the 4-position (wherein R³ is as defined above) together with an associated anion A ⊖ , or a salt thereof, with a compound of formula (III) wherein Y is a leaving group and R² is as defined above in the presence of a base selected from an alkali metal carbonate, hydride, alkoxide, dialkylamide or a disilylamide. A process as claimed in claim 1 wherein reaction is carried out in an ether, amide, ketone, nitrile, nitroalkane, sulphoxide, sulphone, hydrocarbon or ester, or a mixture of two or more thereof. A process as claimed in claim 1 wherein reaction is carried out in a two liquid phase reaction medium in the presence of a phase transfer reagent. A process as claimed in any of claims 1 to 3 wherein the reaction is followed, where necessary or desired, by conversion of the compound of formula (I) initially formed into a different compound of formula (I) by means of one or more of the following reactions (i) reduction of a compound wherein B is S→O to a compound wherein B is S; (ii) conversion of a Δ²-isomer into a Δ³-isomer; (iii) removal of any carboxyl-blocking or amino protecting groups; and (iv) formation of a non-toxic salt or a non-toxic metabolically labile ester. A process as claimed in any of claims 1 to 4 wherein, in the compound of formula (I) obtained, R¹ represents an amino group, R² represents a hydrogen atom or esterifying group, the dotted line represents a ceph-3-em compound and B is S. A process as claimed in claim 1 wherein the compound of formula (II) is (6R,7R)-7-[(Z)-2-Hydroxyimino -2-(2-triphenyl-methylaminothiazol-4-yl)acetamido]-3-(1-pyridinium-methyl)ceph-3-em-4-carboxylate. A process as claimed in claim 6 wherein the compound of formula (II) defined therein is prepared by the removal of the hydroxyl protecting group from (6R,7R)-7-[(Z)-2-(2-methoxyprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol -4-yl)acetamido]-3-(1-pyridiniummethyl)ceph-3-em-4-carboxylate.

Inventors: LOOKER BRIAN EDGAR, LOOKER, BRIAN EDGAR
Applicants: GLAXO GROUP LTD, GLAXO GROUP LIMITED
Application year: 1985
Main classification: C07D501
IPC codes: A61P31, C07D501, A61K31