CH666037A5 - METHOD FOR PRODUCING CEPHALOSPORINE SYN ISOMERS. - Google Patents

Description

DESCRIPTION

The invention relates to processes for the production of cephalosporin syn isomers, the production of corresponding intermediates and new intermediates, according to claims 1 to 15.

The compounds of the formula I represent a known class of valuable cephalosporin antibiotics, as described, for example, in De-OS 2 223 375; 2,556,736; 2,702,501; 2,707,565; 2,715,385 and 2,992,036, and numerous other patents and publications. This class of antibiotics is characterized by the presence of an oximino group in the 7-acylamido side chain attached to the cephalosporin core. It is known that this oximino group can be in the syn or anti configuration, the compounds with the syn configuration being preferred.

The heterocyclic ring in Rj preferably contains one or more oxygen and / or sulfur atoms as the heteroatom (s). However, it can also contain one or more nitrogen atoms. Suitable heterocycles are, for example, furyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl and oxadiazolyl. The heterocycle can be unsubstituted or substituted by amino or azido, preferably by amino. The heterocycle of Rj is preferably thiazolyl, preferably substituted by amino.

A particularly preferred group of syn isomers is that of the formula Ia

IT "1

h i [^ "CO - NH -. - 3-. Ia

0 COOR2

wherein Ri, R2 and R4 have the meaning given in claim 1.

In these structures, Rt can be hydrogen. It can also be carbamoyloxy. But preferably it means acetoxy or -S-Y. Suitable heterocycles which Y can represent are known, for example from the numerous publications mentioned. Preferred heterocycles are, for example, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl and triazinyl. These heterocycles can be unsubstituted or, for example, up to three times substituted. Suitable substituents include (C1-4) alkyl, (Ci_4) alkoxy, halogen, trihalo (Ci ^ t) alkyl, hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di- (Ci_4) alkylamino, carboxymethyl , Carbamoylmethyl, sulfomethyl and methoxycarbonylamino. Heterocycles described as particularly preferred in the literature include tetrazolyl, in particular l-methyl-1H-tetrazol-5-yl, and triazinyl, in particular 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-astriazine 3-yl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl or l, 4,5,6-tetrahydro-4-methyl-5,6-dioxo- as-

5

10th

15

20th

25th

30th

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666 037

4th

triazin-3-yl. R.4 is preferably acetoxy, 1-methyl-1H-tetra-zol-5-yl-thio or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-thio .

In these structures, Ri can be hydrogen. It can also be (Ci ^) alkyl, preferably (Ci-2) alkyl, especially methyl. Suitable phenalkyl groups include phen- (Ci ^ t) alkyl, especially benzyl. R 1 can also be carbalkoxyalkyl, for example carb- (C1-2 alkoxy (Ci-4) alkyl, preferably carb- (Ci-4) alkoxymethyl, for example carbethoxymethyl. Suitable acyl groups include (C2-5) alkanoyl or (Ci ^ t) alk-oxycarbonyl. Ri can also mean carboxyalkyl, in particular carboxy (Ci ^ t) alkyl, for example carboxymethyl.

As is known in the field of cephalosporins, the compounds can be in the form of the free acids (R2 = H) or in the form of salts, for example alkali metal or alkaline earth metal salts, preferably alkali metal salts such as sodium salts. Furthermore, the compounds can also be in the form of esters, for example in the form of the pivaloyloxy methyl ester (R2 = pivaloyloxymethyl). Other carboxy protecting groups which R2 can represent are generally known and include acetoxymethyl, 1-acetoxyethyl, 1-ethoxycarbonyloxyethyl, 5-indanyl or preferably hexanoylmethyl, phthalidyl, carbethoxymethoxymethyl or 3-carbethoxy-1-acetonyl.

Syn isomers of the formula are particularly preferred

. / CH3 N

11 S, H C - CO - NH - .- ^ „Ifc

H2N ~ v. si- 'J CH2R4

0 COOH

wherein RJ is acetoxy, l-methyl-1H-tetrazol-5-yl-thio or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-thio, and their salts .

The compounds of the formula Ib are the known products cefotaxime (RJ = acetoxy), SCE-1365 (Ri = 1-methyl-1 H-tetrazol-5-yl-thio) and ceftriaxone (Ro 13-9904) (RJ = 2, 5-Dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-thio) in the form of their sodium salts (cefotaxime and SCE-1365) or their disodium salt (ceftriaxone).

As mentioned, the compounds of the formula I have been proposed in general. One of these methods involves the acylation of the corresponding, optionally protected 7-aminocephalosporanic acid derivative with a reactive derivative of the acid of the formula

• N.OR1

R3 - $ - COOH A

where Ri and Rs have the above meaning.

The various reactive derivatives proposed also include activated esters. To prepare syn isomers of the formula I, the reactive derivatives of the acid of the formula A should also be in the form of the syn isomers with the highest possible purity, and the syn configuration should as far as possible not be influenced by the further reaction steps, in particular not by the Acylation step. Various reactive derivatives hitherto proposed, in particular activated esters, have the disadvantage that the syn configuration is somewhat labile during their preparation and use, as a result of which the anti isomer is increasingly formed and the yield of the desired syn isomer is consequently reduced.

Another difficulty that arises in the preparation of the preferred compounds of formula Ia is that in practice the amino substituent in the thiazolyl ring of the side chain must be protected from acylation, since otherwise competitive reactions can occur, 5 which lead to severe reductions in the yield of the end product can. The introduction of protective groups before the acylation step and their subsequent cleavage causes or mostly reduced yields and purity of the desired end product and increases the reaction time, energy, effort and costs not insignificantly.

The present invention provides a process by which the desired syn isomers can be obtained in high yield and purity. In particular, the syn isomers of the formula Ia can be obtained in high yield and purity without the amino substituent in the thiazolyl ring of the side chain having to be protected.

The method according to claims 1 to 6 is suitably carried out in an inert organic solvent, e.g. in a chlorinated hydrocarbon, such as dichloromethane, or an ester, such as ethyl acetate, or in a mixture of such a solvent with water. The reaction temperature is suitably from -40 to +60 ° C, especially -15 to + 25 ° C and pre-25 advantageously 0 to 20 ° C, and the reaction time can vary between about Vi to 48 hours. The reactants of the formula II and III can be used in stoichiometric amounts. On the other hand, an excess of up to 25% of the compound of formula II can be used. 30 In the preparation of compounds in which R2 is hydrogen (as well as their salts), the carboxyl group in the starting product of the formula III can advantageously be protected. Suitable protecting groups are known and include not only the 35 possible meanings given for R2 above, but also silyl ester protecting groups, in particular the trimethylsilyl protecting group, which e.g. can be introduced by reaction of the free acid with N, 0-bistrimethylsilyl acetamide.

The 7-amino group of the starting material of formula 40 III can also be protected. Suitable protecting groups are known and include e.g. the trimethylsilyl group, which can be introduced simultaneously, for example, in protecting the carboxyl group.

If R3 contains an amino substituent in the heterocycle, 45 this amino substituent can be present in the corresponding starting material of formula II in free or protected form. As already stated, protection is generally not necessary. If protection is nevertheless desired, this can be achieved in a known manner. Suitable 50 protecting groups are generally known.

Any deprotection reactions can be carried out in a known manner. The conversion of the free acid form (Rz = H) into the salts and vice versa can also be carried out according to methods known per se. 55 The products obtained can be isolated and purified by known methods.

In the process according to the invention according to claims 1 to 6, heterocyclic amides are thus used as reactive derivatives of the acid of the formula A. It was surprisingly found that the production and use of these amides takes place under almost complete control of the -C = N-syn configuration. Furthermore, it was surprisingly found that if an amino group is present in the heterocycle of these amides, this is not self-reactive. Accordingly, protection of this amino group in the subsequent acylation is not necessary, but not excluded, if this is desired for another reason.

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666 037

The syn isomers of formula II are new. The type of ring

-N Hetf

V '

is not critical, the preferred compounds are determined by factors such as ease of manufacture and availability of the starting material. However, the ring is preferably 2-thioxopyrid-l-yl or in particular 2-thioxobenzothiazolin-3-yl. The preferred compounds of formula II correspond to the preferred end products, namely syn isomers, of formulas IIa and IIb

/ 0R1

N

II / \

■ C - CO - N Het.

VX

H2N

No

-! ' J

"-S—

IIa

/ 0ch3

n II

n -c - co h, nj, »!

2nd

ÎJ Het;

II p

IIb wherein Ri and

-N Het}

have the above meaning.

The process according to claims 7 to 9 is preferably carried out in the presence of a tri (lower alkyl) or tri (aryl) phosphine or phosphite, in particular triphenylphosphine. The reaction temperature can preferably be from -30 to +50 ° C, in particular -20 to + 25 ° C and advantageously -5 to +5 ° C. The process is suitably carried out in an inert, non-hydroxyl group-containing organic solvent, e.g. a chlorinated hydrocarbon such as dichloromethane. If a compound of the formula II is desired in which R7 is a heterocycle with a protected amino group, the amino protective group can of course be introduced before or after the reaction.

As already mentioned, the cephalosporin syn isomers of the formula I are generally known antibiotics. In particular, they are indicated for use as antibacterial agents, as evidenced by investigations in vitro with the serial dilution test, at a concentration of e.g. 0.01 to 50 ng / ml, and in vivo at a dose of 0.1 to 100 mg / kg body weight in mice against a variety of strains, e.g. from Staphylococcus aureus, Streptococcus pyoge-nes, Streptococcus faecalis, E. coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Shigella dysenteria, Shigella son-nei, Shigella flexneri, Alcaligenes faecalis, Klebsiata aerogeella nogensella nogensella nogens Salmonella Heidelberg, Salmonella typhimurium, Salmonella enteritidis and Nesseria gonorrhoae.

The compounds can therefore be used as antibacterial antibiotics. For this use, the dose to be administered depends on the compound used and the mode of administration and the type of treatment. Satisfactory results are obtained when a daily dose of about 1 to 6 g is administered, expediently administered in appropriately divided doses of 0.25 to 3 g two to four times a day or in the form of a sustained release.

The compounds in which R 2 is hydrogen can be used in the form of the free acids or their physiologically tolerable salts, the salts having the same activity in terms of size as the 5 free acids. Suitable salt forms include alkali and alkaline earth metal salts, preferably alkali metal salts, especially sodium salts. Conventional pharmaceutically acceptable diluents or carriers and optionally other excipients can be added to the compounds and administered in forms such as capsules or injectable agents.

The processes and intermediates II of the invention according to claims 1 to 15 are with processes and intermediates from EP Pubi. 37380 related. It is surprising, however, that firstly the present intermediates II can be prepared and isolated in largely pure form by the largely same method as described in EP 37380, and secondly that these intermediates as amides, as reactive derivatives 20 of the acids of the Formula IV can function effectively to deliver end products of Formula I.

The present invention relates in particular to the use of largely pure compounds of the formula II or else mixtures (for example with compounds of the formula II from 25 of EP Pubi. 37380) in which the present compounds II are up to at least 60%, in particular 70%, preferably 80% , especially 90% predominate, in the process for the preparation of compounds of formula I.

The following examples, in which all temperatures are in degrees Celsius, illustrate the invention.

Example 1: 7- [2- (2-aminothiazol-4-yl) -2-syn-methoxy-mino] acetamidocephalosporanic acid (cefotaxime)

35 2.72 g of 7-aminocephalosporanic acid are suspended in 50 ml of dichloromethane with 3.5 ml of N, 0-bistrimethylsilyl acetamide and stirring is continued at room temperature until a clear solution is obtained. Now 3.5 g of 3- [2- (2-aminothiazol-4-yl) -2-methoximino-acetyl] benzthiazolin-2-thione 40 are added and the suspension is stirred for a further 15 hours at 35-40 °. For working up, the bare solution is 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, 45 before the phase separation the aqueous phase is saturated with (NH4> S04. The organic phase is washed twice with 100 ml NaCl solution and then evaporated to dryness. The crystallized residue is stirred with 100 ml of ether, then suction filtered and washed with ether. 30 This gives the title compound. Yield: 4.2 g, ds 92% of theory of pure syn. Isomers.

Example 2: 7 - [[2- (2-aminothiazol-4-yl) -2-syn-methoxy-mino] acetamido] -3 - [- [(2,5-dihydro-6-hydroxy-2-methyl- 5-oxo-55 as-triazin-3-yl) thio] methyl] -3-cephem-4-carboxylic acid (ceftriaxone)

The procedure is analogous to that described in Example 1, and the pure title substance is obtained using approximately equivalent amounts of the corresponding starting materials. Mp: 60 120 ° (dec.)

Example 3: 7 - [[2- (2-aminothiazol ~ 4-yl) -2-syn-methoxy-mino] acetamido] -3- (l-methyl-lH-tetrazol-5-yl) thiomethyl-3- 63 cephem-4-carboxylic acid (SCE 1365)

The procedure is analogous to Example 1 and the title substance is obtained using approximately equivalent amounts of the corresponding starting materials.

666 037

Example 4: 3- [2- (2-aminothiazol-4-yl) -2-methoximinoacetyl] benzothiazolin-2-thione (compound of the formula II)

10.1 g of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid, 20.3 g of bis- (benzothiazol-2-yl) disulfide and 0.16 g of benzyl-tributylammonium bromide become absolutely drier Suspended nitrogen atmosphere at room temperature in 100 ml of absolute acetone. The suspension is then mixed with 16 g triphenylphosphine in portions at -5 °. 5.1 g of triethylamine are added dropwise over the course of 30 minutes. The temperature rises to room temperature. The mixture is then stirred for 3 hours at room temperature, the suspension is cooled to -5 ° for isolation, filtered and washed with ice-cold acetone. Recrystallization of the crude product from tetrahydrofuran and drying gives a golden yellow product. Decomposition point: 274 °

5

IR spectrum:

(KB r pill) 3400 (st), 3240 (m, s), 3100 (m), 2940 (f), 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), io 1045 (m), 1020 (w), 985 (st), 940 (m), 880 (w), 865 (vw), 850 (w), 840fw). 790 (f), 750, 740 (st, sh).

Claims (15)

666 037 1 COOH , ch2 *; Ib in which Ri is hydrogen, an alkyl, a phenalkyl, a carbalkoxyalkyl, an acyl or a carboxyalkyl group, wherein RJ is acetoxy, 1-methyl-1H-tetrazol-5-yl-thio or 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-thio, and their pharmaceutically acceptable salts. 1 30th Jf ^ <iL_CH2R4 I COOR- wherein R2 and R4 have the above meaning and R5 is hydrogen or an amino protecting group, in the presence of protected amino as a substituent of the heterocycle R i deprotects this protected amino and in the presence of carboxyl as a group -COOR2 or of salt of this carb in the reaction product -oxyls optionally convert this carboxyl into salt thereof or the salt of this carboxyl into the carboxyl. 2. Process for the preparation of cephalosporin syn isomers of the formula I. ^ R1 a r.-nh— .. 2nd PATENT CLAIMS 1. Process for the preparation of cephalosporin syn isomers of the formula I / 0R1 -Ileo - NH- 'Yy I. coor- -CH2R4 R2 represents hydrogen, R3 represents a nitrogen, oxygen or sulfur-containing, unsubstituted or 5-membered heterocycle or substituted by the amino or azido group and R.4 represents hydrogen, the acetoxy group, the carba-5 moyloxy group or a group -SY, where Y represents an optionally substituted heterocycle, and their salts, characterized in that syn-isomeres of the formula II 3rd 666037 3 I N_ I. _N -ch2r4 h2n_ II Ii / 0ch3 n .c - co - nk_. l_A J-i COOR. 3. The method according to claim 1 or 2 for the preparation of syn isomers of formula Ia III 45 - co - nh 50 l i ^ l_CH2R4 COOR2 Ia in which Ri, R2 and R »have the meaning given in claims 1 and 2, respectively, and their pharmaceutically acceptable 55 salts. 4. The method according to claim 1 or 2 for the preparation of syn isomers of formula Ib R, - C - CO - NH 5. The method according to any one of claims 1 to 4, wherein in the syn isomer of formula II / • "- \ -N Usti \ / r represents 2-thioxobenzthiazolin-3-yl. 5 i // 'O I. -N, -ch2R4 purple coor4 35 wherein R4 has the above meaning, Ri represents a carboxyl protecting group and R5 represents hydrogen or an amino protecting group, which removes the carboxyl protecting group Ri present in the reaction product, in the presence of protected amino as a substituent in the reaction product of the heterocycle R # deprotects this protected amino and optionally the carboxyl -COOR2 in salt thereof or salt of this carboxyl is converted into the carboxyl. 6. The method according to any one of claims 1 to 5, wherein the carboxyl protecting group R2 or Ri is pivaloyloxymethyl. 7. A process for the preparation of a syn isomer of the formula II, as indicated in claim 1, characterized in that a syn isomer of the formula IV / OR1 K. R * - C - COOH IV wherein Ri and Rf have the meaning given in claim 1, correspondingly amidated. 8. The method of claim 7, wherein the amidation by reaction with a compound of formula V in which the two groups are identical and represent a 5- or o-membered heterocycle which, in addition to the nitrogen atom, may also contain and be substituted by 1 or 2 heteroatoms selected from O, N and S and / or condensed with an optionally substituted benzene ring, is carried out. 9. The method according to claim 8, wherein the amidation is carried out by reaction with bis- (benzothiazol-2-yl) disulfide. 10. Syn isomers of formula II, as indicated in claim I. 10th wherein Ri for hydrogen, an alkyl, a phenalkyl, a carbalkoxyalkyl, an acyl or a carboxyalkyl group, R2 for hydrogen or a carboxyl protecting group, R3 for a nitrogen, oxygen or sulfur containing, unsubstituted or substituted by the amino or azido group 5-membered heterocycle and R »are hydrogen, the acetoxy group, the carbamoyloxy group or a group -SY, where Y is an optionally substituted heterocycle, and their salts, characterized in that syn-isomer of the formula II / 0R1 N II C CO - n het; \ y II s II 15 wherein R] has the above meaning, R # for a nitrogen, oxygen or sulfur-containing 5-membered heterocycle which is unsubstituted or substituted by amino, protected amino or azido, and 20th -N Het »\ / 0R1 N II c - co N Het; V'- II s II represents a 5- or o-membered heterocycle which, in addition to the nitrogen atom, may contain and be substituted by one or two further hetero atoms selected from O, N and S, or may be fused with an optionally substituted benzene ring, with a compound of the formula lilac in which Ri has the above meaning, R # for a nitrogen, oxygen or sulfur-containing 5-membered heterocycle which is unsubstituted or substituted by amino, protected amino or azido, and / s. -N hetx. V " represents a 5- or o-membered heterocycle which, in addition to the nitrogen atom, may contain and be substituted by one or two further hetero atoms selected from O, N and S, or may be fused with an optionally substituted benzene ring, with a compound of the formula III -nh 11. Syn isomers according to claim 10, wherein / '> ■ -N Het} v- ' S represents 2-thioxobenzthiazolin-3-yl. 12. Syn isomers according to claim 10 of the formula IIa / 0R1 N Ä / \ II i - C - CO - N Het. IIa v-ILj ■ V " s where Ri and / ' . -N Het / Y ' have the meaning given in claim 1. 13. Syn isomers according to claim 12, wherein / 'N -N Het; V- ' represents 2-thioxobenzthiazolin-3-yl. 14. Syn isomers according to claim 12 with methyl as Ri. 15. The syn isomer of claim 14, wherein -N Het; \ ii S represents 2-thioxobenzthiazolin-3-yl.