SE457351B - TIAZOLE DERIVATIVES USED AS INTERMEDIATE FOR THE PREPARATION OF 3.7 DISUBSTITUTED 3-CEFEM-4-CARBOXYLIC ACID COMPOUNDS AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

Wherein R8 represents lower alkyl, and R9 represents imino, protected imino or oxo, R? denotes an aliphatic hydrocarbon group, which may have suitable substituents, R 3 denotes ev. protected carboxy, and R 'represents acyloxymethyl, hydroxymethyl, formyl or a heterocyclyltiomethyl group, which may have suitable substituents, or R 3 and Ru are joined to form -COOCH 2 -.

The invention thus enables the preparation of the syn-isomer of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds, which are illustrated by the general formula I, and this syn-isomer can be represented by the sub-formula R1-3-CO; in the molecules, while the N-OR that the corresponding anti-isomer is represented by the sub-formula R1-g-CO-. In the present description and claims, the syn-isomers of the compounds and the starting materials represented -fi- CO- are represented in their molecules, with the limitation, N-O- with the sub-formula that when it is known for the understanding of the invention to print both the syn-isomer and the anti-isomer with a general formula, they are illustrated by the sub-formula -fi- CO- NSOI. The compounds of formulas I are hitherto unknown and can be prepared in the following ways.

W / å Process variant a): øzlkws lf gl-c-coox ---> 4 -N / 'R "f N-oaz Ra II III or a reactive derivative at the carboxy group or a salt thereof or a reactive derivative thereof at the amino group or a salt thereof Process variant b): = R1a-c-conn-í 5 ll 4 2 --N / R N-OR Å --- è In elimination of the amino (or imino-) protecting IV group or a salt thereof.

Process variant c) ': = acylation of the hydroxyl group' D fl-Cmwws fs "4 C-CONH / ---» D 4 1:63 H0 || N-OR2 / "" or a salt thereof 457 351 nl-lc-cona SI 4 N_OR2 N / R Ra 0 or a salt thereof Rlb-í-conn 1 / s 4 N-onz / '_' / R ° - 3 R Ia or a salt thereof N-ORZ o 3 Ib 1 or a salt thereof 457 3É1 Process variant d): 1 R -c-coNH N / R * N 14-0137 ol: <3 Va or a salt thereof elimination of carboxy protection s - SPUPPGD S Rl-CII-CONH fi I 4 -'- _: : -> O RB Ic or a salt thereof Process variant e): elimination of amino protection - Sn-'lPPen l__ _ - / 5 R íícomi I -------} Rl- fi- CQN1-1__TS '' 4a N_OR2 n / cuz-ocona R N_OR2 __ / / ~ NO '3 0 / IR 3 CHZ-OCONHZ R vb í ~ _ Id or a salt thereof or a Salt thereof FÖIrfaI-andevariant f): ls nl-c-coun s Rw -sn - '> Rl-í-conn _ 4b _ 4G zuu / ca -R + 2 / SR, N-onz /' 2 N '° RN H2 io - o Å R3; R3 Vc Vd Ia or a salt thereof or e fl re-> elle: e fi in salt _ active derivative-z thereof I thereof at the mercapto group in 5,457,351 Procedure ndevariant 5): l R -c-coma - T / s syre Rl-c-conn ifs H ... N / fl zon -> Log / C52 N-onz / I o Ra O CO-íO ve eller e fl zsalt därav or a salt thereof. Process variant h): 1 - S R1-C-CONH - 1 /'s oxidation R -ç-CONH - fT / N 2} \ n / 'I 0 3' __ / cno. H2 "í" "" _> N-onz / N 0 3 RR Ve I9 or eu; sal: thereof or e fi v Salt thereof 2 3 4 5 In the formulas given above R 1, RRR ° Ch R Öen Above II, while Bla represents a group of the general formula 7a wherein R represents protected amino, or a group of the general formula 15 wherein R ¶ represents protected carboxy-lower alkyl, R 457 351 - wherein R 8 has the meaning given above, and R 9a represents protected R 1b represents a group of the general formula N t HQN -t 4- 3, / or a group of the general formula R%; fi Åï-í% __ // imino, 8 has the meaning given above, R 5a represents hydrogen , halogen, nitro, lower alkoxy or acyloxy, B a denotes acyloxy, Raa be- zb denotes carboxy-lower alkyl, Raa denotes an amino protecting group, Rub denotes a group which can be substituted by a group R CS-, where Rue denotes a heterocyclyl group , which may have suitable substituents, and RC has the meaning given above.

Among the starting compounds, the starting compound of formula III, including the corresponding anti-isomer, is hitherto unknown and can be prepared by the reactions illustrated in the following reaction scheme: fi reaction scheme (1) (i) _ R1o_Y R5b VII coca Rsb o 3 ___- v) H coca : 11100 'vn: (ii) RSC COCH3 R6b IX (iii)' RSC COCOOH RIOO XI (iv) RS -COCOOH R6 XIII (2) (i) R5 COCOOH H0 XV 457 351 - R5c OXidå fi iOn OCOOH ----> Röb X RSC 81 imineri I g I COCOOH H0 XII R2-onnz (xzv) ns or noble salt, _ --C-COOH thereof I _____________; N Rs' ânz IIIa NH¿ÖH or eülsalt Rs thereof C-C008 ”fi-fi I! Hb is OH XVI '457 551 (ii) S, R alkylation - Rsa 8 - cfcoox-I ______) C-COOR 8 å! HO É R 0 oR2 ° šRzd XVII XVIII hydrolysis Rsd _ '* _ å' cl-coon Rso 'I; 0R2d IIIb (3) RS acyïering Rsa ¶ ___.____) __ c-cooa _ IC 'COOH n í N' g _ Röa * m ¿a 2 OR2 OR XIX IIIC (4) (i) _ nitrosering x-crxz-co -C fl z-Z --_--> xcazco-cz Rulb- fi- NH; ll _ NS Xx É XXII NC ~ Z s 7c4 <\ I '> N on 3 š -> S 2 OH XXI XXIII 457 351 elimination N C-COOH __________ + R7C * -_ 4 <\ \ NN 5: a H XXIIIa (ii) N ---- CZ alkylery and CZ Rvd / \ || R? / \; N ä \ S N s än Q šnze XXIV - XXV elimination N \ C-COOH -_- »lm 4; s g. ba ”IIId (5) alkylation halogenation CH3-GO-CZ CH3CO-ï ~ Z X-CH2CO-CZ II å z ll NNN than i cšmze šRze xxvI xxvn - 'xxvIII 457 551 10' lb R ñ-NHZ s,} N -Z XXII R-hL- <elimination E s ~ ----> åR2e XXIX (6) (i) 'aminoscydase agent N l-lzN «> \ CH2-Z XXX (ii) oxidation hydrolysis_ lc lc _ R -caz- z __________9 R co z ¿_________ XXXII XXXIII elimination RZO-NH2 or xïv a salt ¶ thereof 'Rk-cocoon, RIC-cz WN XXXIV or å 2 a salt OR thereof xxxv elimination R7__ c N-š- C -COOH UN ânze IIIe 'R7a -? Šï_cå2-z ______> \ S XXXI n1 ° -cz Il N än XXIIIb 457 351 Nazo fl Rk-c-coøu' II '-or a salt thereof N R1 ° -c-coon oaz? 1IIf ou xxxvx 8 R (iii) N alkylation \ N 7a- $ í c-coon ----- 9 9 c-cooR8 R \ R a__ I S N S I N on § oxze xxxvlx. xxxv1II Rs hydrolys \ N ----- 7 c-coon R9a; 4¿í \ "- SN šnze IIIg (7), N _, N _ Myra Rß fl ffßa. edel SN m \ SN ä _---> š oR2 "~ onz XXXIX IIIh 10. In the above formulas, R 2, R 5, R 6, R 5a, R 6a, R 7a, R and H 9 have the meaning given above, R 5b represents halogen, Y represents an acid residue, R 10 ar-denotes lower alkyl, ESC denotes hydrogen, halogen or nitro, Rób denotes lower alkoxy, ar-lower alkoxy or acylamino, R 2 ° denotes hydrogen, lower alkyl or lower alkenyl, R 5d denotes hydrogen, halogen, nitro, hydroxy or lower alkoxy, X represents halogen, Z represents protected carboxy, R7b represents lower alkyl, amino or lower alkoxy, R7 ° represents lower alkyl, amino or hydroxy, R7d represents lower alkyl, H26 represents le represents a group of the general formula 117 N -ïs / lower alkyl, R _vari R? has the meaning given above, or a group of the general formula 8 R \\ N REA? 8 where R and B9 have the meaning given above, Rzd represents lower alkyl or lower alkenyl, and Za represents ev. protected carboxy.

The other starting compounds of formulas IV, V, Va-Vc and Ve are hitherto unknown compounds and can be prepared in the methods described above under 1-8.

As for the compounds of the formulas I, Ia- and Ic-Ig and the starting compounds of the formulas III, IIIe, IIIf, IIIh, IV, Va- Vc, Ve, XXIII-XXIIIb, XXIX-XXXVII and XXXIX, it is clear that these compounds comprise tautomeric isomers with respect to their thiazole groups. In the case where the group illustrated by the general formula «* is i- S (wherein Te represents amino, protected amino or hydroxy). In the formula for the compounds and starting compounds prepared by the process of the present invention, the general formula has 10 h.) O 25 ÉO 55 40> 13 457 351 “__-__ Rk / Lsj- m (wherein R 7e has the meaning given above), the group of the formula 11 7e S / JR can thus alternatively be represented by its tautomeric formula HN“ ““ “' f} \ »f- (n) // R? S (wherein B7f represents imino, protected imino or oxo). This thus means that the two groups (A) and (B) are in a state of equilibrium as the so-called tautomera forms, which can be represented by the following Equilibrium_ R7e / ¶: ï ;; & _ (A) (B) ”_ in R7 / fs (where B78 and R7f have the meaning given above), These types of tautomerism between 2- amino and 2-hydroxytiazole compounds and 2-imino or 2-oxo-thiazoline compounds listed above are well known in the literature, and it is obvious to those skilled in the art that the two tautomeric isomers are in equilibrium and can be easily converted from each other, so it is obviously, that such isomers fall into the same category as the compound itself. Both the tautomeric forms of the compounds of formula I, Ia and Ic-Ig and the starting compounds of formula III, IIIe, IIIf, IIIh, IV, Va-Vc, Ve, XXIII-XXIIIb, XXIX-XXXVII and XXXIX are within the scope of for the present invention. In the present description, claims and examples, the compounds and the starting compounds, including the group of such tautomeric isomers, are represented by using one of the terms suitable for this purpose, i.e. only the formula: N 20 e n / s for convenience.

As for the compounds of formulas I, Ia-Ic and Ig and the starting compounds of formulas II, IV, V and Va may be carboxy, and Ra is formyl, also considered and R 4 is 457 351 - (A) \ e4- de compounds, wherein R 3 is essentially the same compounds as compounds, wherein R is joined to form a group of the formula: -COOCH (OH) -, 4 i.e. intramolecular hemiacylal type compounds, so both of these should be included in the same category of compounds per se and are therefore within the scope of the invention.

Suitable pharmaceutically acceptable salts of the syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds of formula I are common non-toxic salts, which may be inorganic salts, e.g. a metal salt such as an alkali metal salt (eg the sodium or potassium salt) or an alkaline earth metal salt (eg the calcium or magnesium salt) or an ammonium salt, or an organic salt, e.g. an organic amine salt (eg trimethylamine, triethylamine, ethanolamine, diethanolamine, pyridine, picoline, dicyclohexylamine or N, Nidibenzylethylenediamine salt), an organic acid salt (eg acetate, maleate, tartrate, methanesulfonate, benzenesulfonate or toluenesulfonate), an inorganic acid salt (eg hydrochloride, hydrobromide, sulphate or phosphate) or a salt with an amino acid (eg arginine, aspartic acid or glutamic acid).

In the above and in the description given below, suitable examples and illustrations of various existing definitions are explained in detail. g The term "lower" refers, unless otherwise indicated, to 1-6 carbon atoms.

"Aliphatic hydrocarbon group" means a straight-chain or branched-chain aliphatic hydrocarbon group having 1 to 6 carbon atoms, which may be lower alkyl or lower alkenyl. Such an aliphatic hydrocarbon group may have 1-2 suitable substituents, e.g. carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy or a heterocyclic group.

"Halogen" may suitably include chlorine, bromine, fluorine and iodine.

Lower alkoxy and lower alkoxy moieties in the term "ar-lower alkoxy" may include groups which may be branched, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pedloxy and hexyloxy, and they preferably have 1- carbon atoms, especially 1-2 carbon atoms. Suitable protected amino groups may comprise an acylamino and amino group which is substituted by a common protecting group separate from an acyl group, e.g. a benzyl group.

Suitable lower alkyl groups and lower alkyl moieties in the terms "lower alkylthio", "carboxy-lower alkyl", "protected carboxy-lower alkyl", "ar-lower alkyl" and "di (lower alkyl) amino" may include groups which may be branched, eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl, and such groups preferably contain 1--carbon atoms, especially 1-2 carbon atoms.

Suitable protected imino groups may include acylimino groups and imino groups which are substituted by common protecting groups other than an acyl group, e.g. a benzyl group.

Suitable protected carboxy groups and protected carboxy moieties in the term "protected carboxy-lower alkyl" may include esterified carboxy, wherein the ester may be e.g. a lower alkyl ester (eg a melester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester or 1-cyclopropylethyl ester), wherein the lower alkyl moiety may preferably be one containing 1-4 carbon atoms, a lower alkenyl ester (te; a vinyl ester or allyl ester), a lower alkynyl ester (eg an ethynyl ester or propynyl ester), or a mono- (or di- or tri) -halogen (lower alkyl) ester (eg a 2-iodoethyl ester or 2,2,2-trichloroethyl ester); a lower alkanoyloxy-lower alkyl ester (eg an acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester or 2-propionyloxyethyl ester); lower alkanesulfonyl lower alkyl ester (eg, a mesylmethyl ester or 2-mesylethyl ester); ar-lower alkyl ester, e.g. a phenyl-lower alkyl ester which may bear one or more suitable substituents (eg a benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenylethyl ester, trityl ester, diphenylmethyl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester or 4-hydroxy-3,5-di-tert-butylbenzyl ester); or an aryl ester which may have one or more suitable substituents (eg a phenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester or cumenyl ester).

Preferred examples of protected carboxy may be lower alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, tert.pentyloxycarbonyl or hexyloxycarbonyl) having 2-7 carbon atoms, preferably 2-5 carbon atoms. Suitable aryl groups and aryl moieties in the terms "ar-lower alkyl", "ar-lower alkoxy", "arylthio" and "aryloxy" may include phenyl, tolyl, xylyl, mesityl, cumenyl and naphthyl, wherein the aryl group may bear 1-3 suitable substituents, e.g. halogen (eg chlorine, bromine, iodine or fluorine) or hydroxy.

Suitable heterocyclic groups and heterocyclic moieties in the term "a heterocyclylthiomethyl group which may have suitable substituents" denote saturated or unsaturated, monocyclic or polycyclic heterocyclic groups containing at least one heteroatom such as acid, sulfur or nitrogen.

Particularly preferred heterocyclic groups may e.g. be: unsaturated 3-8-membered (preferably 5-6-membered) heteromonocyclic groups containing 1-4 nitrogen atoms, e.g. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg HH-1,2,4-triazolyl, 1H-1,2,3-triazolyl or 2H-1 , 2,3-triazolyl) or tetrazolyl (eg 1H-tetrazolyl or 2H-tetrazolyl); saturated 3-8 membered (preferably 5-6 membered) heteromonocyclic groups containing 1-N nitrogen atoms, e.g. pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated fused heterocyclic groups containing 1-4 nitrogen atoms, e.g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl or benzotriazolyl; unsaturated 3-8 membered (preferably 5-6 membered) heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g. oxazolyl, isoxazolyl or odadiazolyl (eg 1,2,4-oxadiazolyl, 1,3,3-oxadiazolyl or 1,2,5-oxadiazolyl); -, 'saturated'} - 8-membered (preferably -6-membered) heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g.

I morpholinyl; unsaturated fused heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g. benzoxazolyl or benzoxadiazolyl; unsaturated 3-8 membered (preferably 5-6 membered) heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, e.g. thiazolyl or thiadiazolyl (eg 1,2,4-thiadiazolyl, 1,1}, 4-thiadiazolyl or 1,2,5-thiadiazolyl); . saturated 3-8 membered (preferably 5-6 membered) heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, e.g. thiazolidinyl; . saturated 3-8-leaaae (preferably 5-6-leaade) netheromonocyclic groups containing 1 sulfur atom, e.g. thienyl; Unsaturated fused heterocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, e.g. benzothiazolyl or benzothiadiazolyl; In which the heterocyclic groups may have 1 or 2 suitable substituents such as lower alkyl (eg methyl, ethyl, propyl, ispropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl), preferably having 1-4 carbon atoms; lower alkenyl (eg vinyl, allyl, or butenyl); aryl (eg phenyl or tolyl); halogen (eg chlorine, bromine, iodine or fluorine); amino; or di (lower alkyl) amino-lower alkyl (eg dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl or diethylaminobutyl), preferably having 3-6 carbon atoms.

Suitable lower alkenyl groups are groups having 2-6 carbon atoms, such as e.g. may be vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, or 3-pentenyl, preferably having 2-4 carbon atoms.

Suitable acyl moieties in the terms "acylamino", "acylimino", "acyloxy" and "acyloxymethyl" as defined above may be carbamoyl, aliphatic acyl and acyl containing an aromatic or heterocyclic ring. Suitable examples of such an acyl group may be lower alkanoyl (eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl), preferably having 1-4 carbon atoms, especially having 1-2 carbon atoms lower alkoxycarbonyl having 2 to 7 carbon atoms (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentyloxycarbonyl, tert.pentyloxycarbonyl or hexoxyloxycomeryl 6, carbonicoxomeric 3- lower alkanesulfonyl (eg mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl), preferably having 1-4 carbon atoms, especially having 1-2 carbon atoms; , arenesulfonyl (eg benzenesulfonyl or tosyl); aroyl (eg benzoyl, toluoyl, naphthoyl, phthaloyl or indanecarbonyl); ar-lower alkanoyl (eg phenylacetyl or phenylpropionyl); or lower alkoxycarbonyl (eg benzyloxycarbonyl or phenylethyloxycarbonyl).

The acyl moiety may, as indicated above, bear 1-3 suitable substituents such as halogen (eg chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (eg methoxy, ethoxy, propoxy or isopropoxy), lower alkyl (eg methyl, ethyl, propyl, isopropyl or butyl), lower alkenyl (eg vinyl or allyl), acyl such as halogen-lower alkanoyl (eg chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl) or aryl (eg phenyl or tolyl). Suitable examples of acyl having such substituents may be mono- (or di- or tri-) halogen-lower alkanoyl (eg trifluoroacetyl or trifluoroacetyl). Åfszlošaâekyl), preferably having 2-14 carbon atoms; or mono- (or di- or tri-) halogen-lower alkanoylcarbamoyl (eg trichloroacetylcarbamoyl), preferably having 3-E carbon atoms.

Suitable protecting groups for the amino group Raa may be acyl such as halogen-lower alkanoyl (eg chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl), preferably having 2-3 carbon atoms.

Suitable acid residues may comprise the residue of an acid such as an inorganic acid (eg hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid) or an organic acid (eg methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid).

Suitable items. on a group which may be substituted by a group Rgc-S- may be an acid residue such as halogen, azido or acyloxy, the halogen and acyl moieties of this acyloxy group being the same as indicated above.

Among the suitable examples of each of the groups in the compounds explained and illustrated above, preferred examples thereof are illustrated below: B5 is preferably hydrogen, halogen (preferably chlorine) or nitro.

R6 is preferably hydroxy, lower alkoxy (preferably C1-C4, especially C1-G2), acyloxy (preferably lower alkanoyloxy (preferably C1-C2, especially C1-C2) or carbamoyloxy), acylamino (preferably lower alkanesulfonylamino (preferably C1-C2). C 1, especially C 1 -C 2)) or di (lower alkyl) amino (wherein the alkyl moiety preferably contains C 1 -C 2, especially C 1 -C 2) {R 7 is preferably amino, protected amino such as acylamino (preferably lower alkanesulfonylamino (preferably C 1 -C 4 , especially C1-C2), trihalogen-lower alkanoylamino '(preferably C1-C1, especially C1-C2), lower alkoxycarbonylamino (preferably C2-C7, especially C6-C6) or lower alkanoylamino (preferably C1-C4, especially C1-C2 )), hydroxy or lower alkyl (preferably C1-C4 especially C1-C2).

R is preferably C1-C2-lower alkyl, especially C1-C2-lower alkyl. , H9 is preferably protected imino, e.g. acylimino (preferably lower alkanesulfonylamino) (preferably cL-cä, especially c1-c2)).

R 2 is preferably lower alkyl (preferably C 1 -C 6, especially C 1 -C 2, more preferably C 1), lower alkenyl, ar-lower alkenyl (especially phenyl-lower alkenyl), carboxy-lower alkyl, protected carboxy-lower alkyl (especially lower alkoxycarbonyl (preferably G5-C6) -lower alkyl), arylthio-lower alkyl (especially phenylthio-lower alkyl), lower alkyl (especially phenyl-lower alkyl), which may carry halogen (preferably bromine) and hydroxy, thienyl-lower alkyl or aryloxy-lower alkyl (especially phenoxy-lower alkyl), which may carry hydroxy, and wherein the alkenyl and the alkenyl moiety contain C 2 -C 6, preferably C 2 -C 6, and the alkyldehen preferably is Cl-C¿, especially Cl-G2.

R is preferably carboxy. Ru is preferably acyloxymethyl (preferably lower alkanoyloxymethyl (wherein the alkanoyl moiety is preferably C1-Ca, especially C1-C2; most preferably C2, ie acetyl) or carbamoyloxymethyl, which may carry trihalogen lower alkanoyl (wherein the trihalo moiety is preferably trichloro, and alkano preferably C 2 -C 3)), hydroxymethyl, formyl, tetrazolylthiomethyl, which may bear lower alkyl (preferably C 1 -C 4, especially C 1 -C 2) or di (lower alkyl) amino-lower alkyl (wherein the alkyl moiety is preferably C , especially C1-C2), triazolylthiomethyl, which may carry lower alkyl (preferably C1-Ca, especially C1-C2) or thiadiazolylthiomethyl, which may carry lower alkyl (preferably c1-ch, especially c1-c2); or n5 and R are combined to give -COOCHE The various processes for the preparation of the compounds are described in detail below: Process variant a): The compound of formula I or a salt thereof can be prepared by reacting the compound of formula II or a reactive derivative thereof in the amino group or a salt thereof with a compound of formula III or a reactive derivative thereof at the carboxy group or a salt thereof, which process is the fundamental process for the preparation of the compounds of formula I.

Suitable reactive derivatives at the amino group of the compound of formula II include common reactive derivatives used in amidation, e.g. silyl derivatives, which are formed by reacting the compound of formula II and a silyl compound, e.g. bis (trimethylsilyl) acetamide or trimethylsilylacetamide.

Suitable salts of the compound of formula II include acid addition salts, e.g. an organic acid salt (eg the acetate, maleate, tartrate, benzenesulfonate or toluenesulfonate) or an inorganic acid salt (eg the hydrochloride, hydrobromide, sulphate or phosphate), a salt having an ophthalmic base such as an alkali metal salt (t. eg the sodium salt or the potassium salt), an alkaline earth metal salt (eg the calcium salt or the magnesium salt) or the ammonium salt, or a salt with an organic base (eg the trylstyl salt or the pyridine salt). Suitable reactive derivatives at the carboxy group of the compound of formula III include conventional derivatives used in amidation. The salts of the compound of formula III may be salts with an inorganic base such as alkali metal salts (eg the sodium or potassium salt) or an alkaline earth metal salt (eg the potassium or magnesium salt), a salt having an organic base such as trimethylamine, triethylamine or pyridine or a salt with an acid (eg hydrochloric acid or hydrobromic acid).

The reaction is usually carried out in a common solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction. Among these solvents, hydrophilic solvents can be used in admixture with water.

In the reaction in question, it is preferably carried out in the presence of a condensing agent such as a so-called Vilsmeier reagent, e.g. chloromethylene dimethylammonium chloride, which is formed by reacting dimethylformamide with thionyl chloride or phosgene, or a compound formed by reacting dimethylformamide with phosphorus oxychloride.

The reaction can also be carried out in the presence of an inorganic or organic base, e.g. an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate, tri- (lower alkyl) amine, pyridine, N-lower alkylmorpholine, N, N-di (lower alkyl) -benzylamine or N, N-di (lower alkyl) aniline listed below as When the base or condensing agent is a liquid; it can also be used as a solvent. The reaction temperature is not critical, and the reaction is usually carried out under cooling or at room temperature.

In this reaction, when the starting compound of formula III is reacted with the compound of formula II or a reactive derivative thereof at the amino group or a salt thereof in the presence of e.g. phosphorus pentachloride or thionyl chloride, only the corresponding anti-isomer of the compound of formula I or a mixture of the corresponding anti-isomer and syn-isomer as end product, also the On compound of formula III, i.e. the syn-isomer, was used as starting material. It is obvious that the reaction of the corresponding anti-isomer to the starting material of formula III and the compound II can never lead to the formation of the desired compound of formula I, i.e. the syn isomer. It is clear that such a tendency and uniformity in sales as stated above is due to the less stable visual example. BO 15 40 457 351, 21 the isomer tends to be partially or completely isomerized to the corresponding more stable anti-isomer during the reaction, e.g. 1 det s.k. the activating step of the compound of formula III, so that the isomerized compound, i.e. the anti-isomer corresponding to the desired compound of formula I, is obtained as the end product.

In order to obtain the desired compound of formula I, i.e. the syn isomer, selectively and in high yield, it is necessary to use the starting compound of formula III, i.e. the syn isomer, and to select suitable reaction conditions. The desired compound of formula I, i.e. the syn isomer, can be obtained selectively and in high yield by carrying out the reaction e.g. in the presence of a Vilsmeier reagent indicated above and under approximately neutral conditions.

In the form of the starting material of formula III, in which n1 is a group of the general formula H2N, the desired compound of formula I, i.e. the syn isomer, can be obtained selectively and in high yield by that the reaction of the corresponding starting compound of formula III, i.e. the syn isomer, and the compound of formula II is carried out e.g. in the presence of a Vilsmeier reagent prepared by reacting dimethylformamide and phosphorus oxychloride, and under approximately neutral conditions. In this case, particularly good results can be obtained if the reaction is carried out in the presence of more than two molar equivalents of phosphorus oxychloride in relation to the amount of the starting compound of formula III, i.e. the syn-isomer, and dimethylformamide given in the working examples. Furthermore, good results can be obtained by performing an activation step with the starting compound of formula III, i.e. the syn-isomer, in the presence of a silyl compound (eg bis (trimethylsilyl) acetamide or trimethylsilyl acetamide).

As for the reaction between the compound of formula II and the compound of formula III, it should be noted that: when the compound of formula II, wherein Bh is a carbamoyloxymethyl group having an acyl group, is used as starting material, one can either obtain the desired compound of formula I, wherein R is a carbamoyloxymethyl group having an acyl group or a free carbamoyloxymethyl group, all depending on the reaction conditions, when a compound of formula II, wherein R is a hydroxymethyl group, is used as starting material, e.g. may obtain the desired compound of formula I, wherein H 3 and Ra are joined to form a 457 351 in 2, -COOCH 2 group, and in addition, the protected carboxy group or salt of the compound of formula II may be converted to a free carboxy group, either during the reaction or by post-treatment.

As can be seen from the above, process a) is a superior method which is particularly advantageous for the preparation of the desired compound of formula I, i.e. the syn-isomer.

Process b): The compound of formula Ia or a salt thereof can be prepared by subjecting the compound of formula IV or a salt thereof to an elimination reaction for the amino or imino protecting group. A suitable salt of the compound of formula IV may comprise a metal salt, an ammonium salt or an organic amine salt, as indicated above.

The elimination reaction is carried out in accordance with conventional methods, e.g. by hydrolysis, reduction or by reaction of a compound of formula IV, wherein the protecting group is an acyl group, with an iminohalogenating agent and then with an iminopretinating agent, and, if necessary, hydrolysis of the resulting compound.

The hydrolysis can be performed using e.g. an acid, a base or hydrazine. These methods can be chosen depending on the nature of the protecting group to be eliminated.

Among these methods, the hydrolysis using acid is a general and preferred method for eliminating protecting groups such as e.g. substituted or unsubstituted alkoxycarbonyl, (eg tert. pentyloxycarbonyl), alkanoyl (eg formyl), cycloalkoxycarbonyl Å substituted or unsubstituted aralkoxycarbonyl (eg benzyloxycarbonyl gels or substituted benzyloxycarbonyl), substituted alkylidene; or substituted cycloalkylidene. A suitable acid may be an organic or inorganic acid, e.g. formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or hydrochloric acid, and a preferred acid is an acid which can be easily removed from the reaction mixture in the usual manner, e.g. by distillation under reduced pressure, e.g. formic acid, trifluoroacetic acid or hydrochloric acid. An acid suitable for the reaction can be selected according to the nature of the protecting group to be eliminated. When the elimination reaction is carried out with an acid, it may be carried out in the presence or absence of a solvent. Suitable solvents may comprise an organic solvent, water or a mixed solvent thereof. When using trifluoroacetic acid, the elimination reaction can preferably be carried out in the presence of anisole.

Hydrolysis using hydrazine is widely used to eliminate a protecting group such as e.g. succinyl or phthaloyl.

Hydrolysis with a base is preferably used to eliminate an acyl group, e.g. haloalkanoyl (eg trifluoroacetyl). A suitable base can e.g. be an inorganic base such as an alkali metal hydroxide (eg sodium hydroxide or potassium hydroxide), an alkaline earth metal hydroxide (eg magnesium hydroxide or calcium hydroxide), an alkali metal carbonate (eg sodium carbonate or potassium carbonate), an alkaline earth metal carbonate (t. eg magnesium carbonate or calcium carbonate), an alkali metal bicarbonate (eg sodium bicarbonate or potassium bicarbonate), an alkali metal acetate (eg sodium acetate or potassium acetate), an alkaline earth metal phosphate (eg magnesium phosphate or calcium hydrogen phosphate), eg disodium hydrogen phosphate or dipotassium hydrogen phosphate) or the like, and an organic base may e.g. be trialkylamine (eg trimethylamine or triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diezabicyclo [1 +, 3,0 / non-fs-en, 1, h-diazabicyclo / z, ae / octane or 1,5-diazabicyclo [5.4.0] / indene-5. Hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Of the protecting groups, the acyl group can generally be eliminated by hydrolysis as indicated above or by another common hydrolysis method. In the case where the acyl group is halogen-substituted alkoxycarbonyl or α-quinolyloxycarbonyl, these groups are eliminated by treatment with a heavy metal such as copper or zinc. The reductive elimination is generally used to eliminate a protecting group such as e.g. haloalkoxycarbonyl (eg trichoroethoxycarbonyl), substituted or unsubstituted aralkoxycarbonyl (eg benzyloxycarbonyl or substituted benzyloxycarbonyl) or 2-pyridylmethoxycarbonyl. An appropriate reduction can e.g. include reduction with an alkali metal borohydride (eg sodium borohydride).

Suitable iminohalogenating agents used in any of the above methods may include phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or phosgene. The reaction temperature is not critical, and the reaction is usually carried out at room temperature or under cooling.

Suitable iminopretinating agents which can be reacted with the reaction products thus obtained can be e.g. be an alcohol or a metal alkoxide. A suitable alcohol can e.g. be an alkanol (e.g. methanol, ethanol, propanol, isopropanol, butanol or tert. butanol), which may be substituted by alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy or butoxy). Suitable metal alkoxides may include alkali metal alkoxides (eg sodium alkoxide or kahum alkoxide) or alkaline earth metal alkoxides (eg calcium alkoxide or barium alkoxide). The reaction temperature is not critical, and the reaction is usually carried out under cooling or at room temperature.

The products thus obtained are subjected, if necessary, to hydrolysis. The hydrolysis can be easily carried out by pouring the recovered reaction mixture into water, but a hydrophilic solvent (eg methanol or ethanol), a base (eg an alkali metal bicarbonate or trialkylamine) may be added in advance. or an acid (eg dilute hydrochloric acid or acetic acid) to the water.

The reaction temperature is not critical, and it may be conveniently selected according to the nature of the amino protecting group and the elimination method used, and the reaction is preferably carried out under mild conditions, e.g. during cooling, at room temperature or at slightly elevated temperature.

A protected carboxy group can of course be suitably converted into a free carboxy group. When the compound of formula IV, wherein Ru is carbamoyloxymethyl having an acyl group, is used as a starting material, one can obtain either the desired compound of formula Ia, wherein R is a carbamoyloxymethyl group having an acyl group or a free carbamoyloxymethyl group, depending on the reaction conditions.

When using a compound of formula IV, wherein R is an acyloxymethyl group, as starting material, one can possibly to give the desired compound of formula Ia, wherein R; and R are linked to form an Å -COOCHE group, all depending on the reaction conditions, during the reaction or by post-treatment.

Process c): The compound of formula Ib or a salt thereof can be prepared by acylating the hydroxy group of the compound of formula V or a salt thereof.

Suitable salts of the compound of formula V may be those exemplified in connection with the compound of formula IV.

The acylating agent used for this reaction may be an aliphatic, aromatic or heterocyclic carboxylic acid or the corresponding sulfonic acid and thioic acid, having the above-mentioned ayl groups as their acyl moieties, and reactive derivatives of these acids. Suitable reactive derivatives of the above acids may be acid halides, acid anhydrides, activated amides or activated esters. Suitable examples of this may be an acid chloride, an acid azide, a mixed acid anhydride with an acid such as substituted phosphoric acid (eg dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, or halogenated phosphoric acid), dialkylphosphoric acid, sulfuric acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid (eg pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, or trichloroacetic acid) or an aromatic, eg carboxylic acid) a symmetrical acid anhydride, an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, aimethyliminomethyl ((cH3) 2N = Gli residues, propyl) vinyl ester , p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, py ridyl ester, piperidyl ester, or 8-quinolylthioester) or an ester with N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, or 1-hydroxy-6-chloro-1H- benzotriazole.I These reactive derivatives may ev. selected depending on the nature of the acylating agent used. The acylating agent may further comprise an aliphatic, aromatic or heterocyclic isocyanate or isothiocyanate (eg methyl isocyanate, phenyl isocyanate, trichloroacetyl isocyanate or methyl isothiocyanate) and haloformate (eg chloroformic acid ethyl ester or chloroformate). In this case, for example, when trichloroacetyl isocyanate is used as acylating agent, the trichloroethylcarbamoyl group is introduced as acyl group, and this group can be converted to a carbamovyl group by treatment with base, and when chloroformic acid ethyl ester is used as acylating agent, the ethoxycarbonyl group is introduced as acyl group.

This reaction is carried out under reaction conditions similar to those described for the reaction between the compound of formula II and the compound of formula III, and it is preferably carried out in. In the reaction of the compound of formula V with an acylating agent, the protected carboxy group or salts of the compound of formula V a free carboxy group during the reaction or by post-treatment. When a compound of formula V: wherein Ru is a carbamoyloxymethyl group having an acyl group, is used as the starting material, it is possible to to give a compound of formula Ib, wherein R is a carbamoyloxymethyl group having an acyl group or a free carbamoyloxymethyl group, all depending on the reaction conditions during the reaction or on post-treatment. presence of a base. Process d): The compound of formula Ic or a salt thereof can be prepared by subjecting the compound of formula Va or a salt thereof to an elimination reaction for the carboxy-protecting group.

A suitable salt of the compound of formula Va may be as exemplified for the compound of formula IV.

This elimination reaction is carried out in the usual way, e.g. by hydrolysis. Hydrolysis can be a method in which an acid or base is used. These methods can be selected depending on the nature of the protecting group to be removed. Hydrolysis using an acid is the most common and preferred method of eliminating protecting groups such as phenyl-lower alkyl, substituted phenyl-lower alkyl, lower alkyl or substituted lower alkyl. A suitable acid can e.g. be an inorganic or organic acid, e.g. formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or hydrochloric acid. This reaction can be carried out in the presence of anisole. A suitable acid for this reaction may be selected depending on the protecting group to be removed and other factors.

* Hydrolysis using an acid can be performed in the presence of a solvent, e.g. an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical, and it can be selected according to the nature of the protecting group and the elimination method, and the reaction is preferably carried out under mild conditions, e.g. during cooling, at room temperature or during light heating.

If desired, one can convert the protected carboxy group H3 to a free carboxy group, convert the protected amino group to a free amino group, convert a protected imino group to a free imino group, convert the acyloxy group to a hydroxy group and / or convert the carbamoyloxymethyl group to an ac free carbamoyloxy methyl group during the reaction or by post-treatment.

Process e): The compound of formula Id or a salt thereof can be prepared by subjecting the compound of formula Vb or a salt thereof to elimination reaction for the amino protecting group.

Suitable salts of the compound of formula Vb are those indicated in connection with the compound of formula IV.

This elimination reaction can e.g. be an elimination reaction in which a base is used, e.g. an inorganic base such as an alkali metal hydroxide (eg sodium hydroxide or potassium hydroxide), an alkali metal bicarbonate (eg sodium bicarbonate or potassium bicarbonate) or alkali metal carbonate (eg sodium carbonate or potassium carbonate) , an organic base such as an alkali metal alkoxide (eg sodium methoxide or sodium ethoxide), a trialkylamine (eg trimethylamine or triethylamine), triethanolamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, N-methylmorpholine or pyridine, or an elimination reaction using basic alumina, a basic ion exchange resin, an acid (eg trifluoroacetic acid or trifluoroacetic acid anisole). This elimination reaction is usually carried out in water, a hydrophilic solvent or a mixture thereof.

The reaction temperature is not critical, and the reaction is preferably carried out at room temperature or under cooling.

The protected carboxy group or salts in the compound of formula Vb can be converted to a free carboxy group and resp. a protected amino and / or imino group can be converted to a free amino and / or imino group during the reaction or by post-treatment.

Process ff: The compound of formula Ie or a salt thereof can be prepared by reacting the compound of formula Vc or a salt thereof with a compound of formula Vd or a reactive derivative thereof at the mercapto group.

Suitable salts of the compound of formula Vc may be those exemplified for the compound of formula IV.

Suitable reactive derivatives at the mercapto group of the compound of formula Vd may be a metal salt such as an alkali metal salt (six. A sodium or potassium salt).

This reaction can be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran or dimethyl sulfoxide or any other solvent which does not adversely affect the reaction. , preferably a solvent with Among the solvents, hydrophilic solvents can be carried out. The reaction is preferably carried out in a strong polarity for use in mixing with water. under weakly basic or approximately neutral conditions. When the compound of formula Vc and / or the thiol of formula Vd is used in free form, the reaction is preferably carried out in the presence of a base, e.g. an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal bicarbonate or an organic base such as trialkylamine or pyridine. The reaction temperature is not critical, and the reaction is usually carried out at room temperature or under heating. The reaction product can be isolated from the reaction mixture in a conventional manner.

The reaction between the compound of formula Vc and the compound I of formula Vd comprises the cases where the protected carboxy group or salts in the compound of formula V0 are converted to a free carboxy group, where the protected amino and / or imino group is converted to a free amino and / or imino group, and wherein the acyloxy group is converted to a hydroxy group, either during the reaction or by post-treatment.

Process g): The compound of formula If or a salt thereof can be prepared by treating the compound of formula Ve or a salt thereof with an acid. - Suitable salts of the compound of formula Ve are those exemplified for the compound of formula IV.

A suitable acid for use in this reaction may be e.g. be an inorganic acid (eg hydrochloric acid, hydrobromic acid or sulfuric acid) or an organic acid (eg formic acid or acetic acid).

This reaction is usually carried out in a solvent such as water, acetone, acetic acid or any other solvent which does not adversely affect the reaction. Among these solvents, hydrophilic solvents can be used in admixture with water.

The reaction temperature is not critical, and the reaction is preferably carried out under cooling or heating.

Process h): The compound of formula Ig or a salt thereof can be prepared by oxidizing a compound of formula Ve or a salt thereof.

Suitable oxidizing agents for use in this reaction - can e.g. be a Jones reagent used in a combination of sulfuric acid and chromium trioxide, manganese dioxide, a reagent used in a combination of dimethyl sulfoxide and N, N'-dicyclohexylcarbonamide. This reaction is usually carried out in a solvent such as water, acetone, dimethylformamide or any other solvent which does not adversely affect the reaction. These solvents can be used as mixtures. The reaction temperature is not critical, and the reaction is preferably carried out under cooling or at about room temperature.

Processes for the preparation of the starting material of formula III, i.e. the syn-isomer and the anti-isomer thereof, given by way of example, are explained in more detail below: A) Reaction of VI + VII-4-VIII (Scheme (1) (i)): The compound of Formula VIII can be prepared by reacting the compound of formula VI and the compound of formula VII.

This reaction is usually carried out in a solvent such as water, ethanol, acetone, ether, dimethylformamide or any other solvent which does not adversely affect the reaction. The reaction is preferably carried out in the presence of a base, e.g. an inorganic base or an organic base as indicated above. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating to the boiling point of the solvent.

B) conversion of Ix -> x (Scheme (1) (11)) and XXXII-ä XXXIII (Scheme (6) (ii)).

The compounds of formulas X and XXXIII can be prepared by oxidation of compounds IX and XXXII.

This oxidation reaction is carried out in the usual way, which is used for the conversion of a so-called activated methylene group to a carbonyl group. This means that the oxidation is carried out in the usual way, e.g. oxidation by using a conventional oxidizing agent such as selenium dioxide or potassium permanganate. This oxidation is usually carried out in a solvent which does not adversely affect the reaction, e.g. water, dioxane, pyridine or tetrahydrofuran.

The reaction temperature is not critical, and the reaction is preferably carried out under heating.

C) Reaction of XI - + XII (scheme (1) (iii)).

The compound of formula XII can be prepared by subjecting the compound of formula XI to an elimination reaction for the lower alkyl group. This method of elimination may include any conventional method used to eliminate a lower alkyl group, e.g. hydrolysis or reduction. In Hydrolysis using acid is one of the most preferred methods, and the acid used may comprise an inorganic acid (eg hydrochloric acid, or hydrobromic acid), an organic acid (eg formic acid, acetic acid or trifluoroacetic acid) or a mixture thereof. This reaction can be carried out in a solvent such as vaün, an organic solvent or a mixture thereof or without solvent.

The reaction temperature is not critical, and the reaction is preferably carried out under heating.

D) Reaction of XIII + XIV - IIIa (Scheme (1) (iv), min + xIv -> xxxv (Scheme 6) 11) and XXXIV + XIV -è IIIf (Scheme () (ii). The compounds of formulas IIIa, XXXV and IIIf can be prepared by reacting the compounds of formulas III, XXXIII and XXXIII, respectively.

XXXIV with the compound of formula XIV or a salt thereof.

A suitable salt of the compound of formula XIV may be an inorganic acid salt (eg the hydrochloride, hydrobromide or sulphate) or an organic acid salt (eg the acetate or p-toluenesulphonate).

This reaction is usually carried out in a solvent such as water, an alcohol (eg methanol or ethanol), a mixture thereof or any other solvent which does not adversely affect the reaction.

This reaction is carried out when the compound of formula XIV is used in salt form, preferably in the presence of a base, e.g. an inorganic base such as an alkali metal (eg sodium or potassium), an alkaline earth metal (eg magnesium or calcium) or a hydroxy or carbonate or bicarbonate thereof, or an organic base such as an alkali metal alkoxide (eg sodium methoxide or sodium ethoxide), trialkylamine (eg trimethylamine or triethylamine), N, N-dialkylamine (eg N, N-dimethylaniline), N, N-dialkylbenzylamine (eg N, N-dimethylbenzylamine) or pyridine. The reaction temperature is not critical, and the reaction is usually carried out under cooling or heating.

In this reaction, a mixture of syn- and anti-isomers of the compounds of formulas IIIa, XXXV or IIIf can be obtained depending on the reaction conditions, and in such cases the isomers can be resolved in the usual manner. For example, the mixture is first esterified, and the resulting esters are cleaved, e.g. by chromatography to give each isomer separately. Each of the cleaved isomers of the esters is hydrolyzed in a conventional manner to give the corresponding syn- or anti-carboxylic acid.

To prepare the syn-isomer of the compounds of formula IIIa, XXXV or IIIf selectively and in high yield, the reaction is preferably carried out under approximately neutral conditions. 1-3) conversion of xv-e: m (Scheme (a) (1)) and XXXIV - + XXXVI (Scheme (6) (ii)).

The compounds of the formulas XVI and XXXVI can be prepared by reacting the compounds XV and XXXIV with hydroxylamine or a salt thereof.

Suitable salts of hydroxylamine are those salts which have been mentioned in connection with formula XIV.

The reaction conditions for this reaction are those indicated for the process XIII + XIV -9 IIIa, XXXIII + XIV - + xxxv and 10 15 20} 0 35 40 .31 457 351 XXXIV + XIV - + IIIf as indicated under D).

F) Conversion of xvII -> xvnI (scheme (2) (11)), XXIV - + XXV (scheme (4) (ii), XXVI -4 XXVII (scheme (5)) and XXXVII J »xxxvIII (scheme (6) ) (111)).

The compounds of formulas XVIII, XXV, XXVII and XXXVIII can be prepared by alkylation of compounds XVII, XXIV, XXVI respectively. XXXVII.

The alkylating agent used in this alkylation reaction can e.g. be di-lower alkyl sulphate (tuex. dimethyl sulphate or diethyl sulphate), diazo-lower alkane (eg diazomethane or diazoethane), lower alkyl halide (eg methyl iodide or ethyl iodide) or lower alkyl sulphonate (eg methyl p- toluenesulfonate).

The reaction using di-lower alkyl sulfate, lower alkyl halide or lower alkyl sulfonate is usually carried out in a solvent such as water, acetone, ethanol, ether, dimethylformamide or any other solvent which does not adversely affect the reaction.

This reaction is preferably carried out in the presence of a base, e.g. an inorganic base or an organic base as indicated above.

The reaction temperature is not critical, and the reaction is usually carried out under cooling or heating to about the boiling point of the solvent. The reaction using diazoalkane is usually carried out in a solvent such as ether or tetrahydrofuran.

The reaction temperature is not critical, and the reaction is usually carried out under cooling or at room temperature. e) Reaction of xvIII -ß IIIb (Scheme (2) (11)) and xJocvIII -> Ing (Scheme (6) (111) - The compounds of formulas IIIb and IIIg can be prepared by subjecting compounds XVIII and XXXVIII to hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases can be Lex. be an inorganic base or an organic base such as an alkali metal (eg sodium or potassium), an alkaline earth metal (eg magnesium or calcium), a hydroxide or a carbonate or bicarbonate thereof, trialkylamine (eg trimethylamine or triethylamine), picoline, 1,5-diazabicyclo [3.3.0] non-5-ene, 1,4-aiazatincycloo / z, 2,2 / o1 Suitable acids are e.g. an organic acid (eg formic acid, acetic acid, propionic acid or trifluoroacetic acid) or an inorganic acid (eg hydrochloric acid, hydrobromic acid or sulfuric acid). The reaction is usually carried out in a solvent such as water, an alcohol (eg methanol or ethanol), a mixture thereof or any other solvent which does not adversely affect the reaction. . A liquid base or acid can also be used as a solvent. The reaction temperature is not critical, and the reaction is usually carried out under cooling or heating.

H) Turnover of XIX -å IIIc (Scheme (3)).

The compound of formula IIIc can be prepared by acylating the compound of formula XIX.

The agent used for the acylation and the reaction conditions for this reaction are those exemplified in process c).

I) Turnover of XX -à XXXI (Scheme (4) (1)).

The compound of formula XXI can be prepared by nitrosation of the compound of formula XX.

The nitrosating agent used for this reaction may be any common agent which results in the formation of a C-nitroso compound on reaction with an activated methylene group, e.g. nitric acid, alkali metal nitrite (eg sodium nitrite) or lower alkyl nitrite (eg isopentyl nitrite or tert-butyl nitrite).

When a salt of a nitric acid is used as the nitrosating agent, the reaction is usually carried out in the presence of an acid, e.g. an inorganic acid or an organic acid (eg hydrochloric acid or acetic acid). When using an ester of nitric acid, the reaction is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. This reaction is usually carried out in a solvent such as water, acetic acid, benzene; alcohol (eg ethanol or methanol) or any other solvent which does not adversely affect the reaction.

D The reaction temperature is not critical, and the reaction is usually carried out under cooling or at room temperature.

J) conversion of xx: + xxII -4 xxIn (scheme (4) (within min + 10:11 -> xxïx (scheme (5)).

The compounds of formula XXIII and XXIX can be prepared by reacting the compounds of formulas XXI and XXVIII with a compound of formula XXII.

This reaction is usually carried out in a solvent such as water, an alcohol (eg methanol or ethanol), benzene, dimethylacetamide, dimethylformamide, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely affect the reaction. . 10 15 ha o ß) \ J '| 33 357 351 The reaction temperature is not critical, and the reaction is usually carried out at a temperature between room temperature and approximately the boiling temperature of the solvent.

To prepare the syn-isomer of the compound of formula XXIII or XXIX selectively and in high yield, it is necessary to use the syn-isomer of the starting compound of formula XXI or XXVIII, and this reaction is preferably carried out under approximately neutral conditions in the presence of a base as indicated above.

Preferred examples of bases may be a weak base such as an alkali metal acetate (eg sodium acetate or potassium acetate), alkali metal bicarbonate (eg sodium bicarbonate or potassium bicarbonate) or an alkali metal carbonate (eg sodium carbonate or potassium carbonate) .

K) Turnover of XXIII - + XXIIIa (scheme (Ä) (i)), XXV -4 IIId (scheme (4) (11)), XXIX -å IIIe (scheme (5)) j XXXIII -4-XXXIV (scheme (6) (ii)) and XXXV -9 IIIf (Scheme (6) (ii)).

The compounds of formulas XXIIIa, IIId, IIIe, XXXIV and IIIf can be prepared by subjecting compounds XXIII, XXV, XXIX, XXXIII and XXXV to elimination reactions for the carboxy-protecting group.

In this elimination reaction, conventional methods used to eliminate protected carboxy, e.g. hydrolysis, be used. When the protecting group is an ester, it can be eliminated by hydrolysis.

This hydrolysis is carried out in the same manner as described for reactions XVIII - + IIIb and XXXVIII - + IIIg as indicated under G). '_ L) Turnover of XXVII _- *> XXVIII (Scheme (5)).' The compound of formula XXVIII can be prepared by halogenating the compound of formula XXVII. The halogenating agent used in this reaction may be a conventional halogenating agent used in the halogenation of so-called activated methylene groups, e.g. halogen (eg bromine or chlorine), sulfuryl halide (eg sulfuryl chloride), hypohalite (eg chlorine subacidity, bromine subacidity or sodium hypochlorite) or N-halogenated imides (eg N-bromosuccinimide, Nfbromophthalimide or N- chlorosuccinimide).

This reaction is usually carried out in a solvent such as an organic acid (eg formic acid, acetic acid or propionic acid), carbon tetrachloride or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical, and the reaction is usually carried out under cooling, at room temperature or during heating.

M) Turnover of XXX _) XXXI (scheme (6) (1)) and xxxIx -æ Inn (scheme (7)).

The compound of formula YXXI may be prepared by reacting the compound of formula XXX or a reactive derivative thereof at the amino group or a salt thereof with an amino protecting agent, and the compound of formula IIIh may be prepared by reacting the compound of formula XXXIX or a reactive derivative thereof at the amino group or a salt thereof with an amino protecting agent.

Suitable reactive derivatives at the amino group of the compound of formula XXX or XXXIX and suitable salts of the compound of formula of XXX or XXXIX are the same as indicated in connection with the reactive derivatives of the amino group of the compound of formula II resp. salts of the compound of formula II.

Suitable amino protecting agents may be acylating agents, which may be an aliphatic, aromatic or heterocyclic carboxylic acid and the corresponding sulfonic acid, haloformic acid ester, isocyanic acid ester and uric acid and the corresponding thioacid thereof and the reactive derivatives of the above acids.

Suitable reactive derivatives of the above acids may be the same as those indicated in connection with process c). Examples of protecting groups (eg acyl groups) to be introduced into the amino group of the compound of formula XXX or XXXIX of the above-mentioned amino protecting agent (eg acylating agent) may be the same protecting group (eg acyl group ) as indicated in connection with the protective part (eg the acyl part) in the term "acylamino". This amino-protective reaction is carried out in the same manner as illustrated in connection with the reaction of the compound of formula II and the compound of formula III (process a).

N) Provision of XXIIIb -e- XXXIII (Scheme (6) (11)).

The compound of formula XXXIII can be prepared by hydrolysis of the compound of formula XXIIIb.

This hydrolysis is carried out in the presence of alkali metal bisulfite (eg sodium bisulfite), titanium trichloride, an inorganic; or organic acid such as hydrohalic acid (eg hydrochloric acid or hydrobromic acid), formic acid or nitric acid. Hydrogen halide acid is preferably used in combination with an aldehyde (eg formaldehyde).

This. turnover is usually carried out. in a solvent such as water, aqueous alcohol (eg aqueous methanol or aqueous ethanol), aqueous acetic acid or any other solvent which does not adversely affect the reaction .

The reaction temperature is not critical, and the reaction is usually carried out at room temperature or under heating. In this reaction, a protected carboxy group may. converted to a free carboxy group. In the above reactions and / or in post-treatment after the reactions, the above tautomeric isomer may converted to other tautomeric isomers.

If the compound of formula I is obtained in the form of the free acid in the 4-position, and / or if the compound of formula I contains a free amino group, it can be converted into a pharmaceutically acceptable salt as indicated above by a conventional method.

As for the compound of the invention, more specifically, it is characterized by the formula 1 R -Ü-Za N-oazf wherein R1 is a group of the formula: where R7 is (C1-c6> alkyl and Rzf is (C1-cs) - alkyl, (C 2 -C 6) alkenyl, (C 1 -C 6) -alkylthio (C 1 -C 6) -alkyl, carboxy (C 1 -C 6) -alkyl, (C 1 -C 6) -alk-oxycarbonyl (C 1 -C 6) -alkyl, phenyl (C1-C6) -alkyl, halogen-substituted phenyl (C1-C6) -alkyl, halogen- and hydroxy-substituted phenyl (C1-C6) -alkyl, phenyl (C2-G6) -alkenyl, (C1-C6) -alkanoyloxy ( C 1 -C 6) -alkyl, (C 1 -C 6) -alkoxy (C 1 -C 6) -alkyl or isoxazolyl (C 1 -C 6) -alkyl; or R] is a group of the formula: 'where R 7 is amino, (C 1 -C 6) ) -alkanoylamino, halo (C1-C6) -alkanoylamino, (C1-CG) -alkanesulfonylamino, (C1-C6) -alkoxycarbonylamino or hydroxy and Rzf are butyl, isobutyl, pentyl, hexyl, propyl, benzyl, oinnamyl, ( C1-C6) -alkylthio- (C1-G6) -alkyl, carboxy (C1-C6) -alkyl, (C1-C6) -alkoxycarbonyl (C1-C6) -alkyl, halogen-substituted phenyl (C1-C6) -alkyl, halogen- and hydroxy-substituted phenyl (C1-C6) -alkyl (C1-C6) -alkanoyloxy (C1-C6) -al alkyl, (C1-C6) -alkoxy (C1-C6) -alkyl or isoxazolyl (C1-C6) -alkyl, with the proviso that R7 is (C1-C6) -alkanoylamino, halo (C1-C6) -alkanoylamino, - (C 1 -C 6) -alkanesulfonylamino, (C 1 -C 6) -alkoxycarbonylamino or hydroxy when R is butyl, isobutyl, pentyl, hexyl or propyl; or R 1 is a group of the formula: S wherein R 7 is amino, formamido, t-pentyloxycarbonylamino or mesylamino and R 2f is ethyl, isopropyl or allyl, with the proviso that R 7 is formamido, t-pentyloxycarbonylamino or mesylamino when R 2f is ethyl or isopropyl; or R 1 is a group of the formula: wherein R 7 is formamido, mesylamino, ethoxycarbonylamino, 2,2,2-trifluoroacetamido, acetamido or t-pentyloxycarbonylamino and R 2f is methyl; and Za is carboxy or (G1-C6) -alkoxycarbonyl; and salts thereof. For the process according to the invention for the preparation of the above-mentioned compound it is characterized in that: a) a compound of the formula is reacted: R 1 -co-za wherein R 1 and Za have the meaning given above, or salts thereof, with a compound of the formula : 2f _ R -ONHZ wherein Rzf has the meaning given above, or a salt thereof, - or “b) exposes a compound of the formula: R * -cz g-oazf wherein R1 and Rzf have the meaning given above, and Z is (C1 -C6) -alkoxycarbonyl, for an elimination reaction to remove the carboxy protecting group, to form a compound of the formula: R * -c-coon -Orzf zf each has the meaning given above, or salts wherein R1 and R thereof, or c) reacting a compound of the formula: wherein R 2 is butyl, isobutyl, pentyl, hexyl, propyl, benzyl, cinnam- NY1, (C 1 -C 6) -alkylthio- (CT- C6) -alkyl, carboxy (C1-C6) -alkyl, (C1-C6) -alkoxycarbonyl- (C1-C6) -alkyl, halogen-substituted phenyl- (C1-C6) -alkyl, halogen- and hydroxy-substituted phenyl (C1-C6) -alkyl, (C1-C6) -alkanoyloxy (C1-C6) -alkyl, (C1-C6) -alkoxy (C1-C6) -alkyl or isoxazolyl (C1-C6) -alkyl; and Za is carboxy or (C1-C6) -alkoxycarbonyl, or a reactive derivative thereof at the amino group or a salt thereof, with an amino protecting agent to form a compound of the formula: 7a N-oR2 wherein R2 and Za have the meaning given above, and R7a is (C1-C6) -alkanoylamino, halo (C1-C6) -alkanoylamino, (C1-C6) -alkanesulfonyl-amino or (C1-C6) -alkoxycarbonylamino, or salts thereof, 'or d] react a compound with the formula: X-CH 2 CO-C 2 -OR 2g _, 2 H wherein Z has the meaning given above, X is halogen and R g is (C 1 -C 4) -alkyl, with a compound of the formula: 1 6 _ 7b R R 7b is (c 1 -c 6) -alkyl or (c 1 -C 6) -aalkyl, forming a compound of the formula: -z R 7c 1: 1 E-onzg wherein Z and R 2g have the meaning given above, and R 7c is ( C1-C6) -alkyl or hydroxy.

The compound of formula I and pharmaceutically acceptable salts thereof are all hitherto unknown compounds which have potent antibacterial activity, inhibit the growth of a wide variety of pathogenic microorganisms, including gram-positive and gram-negative bacteria, and they are valuable as antibacterial agents. In particular, the compound of formula I, i.e. the syn-isomer, has a much stronger antibacterial action than the corresponding anti-isomer corresponding to the compound of formula I, therefore the compound of formula I, i.e. the syn-isomer, is characterized by being superior to the corresponding anti-isomer in terms of therapeutic effect. .

In view of the demonstration of the beneficial effect applicable to the compounds of formula I, illustrated by some representative compounds, the experimental data for the in vitro antibacterial activity, the experimental data concerning the protective effect against experimental infections in vivo and the acute toxicity. In addition, comparative experimental data are available. the in vitro antibacterial effect relative to the corresponding anti-isomer of the compound of formula I betr. Comparison.

Test compounds: 1) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] N-carbamoyloxymethyl # 3-cephem-4-carboxylic acid (syn-isomer), 2) 7f / 2-methoxy11mino-2- ( 3-nyaroxyphenyl) acecamido [L3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), 3) 7- [1-methoxyimino-2- ( 3-hydroxyphenyl) acetamido [3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), 4) 7- [2-methoxyimino-2- (3- hydroxyphenyl) acetamido [N- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-N-carboxylic acid (syn isomer), 5) 7-N-methoxyimino-2- (3- acetoxyphenyl) acetamido [1- (1,1, α-thiadiazol-2-yl) thiomethyl-3-cephem4-carboxylic acid (syn-isomer), 6) t 7- [2-methoxyimino-2- (2-amino -1,3-thiazol-4-yl) acetamido [3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), 7) 7- / 2 -methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido [N- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer ), 8) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] befalosporanic acid (syn-isomer),. 9) 7-N-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido / befalosporanic acid (anti-isomer), 10) 7- [ε-methoxyimino-2- (2 -formamido-1,3-thiazol-4-yl) acetamido [3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), II) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -C 3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( anti-isomer), 12) 7- [2-methoxy] amino-2- (2-formamino-1,3-thiazol-4-yl) acetylamino] -1 '457 351 cephalosporanic acid (syn isomer), 13) 7- / 2 -methoxyimino-2- (2-amino-1,3-ciazol-4-yl) acetamino / L3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer), 14) 7- [1-methoxyimino-2- (2-Amino-1,1-thiazol-4-yl) acetamido] - (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), 15) 7β-methoxyimino-2- (2-amino-1,5-thiazol-4-yl) acetamido [β] hydroxymethyl-3-cephem-α-carboxylic acid (syn-isomer), 16) 7- [2- methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido [3- (5-methyl-1,3,3-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn-isomer), 17) 7 - [@ - methoxyimino-2- (2-amino-1,5-tri azol-4-yl) acetamido [1-3- (4-methyl-GH-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) and 18) 7- [ε -methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido [15-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer). 1. In vitro antibacterial activity: Experimental method.

The in vitro antibacterial activity is determined by the dual agar plate dilution method described below.

A wooden loop filled with a culture of each of the test strains, grown overnight, 1 Trypticase soy culture fluid (108 viable cells / ml) is applied to cardiac infusion agar (HI agar) containing graded concentrations of antibiotics, and the minimum inhibitory concentration (MIC) is expressed / ng / hl after incubation at 37 ° C for 20 hours. ~ sid 40 WNW m flfifl ß m ~ o. = mn. @ mn.o = ,. o = .. Q m ~ @ .o wß. ° m..m @ m. ° m ~ .o mc.Q mP.m Q ~ .o @mP mß. @ M ~ w> .o wß. @ -M fifl a wzwpo fi m ß ~ «om fl cQ =: m: a mo.oo ~. @ @ ~ .Q mo. ° oN.om @. @ Om .. n_.m ° m._ @ m._ ° _. ° m ~. @ oP. @ wß.o mß.om ~. @ @mO @mo m flfi w fi wßw fl x m_.m Q ~ .o @ m. @ w ~ .o oP. ° @ m._ @ m. ~ m.N_ wß. @ fi ~. m o_.o m.N_ ° N. ° m. ~, .n_.m om @mP @ m._ ~ -Uw ~: Hz MHQU m fi§ U fl HOSumm ^ w_V AN .. AQPV ñmwv AQPV ñm_u ^ N_V ^ P_v ñopv nav fi mv. ñßv Aov ñmv ñqv nnv ÛNV ^ _v __ .. nmmc fi cunwwmxmmumm ^ Ha \ w = V UH: 4s7% ss1 uNUH3mwHm ¥ ®m% ßm mHHøpx «nmxmmHnm. It is clear from the experimental results that the compounds of formula I in question, i.e. the syn-isomers, have a much higher antibacterial activity than the corresponding anti-isomers. 2- Protective effect against experimental infections in mice: Experimental method: 4 week old male mice of the strain ICR, each weighing 20-23 g, are divided into groups of 8 mice each. The test bacterium is grown overnight at 37 ° C on HI agar and then suspended in 2.5-5% mucin solution to give a cell suspension for each inoculation. The mice are inoculated 0.5 ml of the suspension intraperitoneally.

A solution containing the test compound is injected subcutaneously into the mice at various doses 1 hour after inoculation. EDBO values are calculated based on the number of surviving mice for each dose after one week of observation.

The results are summarized in the following tables: 457 551 maamHhMonnmxLw | Ewmmo | n | Hhuws fl äowhoëmßhmxaHJ \ oU fl Emnmom ^ whu3m | Nvrm | oG fl E Auwëom fl ncæmv flfl äoumëumunß Na Ew fl x; . _ v mcwwwuume m ~ m. «@_c_O omñov @ °« com m ~ wo fi wo fi x °. «_ m fl umuuwm = Ax9š fi mu fi NS AMC« E fl xouswøu Aw fi v ^ n fl v HE \ umH: Huv mw fi »nmwc fi mmmwmwxmxmmx om \ ¶ 7 \ uwHHwu w fi um »xmn_ ^ m: E \ mEv ^ u: mn: xnäwU om ^ HE \ ms V cwssmuw æu: w> cm: mv> m wønm> | uHz wc fl caew amxmmnmß maamcmnoawoHmmmoow fl smml x fl smpm fl PP ~ _. ° .wQ.c mQ °; v mæ fi ov ~ fl. ~ Mß.o @mo no. ° w no. ° w wo fi - _ @ ~ fifl ou m. ~ Ñ m> .Q w> _0 nQ. ow ~. ° wo fl med xw ~ fl nu «» ~; uwm ßmu. ñqv fi mv ^ «_ U Amy« ewu. «. .m. .flfi v .æ. He \ HwH. f fi mo ßw fl »nuwc fl cmnnuwxnwnnm amws fi cmnnmmxæwamm | mmnxw> fl ~ mse om \ 7 _. \ uw fl Hwu m fl uvuxnn ^ msE \ mE. ^ ucmu: xnømv nu ^ ~ E \ m: V cmssmuw æucm> cm cwu> m wønm> aoH2 zmxmmnmm mmms man nmco fi vxwu flfl øa fi upcmë fi aønxw> w: mxu »os ßßä flfl mw-MWSDWQBM -a @> m HHwQd-.m .wc fl cmsw 457 551 43 »m fi hKonnmx |: | Eøwwo | n | Hznms -o fl» ^ ~> | w | HoN «H @ m fl» «@. nH | H» » @ sïmvum-How fi smuwum ^ H> | H | Ho ~ m »» w »» = HV | ~ _ | »| EsH ~» m = ua mz | ~ mu @>. @ ~ .Q ~ .Qw wo fl ~ mH. o mßo.o wmm.o mw fifi oo mH.m @ m. ° mß.o .wo fi mod x m_m m fl zu fl uwzumm mz Nmu ^ HV ^ ~ v «mz | Nmv AH. AN. Ha \ ww ~ .uawomw fi n fl nmwc fl cmhnwwxmwnmw nmwz fl cmnmmwxwmæmu | wmuxw> fl ~ msë om \ \ uwHHwu m fl mmuxmn ^ msE \ mEV ^ ßcm »: xn3wV om. ^ fi E \ m: V cwëëmuw møcw>: m: mv> m m fl nm>. | UHE. m_ ~ H N.o wo fi oø fl fifi ou wm fi. ~ m ~ 0. ° m. ~ H wm_H wo fi vo fi x m_ ~ «fl; uHHw; uwm Ewxøu fl uwu Amy E fl xou fl mwü Amy HE \ umH ramo mw fl u hmww fi nmxmmwc mxmxmwm mmwm mxmmwc mmx. \ nmH ~ wu w fi umuxmn ^ m: E \ mE “fi ucm» Sznsmvømom ^ aE \ m: \. cwëëwum møcw> cm: w fl> @ wønm> 1uH2 uwxwmnmm wc fl case 10 15 20 457 351 44 3. Acute toxicity to mice.

Mice of the same strain as in the above-described protection experiment against experimental infections were used in groups of 10 mice each. The test compound (8) (2 g) is administered intravenously to these mice. All mice survived without but after 1 week of observation.

For therapeutic administration, the compound of formula I prepared is used in the form of a conventional pharmaceutical composition containing this compound as an active substance in admixture with pharmaceutically acceptable carriers, e.g. an organic or inorganic solid or liquid excipient suitable for oral, parenteral or exothermic administration. The pharmaceutical preparations may be in solid form, e.g. as capsules, tablets or dragees, as an ointment or as a suppository or in liquid form, e.g. as a solution, suspension or emulsion. If required, excipients, stabilizers, wetting or emulsifying agents, buffers and other conventionally used tin beads may be incorporated into said preparations.

While the dosage of the compounds may vary from and also depends on the age and condition of the patient, the nature of the disease and the nature of the compound of formula I used, the average single dose is about 50 mg, 100 mg, 250 mg and 500 mg. mg of the compound of formula I has been shown to be effective in the treatment of diseases caused by pathogenic bacteria.

Generally, amounts between 1 mg and 1000 mg or even more can be administered to a patient.

The invention is further illustrated by the following Examples and Preparations. Example 45 In 0.26 g of phosphorus oxychloride is added under ice-cooling to 0.15 g of dimethylformamide, and the mixture is heated for 1 hour to 40 ° C. 1.5 ml of ethyl acetate are added, and to the mixture is added in a portion 0.5 g of 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetic acid (syn-isomer) with stirring and ice-cooling, after which the resulting mixture is stirred for 20 minutes. at 0-5 ° C. On the other hand, 1.2 g of bis- (trimethylsilyl) acetamide is added to a suspension of 0.53 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in 7 ml of ethyl acetate, and the mixture is stirred at room temperature. To this solution is added dropwise the above-described ethyl acetate solution at -20 ° C, and the mixture is stirred for 2 hours at a temperature between -10 and -20 ° C. To the reaction mixture is added 20 ml of water at a temperature below -25 ° C, and 20 ml of ethyl acetate are added, after which the mixture is stirred. Insoluble material is filtered off and the ethyl acetate phase is separated. 1.5 ml of water are added to the ethyl acetate phase, and the mixture is adjusted to pH 7.5 with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous phase is separated and washed with methylene chloride, and the methylene chloride in the aqueous phase is removed by bubbling nitrogen gas. The aqueous solution is adjusted to pH 2.2 with 10% hydrochloric acid, and the precipitated substance is isolated by filtration and dried, whereby phase 0.28 g of 7- / 2-methoxyimino-2- (2-methyl-1,3-thiazole-4) -yl) -acetamido [1- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). _ 2: xx-spektrum (nujan: 1780, 1110 ag 1675 mfl.

NMR Spectrum (do-oM 50) = δ = 9.65 (ia, d, J lonz), 7.66 (ln, S), 5.8l (ln, ad, J = 5, 10z), 5.15 (in, a, J snz), 4.31 (zu, Ang, J = 13H2), 3.93 (BH, s), 3.90 (3u, s), 3.70 (23, Aag, J = isaz) and 2.65 (3H, s) ppm.

Example 2 0.89 g of phosphorus oxychloride and 0.44 g of dry dimethylformamide are mixed under ice-cooling and then heated to 4000 l for 30 minutes. 20 ml of dry methylene chloride are added and then distilled off. To the residue is added 10 ml of dry ethyl acetate and then 1.8 g of 2-methoxy-imino-z- (z- (α, 2,2-trifluoroacetam1a <>) - 1,1-thiazol-h-yl / acetic acid (syn. -isomer) while stirring and ice-cooling. The mixture is stirred for 40 minutes. at the same temperature, whereby a clear solution is obtained. On the other hand, 6.36 g of trimethylsilylacetamide are added to a suspension of 1,65 g of 7-aminocephalosporanic acid in 25 ml of dry ethyl acetate while stirring at room temperature, after which the mixture is stirred for one hour to give a clear solution. To this solution is added at once the ethyl acetate solution recovered as described above with stirring at a temperature between -20 and -25 ° C, and the resulting mixture is stirred for 2 hours at the same temperature. To the reaction mixture is added 30 ml of water at the same temperature, after which the mixture is stirred for 5 minutes. at room temperature. The ethyl acetate phase is separated, and the aqueous phase is further extracted with ethyl acetate. The ethyl acetate phases are combined and 50 ml of water are added.

The mixture is adjusted to pH 7.5 with sodium bicarbonate, and the hydrogen phase is separated. 40 ml of ethyl acetate are added to the aqueous phase, after which the mixture is adjusted to pH 2.5 with 10% hydrochloric acid with stirring and ice-cooling. The ethyl acetate phase is separated, and the aqueous phase is extracted twice more with 30 ml of ethyl acetate. The ethyl acetate phases are combined, washed with an aqueous solution of sodium chloride and treated with activated carbon. The solvent is distilled off to give 3.05 g of 7- [2-methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido / befalosporanic acid (syn-isomer)). m.p. 205 ° C (dec.). 1650 cm_l.

IR Spectrum (nujol): 3250, 1790, 1735, 1680 NMR Spectrum (ds-oMsO) = δ = 9.8 (ln, d, J = 83 :), 7.55 (ln, s), δ, 88 (1H, dd, J = 5, 892), 5.25 (1H, d, J = SHZ), 4.8 (2H, Aßq, J = 13Hz), 3.95 (an, S), 3.59 ( zu, bred S) 2.03 (sn, S) ppm.

Example Q 3.0 g of 2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid and 40 ml of dry ethyl acetate are added at 0-5 ° C with stirring to a suspension of a Vilsmeier reagent prepared in a conventional manner starting from 1, 0 g of dry dimethylformamide and 2.1 g of phosphorus oxychloride in 4.0 ml of dry ethyl acetate, and the resulting mixture is stirred for 30 minutes at the same temperature. (syn-isomer) The solution was added at -10 ° C with stirring to a solution of 3.7 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-U-carboxyl acid, 10.3 g of trimethylsilylacetamide and 6.8 g of bis (trimethylsilyl) -acetamide in 80 ml of dry ethyl acetate, and the mixture is stirred for 1.5 hours at the same temperature. After adding 50 ml of water to the reaction mixture, an insoluble material is filtered off, and the ethyl acetate phase in the filtrate is separated and extracted with 50 ml of aqueous sodium bicarbonate solution. The aqueous extract is washed with ethyl acetate and acidified to pH 2.0 with concentrated hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried to give 2.3 g of 7-L2-ethoxyimino-2- - (2-formamidothiazol-4-yl) acetamido] -5- (1,4,4) -thiadiazol-2-yl) thiomethyl-5-cephem-4-carboxylic acid (syn-isomer) in the form of a powder. iii spectrum (nujoip 5250, 1780 and 1680 cnfl.

NMR Spectrum (d 6 -DMSO): δ (ppm) = 1.31 (BH, t, J = 7.0Hz), 3.77 (2H, m), 4.28 (2H, q, J = 7, 0Hz), 4.45 (2H, ABq, J = 1}, 0Hz), 5.18 (1H, d, J = 5.4Hz), 5.84 (1H, dd, J = 5.4 and 9, 8Hz), 7.42 (1H, s), 8.55 (1H, s,), 9.57 (1H, s), 9.66 (1H, d, J = 9.8Hz).

Example 4 In a conventional manner, a Vilsmeier reagent is prepared from 1.0 ml of dry dimethylformamide, 4 ml of dry ethyl acetate and 2.1 g of phosphorus oxychloride. Then 45 ml of dry ethyl acetate and 2.85 g of 2-methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) are added. This solution is added at -10 ° C to a stirred solution which has been prepared by stirring for 1 hour at 40 ° C a mixture of 4.5 g of 7-amino -} - (1-hexyl-1H-tetrazol-5-yl). ) thiomethyl-5-cephem-4-carboxylic acid, 10.4 g of trimethylsilylacetamide and 90 ml of dry ethyl acetate, and the resulting mixture is stirred for 1.5 hours at -5 - 10 ° C. To the reaction mixture is added 50 ml of water, and the ethyl acetate phase is separated. Then 40 ml of water are added, and the mixture is adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. The aqueous phase is separated, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried under reduced pressure to give 6.18 g of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamide] -5- - (1-hexyl -1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in the form of a powder.

Ira spectrum (nugoi). 5250, 1777 and 1680 cnfl.

Niine spectrum (d6nM 50) = s (ppm) = 0.85 (5H, t, J = 5.5Hz), 1.65 (OHH m), 2.78 (2H, m), 3.72 (2H, m ). 3.93 (3 H, S). 4.07 '* 4.59 (un, m), 5.17 (in, d, J = 5.0Hz), 5.83 »(111, ad, J = 5.0 and 8.2Hz), 7 , 46 (in, s), 9.56 (in, s), 9.70 (in, d, J = 8.2Hz). 7457 351 - 10 15 20 25 30 35 -The mixture is stirred for 50 min. at the same temperature. Example S 0.05 g of water is added to a suspension of 1.0 g of 2-allyloxyimine-2- (2-amine-1,3-thiazin-u-yl) a: t-acid (syn-isons) in 10 and tetrahydrofuran. At 0-5 ° C, 0.84 g of phosphorus oxychloride is added, and the mixture is stirred for 20 minutes at the same temperature. Then 0.66 g of trimethylsilylacetamide is added and the mixture is stirred for 20 minutes at the same temperature, then 0.84 g of phosphorus oxychloride is added, and the resulting mixture is stirred for 20 minutes at 0-5 ° C. Then 0.45 g of dimethylformamide is added, and the resulting mixture is stirred for 1 hour at the same temperature. The resulting solution is initially added at -5 - + 5 ° C and pa value 7.0-8.0 to a solution which has been prepared by adding 1.5 ml of acetone and 15 ml of tetrahydrofuran to a solution of 1.45 g of 7-amino-5- - (1,5, β-thiadiazol-2-yl) thiomethyl-5-cephem-4-carboxylic acid in a mixture of 0.42 g of sodium bicarbonate and 10 ml of water. The resulting mixture is stirred for 1.2 hours under ice-cooling, keeping the pH of the mixture between 7.0 and 8.0 and then adjusting to pH 7.5. An insoluble matter is filtered off, and the filtrate is washed with ethyl acetate. The aqueous phase is adjusted to pH 6.0, and the organic solvent in the aqueous phase is distilled off under reduced pressure. The remaining aqueous phase is adjusted to pH 4.0, and an insoluble material is filtered off. The filtrate is adjusted to pH 5.0, and precipitated material is isolated by filtration and dried to give 1.5 g of 7-E2-allyloxyimino-2- (2-amino-1,5-thiazol-4-yl) acetamido] -5- (1,5,4-thiadiazol-2-yl) thiomethyl-5-cephem-4-carboxylic acid (syn-isomer). IR Spectrum (nujol): 5550, 1780, 1680 and 1650 cm -1.

NMB Spectrum δ (d 6 -EMSO): δ (ppm) = 9.65 (1H, d, J = 8Hz), 9.57 - (1H, S), 7.23 (2H, m), 6.77 ( 1H, S), 6.10 (1H, m), 5.83 (1H, dd, J = 5.3H2), 5.45 (1H, m), 5.25 (1H, m), 5.17 (1H, Ö, J = SHZ), 4.61 (2H, m), 4.47 (2H, ABq, J = 14Hz), 5.72 (2H, m).

Example Vilsmeier's reagent was prepared starting from 0.209 g of dry dimethylformamide, 0.54 g of phosphorus oxychloride and 0.75 ml of dry ethyl acetate in a conventional manner. Dry tetrahydrofuran in an amount of 6.5 ml is added and then 0.65 g of 2-methylthiomethoxyimin-2- (2-phenimethiazion-4-yl) acetic acid (syn-isomer) at 0 ° C.

The resulting mixture is added dropwise at -5 to 0 ° C to a stirred solution of 1.25 g of 7-amino-5- (1-allyl-1H-tetrazol-5-yl) thiomethyl- 5-Cephem-4-carboxylic acid in a mixture of 10 ml of water and 10 ml of acetone, keeping the pH at 7.5 with the aid of triethylamine, and stirring the mixture for 50 minutes. at the same temperature at pH 7.5. To the reaction mixture is added 60 ml of ethyl acetate, and the mixture is adjusted to pH 2.5 with 10% hydrochloric acid. The insoluble matter is filtered off, and the filtrate is extracted twice with ethyl acetate. The combined extracts are washed twice with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. The solvent is distilled off, and the residue is triturated with diethyl ether to give 1.03 g of a yellow powder of 7- (2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -5- (1-allyl-1H- tetrazol-5-yl) thiomethyl-5-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nuJo1): 3250, 3200, 1780, 1670, 1540 cm -1.

NMR Spectrum (do-DMSO), δ (ppm): 2.25 (3H, s), 5.72 (2H, s), 4.58 (2H, ABq, J = 14Hz), 4.8-5 Δ (7H, m), 5.7-6.4 (2H, m), 7.48 (1H, S), 3.55 (1fl in S), 9.75 (1H, d, J = 8Hz) . 12.59 (1H, broad s).

Preparation 1 l) A mixture of 12.4 g of sodium nitrite in 150 ml of water is added dropwise with stirring at 5-700 to a solution of 30 g of ethyl 4-bromoacetoacetate in 200 ml of acetic acid, and the mixture is stirred for 12 hours at 1000. 200 ml water is added to the reaction mixture, and the resulting mixture is extracted with 500 ml of ether. The extract is washed twice with 200 ml of water and with 200 ml of an aqueous solution of sodium chloride and dried over magnesium sulphate. The solvent is distilled off under reduced pressure to give 32.6 g of tan crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of 49 l of syn and anti-isomers).

In-spectrum (f11m) = 3350, 1740, 171o and 1620 cm -1.

NMR Spectrum (CDCl 3): δ = 8.75 (2H, broad s), 4.55 (8H, m) and 1.55 (6H, m) ppm. 2) 160 g of powdered potassium carbonate are added to a solution of 152 g of ethyl 2-hydroxyiminoacetoacetate (a mixture of syn- and anti-isomers) in 500 ml of acetone. 150 g of dimethyl sulphate are added dropwise with stirring over 1 hour at 45-50 ° C, and the mixture. Insoluble material is filtered off, and the filtrate. The filtered insoluble matter is stirred for 2 hours. evaporate under reduced pressure. 10 15 20 ZS 30 35 457 351 c 50 the material is dissolved in 500 ml of water, and this solution is added to the residue. The mixture is extracted twice with 300 ml of ethyl acetate.

The extract is washed twice with 200 ml of water and with 200 ml of a saturated aqueous solution of sodium chloride and dried over magnesium sulphate.

The solvent is distilled off under reduced pressure, and the residue is distilled off under reduced pressure to give 145.3 g of a colorless oil of ethyl 1-2-methoxyiminoacetoacetate (a mixture of syn- and anti-isomer), kpu. 55-64 ° c / b, 5 mm Hg.

Spectrum (film): 1745, 1695 and 1600 cm -1.

NMR Spectrum (CDCl 3): δ = 4.33 (4H, q, J = 8Hz), 4.08 (BH, s), (3H, S), 2.40 (3H, s); 1.63 (3H, S) and 1.33 (6H, t, J = 8Hz). 3) 100 g of bromine are added dropwise over the course of 40 minutes. under reflux to a solution of 100 g of ethyl 2-methoxyiminoacetoacetate 3.95 (a mixture of syn- and anti-isomers) in a mixture of 300 ml of carbon tetrachloride and 300 ml of acetic acid. The mixture is stirred at 70-80 ° C until the evolution of hydrogen bromide has ceased. The reaction mixture is washed twice with 300 ml of water, with an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The solution is treated with 2 g of activated carbon and evaporated under reduced pressure to give 120.8 g of ethyl 1-2 and dried over magnesium sulphate. methoxyimino-4-bromoacetoacetate (a mixture of syn- and anti-isomers).

Spectrum (f11m): 1740, 1705 and 1600 cm -1.

NMR spectrum (cDc13) = δ = 4.17-4.54 (BH, m), (BH, s) and 1.33 (SH, t, J = 8Hz) ppm. 4) A mixture of 11, 1 g of selenium dioxide, 250 ml of dioxane and 5 ml of water are stirred for 15 minutes at 110-11500 to give a yellow solution, 26.4 g of ethyl 2- (2-methylamino-1,3-ciazole-M- After stirring for 1 hour, the reaction mixture is decanted during heating and cooled, precipitating yellow crystals, washing with dioxane and ether and drying to give 23.5. g ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylate.

IR spectrum (nujo1) = 3300, 1718 and 1682 cm -1. 5) 13.9 g of ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylate are added with stirring at room temperature to a solution of 5.0 g of sodium hydroxide in 150 ml of water. temperature, set to pH value 7 with conc. hydrochloric acid and washed with ethyl acetate. The aqueous phase is adjusted to pH 0.5 with conc. hydrochloric acid, whereby yellow crystals precipitate. The crystals are isolated by The crystals are isolated by filtration. The mixture is stirred for 1 hour at room temperature, washed with water and dried to give 10.16 g of 2- (2-mesylamino-1,3- thiazol-4-yl) glyoxylic acid.

In-spectrum (nu¿61) = 3350, 1725 and 1650 6m'l. 6) To a solution of 14 g of ethyl 2- (2-amino-1,3-thiazol-4-yl) acetate in a mixture of 40 g of pyridine and 300 ml of methylene chloride is gradually added 70 ml of a diethyl ether solution of chloroformic acid -tert.pentyl ester_ containing 0.35 mol of chloroformic acid tert.pentyl ester over the course of 10 min. at -20 ° C with stirring, and the mixture is stirred for 2 hours at the same temperature and stirred for another 0.5 hour at 0 ° C.

After the reaction, the reaction mixture is poured out into 200 ml of water, after which the organic phase is separated. The organic phase is washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water in the order indicated and then dried over magnesium sulphate. The solvent is distilled off from the organic phase to give 12 g of a dark brown oil of ethyl 2- (2-tert-pentyloxycarbonylamino-1,1-thiazol-4-yl) acetate.

Ile spectrum (liquid 1667 and 1660 (co) 61151.

NMR Spectrum (CDCl 3): δ = 3.75 (2H, s) and 6.75 (1H, s) ppm. 7) 0.3 g of ethyl 2- (2-tert-pentyloxycarbonylamino-1,1-thiazol-4-yl) -acetate and 0.1 g of selenium dioxide are treated in the same manner as described in Preparations 6 - 4) to give 0.22 of a brown oil of ethyl 2- (2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylate.

IR spectrum (liquid Ea): 1720 and 1690 (CO) cm -1.

NMR Spectrum (CDCl 3): δ = 8.3 (1H, s) ppm. 8) 2.8 g of ethyl 2- (2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylate and a solution of 0.54 g of sodium hydroxide in 20 ml of water are treated in the same manner as described for Preparation 6-5) to give a brown powder of 1.75 g of 2- (2-tert.pentyloxycarbonylamino-1,3-thiazol-H-yl) glyoxylic acid.

Ira spectrum (nugon: 1730 and 1680 (co) cnfl.

NMB Spectrum (d6-dimethylsulfoxide): δ = δ (1H, s) ppm. 9) A mixture of 0.57 g of ethyl 2-hydroxyimino-2- (2-amino-1,5-thiazol-4-yl) acetate (a mixture of syn- and anti-isomers), 5 ml of ethanol, ml of water and 0.72 g of sodium bisulfite are stirred for 12 hours at 65-70 ° C. The reaction mixture is evaporated, and to the residue The resulting mixture is salted out and extracted with ethyl acetate. The extract is dried over magnesium sulphate and evaporated to give 0.18 g of ethyl 2- (2-amino-1,3-thiazol-4-yl) glyoxylate, yellow crystals, amp. 115-12 ° C. add 10 ml of water. IR spectrum (nuJo1): 3Ä20, 3250, 3120, 1750, 1665 and 1612 cm_1. 10) 235 ml of sulfuryl chloride are added dropwise over the course of 20 minutes. : with stirring and ice-cooling to a solution of 500 g of ethyl 2-methoxyiminoacetoaoetate (syn-isomer) in 500 ml of acetic acid, and the mixture is stirred overnight while cooling with water. Nitrogen gas is introduced into the reaction mixture for 2 hours, and the resulting mixture is poured into 2.5 liters of water. After extraction with 500 ml of methylene chloride and extraction twice with 200 ml of methylene chloride, the extracts are combined. The combined extracts are washed with a saturated aqueous solution of sodium chloride and adjusted to pH 6.5 by adding 800 ml of water and sodium bicarbonate. The methylene chloride phase is separated off, washed with aqueous sodium chloride solution and dried over magnesium sulphate. The solvent is distilled off, phase 559 g of ethyl 2-methoxyimino---chloroacetoacetate (syn-isomer). in-spectrum (f11m) = 1735 and 1705 cm -1.

Preparation 2 - 1) A mixture of 22.0 g of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn- and anti-isomers), 7.5 g of thioacetamide and 100 After cooling, 10 g of triethylamine are added, and the mixture is stirred for 1 hour. Insoluble material is filtered off, and the filtrate is evaporated under reduced pressure to give 8.6 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (a mixture of syn- and anti -isomers). This substance is subjected to column chromatography on 80 g of silica gel using benzene as developer. First, the eluate containing the anti-isomer is eluted, which is isolated and evaporated to give 2.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (anti-isomer). m.p. 90-92 ° C.

IR spectrum (nujol) at 1720 cm -1.

NMR Spectrum (d 6 -DMSO): δ = 12.55 (1H, s), 8.25 (1H, s), (2H, Q, J = 7Hz), 2.6? (BH, S) and 1.25 (3H, t, J = 7Hz) ppm- After eluting the eluate containing the anti-isomer, the eluate containing the syn-isomer is eluted, which is isolated and evaporated to give 0.5 g of ethyl hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (syn isomer), m.p. 134-136 °.

IR spectrum (nujo1) = 1720 cm -1.

NMR Spectrum (do-DM 50) = δ = 11.81 (1H, s), 7.81 (1n, 5); (2H, q. J = 7Hz), 2.70 (BH, S) and 1.30 (BH, t, J = 7Hz) ppm-ml benzene is refluxed for 3 hours. In 4.27 4.35 10 3 20 drops of phenolphthalein indicator are added to a solution of 4.2 g of hydroxylamine hydrochloride in 60 ml of dry methanol. To the solution is added dropwise with stirring at room temperature 60 ml of 1N methanol solution of sodium methoxide, until the color of the solution changes to blisters.

The hydroxylamine hydrochloride is added in small portions until the solution becomes colorless. The mixture is stirred for 30 minutes. at room temperature. After precipitation, the sodium chloride is filtered off, whereby 12.5 g of 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylic acid are added to the filtrate, and the mixture is refluxed with stirring for 1.5 hours. The reaction mixture is cooled to precipitate crystals. The crystals are isolated by filtration and dried to give 5.5 g of crude 2-hydroxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (a mixture of syn- and anti-isomers). The filtrate is evaporated to 1/4 volume, and ether is added. Precipitated crystals are isolated by filtration, washed with ether and dried to give 8.78 g of the same compound.

Total yield 14.5 g. 3) A mixture of 2.4 g of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn- and anti-isomers) and 0.76 g of thiourea in 15 ml of ethanol is stirred for 1 hour at 6000 The ethanol is distilled off under reduced pressure, and water is added to the residue. The resulting mixture is adjusted to pH 1.0 and washed with ethyl. The aqueous phase is adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract is washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.

The solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel using a mixture of ethyl acetate and benzene in a ratio of 1: 3 as developing agent. The eluate containing syn isomers is isolated and evaporated to give 0.5 g of ethyl 2-hydroxyimino-2- (2-amino-1,5-thiazol-4-yl) acetate (syn isomer).

In-spectrum (nu¿o1); 3450, 3300, 3200, 1725 and 1620 cm ".

NMR spectrogm (cDc13) = α = 7.65 (ln, s), 5.33 (2H, broad S), (211, q, J = 7.5Hz), 1.38 (BH, t, J = 7.5Hz) ppm- After collecting the eluate containing syn-isomers, the eluate containing a mixture of syn- and anti-isomers is isolated and evaporated to give 0.3 g of ethyl 2-hydroxyimino-2- (2-amino 1,3-thiazol-4-yl) acetate (a mixture of syn- and anti-isomers).

IR spectrum (nujol): 3400, 5300, 3200, 1715 and 1620 cm -1. mms spectrum (die-Janson δ = 12.42 (in, broad s), 11.55 (1H, s), acetate. l 4.40 10 25 25 35 35 _ water. 5457 351 M 7.52 (1H, s), 7.12 (ÄH, broad s), 6.85 (1H, s), 4.23 (ÄH, m) and 1.26 (6H, m) ppm - _ Ä) * A solution of 1, 1g of ethyl 2-hydroxyimino-2- (2-amino-1-,5-thiazol-4-yl) acetate (a mixture of syn- and anti-isomers) in 15 ml of 1N aqueous sodium hydroxide solution is left to stand for 2 hours at room temperature. The reaction mixture is adjusted to pH 5.5 with 10% hydrochloric acid, and precipitated crystals are isolated by filtration, washed with acetone and dried to give 0.52 g of 2-hydroxyimino-2- (2-amino-1,5-thiazole). 4-yl) acetic acid (a mixture of syn- and anti-isomers), m.p. 186-86 ° C (dec.).

IR spectrum (nujol): 5200, Preparation 3 l) 5.8 g of thioacetamide are added to a solution of 12.6 g of ethyl 2-methoxyimino-β-bromoacetoacetate (a mixture of syn- and anti-isomers) in 50 ml ethanol, and the mixture is stirred for 5 hours at 50 ° C. The ethanol is distilled off under reduced pressure, and to the residue is added. The resulting mixture is extracted with ethyl acetate.

The extract is washed with water, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in this order and dried over magnesium sulphate. The solvent is distilled off under reduced pressure to give 9.0 g of ethyl 2-methoxyimino-2- (2-methyl-1,5-thiazol-7-yl) acetate (a mixture of syn- and anti-isomers). 2) A mixture of 7.6 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn- and anti-isomers), 5.0 g of O-ethylthiocarbamate and 5 ml of dimethylacetamide is stirred for 5 hours at 50 ° C. 50 ml of ethyl acetate are added to the reaction mixture, and the prepared mixture is washed with water and with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is distilled off to give a crystalline residue. The residue is washed with diisopropyl ether to give 2.55 g of ethyl 2-methoxyimino-2- (2-oxo-2,5-dihydro-1,5-thiazol-1-yl) acetate (syn-isomer).

IR spectrum (nu3o1) = 3200, 1735, 1680 and 1650 cm -1.

NMR spectra (cDc13) = δ = 9.13 (ln, broad S), 6.37 (ln, s), (2H, Q, J = 6Hz), 4.01 (BH, s) and 1.58 (5H, t, J = 6Hz) ppm.

The mother liquor of diisopropyl ether is evaporated, and the residue is subjected to column chromatography on 70 g of silica gel using a 9: 1 mixture of benzene and ethyl acetate as developing agent. The elutate containing the syn isomer is isolated and evaporated to give an additional 0.65 g of the 1670 and 1530 cm-1 described above. 4.40 10 15 20 25 30 35 '457 351 the recovered syn isomer. Total yield 3.0 g. Then a mixture of benzene and ethyl acetate in the ratio: 5: 1 was used as developing agent. The eluate containing the anti-isomer is isolated and evaporated to give 0.26 g of ethyl 2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazol-4-yl) acetate (anti-isomer ).

IR spectrum (nuJol): 3250, 3200, 1720 and 1690 cm -1.

Nmm spectrum (cnc13) = δ = 9.90 (in, broad s), 7.30 (1n, s), (2H, q, J = 6Hz), 4.03 (3H, s) and 1.38 (3H, t, J = 6Hz) ppm. 3) A solution of 17.4 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn- and anti-isomers) and 5.4 g of thiourea in 100 ml of ethanol is refluxed for 4 hours. The reaction mixture is left to stand and cooled in a refrigerator to precipitate crystals. The crystals are isolated by filtration, washed with ethanol and dried to give 9.5 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl). The filtrates and washings are poured. Acetate hydrobromide (anti-isomer). together and evaporated under reduced pressure. 100 ml of water are added to the residue, and the mixture is washed with ether. The aqueous phase is reacted with a 28% aqueous solution of ammonia and extracted with ethyl acetate. The extract is washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.

The solvent is distilled off under reduced pressure to give 5.2 g of a crystalline substance of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn-isomer).

IR spectrum (nujo1): 3400, 3300, 3150, 1725, NMR spectrum (CDCl): δ = 6.72 (1H, s), 5.91 (2H, broad s), (2H, q, J = 7Hz), 4.03 (BH, s) and 1.38 (ju, c, J = 7nz) ppm. 9.5 g of the ethyl 2-methoxyamino-2- (2-amino-1,3-thiazol-4-yl) acetate hydrobromide (anti-isomer) obtained in the above-described manner are suspended in 200 ml of ethyl acetate. , and 4.0 g of triethylamine are added.

After stirring for 1 hour at room temperature, insoluble matter is filtered off and the filtrate is evaporated under reduced pressure to give 6.15 g of a crystalline substance of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazole-4- yl) acetate (anti-isomer).

IR spectrum (nujo1): 3450, 3250, 3150, 1730 and 1620 cm -1.

NMR Spectrum (CDCl 3): δ = 7.50 (1H, S), 5.60 (2H, broad s), 4.35 (2H, q, J = 7Hz), 4.08 (3H, s) and 1.33 (3H, t, J = 7Hz) ppm. 4) 3 drops of phenolphthalein indicator are added to a solution of 1.25 g of O-methylhydroxylamine hydrochloride in 15 ml of dry methanol. To the solution is added dropwise with stirring at room temperature 13 ml of 1N 1630 and 1559 cm -1. 4.38 10 15 20 25 30 35 å4s7 351 1 S6 t methanol solution of sodium methoxide, until the color of the solution changes to bluish red. The O-methylhydroxylamine hydrochloride is added in small portions until the solution becomes colorless. The mixture is stirred for 30 minutes. At room temperature, after filtration of precipitated sodium chloride, 3.8 g of ethyl 2- (2-mesylamino-1,1-thiazol-4-yl) glyoxylate are added to the filtrate, and the mixture is refluxed under After distilling off the methanol, the residue is dissolved. and ethyl acetate. Insoluble material is filtered off and the filtrate is evaporated. The residue is subjected to column chromatography on silica gel using a mixture of benzene and ethyl acetate in a ratio of 9: 1 as developing agent. The eluate containing the syn isomer is isolated and evaporated to give 2.8 g of ethyl 2-methoxyimino-2- (2-mesylamino-1,5-thiazol-4-yl) acetate (syn isomer).

IR spectrum (nu3o1) = 1725 cm -1.

NMR Spectrum (cDc15): δ = 6.76 (1H, s), 4.44 (2H, q, J = 7Hz), (BH, S), 3.04 (BH, S) and 1.37 ( BH, t, J = 7Hz) ppm-5) 0.33 g of powdered potassium carbonate is suspended in a solution of 0.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,1-thiazol-4-yl) acetate (syn isomer) in 20 ml of acetone. A solution of 0.3 g of dimethyl sulfate in 5 ml of acetone is added dropwise with stirring at -45 ° C. After stirring for 2 hours at the same temperature, insoluble is filtered off and the filtrate is evaporated, and water is added to the residue.

The resulting mixture is extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in the order indicated and dried over magnesium sulphate. The solvent is distilled off under reduced pressure to give 0.5 g of a light yellow oil of ethyl 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (syn-isomer).

IR spectrum (f11m) = 1740, 1710 and 1595 cm -1.

NMR Spectrum (CDCl 3): δ = 7.0 (1H, s), 4.25 (EH, q, J = 7Hz), 4.03 (δH, S), 2.73 (73H, S) AND 1 , 38 (OH, t, J = 7HZ) Ppm-6) The following compound is prepared in the same manner as described in Preparation 3-4) - Ethyl-2-methoxyimino-2- (2-amino-1,3-thiazole) 4-yl) acetate (syn-isomer).

In-spectrum (now01) = 5400, 3300, 3150, 1725, 1650 and 1559 cm -1.

NMR spectrum (cDc1) = δ = 6.72 (ln, s), 5.91 '(2fl, broad s), 4.58 (an, q, Jaaa), 4.03 OH, s) and 1.38 ( than, n, J = 7nz) ppm .. 7) A mixture of 6.1 g of acetic anhydride and 2.8 g of formic acid is stirred for 2 hours at 50 ° C. The resulting mixture is cooled, stirring for 2 hours. 4.04 material. 457 551 S7 and at 15 ° C, 4.6 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer) are added. After stirring the mixture for 3.5 hours at room temperature, 100 ml of cooled water are added. The resulting mixture is extracted with 200 ml of ethyl acetate. The extract is washed with water and then with a saturated aqueous solution of sodium hydrogencarbonate, until the washing liquids change to a weakly basic solution. The extract is further washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off, and the residue is washed with diisopropyl ether, isolated by filtration and dried to give 4.22 g of ethyl 2-methoxyimino-2- (2-formamido-1,1-thiazol-4-yl) acetate (syn- isomer), m.p. 122-124 ° C (dec.).

IR spectrum (nu1o1) = 3150, 1728 and 1700 cm -1. mmm spectrum (coc15) = δ = 12.58 (1n, broad S), 8.95 (1n, S), 7.17 (1H, S), 4.42 (2H, q, J = 8Hz), 4.00 (BH, s), l, §7 (BH, t, J = 8Hz) ppm. 8) 5 g of pyridine are added to a solution of 6.5 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn-isomer) in a mixture of 60 ml of ethyl acetate and 20 ml of dimethylphonamide. To the solution is added dropwise with stirring at 400 g of chloroformic acid ethyl ester. After adding 50 ml of water to the reaction mixture, the organic phase is separated, then washed with water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate.

The solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on 120 g of silica gel using a 5: 2 mixture of ether and petroleum ether as eluent to give 5.4 g of ethyl 2-methoxyimino-2- (2-ethoxycarbonylamino-1,5-thiazole -4-yl) acetate (syn-isomer).

NMB Spectrum (CDCl 3): δ = 9.36 (1H, broad s), 7.10 (1H, s), -4.66 (1H, m), 4.00 (BH, s) and 1.2 -1.60 (6H, m) ppm. 9) 50 g of ethyl 2-methoxyimino-4-chloroacetoacetate (syn-isomer) are added over 5 minutes. with stirring at room temperature to a solution of 18.4 g of thiourea and 19.8 g of sodium acetate in a mixture of 250 ml of methanol and 250 ml of water. After stirring for 35 min. at 40-4500 the reaction mixture is cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium hydrogencarbonate. After stirring for 30 min. at the same temperature the precipitated material is isolated by filtration, washed with 200 ml of water and then with 100 ml of diisopropyl ether and dried to give 37.8 g of colorless crystals of ethyl 2-methoxyimino-2- (2-amino-1,1-thiazole -4-yl) acetate (syn-isomer), 4.00 10 15 20 ZS 30 35 457 551: S8 m.p. 161-162 ° C. : za-sperm (nsjom 5400, 5506, 5150, 1725, 1630 and 1559 cm * - mm-spskzrum (0005): 0 = 6.72 (in, s), 5.91 (an, wide s). 4, 38 (am-q, J = 7Hs), 4.03 (BH, s) and 1.58 (311, t, J = 7Hz) ppm- Preparation 4 - 1) 10 ml of ethanol are added to a suspension of 2.2 g of ethyl 2-methoxyimino-2- (2-amino-1,5-thiazol-4-yl) acetate (syn-isomer) in 12 ml of 1N aqueous sodium hydroxide solution, and the mixture is stirred for 15 hours at room temperature. The reaction mixture is adjusted to pH 7.0 with 10% hydrochloric acid, and the ethanol is distilled off under reduced pressure.

The remaining aqueous solution is washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling to precipitate crystals. The crystals are isolated by filtration, washed with acetone and recrystallized from ethanol to give 1.1 g of colorless needles of 2-methoxyimino-2- (2-amino + 1,3-thiazol-4-yl) acetic acid (syn-isomer). : rf spectrum (nujon: 3150, 1670, 1610 and 1585 snfl. maa spectrum (α-nnsoy a = 7.20 (an, brsa s), 6.85 (111, s) and 5.85 (BH, S) ppm-2) 1.5 ml of 1N aqueous sodium hydroxide solution is added to a solution of 0.3 g of ethyl 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (syn isomer ) in 5 ml of ethanol, and the resulting mixture is stirred for 2 hours at 100 DEG C. The reaction mixture is adjusted to pH 7.0 with 10% hydrochloric acid, evaporated under reduced pressure, adjusted to pH 1.5 with 10% hydrochloric acid and extracted. The mixture is washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. The solvent is distilled off to give 0.14 g of a crystalline substance of 2-methoxyimino-2- (2-methyl-1,3-thiazole). 4-yl) acetic acid (syn-isomer).

IR spectrum (nujol): 1730 cm -1. nME spectrum (do-Dmsm: 0 = 7.80 (1H, s), 3.85 (sa, s), 2.62 (su, s) ppm. 3) The compounds listed below are prepared in the same manner as described for preparation 4-1) to 4-Z). 1) α-methoxyimino-α- (α-oxo-e, ydinyar-1H-thiazol-1z-yl) acetic acid (syn-isomer).

IR spectrum (nuj61) = 5250, 1710 and 1650 cnfl. maa spectrum (α-nmsoh 0 = 10.61 (in, broad s), 6.75 (111, s) sen 5.95 (311, s) pmm- ': r 10 15 20 ZS 30 35 457 351 2 ) 2-methoxyimino-2- (2-mesylamino-1,1-thiazol-11-yl) acetic acid (syn-isomer) In-spectrum (nujo1) = 3150 ooh 1720 om'1.

NMR Spectrum (do-DMSO): δ = 7.17 (1H, s), ((5H, S) ppm-3) 2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl ) acetic acid (syn- isomer), m.p. 15200 (dec.).

In-spectrum (nugo1) = 3200, 2800-2100, 1950 ooh 1600 om'1. mmm spectrum (do-OMsO) = o = 8.60 (1H, s), 7.62 (HL S1, 3.98 (ng sn ppm-4) 2-methoxyimino-2- (2-ethoxycarbonylamino-1, 3-thiazol-N-yl) acetic acid (syn-isomer).

IR spectrum (nujol): NM spectrum (06-nMsO); 7.20 (1H, broad s), 4.25 (2H, q, J = 7Hz), (BH, t, J = 7Hz) ppm-4) 5 ml of pyridine are added to a suspension of 2.0 g of 2- manximinino-2- (2-amino-1,3-thiazol-U-yl) acetic acid (syn-isomer) in 20 ml of ethyl acetate.

A solution of 2.5 g of bis (2,2,2-trifluoroacetic acid) anhydride in 5 ml of ethyl acetate is added dropwise with stirring at 5-7 ° C, and the mixture is stirred for 30 minutes. at 3-5 ° C. 30 ml of water are added to the reaction mixture, and the ethyl acetate phase is separated. The aqueous phase is further extracted with ethyl acetate, and the bath ethyl acetate phases are combined, washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. The solvent is distilled off under reduced pressure to give 0.72 g of 2-methoxyimino-2- [2- (2,2,2-fluorocarbon] -1,3-thiazole-yl] / acetic acid (syn-isomor).

In-spectrum (nuJo1) = 1725 oon 1590 om'l. 1 H NMR Spectrum (d 6 -DMSO): δ = 7.68 (1H, s) and 5.91 (BH, s) ppm. 5) The compound listed below is prepared in the same manner as described for Preparation 4-4). 2-methoxyimino-2- (2-acetamido-1,1-thiazol-4-yl) acetic acid (syn-isomer), m.p. 184-185 ° C (Sun.). in-spectrum (nuJo1) = 3200, 3050, 1695 ooh 1600 om'1. 6) 3 drops of phenolphthalein indicator are added to a solution of 0.84 g of O-allylhydroxylamine hydrochloride in 10 ml of dry methanol. To the solution is added, while stirring at room temperature, 6 ml of 1N methanolic solution of sodium methoxide, until the color of the solution changes to light red. O-allylhydroxylamine hydrochloride is added in small portions until the solution becomes colorless. The mixture is 3.93 (3H, S) AND 3.02 3200, 1730, 1710, 1690 and 1570 cm -1. 0 = 12.16 (ln, broad s), 7.50 (1H, s), 3.93 (BH, S) and 1.25 stirring for 457 351 60 are stirred for 30 minutes. at room temperature. After precipitation, sodium chloride is filtered off, then 2.0 g of 2- (2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylic acid are added to the filtrate, and the mixture is stirred for 1 hour at room temperature. After distilling off the methanol at low temperature, the residue is dissolved in 1N aqueous sodium hydroxide solution. The solution is washed with ether, and ethyl acetate is added.

The mixture is adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is distilled off, and the residue is washed with diisopropyl ether, isolated by filtration and dried to give 1.62 g of 2-allyloxyimino-2- (2-tert.pentyloxycarbonylamino-1,5-thiazol-4-yl) acetic acid (syn- isomer).

IR spectrum (nu3o1) = 3200 and 1712 * om'1.

NMR Spectrum (06-DM 50) = O = 7.40 (1n, 5), (23, dd, J = 9, 10Hz), 4.65 (2H, 0, J = 5Hz), 1.44 (6H , s) and 0.88 (BH, t, J = 8Hz) ppm. 7) The compounds listed below are prepared in the same manner as described for Preparations 4-6). 1) 2-Methoxyimino-2- (2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl) acetic acid (syn-isomer).

IR spectrum (nujo1) = 3200 and 1712 om'1.

NMR spectrum (06-DM 50) = O = 7.40 (15, s), 3.88 (3H, s), q, J = 8Hz), 1.44 (6H, s) and 0.88 (3H , t, J = 8Hz) ppm. 2) 2-allyloxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (syn-isomer). IR spectrum (nuJo1) = 3150, 1710 and 1605 cm -1. 3) 2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn-isomer).

IR spectrum (nujo1) = 3150, 1670, 1610 and 1585 om'1.

NMR Spectrum (α 6 M 0 M 5 O) = 0 = 7.20 (one, broad 5), 6.85 (1n, s) and 3.83 (BH, S) ppm- Preparation 54__ To a solution of 50 g 2- (2 -formamidothiazol-4-yl) glyoxylic acid and 12.6 sodium bicarbonate in 1300 ml of water are added 19.8 g of allyloxyamine hydrochloride, and the mixture is stirred for 7 hours at room temperature and pH 6. To the reaction mixture are added 6.24-5.76 (1H, m), 5.26 1.78 (211. q, J = 8Hz), 1.77 (QH, 7,500 ml of ethyl acetate. After the mixture has been adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate phase is separated off The ethyl acetate phase is washed with an aqueous solution of sodium chloride and dried over magnesium sulphate, then the solvent is evaporated off, the residue is pulverized in diisopropyl ether, isolated by filtration and dried. , 3 g of 2-allyloxylimino-2- (2-formamido-thiazol-4-yl) acetic acid (syn-isomer): xx-spectrum (nuions: 3110, 1730, 1660 and 15140 fmfl. Nun-spectrum (die-shower Δ (ppm) = 4.70 (an, m), 5.13 - 5.60 (2H, m), 5.73 - 6.27 (1H , m), 7.57 (1H, S), 3.35 (1H, S) - Preparation 6 1) 55.2 g of sulfuryl chloride are added in one portion at room temperature to a stirred solution of 48.9 g of ethyl acetate. 2-Ethoxyimino-5-oxo-butyrate (syn-isomer) in 49 ml of acetic acid, and stirring is carried out at the same temperature for 1 hour. After adding the resulting solution to 200 ml of water, the solution is extracted with methylene chloride. The extract is washed with a saturated aqueous solution of sodium chloride, neutralized with an aqueous solution of sodium bicarbonate and washed with water. The solution is dried over magnesium sulphate and evaporated under reduced pressure to give 55.8 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn-isomer) in the form of a pale yellow oil. 2) A mixture of 38.7 g of ethyl 2-ethoxyimino-5-oxo-4-chlorobutyrate (syn-isomer), 13.2 g of thiourea, 14.3 g of sodium acetate, 95 ml of methanol and 95 ml of water is stirred at 4800 1 40 minutes. After the resulting solution has been adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, a precipitate forms which is isolated by filtration and washed with diisopropyl ether to give 1H, 7 g of ethyl 2-ethoxymino-2- ( 2-aminothiazol-4-yl) acetate (syn-isomer), m.p. 150 DEG-131 DEG.

IR Spectrum (nuJo1): 3450, 5275, 3125, 1715 and 1620 cm-1. 3) 5 g of ethyl 2-ethoxyamino-2- (2-aminothiazol-4-yl) acetate (syn-isomer) are added to a mixture of 45.9 ml of 1N sodium hydroxide solution and 30 ml of ethanol and stirred at room temperature 1 5 hours.

After stripping the ethanol from the resulting solution under reduced pressure, the residue is dissolved in 60 ml of water and adjusted to pH 2.0 with 10% hydrochloric acid. The solution is salted out, and the precipitated material is isolated by filtration and dried to give 2.9 g of 2-ethoxylimino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomer).

IR Spectrum (nujol): 3625, 3225 (shoulder), 5100, 1650 and 1615 cm -1.

NMR Spectrum (do-DMSO): δ (ppm) = 1.20 (1H, t, J = 7Hz), 4.09 (2H, q, J = 7Hz), 6.82 (1H, s), δ , 24 (2H, broad s). 10 g 20 35 457 551 5 oz Ä) 100 g of 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn-1somer), 85.5 g of formic acid and 190.1 g of acetic anhydride are treated in the same manner as in Preparations 9-4) to give 99.1 g of 2-ethoxyimino-2- (2-formamidobiazol-4-yl) acetic acid (syn-isomer).

IR-Spectruine (nuj0l): §200, fi lÄO, §05O And 1700 cm-l.

NMR Spectrum (d 6-INSO): δ (ppm) = 1.18 (5H, t, J = 6Hz), 4.22 (2H, q, J = 6Hz), 7.56 (1H, s), δ 56 (1H, s), 12.62 (1H, broad s).

Preparation 7 The compounds listed below are prepared in the same manner as in Preparations S and 6. 1) 2-Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p. 168-169 ° C (probing) .

IR spectrum (nuJo1) = 3200, 3130, 1710, 1600 and 1560 cm -1. 2) 2-butoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer).

IRfSpectrum (nujol): 5350, 5160, 3050, 1700, 1680 and 1570 cm-1. 3) 2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (synphysomic acid), m.p. 115-116 ° C (monocarbon).

IR spectrum (nu1o1) = 3170, 3070, 1720, 1700 and 1660 cm -1.

NMR Spectrum (d 6 -DMSO): δ (ppm) = 0.6-2.1 (IIH, m), 4.15 (2H, t, J = OHH), 7.53 (1H, S), δ , §6 (1H, S), 12.69 (1H, S). 4) 2-propoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomor), m.p. 164 ° C (dec.).

In-space (nu3o1) = 3200, 3120, 3050, 1700 and 1550 cm'1. 5) 2-pentyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p. 12506 (dec.).

In-spcktgum (nu3o1); 3200, 3140, 1700 and 1565 cm-1. 0) 2-Allyloxylmino-2- (2-aminoriazol-4-yl) acylic acid (syn-isomer), m.p. 187 ° C (dec.).

IR spectrum (nu1o1) = 3350, 1630, 1580 and 1460 cm -1. 7) 2-Isobutoxylimino-2- (2-formamidothiazol-4-yl (acetic acid (syn-isomer), m.p. 165 ° C (dec.).

Preparation 8 \ 1) 126, ng Coyl-2-nyaroxylino-2- (2-aminociazol-4-yl) coccac (syn-isomer), 81.5 g formic acid and 180 g acetic anhydride are treated in the same manner as in Preparation 9- 4 to give 109.6 g of ethyl 2-hydroxyamino-2- (2-formamidothiazol-4-yl) acetate (syn-isomer).

In-spectrum (nuJo1) = 3520, 3140, 3050, 1710 and 1555 cm-1 15 15 25 25 35 457 351 63 NMR spectrum (do-Dmso), δ (ppm) = 1.30 (j fl, t , J = 7Hz), 4.33 (QH: q: J = 7HZ): 7:51 * (1H: 5): (1H: 5): 11:98 (JH »5): 12.58 (ln, s). 3 '' ~ 2) -A mixture of 7.97 g of chloromethylthiomethane, 15.1 g of powdered potassium iodide and 79 ml of acetone is stirred at room temperature for 1 hour. The resulting mixture is filtered and washed with a small amount of acetone. The washings and filtrate are combined and added to a stirred suspension of 17.5 g of ethyl 2-hydroxyimino-2- (2-formamidothiazol-4-yl) acetate (syn-isomer) in 300 ml of acetone.

The mixture is stirred at room temperature for 3 hours, filtered and washed with acetone. The washing liquids and the filtrate are combined and evaporated in vacuo. The residue is dissolved in ethyl acetate, washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated in vacuo. The oily residue is subjected to column chromatography on silica gel, eluting with chloroform to give 2.4 g of ethyl 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetate (syn-isomer), m.p. 130-131 ° C.

IR spectrum (nujo1): 3160, 3125, 3050, NMR spectrum (d6-DMSO), δ (ppm): 1.32 (3H, t, J = 7Hz), S), 4.38 (2H, Q J = 7Hz), 5.33 (EH, 5); 7.57 (1H, S), (1H, s). 3) A mixture of 2.4 g of ecyl-2-methylmethylmethoxylimino-2- (2-formamidothiazol-4-yl) acetate (syn isomer), 23.8 ml of 1N aqueous sodium hydroxide solution and 19.8 ml of methanol is stirred at 30 ° C for 2.5 hours. The resulting solution is adjusted to pg value 7 with 10% hydrochloric acid and methanol and evaporated in vacuo. The aqueous solution is adjusted to pH 1 with 10% hydrochloric acid under ice-cooling and extracted three times with ethyl acetate. The extracts are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated in vacuo to give 1.13 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p. 157 ° C (dec.).

IR spectrum (nujo1): NMB spectrum (do-DMSO), δ (ppm). 2.24 (3H, s), - 7.61 (1H, s). 8.57 (1H, s), 12.73 '(1H, - s) - Preparation 9' The following compounds are prepared in the same manner as described in the preceding preparations' 2.22 (BH, 8.56 zaio, 3160, 3075 1700, 1555 cm-1, 5.51 (ÉH, S), 1740, 1695 cm-1, 10 15 20 25 30 35 457 351 64 1) 2-1sopropoxyximinino-2- (2-formamidothiazol-4-yl) acetic acid ( syn-isomer), m.p. 168-169 ° C (dec.).

IR spectrum (nu301) = 3200, 3130, 1710, 1600, 1560 cm -1. 2) 2-Outoxylimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

IR spectrum (nujo1): 3350, 3160, 3050, 1700, 1680, 0 1570 cm -1. 6) 2-hexylxylimino-2- (2-formamidothiazol-4-yl) acetic acid (synisomer), m.p. 115-166 ° C (dec.).

IB spectrum (nuj01): 3170, 3070, 1720, NMR spectrum (d6-DMD0), δ (ppm): 0.6-2.1 (11H, m), J = 6Hz), 7.53 (ln , s), 8.56 (1H, s), 12.69 (ln, s). 4) 2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) -acetic acid (syn-isomer) IR spectrum (nu3o1) = 3200, 1710 and 1690 cm -1. 5) 2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer) IR spectrum (nu361): 3330, 3200, 3100, 1660 and 1590 cm -1. 6) 2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) -acetic acid (syn-isomer), m.p. 11200 (dec.). 13 spectrum (nu561) = 3150, 1740, 1670 and 1550 cm -1.

T) 2-tert.butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p. 117 ° C (dec.).

IR spectrum (nujol): 3180, 3140, 1750, 1690 and 1630 cm-1. 8) 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-yl) -acetic acid (syn-isomer), m.p. 110 ° C (dec.). IR spectrum (nujo1); 3270, 3130, 1680 ,, 1540 @ m'1. 9) 2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomer). Δ IR spectrum (nuj01): 3170, NMR spectrum (do-DMSO), δ (ppm): 1.27 (3H, t, J = 7Hz), (211, q, 127112), 4.77 (2H , s), 6.96 (1H, s) - 10) 2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer) IR spectrum (nujo1): Preparation solution of 17.4 g of 4-bromo-3-hydroxybenzyloxyamine phosphate in 200 ml of water and 200 ml of ethanol is stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 10.0 g 2- (2- 1700 and 1660 cm-1, 4.15 (EH, fi, 1 1660 and 1620 cm-1. 4.25 1720, 3350, 3140, 1740 and 1700 cm-1). PJUI 50 35 40 65 457 351 formamidothiazol-4-yl) glyoxylic acid is added to the solution, and the resulting suspension is adjusted to pH rum, 0-4.5 After stirring the solution at room temperature for 2 hours, ethanol is removed from the the resulting solution in vacuo. Ethyl acetate is added to the aqueous residue, and pH 2.5 is adjusted with 10% hydrochloric acid. The ethyl acetate phase is separated, washed with water and dried over magnesium sulphate. The solution is evaporated in vacuo to give 15.8 g of 2 - (2-formamidothiazol-4-yl) -2- (4-bromo-5-hydroxybenzyloxyimino) acetic acid (syn-isomer).

In-spectrum (nu¿01) \> maX = 5550, 5150, 1720, 1680, 1570 cm'1.

NMR Spectrum (DMSO-d 6), δ (ppm): 5.13 (2H, m), 6.8 (1H, dd, J = 8, 2Hz), 7.02 (1H, d, J = 2Hz) , 7.5 (1H, d, J = 8Hz), 7.58 (1H, s), 8.58 (1n, s), 10.55 (in, broad S), 12.7 (1n, broad s ).

Preparation 511 1) 40.0 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn-isomer), 45.6 g of 4-fluorobenzyl chloride, 60.0 ml of N, N-dimethylformamide, 52.0 g of potassium carbonate and 60.0 ml ethyl acetate is treated in a conventional manner to give 64.4 g of 2- (α-fluorobenzyloxyimino) -5-oxobutyrate (syn-isomer). In-spectrum (f11m) = 3000, 29u0, 1730, 1690 and 1600 cm -1.

Nmm spectrum (nmso-06), δ (ppm) = 1.21 (an, t, J = 7, 0Hz), 2.34 (BH, s), 4.26 (2H, q, J = 7, 0Hz), 5.32 (en, s), 6.97-7.75 (HH, m) -2) 64.0 g of ethyl 2- (4-fluorobenzyloxyimino-5-oxobutyrate (syn isomer), 55 6 g of sulfuryl chloride and 70.0 ml of acetic acid are treated in the same manner as described in Preparation 6-1 to give 29.55 g of ethyl 2- (4-fluorobenzyloxyimino) -5-oxo-4-chlorobutyrate (syn-isomer) In-spectrum (r11m) = 1720 and 1600 cm -1.

NMB Spectrum (DMSO-d 6), δ (ppm): 1.20 (BH, t, J = 7.0Hz), 4.28 (QH: q: J = 7: OHZ): (2Hs 5): ( 2H: 5): 70 ° C 7a75 (HH: m) - 3) 29.0 5 ethyl 2- (4-fluorobenzyloxyimino) -5-oxo-Ä-chlorobutyrate (syn-isomer), 8.8 g of thiourea 7.9 g of sodium acetate, 72.5 ml of water, 60 ml of tetrahydrofuran and 72.5 ml of ethanol are treated in the same manner as described in Preparation 6-2 to give 28.0 g of ethyl 2- (4-fluorobenzyloxyimino). ) -2- (2-aminothiazol-1-yl) -acetate (syn-isomer).

IR spectrum (nujo1): 5450, 5150, 5100, 1710 and 1620 cm -1.

NMB Spectrum (DMSO-d 6), δ (ppm): 1.23 (BH, t, J = 7.0Hz), 9.30 (2H, q, J = 7Hz), 5.15 (2H, s) , 6.90 (1H, S), 6.95-7.60 (HH, m) - 4) 25.5 g of ethyl 2- (4-fluorobenzyloxyimino) -2A (2-aminothiazole). 40 'IR spectrum (nujol fi z 66 457 151-4-yl) acetate (syn-isomer), 1.3 g 1-methylimidazole, 118.3 ml 1N sodium hydroxide solution, 250 ml methanol and 200 ml tetrahydrofuran are treated in the same way as described in Preparation 6-3 to give 22.11 g of 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-1-yl) -acetic acid (syn-isomer) 1 IR spectrum (nujol): 3650 3450, 3300, NMR Spectrum (DMSO-d 6), δ (ppm): 5.16 (2H, s), 7.04-7.66 (1H, m). 5) 23.4 g 2- (4- fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetic acid (syn-isomer), 32.2 g of bis- (trimethylsilyl) acetamide, 49.9 g of 2,2,2-trifluoroacetic anhydride and 234 ml of dry ethyl acetate is treated in the same manner as described in Preparations 4-4 to give 18.9 g of 2- (4-fluorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetic acid (syn-isomer), m.p. 180-18200.

In-spectrum (now 61) = 3200, 3150 and 1730 cm -1.

NMR Spectrum (nmso-66), δ (ppm) = 5.25 (2H, s), 7.02-7.60 (AH, m), 7.72 (1H, s).

Preparation 12 1) The following compound is obtained by reacting ethyl 2-hydroxyimino-3-oxobutyrate (syn-isomer) with 3,4-dichlorobenzyl chloride in a conventional manner: Ethyl 2- (3,4-dichlorobenzyloxyimino) -3- oxobutyrate (syn-isomer), oil. 3150 and 1630 6m'1. 6.88 (1H, s), IR spectrum (f11m) = 1730, 1690, 1600, 1470, 1400, 1370, 1310, 1240, 1130, 1080, 1010 cm -1.

NMR spectrum (CCl 3): δ (ppm): 1.30 (3H, t, J = 6Hz), 2.30 (3H, s), 4.30 (211, ka, a = enz), 4, 47 (211, s), 7, oo-7.53 (BH, m) - 2) The following compound is prepared in the same manner as described in Preparation 6-1: Ethyl 2- (3,4-dichlorobenzyloxyimino) -3- oxo-4-chlorobutyrate (syn-isomer), oil.

IR Spectrum (film): 17A0, 1710, 1590, 1470, 1400, 1370, 1320, 1260, 1200, 1130, 1010 cm -1.

NMR Spectrum (CCl 4), δ (ppm): 1.37 (3H, t, J = 6Hz), 4.23 (2H, Q, J = 6Hz), 4.43 (2H, S), 5.27 (2H, S), 7.10-7.50 (33, m) - 3) The following compound is prepared in the same manner as described in Preparation 6-2: Ethyl 2- (3,4-dichlorobenzyloxyimino) -2- ( 2-aminothiazol-4-yl) acetate (syn-isomer) 3460, 1720, 1600, 1S40, 1160, 1390, 1260, 1180, 1020, 1010, 880, 810 6m -1. Δ BO 55 457 351 67 NMR spectrum (DMSO-d 6), δ (ppm): 1.25 (3H, t, J = 7Hz), 4.30 (2H »Q, J = 7H2), δ, 17 (25, 5) »5.93 (13: 5)» 7.27-7.73 (33, m) - 4) The following compound is prepared in the same manner as described in preparation 6-3: 2- (3 , 4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn-isomer).

IR spectrum (nu3o1) = 5450, 1660, 1590, 1 # o0 a 1010 cm'1.

NMR Spectrum (DMSO-d 6), δ (ppm): 5.23 (2H, s), 6.93 (1H, s), 7.30-7.77 (BH, m). 5) The following compound is prepared in the same manner as described in Preparations 4-4: 2- (3,1'-Dichlorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetic acid (syn -isomer).

IR Spectrum (nujO1): 1720, 1580, 10000, and 1150 cm -1.

Nmm spectrum (nmso-06), δ (ppm) = 5.40 (2H, S), 7.47-7.95 (4H, m).

Preparation To a suspension of 21.0 g of N- (cinnamyloxy) phthalimide 1 1260, 1200, 1160 200 ml of ethanol is added 8.3 g of hydrazine hydrate at 6000, and the mixture is stirred for 1.5 hours at the same temperature. To the mixture is added 22 ml of conc. hydrochloric acid and 220 ml of water, and the resulting mixture is filtered. The filtrate is evaporated to form a precipitate which is filtered off. The filtrate is adjusted to pH 7.0, and to the solution containing O-cinnamylhydroxylamine is added 300 ml of ethanol and 10.0 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid. The mixture is stirred for 2 hours at pH 4.0-4.5. The reaction mixture is evaporated and adjusted to pH 2.0 after the addition of ethyl acetate. The organic phase is washed with an aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated to give 8.6 g of 2-cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer). IR spectrum (nujol): 3400-3100, 1700 and 1550 cm -1.

NMB Spectrum (DMSO-d 6), δ (ppm): δ, 85 (2H, d, J = 5Hz), 6.2-6.93 (2H, m), 7.2-7.72 (SH, m), 7.6 (1H, s), 8.57 (1H, s), 12.7 (1H, broad s).

Claims (2)

457 351 68 PATENT CLAIMS A compound for use as an intermediate for the preparation of cephem compounds of the syn-isomer type of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds, characterized by the formula R * -cz HN 3 -unzf wherein R 1 is a group of the formula: wherein R 7 is (O 1 -C 6} alkyl and R 2f is (C 1 -C 6 alkyl, (C 2 -C 6) alkylene, (C 1 -C 6) -alkylthio (C 1 -C 6) -alkyl, carboxy ( C1-C6) -alkyl, (C1-C6) -alk-oxycarbonyl (C1-C6) -alkyl, phenyl (C1-C6) -alkyl, halogen-substituted phenyl (C1-C6) -alkyl, halogen- and hydroxy-substituted phenyl (C1 -C6) -alkyl, phenyl (C2-C6) -alkenyl, (C1-C6) -alkanoyloxy (C1-C6) -alkyl, (C1-C6) -alkoxy (C1-C6) -alkyl or isoxazolyl (C1- C 6) -alkyl, or R 1 is a group of the formula: R 7, where S 7 is amino, (C 1 -C 6) -alkanoylamino, halo (C 1 -C 6) -alkanoyl-amino, (C 1 -C 6) -alkanesulfonylamino, ( C1-C6) -alkoxycarbonylamino or hydroxy and Rzf are methyl, isobutyl, pentyl, hexyl, propyl, benzyl, cinnamyl, (C1-C6) -alkylthio- (C1-C6) -alkylcarboxy (C1-C6) -alkyl, (C1-C6) -alkoxycarbonyl (C1-C6) -alkyl, halogen substituents ad phenyl (C1-C6) -alkyl, halogen- and hydroxy-substituted phenyl (C1-C6) -alkyl, (C1-C6) -alkanoyloxy (C1-C6) -alkyl, (C1-C6) -alkoxy (C1-C6 ) -alkyl or isoxazolyl (C 1 -C 6) -alkyl, with the proviso that R 7 is (C 1 -C 6) -alkanoylamino, halo (C 1 -C 6) -alkanoylamino, (C 1 -C 6) -alkanesulfonylamino, (C 1 -C 6) -alkoxycarbonylamino or hydroxy when R 2 is butyl, isobutyl, pentyl, hexyl or propyl; or R 1 is a group of the formula: 7 NS where R 7 is amino, formamido, t-pentyloxycarbonylamino or mesylamino and R 2f is ethyl, isopropyl or allyl, with the proviso that R 7 is formamido, t-pentyloxycarbonylamino zf is ethyl or isopropyl; or R 1 is R 11; wherein R 7 is formamido, mesylamino, ethoxycarbonylamino, 2,2,2-tri- or mesylamino when R is a group of the formula: fluoroacetamido, acetamido or t-pentyloxycarbonylamino and Rzf is methyl; and Za is carboxy or (C1-C6) -alkoxycarbonyl; and salts thereof. Process for the preparation of a compound of the formula: R'-c-za H-onzf wherein R 1, R 2f and Za have the meanings given in claim 1, characterized in that: a) reacting a compound of the formula: R 1 -co-za wherein R 1 and Za are as defined above, or salts thereof, with a compound of the formula: R 2f -ONH 2 wherein R 2f is as defined above, or a salt thereof, or b) exposing a compound of the formula: R 1- oz 'Q-onzf wherein R 1 and R 2f are as defined above, and Z is (C 1 -C 6) -alkoxycarbonyl, for an elimination reaction to remove the carboxy protecting group, to form a compound of the formula: R 1 -c-coon _OR 2f wherein R 1 and R 2f each have the meanings given above, or salts thereof, or c) reacting a compound of the formula: 452 351 70 Hzw c- za sf / H-onz wherein R 2 is butyl, isobutyl, pentyl, hexyl, propyl, benzyl, cinn - myl, (C 1 -C 6) -alkylthio- (C 1 -C 6) -alkyl, carboxy (C 1 -C 6) -alkyl, (C 1 -C 6) -alkoxycarbonyl- (C 1 -C 6) -alkyl, halogen-substituted phenyl- ( C1-C6) -alkyl, hal ogen- and hydroxy-substituted phenyl (C1-C6) -alkyl, 1,1 (C1-C6) -alkanoyloxy (C1-C6) -alkyl, (C1-C6) -alkoxy (C1-C6) -alkyl or isoxazolyl (C1-C6) -alkyl; and Za is carboxy or (C1-C6) -alkoxycarbonyl, or a reactive derivative thereof at the amino group or a salt thereof, with an amino protecting agent to form a compound of the formula: R7a <; ¿ä:; §: --- c- za is N-onez wherein R2 and Za have the meaning given above, and R7a is (C1-C6) -alkanoylamino, halo (C1-G6) -alkanoylamino, (C1-C6) -alkanesulfonyl-amino or (C1-C6) -alkoxycarbonylamino , or salts thereof, or d) reacting a compound of the formula: x-c fl zco-c-2 -OR 2g wherein Z has the meaning given above, X is halogen and R 2g is (C 1 -C 6) -alkyl, with a compound of the formula: 7b R 1 -a-NH 2 wherein R 7b is (C 1 -C 6) -alkyl or (c 1 -C 6) -alkoxy, to give a compound of the formula: R 2 E_% α 2; §: ___- E :: R 2g wherein Z and R 2g have as defined above, and R 7c is (C 1 -C 6) -alkyl or hydroxy.