GB2146332A

GB2146332A - 2-Oxoimino acetic acid amides and their use in producing cephalosporin antibiotics

Info

Publication number: GB2146332A
Application number: GB08422785A
Authority: GB
Inventors: Gerd Ascher; Urban Gruntz
Original assignee: Biochemie GmbH
Current assignee: Sandoz GmbH
Priority date: 1983-09-12
Filing date: 1984-09-10
Publication date: 1985-04-17
Also published as: IT8448827A1; JPH0733776A; FR2551757A1; IT1199187B; CH666037A5; IT8448798A0; JPH0662592B2; DE3433147A1; IT8448827A0; JPS6084293A; GB8422785D0; BE900556A; FR2551757B1; JPH0776226B2; GB2146332B

Abstract

2-Oximinoacetic acid amides of formula II <IMAGE> are reacted with 7-amino-3-cephem-4-carboxylic acid derivatives to produce cephalosporins of formula I <IMAGE> wherein R1 is H, alkyl, acyl, carboxyalkyl, phenalkyl or carbalkoxyalkyl R2 is H or carboxy-protecting R3 is 5-membered N-, O- or S- containing ring optionally substituted with amino or azido R4 is H, acetoxy or carbamoyloxy or -S-Het.

Description

SPECIFICATION New process for producing cephalosporin antibiotics The invention relates to a new process for the production of synisomers of formula I,

in which R, is hydrogen, alkyl, phenalkyl, carbalkoxyalkyl, acyl or carboxyalkyl, R2 is hydrogen, pivaloyloxymethyl or a carboxy protecting group, R3 is a 5-membered nitrogen-, oxygen- or suplphur-containing heterocyclic ring, which may be substituted by amino or azido, and R4 is hydrogen, acetoxy, carbamoyloxy or -S-Y, in which Y is a heterocyclic ring which may be substituted.

The compounds of formula I represent a known class of valuable cephalosporin antibiotics disclosed for example in W. German DOS 2,223,375; 2,556,736; 2,702,501; 2,707,565; 2,715,385; 2,992,036; as well as numerous other patent and other publications. This class of antibiotics is characterised by the presence of an oximino group in the 7-acylamido side-chain attached to the cephalosporin nucleus. It is known that this oximino group may have the syn of anti configuration but that the syn isomers are preferred.

The heterocyclic ring in R3 preferably contains one or more oxygen and/or sulphur atoms as heteroatom(s). It may, however, additionally contain one or more nitrogen hetero atoms.

Suitable heterocyclic rings include furyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl and oxadiazolyl.

The heterocyclic ring may as indicated be unsubstituted or substituted by amino or azido, preferably amino. Preferably the heterocyclic ring of R3 is thiazolyl and this is preferably substituted by amino.

A particular preferred group of synisomers is that of formula la,

in which R1, R2 and R4 are as defined above.

In these structures, the radical R4 can be hydrogen. It may also be carbamoyloxy. It is, however, preferably, acetoxy or -S-Y. Suitable heterocyclic groups which Y may represent are well-known, for example from the numerous publications referred to above. Preferred heterocyclic rings include thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl or triazinyl. These heterocyclic rings may be unsubstituted or substituted, for example up to three times. Suitable substituents include C, 4alkyl, C, 4alkoxy, halogen, trihalo-C,4 alkyl, hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-(C1 4)alkylamino, carboxymethyl, carbamoylmethyl, sulphomethyl and methoxycarbonylamino.Heterocyclic moieties indicated in the prior art to be particularly preferred include tetrazolyl, in particular 1-methyí-1 H-tetrazol-5-yl, and triazinyl, in particular 1,2,5, 6-tetrahydro-2-methy1-5, 6-dioxo-as-triazin-3-yl. 2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-astriazin-3-yl or 1 ,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl. Preferably R4 is acetoxy, 1 methyl- 1 H-tetrazol-5-yl, or 2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yI.

In these structures, R, may be hydrogen. It may also be Alkyl preferably C, 2alkyl, in particular methyl. Suitable phenalkyl groups include phen-C14-alkyl, particularly benzyl. R, may also be carbalkoxyalkyl, for example carb(C, 2)alkoxy(C, 4)aíkyl, in particular carb (C, 4)alkoxyme- thyl, e.g. carbethoxymethyl. Suitable acyl radicals include C2 salkanyol or, C14alkoxycarbonyl. R, may also be carboxyalkyl, in particular carboxy-C,4alkyl, e.g. carboxymethyl.

As is well known in the cephalosporin field, the compounds may be in the form of free acids (R2 = H) or of salts, for example alkali or alkaline earth metal salts, preferably alkali metal salts, such as sodium salts. Alternatively, the compounds may be in the form of esters, e.g. the pivaloyloxymethyl ester. (R2 = pivaloyloxymethyl). Other carboxy protecting groups which R2 may represent are well-known and include acetoxymethyl, 1-acetoxyethyl, 1-ethoxycarbonyl- oxyethyl, 5-indanoyl or, preferably, hexanoylmethyl, phthalidyl,carbethoxymethoxymethyl or 3 carbethoxy-1 -acetonyl.

Particularly preferred compounds are synisomers having the formula lb,

in which R4 is acetoxy, 1-methyl-1 H-tetrazol-5-yl, or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as triazin-3-yl, and salts thereof.

The compounds of formula lb are the products known as Cefotaxim (R4 = acetoxy), SCE-1365 (R4, = 1-methyl-1 H-tetrazol-5-yl) and Ceftriaxone (Ro13-9904) (R4 = 2,5-dihydro-6hydroxy-2-methyl-5-oxo-as-triazin-3-yl), in the form of sodium salts (Cefotaxim and SCE-1 365) or the disodium salt (Ceftriaxone).

As indicated, the compounds of formula I are generally known, and various methods for their production have been proposed. One such method involves acylation of the corresponding 7aminocephalosporanic acid derivative, which may be protected, with a reactive derivative of the acid of formula A,

in which R, and R3 are as defined above.

The various reactive derivatives that have been proposed include activated esters. For the production of the synisomers of formula I the reactive derivatives of the acid of formula A should also be in synisomeric form in as high a purity as possible, and the synconfiguration should as far as possible be unaffected by the subsequent steps, in particular the acylation step.

Various reactive derivatives that have previously been proposed, in particular activated esters, suffer from the disadvantage that the synconfiguration is somewhat unstable during production or use thus leading to increased formation of the antiisomer and consequential reduction of the yields of the desired synisomers.

A further difficulty that arises in the production of the preferred compounds of formula la is that in practice it is essential to protect the amino substituent in the thiazolyl ring of the sidechain prior to the acylation step. Otherwise competing reactions can occur leading to greatly reduced yields of the final products. The introduction, however, of suitable protecting groups prior to the acylation step, and their subsequent removal is in general accompanied by reduced yield and purity of the desired final product and not insubstantial additional reaction time.

energy, effort and cost.

The present invention provides a method by which the desired synisomers may be obtained in high purity and yield; in particular, the synisomers of formula la may be obtained in high purity and yield without the necessity to protect the amino substituent in the thiazolyl ring of the side-chain.

More particularly, the present invention provides a process for the production of synisomers of formula I and salts thereof, comprising reacting a synisomer of formula II,

in which R, is as defined above, R3 is a 5-membered nitrogen-, oxygen- or sulphur-containing heterocyclic ring, which may be substituted by amino, protected amino, or azido, and

represents a 5- or 6-membered heterocyclic ring, which may contain in addition to the nitrogen atom, one or two further hetero atoms, selected from oxygen, nitrogen and sulphur, and which may be substituted or fused to a benzene ring which may itself be substituted, with a compound of formula III.

in which R2 and R4 are as defined above, and R5 is hydrogen or an amino protecting group, where required, disprotecting the resulting product, and, where required, converting a resulting product in which R2 is hydrogen into a salt thereof or vice versa.

The process is suitably carried out in an inert organic solvent, such as a chlorinated hydrocarbon, e.g. methylene dichloride, or an ether, e.g. ethyl acetate, or in a mixture of such solvents with water. The reaction temperature is suitably from - 40" to + 60"C, in particular - 15" to + 25"C, especially 0 to 20"C, and the reaction time may typically vary from + to 48 hours. The reactants of formula II or Ill may conveniently be employed in stoichiometric quantities. Alternatively, an excess of up to 25% of the compound of formula II is conveniently employed.

As indicated, the production of compounds in which R2 is hydrogen (as well as salts thereof), the carboxylic acid group in the starting material of formula II, is conveniently protected.

Suitable protecting groups are well known and include not only those referred to above as possible significances for R2, but also silyl ester protecting groups, in particular the trimethylsilyl protecting groups, which may for example be introduced by reaction of the free acid with N,0bis-trimethylsilylacetamide.

The 7-amino group of the starting material of formula Ill may, as indicated, also be protected.

Again, suitable protecting groups are well-known and include for example the trimethylsilyl group, which may for example be introduced simultaneously when protecting the carboxylic acid group.

When R3 in the desired product contains an amino substituent in the heterocyclic ring, the corresponding starting material of formula li may have this amino substituent in free or in protected form. As discussed, in general protection is not necessary. If protection is nevertheless desired, this may be accomplished in conventional manner, suitable protecting groups being well-known.

After reaction of the compounds of Formula II and Ill, any subsequent disprotection steps may be effected in conventional manner. Likewise, interconversion of the free acid (R2 = H) and salts thereof may be accomplished in well-known manner.

The resulting products may be isolated and purified using conventional techniques.

The process of the invention thus employs as reactive derivatives of the acid of formula A, heterocyclic thioesters. It has been surprisingly found that these amides may be prepared and employed with virtually complete control of the geometry of the -C = N- synconfiguration.

Furthermore, it has surprisingly been found that when there is an amino group in the heterocyclic ring of these am ides, the esters are not self-reacting. Accordingly, protection of this amino group in the subsequent acylation is not essential (although of course not ruled out if for any reason desired).

The synisomers of formula 11 are novel and also form part of the present invention. The nature of the

ring therein is not critical, the preferred compounds being determined by such factors as ease of formation and availability of starting materials. Preferably, however, this signifies 2-thioxo pyridin- 1 -yl-2-thioxo-benzothiazolin-3-yl. The preferred compounds of formula II correspond to the preferred end products, namely syn isomers of formula Ila and llb,

in which R and

are as defined above.

In accordance with the invention, the syrrisomers of formula II may be prepared by appropriately amidating a synisomer of formula IV,

in which R, and R3 are as defined above.

The amidation may for example be accomplished by reaction with a compound of formula V,

in which the two groups

are the same and signify a 5- or 6-membered heterocyclic ring, which may contain in addition to the nitrogen atom, one or two further hetero atoms selected from oxygen, nitrogen or sulphur, and which may be substituted or fused to a benzene ring which may itself be substituted.

The reaction is suitably effected in the presence of a tri-(lower alkyl)- or tri(aryl) phosphine or phosphite, in particular triphenylphosphine. The reaction temperature may for example be from - 30' to + 50'C, in particular - 20" to + 25"C, preferably - 5' to + 5'C. The reaction is suitably effected in an inert, non-hydroxy-contaning-, organic solvent, for example a chlorinated hydrocarbon, such as methylene chloride. Where a compound of formula II in which R3 is a protected-amino-substituted heterocycle is desired, the amino protecting group may of course be introduced prior to or subsequent to the reaction.

The synisomers of formula I are as indicated in general known antibiotics. In particular they are indicated for use as antibacterial agents as indicated in vitro in the series dilution test, at a concentration for example of 0.01 to 50 jug/ml, and in vivo in the mouse at a dosage of for example from 0.1 to 100 mg/kg of animal body weight, against a wide variety of strains, such as Staphylococcus aureus, Streptococcus pyrogenes, Streptococcus fecalis, E. coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Shigella dysenteria, Shigella sonnei, Shigella flexneri, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella penumoniae, Serrata marcescens, Slamonella Heidelberg, Salmonella typhimurium, Salmonella enteritidis and Nesseria gonorrhoae.

The compounds are therefore useful as bacterially active antibiotics. For this usage, the dosage will of course vary depending on the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from 1 to 6 g conveniently given in divided dosages of from about 0.25 to about 3 g of the compound two to four times daily, or in sustained release form.

The compounds in which R2 is hydrogen may be employed in free acid form or in the form of their physiologically acceptable salts, which salt forms have the same order of activity as the free acid forms. Suitable salt forms include alkali metal and alkaline earth metal salt forms, in particular alkali metal, such as sodium salt forms. The compounds may be admixed with conventional pharmaceutically acceptable diluents and carriers and optionally other excipients and administered in such forms as capsules or injectable preparations.

The process and intermediates II of the invention are similar to processes and intermediates in European Patent Publication No. 37380. It is however surprising firstly that the present intermediates II can be produced and isolated in substantially pure form by substantially the same process as described in said European patent application, and secondly that these inermediates, being amides, will act effectively as reactive derivatives of the acids of formula IV in order to provide the end products of formula I.

The present invention particular relates to the use of substantially pure compounds of formula II or at least mixtures (for example with compounds of formula II of said European patent application) in which the present cmpounds II predominate, to the extent of at least 60, preferably 70, more preferably 80, most preferably 90%, in the process to produce compounds The following Examples in which all temperatures are in degrees Centigrade, illustrate the invention.

EXAMPLE 1: 7- (f2-(2-AminoThiazol-4-yi)-2yn- methoximinojacetamido) cephalosporanic acid (Cefotaxim) 2.72 g of 7-Aminocephalosporanic acid are suspended in 50 ml of methylene dichloride. 3.5 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 of 3-[2-(2-aminothiazol-4-yl)-2-syn-methoximino acetyl]benzthiazolin-2-thion are added and the mixture is stirred for 1 5 hours at 35-40". The solution is then extracted with 2 g of KHCO3 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 phase separation, the aqueous phase is saturated with (NH4)2SO4.The organic phase is washed twice with 100 ml of NaCI solution and evaporated to dryness. The crystalline residue is shaken with 100 ml of diethyl ether, filtered and washed with ether. The title product is obtained. M.P. 205 (decomp.). Yield 4.2 g; 92% of theory based on pure syn isomer.

EXAMPLE 2: 7- 6[2-(2-Aminothiazol-4-yl)-2-syn- methoximino]acetamido} -13- (f2, 5-dihydro-6-hy droxy-2-methyl-5-oxo-a, s-triazin-3-yl)-thio]methyl) -3-cephem-4-carboxylic acid (Ceftriaxon) In manner analogous to Example 1 employing appropriate starting materials in approximately equivalent amounts, the heading compound may be obtained in pure form, M.P. 120 (decomp.).

EXAMPLE 3: 7- (r2-Aminothiazol-4-yl)-2-syn-methoximinoj-acetamido) -3-(1-methyl- H-tetrazo 1- 5- yl)-thiomethyl-3-cephem-4-carboxylic acid (SCE 1365) In manner analogous to that of Example 1, employing appropriate starting materials in approximately equivalent amounts, the heading compound may be obtained.

EXAMPLE 4: 3-[2-(2-Aminothiazol-4-yl)-2-syn-methoximino-acetyl]benzthiazolin-2-thione (Compound II) 10.1 g of 2-(2-Aminothiazol-4-yl) 2-syn-methoximinoacetic acid, 20.3 g of bis-(benzthiazol-2yl)disulphide and 0.16 9 of benzyltributylammonium bromide are suspended under an absolutely dry nitrogen atmosphere at room temperature in 100 ml of absolute acetone. The suspension is then mixed at - 5 portionwise with 16 9 of triphenylphosphine. 5.1 g of triethylamine are then added dropwise over 30 minutes, whereupon the temperature rises to room temperature. The mixture is stirred for 3 hours at room temperature, cooled to - 5, filtered and washed with ice-cold acetone. Recrystallisation of the crude product from tetrahydrofuran and drying gives a gold-yellow product, decomp. pt. 274.

IR-Spectrum: 3400(st), 3240(m,s), 3100(m), 2940(w), 1722(st), 1600(vst), 1533(vst), 1460(vst), 1370(st), 1315, 1305(vst,sh), 1280(st), 1230(vst), 1185(w), 1150(st,sh), 1120(w), 1080(m), 1045(m), 1020(w), 985(st), 940(m), 880(w), 865(vw), 850(w), 840(w), 790(w), 750, 740(st,sh).

Claims

1. A process for the production of syn-isomers of formula I,

in which R1 is hydrogen, alkyl, phenalkyl, carbalkoxyalkyl, acyl or carboxyalkyl, R2 is hydrogen, pivaloyloxymethyl or a carboxy protecting group, R3 is a 5-membered nitrogen-, oxygen- of sulphur-containing heterocyclic ring, which may be substituted by amino or azido, and R4 is hydrogen, acetoxy, carbamoyloxy or -S-Y, in which Y is a heterocyclic ring which may be substituted:: and pharmaceutically acceptable salts thereof, which comprises reacting a synisomer of formula 11,

in which R, is as defined above, R3 is a 5-membered nitrogen-, oxygen- or sulphur-containing heterocyclic ring, which may be substituted by amino or azido, and

represents a 5- or 6-membered heterocyclic ring, which may contain in addition to the nitrogen atom, one or two further hetero atoms, selected from oxygen, nitrogen and sulphur, and which may be substituted or fused to a benzene ring which may itself be substituted, with a compound of formula Ill.

2. A process according to Claim 1 for the production of syrrisomers of formula Ia,

in which R1, R2 and R4 are as defined and pharmaceutically acceptable salts thereof.

3. A process according to Claim 1, for the production of synisomers of formula Ib,

in which R4 is acetoxy, 1-methyl-1 H-tetrazol-5-yl, or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as triazin-3-yl, and pharmaceutically acceptable salts thereof.

4. A process according to any one of Claims 1 to 3, in which, in the syrsisomer of formula II,

is 3-thioxo-benzthiazolin-2-yl.

5. A process for the production of a syrrisomer of formula II, stated in Claim 1, comprising appropriately amidating a syrpisomer of formula IV,

in which R1 and R3 are as defined in Claim 1.

6. A process according to Claim 5, in which the esterification is effected by reaction with a compound of formula V,

in which the two groups

7. Syrrisomers of formula II, stated in Claim 1.

8. Syrrisomers of Claim 7 of formula Ila,

in which R1 and

are as defined in Claim 1.

9. Syrrisomers of Claim 7 of formula llb,

in which

is as defined in Claim 1.

10. The compound of Claim 7 which is 3-[2-(2-aminothiazol-4-yl)-2-synmethoximinoacel]- benzthiazolin-2-thione.