FR2551757A1 - NOVEL PROCESS FOR THE PREPARATION OF ANTIBIOTICS OF THE CEPHALOSPORINE TYPE - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS A PROCESS FOR THE PREPARATION OF KNOWN DERIVATIVES OF 2-OXIMINO-ACETAMIDO-3-CEPHEME-4-CARBOXYLIC ACID, INCLUDING ACYLATION OF 7-AMINO-3-CEPHEME-4- ACID DERIVATIVES CARBOXYL WITH NEW 2-OXIMINOACETAMIDES, AS WELL AS THESE AMIDS AND THEIR PREPARATION.

Description

The object of the present invention is a new one.

  process for the preparation of syn isomers of formula I

/

N / R

IF)

R 3-C-CO-1

NCH 2 R 4

  Wherein R 1 is hydrogen, alkyl, phenylalkyl, alkoxycarbonylalkyl, acyl or carboxyalkyl, R 2 is hydrogen, pivaloyloxymethyl or a carboxy protecting group, R 3 is a 5-membered heterocyclic group, linkages containing nitrogen, oxygen or sulfur, optionally substituted by an amino or azido group, and R 4 represents hydrogen, an acetoxy, carbamoyloxy or -SY group, wherein Y is a heterocyclic radical optionally substituted. The compounds of formula I represent a known class of valuable cephalosporin antibiotics described for example in DOS of the Federal Republic of Germany Nos. 2,223,375, 2,556,736, 2,702,501, 2,707,565, 2,715,385. , 2,992,036 and in many other patents and publications This class of antibiotics is characterized by the presence of an oximino group

  on the 7-acylamido side chain attached to the cephalosporin nucleus It is known that this oximino group may have the syn or anti configuration but that the syn isomers are preferred.

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  The heterocyclic moiety represented by R 3 preferably contains one or more oxygen and / or sulfur atoms as hetero atoms. However, it may additionally contain 1 or more nitrogen atoms. Suitable heterocyclic radicals include furyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl and oxadiazolyl As indicated, the heterocyclic residue may be unsubstituted or substituted by an amino or azido group, preferably an amino group R 3 is preferably a group

  thiazolyl, preferably substituted by an amino group.

  A particularly preferred group of syn isomers is that of the formula ## STR1 ##

H 12 N '1 CH R

s 24

COOR 2

  wherein R 1, R 2 and R 4 are as defined above.

  In these structures, the symbol R 4 can represent

  Hydrogen It can also represent a carbamoyloxy group.

  However, it is preferably acetoxy or -S-Y.

  The appropriate heterocyclic groups which Y may represent are known, for example from the many publications mentioned above. The preferred heterocyclic radicals include thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, triazolylpyridyl, purinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl or triazinyl These heterocyclic residues may be unsubstituted or may carry 1, 2 or 3 substituents. Suitable substituents include C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogens, trihalo-C 1 -C 4 alkyl, hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-C 1 -C 4 alkylamino, carboxymethyl, carbamoylmethyl, sulfomethyl and methoxycarbonylamino groups. The heterocyclic radicals indicated in the state of the art as being particularly preferred include the tetrazolyl group, in particular 1-methyl-1H-tetrazol-5-yl, and the triazinyl group,

  especially 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-astriazin-3-yl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-astriazine 3-yl or 1,4,5,6-tetrahydro-4-methyl-5,6-dioxoas-triazin-3-yl R 4 is preferably acetoxy, 1-methyl-1H-tetrazol-5-yl or 2,5dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl.

  In these structures, R 1 may represent hydrogen. It may also represent a C 1 -C 4 alkyl group, preferably a C 1 -C 2 alkyl group, in particular a methyl group. Suitable phenylalkyl groups include phenyl group. C 1 -C 4 alkyl, in particular the benzyl group R 1 may also represent an alkoxycarbonylalkyl group, for example a C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl group, in particular an (alkoxy) group; C 1 -C 4) carbonylmethyl, for example ethoxycarbonylmethyl Suitable acyl radicals include C 2 -C 5 alkanoyl or C 1 -C 4 alkoxycarbonyl R 1 may also be a carboxyalkyl group, particularly a group

  (carboxy) C 1 -C 4 alkyl, for example a carboxymethyl group.

  As is known in the field of cephalosporins, the compounds can be in the form of free acids (R 2 = H) or salts, for example alkaline salts or alkaline earth metals, preferably metal salts. The compounds may also be in the form of esters, for example a pivaloyloxymethyl ester (R 2 = pivaloyloxymethyl). Other protecting groups of the carboxy group that may be represented by R 2 are known and include acetoxymethyl, 1-acetoxyethyl, ethoxycarbonyloxyethyl, 5-indanoyl or preferably hexanoylmethyl, phthalidyl,

  ethoxycarbonylmethoxymethyl or 3-ethoxycarbonyl-1-acetonyl.

  Particularly preferred compounds are the syn isomers of formula Ib, OCH 3 N M S (Ib) C-CONH Hb

OOH

  wherein R'4 is acetoxy, 1-methyl-1H-tetrazol-5yl or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl,

and their salts.

  The compounds of formula Ib are the products known as

  Cefotaxime (R'4 = acetoxy), SCE-1365 (R'4 = 1-methyl-1H-tetrazol-5yl) and Ceftriaxone (Ro 13-9904) (R'4 = 2,5-dihydro-6-hydroxy) 2-methyl-5-oxo-astriazin-3-yl), in the form of sodium salts (Cefotaxime and SCE-1365) or disodium salt (Ceftriaxone).

  As already indicated, the compounds of formula I are generally known, and various methods have been proposed for their preparation. One of these processes involves the acylation of the corresponding derivative of aminocacephalosporanic acid, which can be protected, with a reactive derivative of the acid of formula A

N-OR (A)

R 3-C-COOH

  wherein R 1 and R 3 are as defined above;

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  The various reactive derivatives which have been proposed include activated esters. For the preparation of the syn isomers of formula I, the reactive derivatives of the acid of formula A must also be in the form of syn isomers with a purity as high as possible and the syn configuration should if possible not be affected by the subsequent steps, in particular by the acylation step. The various reactive derivatives which have been proposed previously, in particular the activated esters, have the disadvantage of having a syn specific configuration. little unstable during preparation or use which increases the formation of the anti isomer and consequently reduces the yield of the isomers

syn wanted.

  Another difficulty occurring in the preparation of the preferred compounds of formula Ia is that in practice it is necessary to protect the amino substituent on the thiazolyl ring of the side chain prior to the acylation step in the absence of such protection. however, the introduction of suitable protecting groups before the acylation step and their subsequent removal are generally accompanied by a loss of yield and purity of the product. final product desired and a significant increase in the reaction time, energy,

effort and costs.

  The present invention relates to a process according to which the desired syn isomers can be obtained with high purity and yield; the syn isomers of formula Ia can in particular be obtained with high purity and yield without the need to protect the amino substituent in the nucleus

thiazolyl of the side chain.

  The invention relates more particularly to a process for the preparation of syn isomers of formula I and their salts.

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  wherein a syn isomer of formula II is reacted

N OR 1

  (II) R'-C-CO-N Het S in which R 1 is as defined above, R '3 represents a 5-membered heterocyclic residue containing nitrogen, oxygen or sulfur, and optionally substituted with an amino, protected amino or azido group, and -N Het = N e e 'represents a 5- or 6-membered heterocyclic group which may contain in addition to the nitrogen atom, one or two other heteroatoms chosen from oxygen, nitrogen and sulfur, and which may be substituted or fused to an optionally substituted benzene ring, with a compound of formula III ## STR3 ## , CH 2 R 4

COOR 2

  wherein R 2 and R 4 are as defined above, and R 5 represents hydrogen or a protecting group of the amino group, if necessary the protecting group is removed in the resulting product, and, if necessary, transformed into a resulting product

  wherein R 2 represents hydrogen in a salt or vice versa.

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  The process is suitably carried out in an inert organic solvent such as a chlorinated hydrocarbon, for example methylene chloride or an ether, for example ethyl acetate, or in a mixture of such solvents with water. The reaction temperature is advantageously between -40 and + 60 ° C, in particular between -15 ° and + 25 ° C, especially between O and C, and the reaction time may vary usually between 1/2 and 48 hours. Formula II or III can be advantageously used in stoichiometric amounts. It may also be advantageous to use an excess of up to 25% of the

compound of formula II.

  As indicated, for the preparation of compounds in which R 2 represents hydrogen (as well as the salts of these compounds), it is advantageous to protect the carboxy group of the starting material of formula II. The appropriate protecting groups are known and do not include not just those mentioned above at

  reference title as the possible meanings of R 2, but also protective groups such as silyl esters, especially trimethylsilyl groups, which may for example be introduced by reaction of the free acid with N, O-bistrimethylsilylacetamide.

  As already indicated, the 7-amino group of the starting material of formula III can also be protected. Again, suitable protecting groups are known and include, for example, trimethylsilyl, which may for example be

  introduced simultaneously during the protection of the carboxy group.

  When in the desired product R 3 contains an amino substituent in the heterocyclic ring, the corresponding starting material of formula II may contain this amino substituent in free form or protected form. As already indicated, protection is generally not necessary. If, however, protection is desired, it may be carried out according to the usual methods,

  the appropriate protecting groups being known.

  After reaction of the compounds of formula II and III, any subsequent step to remove the protecting groups can be carried out according to the usual methods. The conversion of the free acid (R 2 = H) into its salts and vice versa can also be carried out.

  be carried out according to known methods.

  The resulting products can be isolated and purified

according to usual methods.

  The process of the invention thus uses, as reactive derivatives of the acid of formula A, heterocyclic thioesters. The Applicant has surprisingly found that these amides can be prepared and used with virtually complete control of the geometry of the syn-C configuration. In addition, it has surprisingly been found that when there is an amino group in the rest

  heterocyclic of these amides, the esters are not self-reactive.

  Protection of this amino group before subsequent acylation is therefore not essential (although it is not excluded if it proves to be

necessary for some reason).

  The syn isomers of formula II are new and are also not critical, the preferred compounds being determined by such factors as the ease of formation and the availability of the compounds. Starting materials However, it preferably means a 2-thioxo-pyridin-1-yl-2-thioxobenzothiazolin-3-yl group. The preferred compounds of formula II correspond to the preferred end compounds, namely the syn isomers of formulas I Ia and I Ib 30

N JOR 1

N C-CO-N Het, (I Ia) 2 S s

N, OCH 3

- ",, (I Ib) N t -C-CO-N Het,

  in which R1 and S are as defined above.

  According to the invention, the syn isomers of formula II can be suitably prepared by converting to amide a syn isomer of formula IV ## STR2 ##

  wherein R 1 and R'3 are as defined above.

  The conversion to amide can for example be carried out by reaction with a compound of formula V Hat C Hs S and

(V)

  in which the two Het C groups are identical and signify a 5- or 6-membered heterocyclic residue, which may contain in addition to the nitrogen atom, one or two other heteroatoms selected from oxygen, nitrogen or sulfur and which may be substituted or fused to an optionally substituted benzene ring. The reaction is suitably carried out in the presence of a tri- (lower alkyl) or tri (aryl) phosphine or a tri- (lower alkyl) or triaryl phosphite, in particular triphenylphosphine.

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  for example, between -30 and + 50 ° C., in particular between -20 ° C. and + 25 ° C., preferably between -5 ° and + 5 ° C. The reaction is suitably carried out in an organic solvent which is inert and free from hydroxyl groups, for example a chlorinated hydrocarbon such as methylene chloride When a compound of formula II is desired wherein R 3 is a group-substituted heterocycle

  protected amino, the protecting group of the amino group can naturally be introduced before or after the reaction.

  As indicated above, the syn isomers of formula I are generally known antibiotics. In particular, they are indicated as antibacterial agents as evidenced in in vitro tests, for example in series dilution tests, at a concentration of for example between 0.01 and 50 μg / ml, and in in vivo tests in mice at doses of, for example, 0.1 to 100 mg / kg, against a wide variety of strains such as Staphylococcus aureus, Streptococcus pyrogenes. Streptococcus faecalis, E Coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Shigella dysenteria, Shigella sonnei, Shigella flexneri, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella pneumoniae, Serrata marcescens, Salmonella Heidelberg, Salmonella typhimurium, Salmonella enteritidis and Nesseria gonorrhoae. The compounds are therefore useful as antibiotics active against bacteria For this use, the dose will vary naturally depending on the compound used, the mode of administration and the desired treatment. However, satisfactory results are generally obtained when the compounds are administered at a specific dose. a daily dose of between 1 and 6 g, preferably in divided doses of 2 to 4 times per day in the form of unit doses each containing from about 0.25 to about 3 g of

  active substance, or in delayed release form.

  The compounds in which R 2 represents hydrogen may be used in free acid form or in the form of a physiologically acceptable salt, these salts having the same order of activity as free acids. Suitable salts include metal salts alkali and alkaline earth metals, in particular alkali metals such as the sodium salt The compounds may be combined with usual pharmaceutically acceptable diluents or carriers and optionally other excipients; they can be administered in the form of

  capsules or injectable preparations.

  The process for the preparation of the compounds of the formula II and the compounds of the formula II are similar to those given in European Patent 37380. However, it is surprising firstly that the intermediates of the formula II can be produced and isolated in essentially pure form. according to a process substantially identical to that described in said European patent, and secondly that these amide intermediates act effectively as reactive derivatives of the acids of formula IV to provide the final products of formula I. The present invention relates to especially the use of essentially pure compounds of formula II or at least mixtures (for example with the compounds of formula II of said European patent) in which the compounds of formula II of the present invention predominate, in proportions of at least 60, preferably 70, more preferably 80, especially 90% in the process for the preparation of compounds I. The following examples illustrate the present invention

  without in any way limiting its scope In these examples, all temperatures are indicated in degrees Celsius.

  EXAMPLE 1 7-It-2- (2-aminothiazol-4-yl) -2-syn-methoximinol acetamido-3 cephalosporanic acid (Cefotaxime) 2.72 g of 7-aminocephalosporanic acid are suspended in 50 ml of chloride. 1.5 ml of N, O-bis- (trimethylsilyl) acetamide are added and the mixture is stirred at room temperature until a clear solution is obtained. 3.5 g of 3- (2- 2-aminothiazol-4-yl) -2-synmethoximinoacetylbenzothiazolin-2-thione and the mixture is stirred for 15 hours at a temperature between 35 and 40. The solution is then extracted with 2 g of KHCO 3 and 40 ml of water. and the phases are separated by filtration. The aqueous phase is extracted with a mixture of ethyl acetate / n-butanol (8/2) at pH 2 and before the separation of the phases, the aqueous phase is saturated with (NH 4 The organic phase is washed twice with 100 ml of a solution of Na C1 and evaporated to dryness. The crystalline residue is stirred with 100 ml of diethyl ether. It is filtered and washed with ether. The title compound F = 2050 (decomp) is obtained; yield 4.2 g; which corresponds to a theoretical yield of 92% in pure syn isomer. EXAMPLE 2: 7-amino-2- (2-aminothiazol-4-yl) -2-syn-methoximino) acetamido-3-fluo-2,5-dihydro-6-hydroxy-2-methyl-5-oxo, s-triazine-3 acid 3-Cephhma-4-carboxylic acid (Ceftriaxone) By proceeding in a manner analogous to that described in Example 1 and using the appropriate starting materials in approximately equivalent amounts, the compound of

  title in pure form; F = 120 (decomp).

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  EXAMPLE 3 7-i (2-Aminothiazol-4-yl) -2-syn-methoximinolacetamido-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid

(SCE 1365)

  By proceeding in a manner analogous to that described in Example 1, and using the appropriate starting materials in approximately equivalent amounts, the title compound is obtained. EXAMPLE 4: 3- [2- (2-Aminothiazol-4-yl) -2-syn-methoximino-acetyll] benzothiazolin-2-thione (Compound II) Under an absolutely anhydrous nitrogen atmosphere and at room temperature, the suspension is suspended. 10.1 g of 2- (2-aminothiazol-4-yl) -2-syn-methoximinoacetic acid, 20.3 g of bis (benzothiazol-2-yl) disulfide and 0.16 g of sodium bromide were added. benzyl tributylammonium in 100 ml of anhydrous acetone is then mixed in portions at -5 with 16 g of triphenylphosphine 5.1 g of triethylamine are then added dropwise over a period of minutes, after which the temperature increases to room temperature The mixture is stirred for 3 hours at room temperature, cooled to -5, filtered and washed with ice-cold acetone After recrystallization of the crude product from tetrahydrofuran and drying, a golden yellow product is obtained; decomposition point = 274. IR spectrum: 3400 (strong), 3240 (medium strong), 3100 (medium), 2940 (weak), 1722 (strong), 1600 (very strong), 1533 (very strong), 1460 (very strong), 1370 ( strong), 1315, 1305 (very strong, shoulder), 1280 (loud), 1230 (very loud), 1185 (weak), 1150 (loud, shoulder), 1120 (weak), 1080 (average), 1045 (medium) ), 1020 (low), 985 (high), 940 (medium), 880 (low), 865 (very low), 850 (low), 840 (low), 790

  (weak), 750, 740 (strong, shoulder).

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Claims (11)

  A process for the preparation of syn isomers of formula I "D ES (I) R 3-C-CO-NH 1 -; - 'CH 2 R 4   wherein R 1 is hydrogen, alkyl, phenylalkyl, alkoxycarbonylalkyl, acyl or carboxyalkyl, R 2 is hydrogen, pivaloyloxymethyl or a carboxy protecting group, R 3 is a 5-membered heterocyclic group, linkages containing nitrogen, oxygen or sulfur, optionally substituted by an amino or azido group, and R 4 represents hydrogen, an acetoxy, carbamoyloxy or -SY group, wherein Y is a heterocyclic radical optionally substituted, and their pharmaceutically acceptable salts, characterized in that a syn isomer of formula II is reacted N OR 1   RC-CO-N Het S in which R 1 is as defined above, R '3 represents a 5-membered heterocyclic residue containing nitrogen, oxygen or sulfur and optionally substituted by an amino or azido group and - Het represents a 5- or 6-membered heterocyclic group which may contain in addition to the nitrogen atom, one or two other heteroatoms selected from oxygen, nitrogen and sulfur, and which may be substituted or fused to an optionally substituted benzene ring with a compound of formula III 1 (III) Due "" N <C H 2 R 4 COOR 2   in which R 2 and R 4 are as defined above, and R 5 represents hydrogen or a protecting group of the amino group, if necessary the protective group is removed in the product   resulting, and, if appropriate, converting a resulting product wherein R 2 is hydrogen to a salt or vice versa.   A process according to claim 1, characterized in that the syn isomers of formula Ia OR 1 are prepared S N C-CON H <(Ia) H 2 N 52 O 7 SCHH 2 R 4 COOR 2   1A in which R 1, R 2 and R 4 have the meanings given to the   claim 1 and their pharmaceutically acceptable salts.   3. A process according to claim 1, characterized in that the syn isomers of the formula Ib JAE 3 N N -c "1 (Ib) H 2 N are prepared. 2 S   wherein R'4 is acetoxy, 1-methyl-1H-tetrazol-5yl or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl,   and their pharmaceutically acceptable salts.   A process according to any one of claims 1   at 3, characterized in that in the syn isomer of formula II, the   remaining N Het is the 3-thioxo-benzothiazolin-2-yl group. S   A process for the preparation of a syn isomer of formula II as specified in claim 1, characterized in that a syn isomer of formula IV is converted GOLD / (1 R-C-COOH (IV)   wherein R 1 and R'3 are as defined in claim 1, amide.   A process according to claim 5, characterized in that the amide conversion is carried out by reaction with a compound of formula V (see formula on next page) 17 2551757   Wherein the two Jetc groups are the same and signify a 5- or 6-membered heterocyclic residue, which may contain in addition to the nitrogen atom, one or two other heteroatoms selected from 1 oxygen, nitrogen or sulfur, and which may be substituted or condensed to an optionally substituted benzene ring.   The syn isomers of formula II according to claim 1.   The syn isomers according to claim 7, characterized in that they correspond to the formula I Ia, NJ OR / g-C ON Het (I Ia) H 2 N t S $ in which R 1 and -N Het, are As defined in claim 1, the syn isomers according to claim 7, characterized in that they correspond to the formula I Ib, Nr OCH 3 N -c ON Het (I Ib) H 2 N -SJ S   wherein -N Het a is as defined in claim 1.   S compound according to claim 7, characterized in   it is 3- [2- (2-aminothiazol-4-yl) -2-synmethinoximinoacetyl] benzothiazolin-2-thione.   The syn isomers of formula I OR 1 O OOR 2   in which R 1 to R 4 have the meanings given to the   claim 1 and their pharmaceutically acceptable salts, characterized in that they are obtained according to the process as specified in claim 1.