FI72122B - FRAMEWORK FOR FRAMSTAELLNING AV DERIVAT AV AVFALOSPORIN - Google Patents

Description

The present invention relates to a novel process for the preparation of a 7β-acylamino-3-heterocyclylthiomethyl-7ar-methoxy-3-cephem-4-carboxylic acid derivative of the formula: Iβ-acylamino-3-heterocyclylthiomethyl-7-coxem-4-carboxylic acid derivative: f- (II J-, O Y CH2SR3 15 C00R2 2 (where R represents a hydrogen atom; 3 R represents a substituted 1H-tetrazol-5-yl group; and 20 represents a conventional acyl group in cephaloporin chemistry, such as a chloroacetyl or cyanomethylthioacetyl group) and .

25 These products are valuable antibiotics.

The invention of cefamycin C, which can be obtained by fermentation of various microorganisms, has led to the invention of a wide variety of cephalosporin derivatives which, unlike the first invented cephalosporin derivatives, have a methoxy group (and not a hydrogen atom) at the 7a position.

Cefamycin C itself is 7β- (D-5-amino-5-carboxivaleramido) -3-carbamoyl-3-oxymethyl-7α-methoxy-3-cephem-4-carboxylic acid. To convert this compound to some particularly useful antibiotics, it is necessary to convert the carbamoyloxymethyl group at the 3-position to a heterocyclylthio-2,712,212 methyl group and replace the 5-amino-5-carboxyvaleryl group at the 78-position with a variety of other acyl groups. In general, such a method is carried out by the following steps: (a) protecting the amino group 7 in the 3-side chain; (b) converting the carbamoyloxy group at the 3-position in the side chain to a heterocyclylthio group; (C) esterifying the carboxyl groups at the 4-position and 78-side chain; and (d) subjecting the product to an exchange acylation reaction to replace the protected 5-amino-5-carboxyvaleryl group on the 7B side chain with another desired acyl group.

15

The last step in particular causes difficulties. For example, Japanese Patent Application Kokai (i.e., made public) No. 105 687/75 describes exchange acylation using a molecular sieve or zeolite, Japanese Patent Application Kokai No. 85 386/75 describes exchange acylation after silylation, and Japanese Patent Application No. Kokai No. 20 723/80 explains exchange acylation without any such silylation or catalyst. When performing these exchange acylations, it is necessary to protect the carboxy group of the cefamycin derivative. Japanese Patent Application Kokai No. 20 723/80 explains that 25 preferred protecting groups are a phenacyl group and a benzhydryl group. After the reaction, these protecting groups must be removed. One way to remove the phenacyl protecting group is to react the protected compound with the potassium or sodium salt of thiophenol; however, if there is a heterocyclylthiomethyl group in the 3-position of the cefamycin derivative, this removal reaction results in the transfer of the double bond in the cephem backbone, causing a very high proportion of 2-cephem isomers in the final product. When zinc and acid are used to remove the phenacyl protecting group, significant amounts of the corresponding exomethylene compound are formed. Thus, the yield of the desired 3-cephem-4-carboxylic acid compound is much lower in these cases.

'35 In addition, it is difficult to produce benzhydryl ester on a commercial scale.

72122 1 We have now surprisingly found that the desired product can be obtained in good yields if the carboxy groups are protected by conversion to alkoxymethyl or aralkyloxymethyl ester groups and the exchange acylation reaction is carried out using a halogenated hydrocarbon solvent containing a certain amount of water together with an epoxide acid scavenger.

The process according to the invention is thus characterized in that 10 (a) is reacted with a compound of formula (II): R 1 s chich2) 3cohh-rr 1 im COOR20 ^ ch2sr3 C00R2a 2a R represents a lower alkoxymethyl group, a lower alkoxycarbonyl-alkoxymethyl group or an aralkyloxymethyl group, and 3 R is as defined above) with a compound of formula (III): R 5 to X (III) (wherein R 5 is as defined above and X is a halogen atom) ), in the presence of a halogenated hydrocarbon solvent containing at least 35 moles of water per mole of compound of formula (II) and in the presence of an epoxide of formula (IV): 4 72122 R4 C \ ~ ^ CH2 (Π) Χ (Γ 5 4 (where R represents an aryloxyalkyl group), a compound of formula (I) wherein R represents a lower alkoxymethyl group, a lower alkoxycarbonylalkoxymethyl group or an aralkyl a yloxymethyl group, 10; (b) optionally treating the product of step (a) with an acid to prepare a compound of formula (I) 2 wherein R represents a hydrogen atom; and (c) optionally forming a salt from the product of step (b) to produce a pharmaceutically acceptable salt thereof.

The compounds of formula (II) which are the starting materials in the process of this invention can be obtained by protecting the amino group in the side chain at the 7-position of cefamycin C, converting the carbamoyloxymethyl group in the 3-position to the desired heterocyclylthiomethyl group and protecting the carboxy groups in the 4-position and side In the 7-position with an alkyloxymethyl group (wherein the alkyl group may be unsubstituted or substituted by alkoxycarbonyl or aryl).

The process of this invention allows the groups at the 3- and 7-positions of cefamycin C to be continuously converted to other desired groups to produce compounds with more potent antibacterial properties. The method of the present invention thus has considerable industrial value. For example, 7S-cyanomethylthioacetamido-7a-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid

formula (I) wherein R represents a cyanomethylthioacetyl group, R

2 represents a 1-methyl-1H-tetrazol-5-yl group and R represents a hydrogen atom, is a very valuable antibacterial agent, as described in GB 1 449 420.

The group represented by R121212 in the compound of formula (II) is a protected amino group. The protecting group may be: an acyl group (R 1 represents an acyl amido group) such as benzoyl, p-nitrobenzoyl, 3,5-dinitrobenzoyl, toluoyl, p-chlorobenzoyl, 3,5-dichlorobenzoyl, a bromobenzoyl, pt-butylbenzoyl, or acetyl group; an alkoxycarbonyl group (R 1 is an alkoxycarbonylamido) such as a methoxycarbonyl, ethoxycarbonyl, isopropoxocarbonyl, or iso-butoxycarbonyl group; an aralkyloxycarbonyl group (R 1 is Aralyloxycarbonylamido) such as benzyloxycarbonyl or p-10 nitrobenzyloxycarbonyl; or a phthaloyl group (R * is phthaloylamino). Particularly preferred amino protecting groups are p-nitrobenzoyl and p-chlorobenzoyl groups.

3

Preferred groups represented by R in the compounds of formulas (I) and (II) are the 1-methyl-1H-tetrazol-5-yl group, the 1-dimethylaminoethyl-1H-tetrazol-5-yl group, the 5-methyl- 1,3,4-thiadiazol-2-yl-2 group and 1-methyl-1H-1,2,3-triazol-5-yl group. Preferred groups represented by R and 2a in compounds 2 of formulas (I) and (II) (except for the hydrogen atom represented by R) are methoxymethyl, ethoxy-20-carbonylmethoxymethyl, ethoxymethyl, benzyloxymethyl, p-nitrobenzyloxymethyl- and p-chlorobenzyloxymethyl groups. Of these, methoxymethyl and benzyloxymethyl groups are preferred.

The esterification of the carboxy groups at the 4-position and the side chain at the 73-position can be carried out in cefamycin C starting material or a derivative thereof by conventional means, for example by mixing the starting material with chloromethyl alkyl ether or chloromethyl aralkyl ether and then adding a base to the resulting mixture.

In the process of this invention, exchange acylation at the 73-position of the acyl group in a compound of formula (II) can be readily accomplished by contacting a compound of formula (II) with a compound of formula (III) in the presence of an epoxide of formula (IV) in an aqueous halogenated hydrocarbon solvent. Suitable halogenated hydrocarbon solvents include methylene chloride, chloroform, 1,2-dichloroethane and trichlorethylene, most preferably 1,2-dichloroethane. The amount of water in the solvent is at least 1 mole per mole of the compound of formula (II), preferably 1.0 to 3.0 moles and most preferably 1.2 to 2.5 moles per mole of the compound of formula (II).

Suitable epoxides of formula (IV) for use as acid scavengers in the process of the invention include propylene oxide, butylene oxide, styrene oxide, 1,2-epoxy-3-phenoxypropane, 1,2-epoxy-3- (p-tolyloxy) propane and 1,2-epoxy-3- (p-chlorophenoxy) propane, preferably 1,2-epoxy-3-phenoxypropane. The amount of the epoxide (IV) to be used is preferably 3 to 7 moles per mole of the compound of the formula (11).

The process according to the invention is generally applicable to all acyl groups represented by a compound of formula (I) and the nature of the group represented by R 1 is limited only in so far as the nature of the acyl groups desired for the final product can be limited.

Thus, the examples of such acyl groups provided herein are intended as a model only and are not intended to be limiting in any way. Examples of suitable groups which R 1 may represent in the compounds of formulas (I) and (II) include thienylacetyl, chloroacetyl, dichloroacetyl, bromoacetyl, dibromoacetyl and cyanomethylthioacetyl. Preferred halogen atoms represented by X in the compounds of formula (III) are chlorine and bromine atoms. The amount of the acid halide (III) to be used is preferably 1 to 15 moles, most preferably 5 to 12 moles per mole of the compound of formula (II).

Step (a) of the process according to the invention is preferably carried out at a temperature of 50-100 ° C. The progress of the reaction can be monitored by thin layer chromatography methods. The time required for the reaction varies from one to 30 ti, depending on the temperature and the reactants, but usually the reaction is completed within 10 minutes to 10 hours.

After step (a) of the exchange acylation reaction of the process of the invention, the resulting alkoxymethyl (or substituted alkoxymethyl) ester group at the 4-position can be readily converted to the free acid by distilling off the solvent, dissolving the residue in a water-miscible solvent (e.g. methanol, ethanol, acetone). , tetrahydrofuran or li 7 72122 L of acetonitrile) and then treating the resulting solution with an acid The acid used is preferably a mineral acid such as hydrochloric acid or sulfuric acid, preferably 0.2 to 1.0 grams per gram of product of step (a). preferably at a temperature of 0 to 30 ° C and the time required for the reaction generally ranges from 10 minutes to 2 hours.

2

At the end of the reaction, the compound of formula (I) in which R is a hydrogen atom can be recovered from the reaction medium by conventional means.

For example, the solvent can be removed by distillation from the reaction mixture and diisopropyl ether can be added to the residue. If desired, in addition to diisopropyl ether, a suitable base (e.g., dicyclohexylamine, dimethylbenzylamine, picoline, or lutidine) may be added to the mixture to isolate the desired compound as crystals.

15

The product of the present invention may contain as a by-product acylaminoadipic acid, which is not always removed by the procedure proposed above. Thus, it is advantageous to further treat the product of the process of the invention to remove this by-product. This further processing may take place before, after or instead of the recovery procedure proposed above. Following further work-up following the recovery procedure proposed above, the crystals of the compound of formula (I) are first dissolved in a suitable organic solvent such as acetone. The reaction mixture or solution in an organic solvent is then contacted with methanol in the presence of an acid to convert the acylaminoadipic acid (by-product) to its dimethyl ester. The desired compound of formula (I) is then isolated as a basic aqueous solution while the dimethyl ester of acylaminoadipic acid remains in the organic phase. The aqueous solution is then acidified and the compound of formula (I), if R is a hydrogen atom, is extracted as an organic solvent (such as ethyl acetate) to give the compound in substantially pure form. The solvent is then preferably removed by distillation from this extract and diisopropyl ether and optionally a suitable base (as described above) are added to recover the desired compound as crystals.

The product can then, if necessary, be further purified by various known methods, for example by column or thin layer chromatography.

35 2 72122 1 The compound of formula (I) wherein R is a hydrogen atom may, if necessary, be converted into pharmaceutically acceptable salts by conventional salt-forming methods. Suitable salts include metal salts (e.g., lithium, sodium, potassium, calcium, or magnesium salts), ammonium salts, and salts of organic amines (e.g., cyclohexylammonium, diisopropylammonium, or triethylammonium salts).

2

Compounds of formula (I) in which R represents a lower alkoxymethyl group, a lower alkoxycarbonylalkoxymethyl group or an Aral-10 cyloxymethyl group may, if desired, be used directly, without intermediate purification, as intermediates for the preparation of other esters by known transesterification methods.

The process of the present invention is further illustrated by the following non-limiting examples.

Example 1

Preparation of di (methoxymethyl) ester 20 g of 7β- (D-5-carboxy-5-p-nitrobenzoylaminovaleramido) -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem The ethyl acetate adduct of 4-carboxylic acid was dissolved in 75 ml of acetone. The resulting solution was cooled to 3 ° C with an ice bath, and 0.7 ml of chloro-methyl ether was added thereto. A solution of 1.16 ml of triethylamine in 10 ml of acetone was added dropwise to the mixture, with stirring, over 20 minutes. After this addition, the mixture was further stirred for 20 minutes, after which the precipitated triethylamine hydrochloride was removed by filtration. The precipitate was washed with acetone. The filtrate and washings were combined and concentrated by evaporation under reduced pressure. To the resulting oily residue was added 50 ml of ethyl acetate, and the mixture was stirred at room temperature for about 15 minutes, whereupon a little more triethylamine hydrochloride precipitated. The precipitate was removed by filtration and washed with ethyl acetate. The filtrate and washings were combined and evaporated to dryness under reduced pressure to give 3.2 g of the starting di (methoxymethyl) ester.

1 Exchange acylation 72122 9

All of the di (methoxymethyl) ester obtained above was dissolved in 90 ml of 1,2-dichloroethane with 120 mg of water. To the resulting solution were added 3.2 ml of 1,2-epoxy-3-phenoxypropane and 4.5 ml of monochloroacetyl chloride. The mixture was then refluxed for 3 hours with stirring, after which it was concentrated by evaporation under reduced pressure. To the residue was added 60 ml of diisopropyl ether, and the mixture was stirred. The supernatant solution was removed by decantation.

To the oily residue were added 60 ml of acetone and 3.0 ml of concentrated hydrochloric acid, and then the mixture was stirred at room temperature for 45 minutes. At the end of this time, 20 ml of methanol were added and the solution was further stirred for 1 hour, after which it was concentrated by evaporation under reduced pressure. To the residue were added 40 ml of water and 50 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 6.5-7.0 by adding powdered sodium bicarbonate with stirring. The ethyl acetate layer was then separated and extracted with aqueous sodium chloride solution. The extract was combined with the aqueous layer. To the combined aqueous solution was added 50 ml of ethyl acetate, and then the pH of the mixture was adjusted to 1.8 by adding hydrochloric acid. The mixture was shaken and then the ethyl acetate layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the extracts were added to the ethyl acetate layer. The combined ethyl acetate solution was concentrated by evaporation under reduced pressure. Diisopropyl ether was then added to the residue and the mixture was stirred to give a powder which was collected by filtration, washed with diisopropyl ether and dried to give 1.5 g of 7β-chloroacetamido-7α-methoxy-3- (1-methyl-1H -tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.

NMR Spectrum (deuteroacetone) ppm: 3.5 (3H, singlet); 3.68 (2H, singlet); 3.98 (3H, singlet); Δ 4.42 (2H, broad singlet); 5.08 (1H, singlet).

72122 1 Example 2 32 g of di (methoxymethyl) ester, synthesized as described in Example 1, were dissolved in 90 ml of 1,2-dichloroethane with 5,100 mg of water. To the resulting solution were added 3.0 ml of 1,2-epoxy-3- (p-tolyloxy) propane and 5.0 ml of cyanomethylthioacetyl chloride. The mixture was refluxed with stirring for 2 hours, then worked up as described in Example 1 to give 1.4 g of 7S-cyanomethylthioacetamido-7α-methoxy-3- (1-methyl-1H-tetrazol-10-yl) thiomethyl -3-cephem-4-carboxylic acid.

Nuclear Magnetic Resonance Spectrum (deuteroacetone) ppm: 3.50 (3H, singlet); 3.60 (2H, singlet); 3.5-3.7 (2H, quartet); 3.70 (2H, singlet); 3.98 (3H, singlet); 4.3-4.6 (2H, quartet); Δ 5.10 (1H, singlet).

Example 3

Preparation of di (benzyloxymethyl) ester 25 g 2.6-7- (D-5-carboxy-5-p-nitrobenzoylamino-valeramido) -7a-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl Ethyl acetate addition of 3-cephem-4-carboxylic acid was dissolved in 50 ml of acetone, and then 1.21 g of benzyl chloromethyl ether was added to the solution with stirring, in an ice bath. To the solution thus obtained was added dropwise, over 30 minutes, 1 ml of triethylamine dissolved in 10 ml of acetone. After this addition, the mixture was further stirred for 30 minutes and then treated as in the preparation of the di (methoxymethyl) ester in Example 1 to give 3.12 g of the starting di (benzyloxymethyl) ester, 11.11, 72122 l.

All of the di (benzyloxymethyl) ester obtained above was dissolved in 90 ml of 1,2-dichloroethane with 100 mg of water. To the resulting solution were added 2.6 ml of 1,2-epoxy-3-phenoxypropane and 3.9 ml of monochloroacetyl chloride, and the mixture was refluxed for 3 hours. The reaction mixture was then treated as described in Example 1 to give 1.1 g of 76-chloroacetamido-7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid having 10 same NMR spectrum as the product of Example 1.

15 20 25 30 35

Claims (15)

A process for the preparation of a 78-acylamino-3-hetorocyclylthiomethyl-7cx-methoxy-3-cephem-4-carboxylic acid derivative of formula (I): 5 AND ·, 1 R-UH T X where R is a hydrogen atom; R 3 is a substituted 1H-tetrazol-5-yl group; and R 2 salts thereof, characterized in that (a) a compound of formula (II): R1. CH (CH2l3CONH-ir Ί (EL) COOR20 QJ-H \ ^^ CH2SR3 C00R2a (where R4 represents an acylamido group, an alkoxycarborylamido group, an aralkyloxycarbonylamido group or a phthaloylate amino group; lower alkoxycarbonylalkoxymethyl group or an aralkyloxymethyl group; and R 3 is the one defined above) is reacted with a compound of formula (III): R 5 - X (111) 10 (where R 1 is the above defined and X represents a halogen atom) in the presence of a compound of formula (IV): C »(E | τ 4 (where R represents an aryloxyalkyl group) and in a halogenated hydrocarbon solvent containing at least one mole of water per mole of the compound of formula (II) ), for the preparation of a compound of formula (I) wherein R 2a represents any of the groups to which R refers; (b) the product of step (a) is optionally reacted with an acid 2 to produce a compound of formula (I) I) where R represents a hydrogen atom and (c) a site is formed choice free of the product of step (b) to produce a pharmaceutically acceptable site thereof. 1 Patent claim A process according to claim 1, characterized in that R is a 1-methyl-1H-tetratsol-5-yl group. 3. A process according to claim 1 or 2, characterized in that R is a methoxymethyl or benzyloxymethyl group. 35 4. A process according to any one of claims 1-3, characterized in that the amount of water is 1-3 moles per mole of the compound of formula (II). li