IE45597B1 - Syn isomer of 3,7-disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof - Google Patents

Abstract

Novel syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds are provided of the formula: in which R1 is a group of the formula: wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino; a group of the formula: wherein R7 is amino, protected amino, hydroxy or lower alkyl; or a group of the formula: wherein R8 is lower alkyl and R9 is imino, protected imino or oxo; R2 is an aliphatic hydrocarbon group which may have suitable substituent (s); R3 is carboxy or protected carboxy; and R4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have suitable substituent (s); or R3 and R4 are linked together to form -COOCH2-, and pharmaceutically acceptable salts and tautomers thereof; the novel compounds are highly active against a number of pathogenic bacteria.

Description

The present invention relates to new syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new syn-isomer of 3,7-disubstituted-3-cephem-45 carboxylic acid compounds and pharmaceutically acceptable salts thereof which have antibacterial activities and to processes for the preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment of infectious diseases in non human - animals. , Accordingly, it is one object of the present invention to provide syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic bacteria.

Another object of the present invention is to provide processes for the preparation of syn-isomer of 3', 7-disubstitute d3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceutical composition comprising, as active ingredients, said syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a method for the treatment of infectious diseases caused by pathogenic bacteria in non human anim&ls. - 2 Patent Specification No. 2/> 8 is directed to a substituted acetic acid of the formula: R1-C-Z N-OR' 2f in which R is a group of the formula: „5 wherein R3 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R8 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino: a group of the formula: N. wherein r' is hydroxy or lower alkyl; or a group of the„formula R8 9 wherein R is lower alkyl and R is imino, protected imino or oxot 2f R is an aliphatic hydrocarbon group-which may have suitable substituent(s); and Z is carboxy or protected carboxy, and salts a thereof, which are useful in the preparation of the object syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of this invention.

The object syn-siomer of 3,7-disubstituted-3-cephem4-carboxylic acid compounds are novel and can be represented by the following formula:20 in which R1 is a gropp of the formula R-C-CONH ·· 2 N-OR wherein R is hydrogen, halogen, nitro, fi hydroxy, lower alkoxy or acyloxy and R is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino; a group of the formulas wherein R hydroxy or lower alkyl; or a group of the formulas is amino, protected amino, ,8 .8 R wherein Rw is lower alkyl and R __ imino, protected imino or oxo; R is an aliphatic hydrocarbon group which may have suitable substituent (s); ’ R is carboxy or protected carboxy; and R is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl· group which may have suitable substituent(s); 3 4 or R and R are linked together to form -COOCH, with z proviso that R is not acetoxymethyl, 1-methyl-tetrazolylthiomethyl or 2-methyl-l,3,4-thiadiazolylthiomethyl when R1 is a group of the formula: »’-0S . 7 wherein R amino or protected amino and R3 is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms.

With regard to the present invention, it is to be noted that this invention is characterized by providing syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds, which is represented by the formula (I),. and the said syn-isomer can be represented by the partial structure of the formula: -CO- in their molecules, while the corresponding N-OR anti-isomer is represented by the partial structure Of the -445597 formula : R -G-CORZO-N Accordingly, in the following detailed explanations of this invention in this specification and claims, it is to be understood that the syn-isomers of the object compounds as well as the starting compounds of this invention are represented by the partial structure of the formula: -C-CO- in their molecules, H N-Oprovided that, in case that it is convenient for the explanation of this invention to express both of the syn-isomer and antiisomer by one general formula, they are represented by the partial structure of the formula: -C-COf I The object compounds of the present invention (I) are novel compounds and can be prepared by the Processes 1 to 8 as mentioned below.

Process 1 R -C-COOH 11 2 N-ORZ (ΠΙ) or a salt thereof or its reactive derivative at the amino group or a salt thereof or its reactive derivative at the carboxy group or a salt thereof π SS597 Process 2 Rla-C-CONH-j—τ' Ί n-or2oJny~r4 (IV) or a salt thereof Process 3 R‘ HO XH[ Rlb-C-CONH-,— N-OR2 Elimination of the protective group of the amino (or imino) Acylation of the hydroxy group ft5a N-OR' CONH2 n6aCV) or a salt thereof Process 4 R -C-CONH—i— N-OR2ao^“ N Elimination of the protective group g. of the carboxy 4 _ OV or a salt thereof Process 5 R1-C-CONH II N-OR2 CV or a salt thereof ^-C-CONH-j—<S S n-or2 γ-1 R3 db) or a salt thereof or a salt thereof Elimination of the protective group of the amino CH,-OCONH-R4^-* R1-C-CONH (Vb) or a salt thereof N-OR2 „ CH»-OCONH. ^0 dd) or a salt thereof 4ES97 Process 6 R1-C-CONH-i— (Vc) or a salt thereof or its reactive derivative at the mercapto group Acid (Vd) 4c or a salt thereof R1-C-CONH-i— N-OR* CO—0 (If) or a salt thereof Process 8 or a salt thereof wherein R1, R2, R3, R4 and R5 are each as defined above; la R is a group of the formula: 7a Ν ϋ 7a R Jj- in which R is protected amino; or a group of the formula R8-N -N-n g 9a Hj- in which R is as defined above and R is protected R9a imino; “ ** Μ β f Rlb is a group of the formula: H, or a group of the formula: ,8 R“— Ν—, XI1 in which R is as defined above; HN R is hydrogen, halogen, nitro, lower alkoxy or acyloxy; Aa R. is acyloxy; 2a R is protected carboxy(lower)alkyl; RZb is carboxy(lower)alkyl; R^a is a protective group of amino; R^b is a group which can be substituted by a group R4c-Swherein R is a heterocyclic group which may have suitable substituent(s); and 4c R is as defined above.

Among the starting compounds, the starting compound (IXI), including the corresponding anti-isomer are novel and can be prepared by the processes which are illustrated by the following scheme. (1) (i) (ii) ,5b HO TD (VI) COCH, R10- Y (VII) ,5b R10O COCH, (VIII) ,5 c ...» COCH, Oxidation R5c COCOOH (IX) (X) (iii) ’5c Elimination R' R100 (iv) (2) (i) 5c COCOOH COCOOH (xi) COCOOH (XIII) HO (XII) R2-ONH2 (XIV) or a R5 salt thereof ΝΗ,ΟΗ or a salt p5 R — 2 thereof R -COCOOH -*· HO (XV) (ii) R HO X>i(XVII) COOH ,2 c Alkylation Hydrolysis R 5d R80 X>5<0-5· COOH N 2 OR (IIIa) C00I1 HO N § Oil (XVI) ,5a DOiR80 n $ OR (XVIII) COOR 2d COOH OR 2d (IIIb) 435»'* (3) R sjTλ Acylation C C-COOH -* KqD=/ II N $ 2 OR3 (4) (i) Acylation 5a jQ-?I N 2 OR3 COOH (XIX) (IIIc) Nitrosation x-ch2-co-ch2-z—► xcHoCo-c-z R (XX) .n—ri· s 5 OH 7b OH (XXI) (XXIII) Elimination ?cΛ G-COOH (XXIIIa) (ii) N-r?-Z i7±/T1 S> N Alkylation G-Z •S' OR (XXV) 2e to (5) 43597 CH.-CO-C-Z 3 ll N OH (XXVI) Alkylation CH,CO-C-Z 3 11 N OR26 (XXVII) Halogenation -+ x-ch2co-c-z Elimination (6) (i) (XXIX) // w sz OR' (XXVIII) C-COOH li N OR2® (IIIe) (ii) S' (XXX) ch2-z Amino-protecting agent R7a-/ R1c-CH2-Z (XXXII) Oxidation Rlc-CO-Z +S (XXXI) Hydrolysis ch2-z 2e (XXXIII) thereof N OH (III£) - Rlc-C-Z II N 3 OH (XXIII. ) (XXXVI) (iii) COOH Alkylation R/n4R9a-=4 ? C-COOR Hydrolysis (7) H2N -jfrIS N OH N j OR' 2e (XXXVII) (XXXVIII) /N^-C-COOH r OR' 2e (IHg) C-Z II 3 N 5 2 OR2 Amino-protecting agent ....... .;--h 7n N n R7tJ c-za II a N . $ 2 OR4 (XXXIX) in which R2, RS, R6 defined above; RSb is halogen; Y is an acid residue; R10 is ar(lower)alkyl; 5c R is hydrogen, halogen or nitro; R^b is- lower alkoxy, aT(lower)alkoxy or acylamino; 2c R is hydrogen, lower alkyl or lower alkenyl; R3^ is hydrogen, halogen, nitro, hydroxy or lower alkoxy; X is halogen; is protected carboxy; R/o is lower alkyl, amino or lower alkoxy; 7c R is lower alkyl, amino or hydroxy; ,5a n6a n7a „8 Cinh) R , R and R are each as 5 9 7 rl R is lower alkyl; 2e R is lower alkyl; lc R is a group of the formula: Ν~λ A 7 R —jy in which R is as defined above, or a group of the formula: R8— N,2d .

AT in which R° and Ry are each as defined above; R is lower alkyl or lower alkenyl; and Z is carboxy or protected carboxy.

The other starting compounds ( IV), (V), (Va)-(VC) and (Ve) are all novel compounds and can be prepared by the aforesaid Processes 1 to 8.

Regarding the object compounds of the formulae (I), (I ) and (Ir)-(I_), and the starting compounds of the formulae Λ C g (III), (IIIe), (IIIf), (IIIh), (IV), (Va)-(VC), (Ve), (XXIII)(XXIIIb), (XXIX)-(XXXVII) and (XXXIX), it is to be understood that said object and starting compounds include tautomeric isomers relating to their thiazole groups. That is, in case that the group represented by the formula: NS' in the formula of said object and starting compounds take the R7e-{j-TJ-(wherein R7e is amino, protected amino or hydroxy) N—jl 7 formula: 7 ji ir (A) (R is as defined above), said group of R'e-J'-Sy the formula: , Jl 1— can be also alternatively represented by R/e^ S ΗΝ—Π R'x Agz protected imino or oxo). That is, both of the said groups (A) and (B) are in the state of equilibrium as so-colled its tautomeric formula: ,7f A J“ (B) (wherein R7^ is imino, 4S597 <; tautomeric forms which can be represented by the following equilibrium: HN' (A) (B) 7e 7£ (wherein R and R are each as defined above).

These types of tautomerism between 2-amino- and 2hydroxythiazole compounds and Z-imino-or 2-oxo-thiazoline compounds as stated above have been well known in the literature, and it is obvious to a person skilled in arts that both of the tautomeric isomers are. equilibrated and easily convertible reciprocally, and accordingly it is to be understood that such isomers are included within the same category of the compound per se. Accordingly, both of the tautomeric forms of the object compounds (I), (Xa) and (Ic)-(Ig), and the starting compounds (III), (ΙΙΙθ), (ΠΙ£), (ΙΠ^), (IV), (Va)-(VC), (Vg), (ΧΧΙΠ) -(XXIIIb), (XXIX)-(XXXVII) and (XXXIX) ar.e clearly included within the scope of the present invention. In thepresent specification, claims and examples, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions therefor, that is the formula: jfT- only for the sake of convenience.

R7e (A) Furthermore, regarding the object compounds (I), (I.)(Ic) and (Ig), and the starting compounds (II), (IV), (V) and (Va), the compounds wherein R is carboxy and RQ is formyl can be also regarded as substantially the same compounds as the compounds 3 4 wherein R and R are linked together to form a group of the 43597 formula: -COOCH(OH)- , i.e. so-called intramolecular hcmiacylal type compounds, and accordingly both of them arc understood to be included within the same category of the compound per se and therefore within the scope of the present invention.

Suitable pharmaceutically acceptable salt of the object syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) are conventional non-toxic salts and may include an inorganic salt, for example, a metal salt such as an v alkali metal salt (e.g., sodium salt or potassium salt) and an alkaline earth metal salt (e.g., calcium salt or magnesium salt), ammonium salt etc., an organic salt, for example, an organic amine salt (e.g., trimethylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, picoline salt, dicyclohexylamine salt or N,N'-dibenzylethylene15 diamine salt), an organic acid salt (e.g., acetate, maleate, tartTate, methanesulfonate, benzenesulfonate or toluenesulfonate), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate or phosphate), or a salt with an amino acid (e.g., arginine, aspartic acid or glutamic acid). 2o In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intend to include within the scope thereof are explained in details as follows.

The term lower is intended to mean 1 to 6 carbon atom(s), unless otherwise provided.

Aliphatic hydrocarbon group is intended to mean straight or branched aliphatic hydrocarbon having 1 to 6 carbon atom(s) and may include lower alkyl and lower alkenyl. And said aliphatic hydrocarbon group may have 1 to 2 suitable . 4S5&7 substituent(s) such as carboxy, protected carboxy, arylthio, . lower alkylthio, aryl, acyloxy, lower alkoxy, aTyloxy or a heterocyclic group· ’ Suitable halogen may include chlorine, bromine, fluorine and iodine.

Suitable lower alkoxy and lower alkoxy moiety in the term ar(lower)alkoxy may include one which may be branched, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy, and preferably one having 1 to 4 carbon atom(s), and more preferably one having 1 to 2 carbon atom(s).

Suitable protected amino may include an acylamino and amino group substituted by a conventional protective group other than the acyl group such as benzyl.

Suitable, lower alkyl and lower alkyl moiety in .the terms lower alkylthio, carboxy(lower)alkyl, protected carboxy(lower)alkyl, ”ar(lower)alkyl and di(lower)alkylamino may include one which may be branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl and hexyl, and preferably one having 1 to 4 carbon atom (s),, and more preferably one having 1 to 2 carbon atomfs).

Suitable protected imino may include an acylimino and imino group substituted by a conventional protective group other than the acyl gTdup such as benzyl.

Suitable protected carboxy and protected carboxy moiety in the term protected carboxy(lower)alkyl may include esterified carboxy in which said ester may be the ones sueh as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester or l-cycloprajylethyl·. ester), wherein lower alkyl moiety may be preferably one having 1 to 4 carbon atom(s); lower alkenyl ester (o.g., vinyl ester or allyl ester); lower alkynyl ester (e.g., ethynyl ester or propynyl ester); mono(or di or tfi)-halo(lower)5 alkyl ester (e.g., 2-iodoethyl ester or 2,2,2-trichloroethyl ester. lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxy10 ethyl ester or 2-propionyloxyethyl ester. lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester 2-mesylethyl ester ) ; ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bisitmethoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester or 4rhydroxy-3,5ditertiarybutylbenzyl ester ); aryl ester which may have one or more suitable substituent(s) (e.g., phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl ester or cumenyl ester).

Preferable example of protected carboxy may be lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,, t-bptoxycarbonyl, t-pentyloxycarbony) or hexyloxv25 carbonyl) having 2 to 7 carbon atoms, preferably one having 2 to 5 carbon atoms.

Suitable aryl and aryl moiety in the terms ar(lower)alkyl, ar(lower)alkoxy, arylthio and aryloxy may include phenyl, tolyl, xylyl, mesityl, cumenyl and naphthyl, wherein said aryl group may have 1 to 3 suitable substituent(s) . 43537 κ. such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy .

Suitable heterocyclic group and heterocyclic moiety in the term a heterocyclicthiomethyl group which may have suitable substituent(s)” means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur and nitrogen atom.

And, especially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic·group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl,.pyrxolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazoly] or 2H-l,2,3rtriazolyl), tetrazolyl (e.g., ΙΗ-tetrazolyl or 2H-tetrazolyl); saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl of benzotriazolyl; unsaturated 3-to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl); saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 i'8 5 9 7 nitrogen atom(s), for example, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example or benzoxazolyl benzoxadiazolyl ; unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,thiazolyl, tliiadiazolyl (e.g,, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl). saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl-; unsaturated 3 to 8 membered (preferably 5 to 6 membered) heteromonocyclic group containing a sulfur atom, for example, I thienyl ; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl or benzethiadiazolyl ; wherein said heterocyclic group may have 1 to 2 suitable substituent(s) such as lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl), preferably one having 1 to 4 carbon atom(s); lower alkenyl (e.g., vinyl, allyl or butenyl); aryl (e.g., phenyl or tolyl); halogen (e.g., chlorine, bromine, iodine or fluorine); amino; di(lower)alkylamino(lower)alkyl (e.g. dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl or diethylaminobutyl), preferably one having 3 to 6 carbon atoms; Suitable lower alkenyl is one having 2 to 6 carbon atoms and may include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl and 3-pentenyl, and preferably one having 2 to 4 carbon atoms.

Suitable acyl moiety in the terms acylamino, acylimino, acyloxy” and acyloxymethyl as mentioned above may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g·, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl), preferably, one having 1 to 4 carbon atom(s), more preferably one having 1 to 2 carbon atom(s); lower alkoxyearbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycaTbonyl or hexyloxycarbonyl), preferably one having 3 to 6 carbon atoms; lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfOnyl or butanesulfonyl), preferably one having 1 to 4 carbon atom(s), more preferably one having 1 to 2 carbon atom(s); arenesulfonyl (e.g., benzenesulfonyl or tosyl); aroyl (e.g., benzoyl, toluoyl, naphthoyl, phthaloyl or indancarbonyl. ar(lower)alkanoyl (e.g., phenylacetyl orphenylpropionyl); ar(lower)alkoxyearbonyl (e.g., benzyloxycarbonyl or phenethyloxycarbonyl) ; The acyl moiety as stated above may have 1 to 3 suitable substituent(s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g,, methoxy, ethoxy, propoxy or isopropoxy), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl or butyl), lower alkenyl (e.g., vinyl or allyl), acyl such as halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl) or aryl, (e.g., phenyl or tolyl).

Suitable examples of the acyl having said subs'tituent(s) may be mono(or di or tri)halo(lower)alkanoyl (e.g., trifluoroacetyl or trichloroacetyl ) , preferably one having 2 to 4 carbon atoms; monofor di or tri)halo(lower)alkanoylcarbamoyl (e.g., trichloroacetylcarbamoyl) , preferably one having 3 to 4 carbon atoms . 4a Suitable protective group of amino for R may include acyl such as halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl), preferably one having 2 to 3 carbon atoms .

Suitable acid residue may include a residue of an acid such as an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydriodic acid or sulfuric acid) or an organic acid (e.g., methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid ) .

Suitable example of a group which can be substituted 4 c by a group R -S- may include an acid residue such as halogen, azido or acyloxy wherein said halogen and acyl moiety of said acyloxy are the same ones as aforementioned.

Among the suitable examples of each of the groups of the object compounds as explained and illustrated above, the prefered examples thereof are illustrated as follows.

Preferable example of R5 may be hydrogen halogen (preferably chlorine) or nitro; preferable example of R^ may be hydroxy, lower alkoxy (preferably Cj-C^, more preferably C^-C2), acyloxy[preferably lower alkanoyloxy (preferably more preferably C^-C2) or carbamoyloxy], acylamino [preferably lower alkanesulfonylamino (preferably C^-C^, more preferably (C^-cp] or di(lower)alkylamino (wherein the alkyl moiety is preferably C|-C4, more preferably C^-Cpί preferable example of R may be amino, protected ammo such as acylamino [preferably lower alkanesulfonylamino (preferably Cj-C^, more preferably C-^-cp , trihalo (lower) alkanoylamino (preferably C^-C^, more preferably C^-cp lower alkoxycarbonylami.no (preferably C2*Cy, more preferably Gj-Cg) or lower alkanoylamino (preferably C^-C^, more preferably Cj-C2)], hydroxy or lower alkyl (preferably C^-C^, more preferably C^-Cp; preferable example of R is C^-C^ lower alkyl, more preferably C^-Cj lower alkyl; preferable example of R may be protected imino such as acylimino [preferably lower alkanesulfonylimino (preferably C^-C^, more preferably C^-C2)]< preferable example of R may be lower alkyl (preferably Cj-C^j, more preferably C^-C2, most preferably cp , lower alkenyl, ar(lower)alkenyl [more preferably phenyl(lower)alkenyl], carboxy(lower)alkyl, protected carboxy(lower)alkyl [more preferably lower alkoxycarbonyl (preferably Cj-Cg) (lower)alkyl], arylthio(lower)alkyl [more preferably phenylthio(lower)alkyl], ar(lower)alkyl [more preferably phenyl(lower)alkyl] which may have halogen (preferably bromine) and hydroxy, thienyl(lower)alkyl or aryloxy(lower)alkyl [more preferably phenoxy(lower)alkyl] which may have hydroxy, in which alkenyl and alkenyl moiety is C2-Cg, preferably and alkyl moiety is preferably C^-C^, more preferably C^-C2; 5 9 7 τ preferable example of R may be carboxy; preferable example of R4 may be acyloxymethyl[preferably lower alkanoyloxymethyl (in which alkanoyl moiety is preferably Cj-C^, more preferably Cj-Cg, most preferably C2, i.e. acetyl) or carbamoyloxymethyl which may have trihalo(lower)alkanoyl (in which trihalo moiety is preferably trichloro and alkanoyl moiety is preferably C2-Cj5), hydroxymethyl, formyl, tetrazolylthiomethyl which may have lower alkyl (preferably more preferably C^-Cp or di(lower)alkylamino(lower)alkyl (in which 1° alkyl moiety is preferably C^-C^, more preferably (J-cp , triazolylthiomethyl which may have lower alkyl (preferably C^-C^, more preferably CJ-cp or thiadiazolylthiomethyl which may have lower alkyl (preferably C^-C^, more preferably C^-Cp; 4 or R and R are linked together to form -COOCH215 The various processes for preparing the object compounds of the present invention are explained in details in the following. Process 1: The object compound (I) or a salt thereof can be 20 prepared by reacting the compound (IX) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or a salt thereof, which is a fundamental method for preparing the object compound (I) Suitable reactive derivative at the amino group of the 25 compound (II) may include conventional reactive derivative used in amidation, for example, a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide or the like.

Suitable salt of the compound (II) may include an acid ·> 45597 ‘-'Χ _ addition salt such as an organic acid salt (e.g., acetate, maleate, tartrate, benzenesulfonate or toluenesulfonate) or an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate or phosphate); a salt with an inorganic base such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt)· or ammonium salt; and a salt with an organic base (e.g., triethylamine salt or pyridine salt); Suitable reactive derivative at the carboxy group of 10 the compound (III) may include conventional one used in amidation.

The salts of the compound (III) may be salts with an inorganic base such as an alkali metal salts (e.g., sodium or potassium salt), or an alkaline earth metal salt (e.g., calcium IS or magnesium salt), a salt with an organic base such as trimethylamine, triethylamine, pyridine pr a salt with an acid (e.g., hydrochloric acid or hydrobromic acid).

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν,Ν-dimethylformamide, pyridine or any other organic solvent which does not adversely influence to the reaction.

Among these solvents, hydrophilic solvents may be used in a mixture with water.

The present reaction is preferably carried out in the presence of a condensing agent such as so-called Vilsmeier reagent, for example, (chloromethylene)-dimethylammonium chloride produced by the reaction of dimethylformamide with thionyl chloride or phosgene, a compound produced by the reaction of dimethylformamide with phosphorus oxychloride.

The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal bicarbonate, alkali metal carbonate, alkali metal acetate, tri(lower)alkylamine, pyridine, N-(lower)5 alkylmorphorine, N,N-di(lower)alkylbenzylamine or N,N-di(lower)alkylaniline as exemplified below. when the base or the condensing agent is in liquid, it can be used also as a solvent. The reaction temperature is not critical, and the reaction is usually carried out under cooling or at ambient temperature.

In the present reaction, it is to be noted that, in case that the starting compound (III) is reacted with the compound (II) or its reactive derivative at the amino group or a salt thereof in the presence of, for example, phosphorus pentaehloride or thionyl chloride, only the corresponding anti-isomer to the object compound (I) or a mixture of the corresponding anti-isomer and syn-isomer is always given .as an object compound even if the compound (HI), i.e., syn-isomer is used as a starting compound. It is of course to be noted that the reaction of the corresponding anti-isomer to the starting compound (III) with the compound (II) can never produce the object compound (I) of the present invention, i.e. syn-isomer.

It may be understood that such tendency and singularity of the reaction as mentioned above is due to the fact that the less stable syn-isomer tends to isomerize partially or wholly to the corresponding more stable anti-isomer in the course of the reaction, for example, in so-called activation step of the compound (III) so that the isomerized compound, i.e. the anti-isomer corresponding to the object compound (I) can be produced as an object compound.

Accordingly, in order to obtain the object compound · (I), i.e., syn-isomer selectively and in high yield, it is necessary to use the starting compound (III), i.e., syn-isomer and to select a suitable reaction condition. That is, the object compound (I), i.e., syn-isomer can be obtained selectively and in high yield by conducting the reaction, for example, in the presence of a Vilsmeier reagent as mentioned above and under around neutral condition.

Especially, in case that the starting compound (III) wherein R^ is a group of the formula: is used, the object compound (I), i.e., syn-isomer can be obtained selectively and in high yield by conducting the present reaction of the corresponding starting compound (III), i.e., syn-isomer IS with the compound (II), for example, in the presence of a Vilsmeier reagent produced by the reaction of dimethylformamide with phosphorus oxychloride and under around neutral condition. And, in this case, it is to be noted that particularly good results can be achieved by conducting the reaction in the presence of more than two molar equivalents of phosphorus oxychloride to each amount of the said starting compound (III), i.e., syn-isomer and dimethylformamide as shown in the working examples.

Further, in this case, it is to be also noted that good results can be achieved by conducting an activation step of the starting compound (III), i.e., syn-isomer in the presence of a silyl compound [e.g. bis(trimethylsilyl)acetamide or trimethylsi-lylacetamide] · With regard to the reaction of the compound (II) with the compound (III), it is to he noted that; when the compound (II) wherein R^ is carbamoyloxymethyl group having acyl group is used as a starting compound, there may be obtained occasionally either the object compound (I) wherein R4 is carbamoyloxymethyl group having acyl group or free carbamoyloxymethyl group according to reaction conditions; when the compound (II) wherein R4 is hydroxymethyl group is used as a starting compound, there may be obtained occasionally the 3 4 object compound (I) wherein R and R are linked together to form -COOCl·^- ; and further the protected carboxy group or salts in the compound (II) may be converted into free carboxy group; in the course of the reaction or in post-treatment. These cases are also included within the scope of the present invention.

As clear from the explanation as stated above, it is to be understood that the Process 1 is a fundamental and the most advantageous method for preparing the object compound (I), i.e. syn-isomer.

Process 2: The object compound (I&) or a salt thereof can be prepared by subjecting the compound (IV) or a salt thereof tc elimination reaction of the protective group of the amino or imino.

Suitable salt of the compound (IV) may include a metal salt, ammonium salt and an organic amine salt as aforementioned.

The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis; reduction; a method by reacting the compound (IV) wherein the protective group is acyl group with iminohalogenating agent and then with iminoetherifying agent, and, if necessary, subjecting the resulting compound to hydrolysis . 397 The hydrolysis may include a method using an acid or base or hydrazine . These methods may be selected i -- · depending on the kind of the protective groups to be eliminated.

Among these methods, hydrolysis using an acid is one of the common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl (e.g., t-pentyloxycarbonyl)., alkanoyl (e.g., formyl), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbony3 or substituted .10 carbonyl), substituted phenylthio, substituted aralkylidene, substituted alkylidene or substituted cycloalkylidene.

Suitable acid may include an organic or an inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and hydrochloric acid, and pre15 ferable acid is an acid which can be easily removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, for example, formic acid, trifluoroacetic acid or hydrochloric acid. The acid suitable for the reaction can be selected according te the kind of protective group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Suitable solvent may include an organic solvent, water or a mixed solvent thereof. When trifluoroacetic acid is used, the elimination reaction may be preferably carried out in the presence of anisole.

The hydrolysis using hydrazine is commonly applied for eliminating the protective group, for example, succinyl or phthaloyl.

The hydrolysis with a base is preferably applied for eliminating acyl group, for example, haloalkanoyl (e.g., trifluoroacetyl ). Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), alkaline earth metal hydroxide (e.g., magnesium hydroxide or calcium hydro5 xide), alkali metal carbonate (e.g., sodium carbonate or potassium carbonate ), alkaline earth metal carbonate (e.g., magnesium carbonate or calcium carbonate), alkali metal bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate), alkali metal acetate (e.g., sodium acetate or potassium acetate), alkaline earth metal phosphate (e.g., magnesium phosphate or calcium phosphate ), or alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate or dipotassium hydrogen phosphate and an organic base such as trialkylamine (e.g., trimethylamine or triethylamine), picoline, N-methyl15 pyrrolidine, N-methylmorpholine, l,5-diazabicyclo[4,3,0]non-5-ene, l,4-diazabicyclo[2,2,2]octaneor l,5-diazabicyclo[5,4,0]undecene-5 The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Among the protective groups, the acyl group can be generally eliminated by hydrolysis as mentioned above or by the other conventional hydrolysis. In case that the acyl group is halogen substituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminated, by treating with a heavy metal such as copper or zinc.

The reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g., trichloroethoxycarbonyl ), substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl or substituted benzyloxy30 carbonyl) , 2-pyridylmethoxycarbonyl. Suitable 4S597 reduction may include, for example, reduction with an alkali - metal borohydride (e.g., sodium borohydride) .

Suitable iminohalogenating agent usq.d in a method as mentioned above may include phosphorus trichloride, phosphorus pentaehloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride and phosgene.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under cooling. Suitable iminoetherifying agent reacted with thus obtained reaction product may include an alcohol and metal alkoxide Suitable alcohol may include alkanol (e.g., methanol, ethanol, propanol, isopropanol, butanol or t-butanol) which may be substituted with alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy or butoxy). Suitable metal alkoxide may include alkali metal alkoxide (e.g., sodium alkoxide or potassium alkoxide) and alkaline earth metal alkoxide (e.g., calcium alkoxide or barium alkoxide) The reaction temperature is not critical, and the reaction is usually carried out under cooling or at ambient temperature.

Thus obtained product is, if necessary, subjected to hydrolysis. The hydrolysis can be readily carried out by pouring the reaction mixture obtained above into water, but there may be previously added a hydrophilic solvent (e.g., methanol or ethanol), a base (e.g., alkali metal bicarbonate or trialkylamine), or an acid (e.g., diluted hydrochloric acid or acetic acid) to the water.

The reaction temperature is not critical and may be suitably selected in accordance with the kind of the protective group of the amino group and the elimination method as mentioned above, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly elevated temperature.

The present invention includes, within its scope, the cases that the protected carboxy is transformed into the free carboxy group; that when the compound (IV) wherein R4 is carbamoyloxymethyl group having acyl grup is used as the starting compound, there may be obtained occasionally either the object compound (I ) wherein R4 is carbamoyloxymethyl group having acyl group a or free carbamoyloxymethyl group according to reaction conditions; and that when the compound (IV) wherein R4 is acyloxymethyl group is used as the starting compound, there may be obtained occasional15 ly the object compound (I„) wherein R3 and R4 are linked together a. to form -COOCl·^- according to reaction conditions; in the course of the reaction or in post-treatment..

Process 3: The object compound (IJ or a salt thereof can be 20 prepared by acylating the hydroxy group of the compound (V) or a salt thereof.

Suitable salt of the compound (V) can also be referred to the ones exemplified for the compound (IV).

The acylating agent to be used for the present reaction 25 may include an aliphatic, aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid and thio acid which have aforesaid acyl group as their acyl moieties, and reactive derivatives of the above-mentioned acids. Suitable reactive derivative of the above-mentioned acids may include an acid halide, an acid anhydride, an activated amide and an activated ester. «.· 45597 Suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated. phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid ) or aromatic carboxylic acid (e.g., benzoic 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, dimethyliminomethyl ((CHj)2N = ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,415 dihitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8quinolyl thioester], or an ester with N,N-dimethylhydroxylamine, 1-hydroxy-2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or i-hydroxy-6-chloro-lH-benzotriazole.

These reactive derivatives can be optionally selected from them according to the kind of the acylating agent to be used.

The acylating agent may further include aliphatic, aromatic or heterocyclic isocyanate or isothiocyanate (e.g., methyl isocyanate, phenyl isocyanate, trichloroacetyl isocyanate or methyl isothiocyanate) and haloformate (e.g., ethyl chloroformate or benzyl chloroformate). In this case, for example, when trichloroacetyl isocyanate is used as an / acylating agent, trichloroacetylcarbamoyl group is introduced as acyl group and said group may be converted to carbamoyl group by treating with base, and when ethyl chloroformate is used as an acylating agent, ethoxycarbonyl group is introduced as acyl group.

The present reaction is carried out according to similar reaction conditions to those of aforesaid reaction of the compound (IX) with the compound (III), and is preferably carried out in the presence of a base. In the reaction of the compound (V) with an acylating agent, the protected carboxy group or salts in the compound (V) may be converted into free carboxy group in the course of the reaction or in post-treatment; and when the compound (V) wherein R4 is carbamoyloxymethyl group having acyl group is used as the starting compound, there may be obtained occasionally either the object compound (1^) wherein R is carbamoyloxymethyl group having acyl group or free carbamoyloxy methyl group according to reaction conditions in the course of the reaction or in post-treatment. These cases are also included in the scope of the present invention.

Process 4: The object compound (Ic) or a salt thereof can be prepared by subjecting the compound (V ) or a salt thereof to elimination reaction of the protective group of the carboxy.

Suitable salt of the compound (V ) can be referred to the ones exemplified for the compound (IV).

The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis The hydrolysis may Include a method using an acid or base. These methods may be selected depending on kind of the protective groups to be eliminated.

The hydrolysis using an acid is one of the most common 4559 7 and preferable methods for eliminating the protective groups such as phenyl(lower)alkyl, substituted phenyl(lower)alkyl, lower alkyl or substituted lower alkyl. Suitable acid may include inorganic or organic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid hydrochloric acid. The present reaction may be carried out in the presence Of anisole. The acid suitable for the reaction can be selected according to the protective group to be eliminated and other factors.

The hydrolysis using an acid may be carried out in the presence of a solvent, such as an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical and may be suitably selected in accordance with the kind of the protective group and the elimination method, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly warming.

The present invention includes, within its scope, the 3 cases that the protected carboxy group for R is transformed into the free carboxy group; that the protected amino group is transformed into the free amino group; that the protected imino group is transformed into the free imino group; that the acyloxy group is transformed into the hydroxy group; and/or that the carbamoyloxymethyl group having acyl group is transformed into the free carbamoyloxymethyl group; during the reaction or posttreating in the present reaction.

Process 5: The object compound (Ij) or a salt thereof can be prepared by subjecting the compound (V^) or a salt thereof to elimination reaction of the protective group of the amino. «5597 Suitable salt of the compound (Vg) can be referred to the ones exemplified for the compound (IV).

The present elimination reaction may include an elimination method using a base, for.example, an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), an alkali metal bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate) or alkali metal carbonate (e.g., sodium carbonate or potassium carbonate), an organic base such as an alkali metal alkoxide (e.g., sodium methoxide or sodium ethoxide), a trialkylamine (e.g., trimethylamine or triethylamine), triethanolamine, N,Ndimethylaniline, Ν,Ν-dimethylbenzylamine, N-methylmorpholine or pyridine; and an elimination reaction using basic alumina, basic ion exchange resin, acid (e.g., trifluoroacetic acid or trifluoroacetic acid-anisole). The present elimination reaction is usually carried out in water, hydrophilic solvent or a mixture thereof. The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or under cooling.

The present invention includes, within its scope, the cases that the protected carboxy group or salts in the compound (Vg) may be converted into free carboxy group, and that the protected amino and/or imino group may be converted into the free amino and/or imino group, respectively in the course of the reaction or in post-treatment.

Process 6: The object compound (Ig) or a salt thereof can be prepared by reacting the compound (Vc) or a salt thereof with the compound (V^) or its reactive derivative at the mercapto group. 4SSS7 Suitable salt of the compound (V ) can he referred to the ones exemplified for the compound (IV).

The suitable reactive derivative at the mercapto group of the compound (V^). may include a metal salt 'such as alkali 3 metal salts (e.g., sodium salt or potassium salt).

The present reaction may be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or any other solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carried out in weekly basic or around neutral condition. When the compound (Vc) and or the thiol 15 compound (Vj) is used in a free form, the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base such as trialkylamine and pyridine. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming. The reaction product can be isolated from the reaction mixture by conventional methods.

The reaction of the compound (Vc) with the compound (Vd) includes, within its scope, the cases that the protected 25 carboxy group or salts in the compound (V ) may be converted into free carboxy group; that the protected amino and/or imino group may be converted into free amino and/or imino group; and that the acyloxy group may be converted into hydroxy group; respectively in the course of the reaction or in post-treatment. 30 Process 7: The object compound (1^) or a salt thereof can be prepared by treating the compound (Ve) or a salt thereof with an acid.

Suitable salt of the compound (Ve) can be referred to the ones exemplified for the compound (IV).

Suitable acid to be used in the present reaction may include an inorganic acid (e.g., hydrochloric acid, hydrobromic acid or sulfuric acid) or an organic acid (e.g., formic acid or acetic acid).

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

The reaction temperature is not critical and the reaction is preferably carried out under cooling to warming.

Process 8: The object compound (Ig) or a salt thereof can be prepared by oxidizing the compound (Ve) or a salt thereof.

Suitable oxidizing agent used in the present reaction may include Jones reagent being used by a combination of sulfuric acid and chromium trioxide, manganese dioxide, a reagent being used by a combination of dimethylsulfoxide and N,Ν'-dicyclohexylcarbodiimide.

The present 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 may be used as a mixture thereof.

The reaction temperature is not critical and the reaction is preferably carried out under cooling or around ambient temperature.

Processes for preparing the starting compound (III) i.e., syn-isomer and anti-isomer thereof used-for References are explained in details as follows.

(A) Process of (VI)+(VII) -» (VIII) [Scheme (1) (i)] The compound (VIII) can be prepared by reacting the compound (VI) with the compound (VII).

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

IS (B) Processes of (IX) > (X) [Scheme (1) (ii)] and (XXXII) -m-CXXXIII) [Scheme (6) (ii)] The compounds (X) and (ΧΧΧΙΙΙ) can be prepared by oxidizing the compounds (IX) and (XXXII), respectively.

The present oxidation reaction is conducted by a conventional method which is applied for the transformation of so-called activated methylene group into carbonyl group. That is, the present oxidation is conducted by a conventional method such as oxidation by using a conventional oxidizing agent such as selenium dioxide or potassium permanganate. The present oxidation is usually carried out in a solvent which does not adversely influence the reaction, for example, water, dioxane, pyridine and tetrahydrofuran.

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

(C) Process of (Xl)f(XII) [Scheme (1) (iii)] The compound (XII) can be prepared by subjecting tee compound (XI) to elimination reaction of the ar(lower)alkyl group.

The present elimination method may include all 5 conventional methods used in the elimination reaction of the ar(lower)alkyl group, for example, hydrolysis or reduction.

The hydrolysis using acid is one of the most preferable method and the acid to be used may include an inorganic acid (e.g., hydrochloric acid or hydrobromic acid), an organic acid (e.g., formic acid, acetic acid or trifluoroacetio acid ) and a mixture thereof. The present reac.tion can be carried out in a solvent such as water, an organic solvent or a mixture thereof or without solvent.

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

(D) Processes of (XIII) + (XIV) >· (Ilia) [Scheme (1) (iv)), (XXXIII) + (XIV) (XXXV) [Scheme (6) (ii)] and (XXXIV) + (XIV)-»· (IIIf) [Scheme (6) (ii)] The compounds (III )., (XXXV) and (IIIJ can be pre20 pared by reacting the compounds (XIII), (XXXIII) and (XXXIV) with the compound (XIV) or a salt thereof, respectively.

Suitable salt of the compound (XIV) may include an inorganic acid salt (e.g., hydrochloride, hydrobromide or sulfate), an organic acid salt (e.g., acetate or p-toluenesulfon-. ate).

The present reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol) , a mixture thereof or any other solvent which does not adversely influence the present reaction.

The present reaction, in case that the compound 4S597 (XIV) is used in its salt form, Is preferably carried out in the presence of a base, for example, an inorganic base such as alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., magnesium or calcium), the hydroxide or carbonate or bicarbonate thereof or the like, and an organic base such as alkali metal alkoxide (e.g., sodium methoxide or sodium ethoxide), trialkylamine (e.g., trimethylamine or triethylamine), N,N-dialkylamine (e.g., Ν,Ν-dimethylaniline), N,N-dialkylbenzylamine (e.g·» N,N-dimethylbenzylamine) or pyridine The reaction temperature is not critical and the reaction is usually carried out uiider cooling to heating.

In the present reaction, the mixture of syn- and anti-isomers of the compound (ΙΙΙ&), (XXXV) or (III£) may be IS obtained according to reaction conditions , and in such case, both isomers may be resolved by conventional manners from the mixture. For example, the mixture is firstly esterified and the resulting esters are resolved, for example, by chromatography into each isomer. The resolved each isomer of . esters is hydrolyzed by a conventional method to give the corresponding syn- or anti-carboxylic acid.

In order to obtain syn-isomer of the compound (III ), (XXXV) or (III£) selectively and in high yield the present reaction is preferably carried out around neutral condition. (9) Processes of (XV)-> (XVI) [Scheme (2) (i)] and (XXXIV)-»-(XXXVI) [Schme (6) (ii)] The-compounds (XVI) and (XXXVI) can be prepared by reacting the compounds (XV) and (XXXIV) with hydroxylamine or a salt thereof, respectively.

Suitable salt of hydroxylamine can be referred to the ones exemplified for the compound (XIV).

The reaction conditions of the present reaction can also be referred to the ones exemplified for the processes of (XI11) +(XIV) + (IIIJ, (XXXIII) + (XIV) + (XXXV) and a (XXXIV)+(XIV) +(II1^) as mentioned ih aforementioned (D).

(F) Processes of (XVII) +(XVIII) [Scheme (2) (ii)], (XXIV) +(XXV) [Scheme (4) (ii)] (XXVI) +(XXVII) [Scheme (5)] and (XXXVII) +(XXXVIII) [Scheme (6) (iii)] The compounds (XVIII), (XXV), (XXVII) and (XXXVIII) can be prepared by alkylating the compounds (XVII), (XXIV), (XXVI) and (XXXVII), respectively.

The alkylating agent to be used in the present alkylation reaction may include di(lower)alkyl sulfate (e.g., dimethyl sulfate or diethyl sulfate), diazo(lower)alkane (e.g., diazomethane or diazoethane), lower alkyl halide (e.g., methyl iodide or ethyl iodide) and lower alkyl sulfonate (e.g., 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 influence the reaction.

The present reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base as aforementioned.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating around boiling point of the solvent.

The reaction using diazoalkane is usually carried out ih a solvent such ad ether or tetrahydrofuran.

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

CG) Processes of (XVIII) +(Ilty [Scheme (2) Cii)1 and (XXXVIII) + (Illg) [Scheme (6) (iii)] The compounds (111^) and (HI ) can be prepared bysub jecting the compounds (XVIII) and (XXXVIII) to hydrolysis, respectively.

The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inorganic base and an organic base such as an alkali metal (e.g., sodium or potassium), an alkaline earth metal (e.g., magnesium or calcium), the hydroxide or carbonate or bicarbonate thereof, trialkylamine (e.g., trimethylamine or triethylamine), picoline, l,5-diazabicyclo[4,3,0]non5-ene, l,4-diazabicyclo-[2,2,2]octane or l,5-diazabicyclo[5,4,0] undecene-5.

Suitable acid may include an organic acid (e.g., formic acid, acetic acid, propionic acid or trifluoroacetic acid). and an inorganic acid (e.g., hydrochloric acid, hydrobromic acid or sulfuric acid).

The reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol), a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can also be used as the solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

(H) Process of (XIX) +(IIIC) [Scheme (3)] The compound (IIIC) can be prepared by subjecting the compound (XIX) to acylation.

The acylating agent to be used for the present 5 reaction and the reaction conditions of the present reaction can be referred to the ones exemplified for Process 3.

(I) Process of (XX)->-(XXI) [Scheme (4) (i)] The compound (XXI) can be prepared by subjecting the compound (XX) to nitrosation. 1θ The nitrosating agent to be used for the present reaction may include conventional agent which give c-nitroso compound by reacting with activated methylene group, such as nitrous acid, alkali metal nitrite (e.g., sodium nitrite), lower alkyl nitrite (e.g., isopentyl nitriteor t15 butyl nitrite.).

In case that salt of nitrous acid is used as nitrosating agent, the present reaction is usually carried out in the presence of an acid such as an inorganic acid or an organic acid (e.g., hydrochloric acid or acetic acid).

In case that ester of nitrous acid is used, the present reaction is preferably carried out in the presence of a strong base such as alkali metal alkoxide .

The present reaction is usually carried out in a solvent such as water, acetic acid, benzene, alcohol (e.g., ethanol or methanol) or any other solvent which does not adversely influence the reaction.

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

IS (J) Processes of (XXI)+(XXII)->· (XXIII) [Scheme ¢4) (i)] and (XXVIII) + (XXII)-· (XXIX) [Scheme (5)] The compounds (XXIII) and (XXIX) can be prepared by reacting the compounds (XXI) and (XXVIII) with the compound (XXII), respectively.

The present reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol) , benzene, dimethylacetamide, dimethylformamide, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usually carried out from ambient temperature to under heating around the boiling point of the solvent.

In order to obtain syn-isomer of the compound (XXIII) or (XXIX) selectively and in high yield, it is necessary to use syn-isomer of the starting compound (XXI) or (XXVIII) and the present reaction is preferably carried out around neutral condition in the presence of a base as aforementioned. Preferable example of base may be week base such as alkali metal acetate (e.g., sodium acetate or potassium acetate), alkali metal bicarbonate (e.g., sodium bicarbonate or potassium bicarbonate ), or . alkali metal carbonate (e.g., sodium carbonate or potassium carbonate).

(K) Processes of (XXIII)(XXIIIa) (Scheme (4) (i)], (XXV)+(IIId) [Scheme (4) (ii)], (XXIX) + (IIIe) [Scheme (5)], (XXXIII) *(XXXIV) [Scheme (6) (ii)] and (XXXV)-(IIIf) [Scheme (6) (ii)] - The compounds (XXIIIa), (IIId), (IHg), (XXXIV) and (Hip can be prepared by subjecting the compounds (XXIII), (XXV), (XXIX), (XXXIII) and (XXXV) to elimination reaction of 46SS7 the protective group of the carboxy, respectively.

In the present elimination reaction, conventional methods used in .the elimination reaction of the protected carboxy, for example, hydrolysis can be applicable.

When the protective group is an ester·, it can be eliminated by hydrolysis.

The present hydrolysis is carried out according to similar manners to those of processes (XVIII) +and (XXXVIII) ·* (Illg) as mentioned in aforesaid (G).

W Process of (XXVII) ·> (XXVIII) [Scheme (5)] The Compound (XXVIII) can be prepared by halogenating the compound (XXVII).

The halogenating agent to be used in the present reaction may include a conventional halogenating agent used in halogenation of so-called activated methylene group such as halogen (e.g., bromine or chlorine), sulfuryl halide (e.g., sulfuryl chloride), hypohalite (e.g., hypochlorous acid, hypobromous acid or sodium hypochlorite) and Nhalogenated-imide (e.g., N-bromosuccinimide, N-bromophthalimide or N-chlorosuccinimide ).

The present reaction is usually carried out in a solvent such as an organic acid (e.g., formic acid, acetic acid or propionic acid), carbon tetrachloride or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling?at ambient temperature, under warming or heating.

(M) Processes of (XXX)(XXXI) [Scheme (6) (i)] and (XXXIX)-»· (IIIh) [Scheme (7)] The compound (XXXI) can be prepared by reacting the <**·. 4SSS7 compound (XXX) or its reactive derivative at the amino group or a salt thereof with an amino-protecting agent and the compound (IIIJ can be prepared by reacting the compound (XXXIX) or its reactive derivative at the amino group or a salt thereof with an amino-protecting.agent.

Suitable reactive derivative at the amino group of the compound (XXX) or (XXXIX) and suitable salt of the compound (XXX) or (XXXIX) may include the same ones as illustrated in the explanations of the reactive derivative at the amino group of the compound (II) and salt of the compound (II), respectively.

Suitable amino-protecting agent may include acylating agent which may include an aliphatic, aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid, haloformic acid ester, isocyanic acid ester and carbamic acid, and the corresponding thio acid thereof, and the reactive derivative of the above acids.

Suitable reactive derivative of the above acids may include the same ones as illustrated in the explanation of Process 3. The example of the protective group (e.g. acyl group) to be introduced into the amino group in the compound (XXX) or (XXXIX) by the above amino-protecting agent (e.g. acylating agent) may be the same protecting group (e.g., acyl group) as illustrated in the explanation of the protective group moiety (e.g., acyl moiety) in the term acylamino.

The present amino-protecting reaction is carried out in a similar manner as illustrated in the reaction of the compound (II) with the compound (III) (Process 1).

(N) . Process of (XXIIIJ-* (XXXIII) [Scheme (6) (ii)] The compound (XXXIII) can be prepared by subjecting the compound (XXIIIJ to hydrolysis.

!· The present hydrolysis is carried out in the presence of alkali metal bisulfite (e.g., sodium bisulfite) titanium trichloride, inorganic or organic acid such as hydrohalogenic acid (e.g., hydrochloric acid or hydrobromic acid), formic acid or nitrous acid. Hydrohalogenic acid is preferably used in a combination of aldehyde (e.g., formaldehyde).

The present reaction is usually carried out in a solvent such as water, aqueous alcohol (e.g., aqueous methanol or aqueous ethanol), water-acetic acid or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, under warming or heating.' In the present reaction, protected carboxy group may be occasionally transformed into free carboxy group. This case is also included in the scope of the present invention.

In the aforementioned reactions and/or the posttreating of the reactions of the present invention, the afore20 mentioned tautomeric isomers may be occasionally transformed into the other tautomeric isomers and such case is also included in the scope of the present invention.

In case that the object compound (I) is obtained in a form of the free acid at 4 position and/or in case that the object compound (I) has free amino group, it may be transformed into its pharmaceutically acceptable salt as aforementioned by a conventional method.

The object compound (I) and pharmaceutically acceptable salt thereof of the present invention are all novel compounds which exhibit high antibacterial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antibacterial agents. Particularly, it is to be noted that the object compound (I), i.e., syn-isomer has much higher S antibacterial activities than the corresponding anti-isomer to the compound (I), and accordingly the object compound (I), i.e., syn-isomer is characterized by having much superiority to the corresponding anti-isomer in the therapeutic value.

Now, in order to show the utility of the object 10 compound (I), with regard to some representative compounds of this invention, there are shown the test data on the in vitro anti-bacterial activity, the test· data on in vivo, i.e. the protecting effect against experimental infections and the acute toxicity in the following. Additionally, there are also shown the comparative test data on in vitro antibacterial activities relating to the corresponding antiisomer to the object, compound (I) for the sake of reference •in the following.

Test compounds (1) 7-{2-Methoxyim£no-2-(3-hydroxyph.enyl)acetamidoj-3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2) 7 -[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(lmethyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (4) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(l,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 5 9 7 (5) ·7-[Z-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (6) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]S 3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (7) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer). (8) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (9) 7-[2-Methoxyimino-2-(2-amino-1,3 -thiazol-4-yl)acetamido]cephalosporanic acid (anti isomer) (10) 7 -[2-Methoxyimino-2-(Z-formamido-1,3 -thiazol-4-yl)acet15 amido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer) (11) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido] -3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (12) 7-[2-Methoxyimino-2-(2-formamido-l,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (13) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (14) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]25 3-(1,3,4-thiadiazol-Z-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (15) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (16) 7-[2-Methoxyimino-2-(2-amino-l, 3-thiazol-4-yl)acetamido]30 3-(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl-3-ceph.em-44? 45^97 carboxylic acid (syn isomer) (17) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]3-(4-methyl-4H-l,2,4-triazol-3-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer) (18) 7-t2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-l,3th.iazol-4-yDacetamido] -3 -carbamoyloxyme thyl-3-cephem-4 carboxylic acid (syn isomer) 1· *n antibacterial activity: Test Method In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described below.

One loopful of an overnight culture of each test o strain in Trypticase-soy broth (10 viable cells per ml.) was streaked on heart infusion agar (HI-agar) containing graded concentrations of antibiotics, and the minimal inhibitory concentration (MIC) was expressed in terms of pg/ml. after incubation at 37°C for 20 hours. tn -fl X Z BI ts) rt rt hs w tn Q *4 ffi O ff cr w p. ftp- 2 0 H to 0 K 0 rt rt rt ΙΛ g rt Π o r* & P ι £/ W w *3 tan· n* P P 12 s O o rt· rt V) 3 o 0 rt K p. rt rt P P 0 © © rt r~\ *4 CM rt CO © © O © rt 04 © ts) *4 CO tn © ts) © tn Z—s cn • © 04 ts) tn © © 04 • *4 00 .78 £ •fl rt o H /rt * Is) tn tn *4 © 00 tn o © © • © rt rt ts) ss O © © H ss 04 O' rt 0 * • ts) *4 Co 13 ts) tn tn u/ rt rt n n o © © z—\ o • • • 00 o cn s s ►d 0 OO c *rt © rt 04 r~\ 5 fl • ·- © ft •4 00 tn © £ S-J tn kJ z—s o rt © rt © w tn «4 to © © zrt 04 04 rt rt Cs) rt ί-* w 13 tn zrt © rt rt .78 tn © tn © ts) s—> © a p rt • zrt rt 025 © tn tn © 04 o © © zrt « « rt rt ts) fl © © o rtz © © © zrt rt rt © •4 tn © tn a sj © © o zrt • • rt OJ rt 04 © © © © © a © rt ig ts) O ts) © *4 uz © © 04 zrt rt 025 © tn £ 00 srt rt o w 45S97 As clearly seen from the above test results, the object compounds (I) of the present invention, i.e., synisomers have much higher antibacterial activity as compared with the corresponding anti-isomers thereof. 2. Protecting effect against experimental infections in mice; Test Method Male ICR strain mice aged 4 weeks, each weighing 20-23 g were used in groups of 8 mice. The test bacteria were cultured overnight at 37°C on HI-agar and then suspended in 2.5 - 5% mucin solution to obtain the suspension correspond ing to each challenge cells. Mice were inoculated intraperitoneally with 0.5 ml of the suspension. A solutioncontaining each test compounds was given subcutaneously to the mice in various dosage one hour after challenge. The ED5Q values were calculated from the number of surviving mice for each dosage after one week of observation. Ο υ •Η Ρί «Η (Λ α ο •rl Ρ υ Θ ΜΗ β to Ρ •Η Ρ Φ CU X U4 Ρ W C •Η cj »30 « Ρ υ 5J Μη tp ω bO G •Η Ρ υ φ Ρ Ο ρ <Λ Ρ Ρ Ρ ΙΛ 0> Ε- G) I e s~i J W Ο tn S 1 1 (J P w <υ H 3 j 1.402 S 0.111 Λ 0.081 *p p- P _/ <0.005 M <0.005 MIC of used strain (pg/mfc) 1 a- IS δ P (Λ r9 Ep b (Λ cJ P Ώ P tn 5> |0.78 | 0.78 tn 0.78 | j 0.39 5* ip / [ <0.03 | <0.03 r—\ CO u_/ CJ O <0.03 viable ί cells/ml 00 o rp kO © P Challenge J cells/mouse Ό § Ο Test Bacteria Escherichia coli 29 'e? ! a • υ ω ο θ 1 5 $ I δ cn CJ tn a 0.018 rn P KO tr r· 9 MIC of used strain. (Ug/mt) [ Test Compounds 1 it· 1 s 3§ SS 400 o tn '“A 3 200 6,25 in* P 25 tn CJ © l viable i cells/ml !......... 00 3 KO o P Challenge cells/mouse ko 1 P Test Bacteria Serratia marcesens 4 j a I Μ ι Ο «“S .'S u § .1 MS b ©5 tn Θ 1 Test Comnounds 1 I O δ i 1.158 0.023 ί aa 3 .3 a) ΰ U1 •s »w o o 1-1 a 1 o J P cn s ί s ss s-s 12.5 12.5 s 1.56 CJ © viable cells/ml 30 s © s i Challenge cells/mouse in tn Test Bacteria Escherichia coli 100 . 4 δ-S 9 7 ζ~\ φ 1 S /“ν U S ο ΙΩ θ- Test Compounds & CJ 8 0.182 •P C7> O . O CJ x£ (X Ν' C ) ) 1 > MIC of used strain (ug/mK) J Test Compounds NJ 8 3.13 00 r- o s* 0.39 0.2 /—> CJ ν—z 0.78 r4 O VJ viable cells/ml I ao © r4 Ό 3 Challenge cells/mouse in O r-l M m m i Test Bacteria Escherichia coli 29 t ο •Η Λ CJ I ιΗ Ο Η rt ♦Η Ό rt ♦Η Ρ ι -Φ ι—I X 45 Ρ ο •S ΙΌ I Ο *d rt Ρ ο υ rt X ι ι-4 ί r4 Ο Ν rt Μ Ρ Θ Ρ ι a I CJ C· •Η Ο <Λ rt CJ W U * & ο Ρ rt Ο Φ Λ Φ υ I Κ) 5 9 7 3. Acute Toxicity in Mice: The same strain mice as aforesaid protecting test against experimental infections were used in groups of 10 mice.

Test compound (8) (2 g) was administered intravenously to said mice. All mice survived without showing any disorder after one week observation.

For therapeutic administration, the object compound (I) of the present invention is used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solid form such as capsule, tablet, dragee, ointment or suppository, or in liquid form such as solution, suspension, or emulsion. If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and the other commonly used additives.

While the dosage of the compounds may vary from and also depend upon the age, conditions' of the patient, a kind of disease, a kind of the compound (I) to be applied, etc., an average single dose of about 50 mg,, 100 mg., 250 mg., and 500 mg, of the object compound (I) of the present invention has proved to be effective in treating diseases infected·by pathogenic bacteria.

In general, amounts between 1 mg. and about 1000 mg. or even more may be administered to a patient.

The following examples are given for the purpose of illustrating the present invention:30 4559 7 Comparative Activity Test Test compounds (1) 7-|_2-Methoxyimino-2-(3-hydroxyphenyl) acetamidl·., 3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2) Sodium 7-£2-methoxyimino-2(3-hydroxyphenyl) acetamidoj-cephalosporanate (syn isomer) (3) 7-^2-Methoxyimino-2-(3-hydroxyphenyl)acetamidoj 3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (4) 7-|^2-Allyloxyimino-2- (3-hydroxyphenyl) acetamido. 3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (5) Sodium 7-£2-methoxyimino-2-(3-carbamoyloxyphenyl)acetamidoJ-3-(1,3,4-thiadiazol~2-yl)thiomethyl-3-cephem15 4-carboxylate (syn isomer, (6) 7-[^2-Methoxyimino-2-phenylacetamidoJcephalosporanic acid (syn isomer) (7) 7-r2-Hydroxyimino-2-(4-chlorophenyl)acetamidoJ cephalosporanic acid (syn isomer) The test compounds (1) to (5) are the compounds of our invention and compounds (6) and (7) are those of British Patent Specifications Nos. 1,399,086 and 1,389,194, respectivel; A) Test Method In vitro antimicobial activity was determined by the two-fold agar-plate dilution method as described below.

One loopful of an overnight culture of each test 0 strain in Trypticase-soy broth (10 viable cells per ml) was streaked on heart infusion agar (HI-agar containing graded concentrations of antibiotics, and the minimal inhibitory con30 centration (MIC) was expressed in terms of ug/ml after incubation at 37°C for 20 hours. 45S3 7 B) Test Results Example 1 A mixture of dimethylformamide (2.81 g.) and phosphorus oxychloride (5.36 g.) was warmed· at 40°C for 1 hour. After cooling, methylene chloride (60 ml.) was added thereto and distilled off. To the residue was added dry ethyl acetate (50 ml.). Then, 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.83 g.) was added thereto at 5°C with stirring under ice-cooling. The resultant mixture was then stirred for 50 minutes at the same temperature. On the other hand, 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (11.5 g.) and bis(trimethylsilyl)acetamide (28.4 g.) were dissolved in dry ethyl acetate (150 ml.) and stirred under cooling, to which was at a time added the above obtained solution at -40°C. After stirring for 2 hours at -30 to -20°C, a saturated sodium chloride aqueous solution (100 ml.) was added at -20°C to the reaction mixture. The mixture was stirred ft»T 5 minutes. The precipitates were filtered off and ethyl acetate layer in the filtrate was separated. The aqueous layer was extracted twice with ethyl acetate (50 ml.). Ethyl acetate layer separated from the filtrate and the extracts were combined. The combined ethyl acetate solution was washed with a saturated sodium chloride aqueous solution (50 ml.).

To the ethyl acetate layer Was added activated charcoal and the mixture was stiTred for 5- minutes and filtered. Water (100 ml.) was added to the filtrate and the resulting mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate.

The aqueous layer was separated and washed with methylene chloride. After the aqueous layer was separated, methylene chloride was removed from the aqueous layer by bubbling of nitrogen gas under ice-cooling. After fi-ltration, the aqueous layer was adjusted $ 43597 to pH 2 with ΙΟί hydrochloric acid with stirring and ice-cooling. Precipitating crystals were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(3-hydrcxyphenyl)acetamido] -3- (1 -methyl -IH-tetrazol- 5-y-1) thiomethyl-3cephem-4-carboxylic acid (syn isomer) (11.3 g.).

I.R. spectrum (Nujol) 3250, 1770, 1725, 1670 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.76 (IH, d, J=8Hz) 6.7-7.40 (4H, m) .86 (IH, dd, J=5,8Hz) .18 (IH, d, J=5Hz) 4.34 (211, ΑΒ^, J»13Hz) 3.92 (6H, s) 3.72 (2H, ΑΒ^, J=17Hz) Example 2 A mixture of dimethylformamide (1.41 g.) and phosphorus oxychloride (2.95 g.) was warmed for 1 hour at 40°C. After cooling, methylene chloride (30 ml.) was added thereto and distilled off. To the residue was added dry ethyl acetate (20 ml.). 2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (3.4 g.) was added thereto with stirring and icecooling and the mixture was stirred for 30 minutes under icecooling. On the other hand, 7-amino-3-carbamoyloxymethyl-5cephem-4-carboxylic acid (4.8 g.) was dissolved in a solution of trimethylsilylacetamide (27.5 g.) in dry ethyl acetate (70 ml.). To the solution was at a time added the above obtained solution at -30°C and the mixture was stirred for 1.5 hours at -30 to -10°C. A saturated sodium chloride aqueous solution was added to the reaction mixture at -20°C. The ethyl acetate Π -4 5 59 7 layer was Separated, and the aqueous. layer was extracted with ethyl acetate. Two ethyl acetate layers were combined, washed with a sodium chloride aqueous solution and treated with activated charcoal. After filtration, water (100 ml.) was added to the filtrate and the mixture was adjusted'to pH 7 with a sodium bicarbonate aqueous solution. The aqueous layer was separated and ethyl acetate was added thereto. The mixture was adjusted to pH 5 with 10¾ hydrochloric acid and the aqueous layer was separated. Ethyl acetate was added thereto and the mixture was adjusted to pH 2 with 10¾ hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was further extracted with ethyl acetate. Two ethyl acetate layers were combined, washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled IS off and the residue was pulverized with diisopropyl ether.

The powder was collected by filtration and dried to give 7-[2methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyl-oxymethyl3-cephem-4-carboxylic acid (syn isomer) (3.26 g.).

I.R. spectrum (Nujol) 3500-3200, 1765, 1720, 1655 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.64 (IH, d, J=8Hz) 6.70-7.20 (4H, m) 6.78 (2H, s) .92 (IH, dd, J»5,8Hz) .16 (IH, d, J=5Hz) 4.73 (2H, AB , J=13Hz) h 3.91 (3H, s) 3.72 (2H, ABq, J=17Hz) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer] (1.98 g.) was suspended in water (15 ml.) and dissolved by adding sodium bicarbonate (0.35 g.) with stirring at ambient temperature. The solution was lyophilized and dried to give sodium 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem4-carboxylate (syn isomer) (1.9 g.).

I.R. spectrum (Nujol) 3300, 1765, 1715, 1665 cm'1 N.M.R, spectrum (D20, δ) ppm 6.83-7.60 (4H, m) 5.85 (IH, d, J=5Hz) 5.17 (IH, d, J=5Hz) 4.77 (2H, ABq, J=13Hz) 4.03 (3H, s) 3.48 (2H, ABq, J=18Hz) Example 3 A mixture of dry dimethylformamide (0.18 g.) and phosphorus oxychloride (0.38 g.) was stirred for 30 minutes at 40°C. Dry. methylene chloride (15 ml.) was added thereto and distilled off under reduced pressure. To the residue was added dry ethyl acetate (15 ml.) and 2-methoxyimino-2-(3-chloro4-hydroxyphenyl)acetic acid (syn isomer) (0.53 g.) was added thereto with stirring at -20°C. The mixture was stirred for 1 hour below -10°C. On the other hand, a mixture of 7-amino3-trichloroacetylcarbamoyloxymethy1-3-cephem-4-carboxylie acid (1 g.), trimethylsilylacetamide (5 g.) and dry ethyl acetate (25 ml.) was stirred for 1 hour at ambient temperature.

To this solution was dropwise added the above obtained solution with stirring below -10° and the resulting mixture was stirred 6/ 5597 for 2 hours at the same temperature. Water (50 ml.) and ethyl acetate (50 ml.) were added to the reaction mixture at -20°C and the mixture was shaken. The organic layer containing 7-[2-methoxyimino-2-(3-chloro-4-hydroxypheny!)acetamido]-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) was adjusted to pH 7.0 by adding water (SO ml.) and sodium bicarbonate and the mixture was stirred for 2 hours at ambient temperature. Ethyl acetate (50 ml.) was added to the aqueous layer and the mixture was adjusted to pH 5.0 with 10i hydrochloric acid. The aqueous layer was separated, adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (50 ml.). The extract was washed with icewater and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was thoroughly washed with ether, collected by filtration and dried to give 7-[2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]3-carbamoyloxymethyl-3-eephem-4-carboxylic acid (syn isomer) (0.3 g.).

T.R. spectrum (Nujol) 3450, 3300, 1770, 1730, 1715, 1660, 1650, 1600 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.72 (IH, d, J=8Hz) 7.48 (IH, d, J=2Hz) 7.40 (IH, dd, J=2,8Hz) 6.98 (lH, d, J=8Hz) 6.60 (2H, s) .70 (IHj q, J=5Hz) ,20 (IH, d, j*5Hz) 4.74 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.50 (2H, AB , J-18HZ) H Example 4 2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.1 g.) and 7-amino-3-trichloroacetylcarbamoyloxymethyl3-cephem-4-carboxylic acid (2.35 g.) were reacted and post-treated according to a similar manner to that of Example 3 to give 7-[2methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyi3- cephem-4-carboxylic acid (syn isomer) (0.5 g.). This compound is identified with the compound obtained in Example 2 by I.R. and N.M.R. spectra. 1° Example 5 (a) 2-t-Butoxycarbonylmethoxyimino-Z-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer)(Ig.) and 7-amino-3-(1-methyl-lHtetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1 g.) were reacted according to similar manners to those of Examples 1 and 2 to give powder of 7-[2-t-butoxycarbonylmethoxyimino-2-(3-chloro4- hydroxyphenyl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g.). (b) The powder obtained in Example 5(a) (1.5 g.) was added to a mixture of anisole (1.5 ml.) and trifluoroacetic acid (6 ml.) and the resulting mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was adjusted to pH 8 by adding a sodium bicarbonate aqueous solution (50 ml.), ethyl acetate (50 ml.) and sodium bicarbonate under ice-cooling. The aqueous layer was separated, adjusted to pH 5.0 with 10% hydro25 chloric acid and washed with ethyl acetate (50 ml.). The aqueous layer was further adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (100 ml.). The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was dissolved in pH 5.0 acetate buffer and subjected to column 42597 chromatography on Woelm neutral alumina (trade mark: made by ICN Company) using pH 5.0 acetate·buffer as developing solvent. The eluate was adjusted to pH 2.0 with 101 hydrochloric acid under ice-cooling. Precipitating materials were collected by filtration, washed with water and dried to give 7-[2-carboxy methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(l-methyl lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g.), mp 145 to 148°C (dec.).

I.R. spectrum (Nujol) 3400,· 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm-1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.70 (IH, d, J=8Hz) 7.50 (IH, d, J«=2Hz) 7^45 (IH, dd,J=2,8Hz) 7.10 (IH, d, J-8Hz) S.90 (IH, q, J-5Hz) 5.22 (IH, d, J=5Hz) 4.70 (2H, s) 4.35 (2H, ABq, J-13Hz) 3.95 (3H, s) 3.75 (2H, ABq, J=18Hz) Example 6 (a) 2-(l-t-Butoxycarbonylethoxyimino)-2-(3-chloro-4hydroxyphenyl)acetic acid (syn isomer) (2 g.) and 7-amino-3(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) were reacted according to similar manners to those of Examples 1 and 2 to give powder of 7r[2-(1-t-butoxycarbonylethoxyimino)-2 -(3-chloro-4-hydroxyphenyl)acetamido]-3- (1-methyl lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.6 g.). (b) The powder obtained in Example 6(a) (3.6 g.), anisole (4 ml.) and trifluoroacetic acid (16 ml.) were reacted according to a similar manner to th.at of Example 5(b) to give yellow powder of 7-[2-(l-carboxyethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido) -3-(l-mqthyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g.), mp 147 to 151°C (dec.).

I.R. spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1730, 1660, 1630, 1600 cm1 spectrum td6 DMSO, δ) 9.62 (1H, d, J=8Hz) 7.46 (IH, d, J=2Hz) 7.34 (IH, dd, J=2,8Hz) 7.04 (IH, d, J=8Hz) 5.90 (IH, q, Jc5Hz) 5.22 (IH, d, J=5Hz) 4.73 (IH, q, J-6Hz) 4.33 (2H, ΑΒ^, J=13Hz) 4.00 (3H, s) 3.73 (2H, AB , J-18Hz) 1.37 (3H, d, J=6Hz) Example 7 The following compounds were obtained according to similar manners, to those of Examples 1 and 2 (1) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido)- 3-(4Hl,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1775, 1710, 1665 cm1 4S5S7 N.M.R. spectrum (dg-DMSO, δ) ppm 9.67 (IH, d, J=8Hz) 8.40 (IH, s) 6.70- 7.43 (4H, m) .82 (IH, dd, J»5,8Hz) .13 (IH, d, J=5Hz) 4.18 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.67 (2H, broad s) (2) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.78 (IH, d, J=8Hz) 9.55 (IH, s) 6.70- 7.40 (4H, m) .89 (IH, dd, J=5,8Hz) .22 (IH, d, J=5Hz) 4.46 (2H, AB , J*13Hz) H 3.92 (3H, s) 3.76 (2H, ABq, J»18Hz) (3) 7-[2-Methoxyinpno-2-(3-hydroxyphenyl)acetamido]-3-(5 methyl-1,3,4-thiadxazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.72(1H, d, J=8 Hz) 6.62-7.4O(4H, m) , 66 ... f .94 (IH, dd, J=5,8Hz) 5.18 (IH, d, J=5Hz) 4.18 <2H, ΑΒς, J=13Hz) 3.89 (3H, s) 3.70 (2H, ABq, J=17Hz) 2.65 (3H, s) (4) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]cephalosporanic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1785, 1740, 1720 cm*1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.78 (IH, d, J=8Hz) 6.86-7.36 (4H, m) .86 (IH, dd, 1=5,8Hz) .18 (IH, d, J=5Hz) 4.84 (2H, ABq, J«13Hz) 6/ . <45597 3.98 (3H, s) 3.54 (2H, AB , J«17Hz) H 2.00 (3H, s) C5) 7-[2-Methoxyimino-2-(3-methoxyphenyl)acetamido]-3-(15 methyl-ΙΗ-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm*1 N.M.R. spectrum (dg-DMSO, 6) 10 ppm 9.78 (IH, d, J«8Hz) 6.9S-7.54 (4H, m) 5.94 (IH, dd, J=5,8Hz) 5.18 (IH, d, J=5Hz) 4.12 (2H, AB , J=13Hz) 15 β 3.92 (6H, s) 3.76 (3H, s) 3.72 (2H, ABq, J=18Hz) (6) 7-[2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(lmethyl-lH-tetrazol-5-yl)thxomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm’1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.70 (IH, d, J-8Hz) 7.44 (2H, d, J»8Hz) 6,84 (2H, d, J=8Hz) .86 (IH, dd, J=5,8Hz) .18 (IH, d, Jc5Hz) 4.34 (2H, ΑΒ^, J=13Hz) 3.93 (3H, s) 63· 59 7 3.87 (3H, s) 3.74 (2H, ABq, J«=18Hz) (7) 7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxyIic acid (syn isomer), mp 145 to 148°C (dec).

I.R. spectrum (Nujol) 3500, 3250, 2500 -2600, 1780, 1655, 1625, 1600 cm*1 :. spectrum (d6-Dl MSO, 6) i 10.80 (IH, broad s) 9.68 (IH, d, J«2Hz) 7.46 (IH, d, J«2Hz) 7.32 (IH, q, J=2,8Hz) 7.00 (IH, d, J»8Hz) S.80 (IH, q, J=5Hz) 5.16 (IH, d, J=5Hz) 4.28 (2H, ABq, J=13Hz) 3.92 (3H, s) 3.87 (3H, s) 3.72 (2H, AB , J=18Hz) H (8) 7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acetamido] -3- (l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer), mp 143 to 145°C (dec.).

I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm N.M.R. spectrum (d6-DMSO, δ) ppm 9.76 (IH, d, J=8Hz) 7.56 (IH, d, J=2Hz) 7.48 (IH, dd, J«2,8Hz) 7.22 (IH, d, J=8Hz) ,. '4553 7 .84 (IH, •q, J=5Hz) 5.18 (IH, d, J-5Hz) 4.27 (2H, AB , J=13Hz) H 3.90 (6H, S) 3.88 (3H, s) 3.70 (2H, AB , J=18Hz) M. ( 9) 7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido] 3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 149 to 152°C (dec.).

I.R. spectrum (Nujol) 3400-3450, 3200, 2500-2600, 1780, 1720, 1660, 1620, 1600, 1535, 1350 cm’1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.72 (IH, d, J=8Hz) 15 7.97 (IH, d, J=2Hz) 7.72 (IH, dd, J'2,8Hz) 7.21 (IH, d, J=8Hz) 5.82 (IH, q, J“5Hz) 5.16 (IH, d, J=SHz) 20 4.3 (2H, AB , J-=13Hz) H 3.92 (3H, s) 3.87 (3H, s) 3.72 (2H, ABq, J“18Hz) 0.0 ) 7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acet25 amido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer), mp 163 to 165°C (dec.).

I.R. spectrum (Nujol) 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm'1 S 5 9 7 N.M.R. spectrum (dg'DMSO, 6) ppm 9.70 (IH, d, J=8Hz) 7.40 (IH, d, J=2Hz) 7.30 (IH, dd, J=2,8Hz) 6.95 (IH, d, J=8Hz) .80 (2H, m) .30 (2H, d, J=8Hz) .10 (IH, d, J=5Hz) 4.60 (2H, d, J*5Hz) 4.27 (2H, ABq, J=13Hz) 3.85 (3H, s) 3.65 (2H, AB , J=18Hz) H (11) 7-[2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]- 3(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 149 to 152°C (dec.). liR. spectrum (Nujol) 3250-3350, 2550-2600, 1780, 1730, 1670, 1650, 1600 cm*1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.70 (IH, d, J=8Hz) 7.2-6.8 (4H, m) 6.1-5.8 (2H, m) .35 (2H, d, J-8Hz) 5.17 (IH, d, J=5Hz) 4.7 (2H, d, J=5Hz) 4.17 (2H, ABq, J=13Hz) 3.93 (3H, S) 3.75 (2H, AB , J»18Hz) H (12) Sodium 7-{2-methoxyimino-2-(3-hydroxyphenyl)acetamido]cephalosporanate (syn isomer). . 4559^ I.R. spectrum (Nujol) 3250, 1765, 1730, 1665 cm N.M.R. spectrum (D2O, δ) ppm 6.83-7.13 (4H, m) 5 5.83 (IH, d, J=5Hz) 5.17 (IH, d, J=5Hz) 4.82 (2H, AB , J=13Hz) H 4.03 (3H, s) 3.50 (2H, ABq, J=17Hz) 10 2.1 (3H, s) (13) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino)-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem -4-carbOxylic acid (syn isomer), powder.

I.R. spectrum (Nujol) 3150, 1780, 1720 , 1670 cm*1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.60 (IH, d, J=8Hz) 6.72-7.52 (7H,. m) 5.80 (IH, dd, J=4,8Hz) 20 5.15 (IH, d, J=4Hz) 5.00 (2H, s) 4.28 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.65 (2H, AB , J=18Hz) H (14) 7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer), powder.

I.R. spectrum (Nujol) 3200-3300, 1780, 1720, 1660 cm*1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.77 (IH, d, J=8Hz) 6.7-7.7 (7H, m) .83 (IH, dd, J=5,8Hz) .29 (2H, s) .15 (IH, d, J=5Hz) 4.3 (2H, AB , J=13Hz) 3.92 (3H, s) 3.72 (2H, ABq, J=18Hz) (15) 7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), colorless powder, mp 153 to 156°C (dec.).

I.R. spectrum (Nujol) 3450, 3250, 2550-2600, 1780, 1725, 1665, 1630, 1600 cm'1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.71 7.50 7.36 7.03 .83 .17 4.33 4.17 3.97 3.73 1.25 (IH, d, J=8Hz) (IH, A J=2Hz) (IH, dd , J=2,8Hz) (IH, d, J=8Hz) (IH, q. J=5Hz) (IH, d, J=5Hz) (2H, AB , J=13Hz) (2H, q, J=7Hz) (3H, s) (2H, AB , J=18Hz) H (3H, t, J=7Hz) (16) 7-(2-Allyloxyimino-2-(3-methoxyphenyl)acetamido]-3-(1methyl-ΙΗ-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder, mp 135 to 138°C (dec.) I.R. spectrum (Nujol) 3300, 2600, 1785, 1.730, 1.670, 1645, 1600 N.M.R. spectrum ppm 9.82 (d6-DMSO, δ) (IH, d, J=8Hz) 5 7.0-7.45 (4H, m) 5.8-6.2 (2H, m) 5.36 (2H, t, J=10Hz) 5,21 (IH, d, J=5Hz) 4.72 (2H, d, J=5Hz) 10 4.36 (2H, ABq, J=13Hz) 3.95 (3H, s) 3.91 (3H, S) 3.87 (2H, AB , J=18Hz) H (17) 7-[2-Ethoxyimino- -2-(3-hydroxyphenyl)acetamido] methyl-ΙΗ-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), yellow powder, mp 145 to 148°C (dec.).

I.R. spectrum (Nujol) 3450, 3250, 2500-2600, 1775, 1720, 1665, 1620, 1600 cm1 N.M.R. spectrum (dg-DMSO, δ) 9.70 C1H, a, J=8Hz) 6.8-7.4 (4H, m) 5.90 (IH, q, J-5HZ) 5.20 (IH, d, J=5Hz) 4.36 (?H, ABq, J=13Hz) 4.20 (2H, q, J=7Hz) 4.00 (3H, s) 3..76 (2H, ABq, J=18Hz) 1.33 (3H, t, J=7Hz) (ΐβ) 7-[2-Ethoxyimino-Z-(3-methoxyphenyl)acetamido]-3-(1methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylie acid (syn isomer), pale yellow powder, mp 140 to 143°C (dec.).

I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm N.M.R. spectrum (dg-DMSO, δ) 9.71 (IH, d, J=8Hz) 7.5 (4H, m) 5.90 (IH, q, J=5Hz) 5.17 (IH, d, J=5Hz) 4.33 (2H, AB , J=13Hz) 4 4.20 (2H, q, J=7Hz) 3.95 (3H, s) 3.85 (3H, s) 3.75 (2H, ABq, J=18Hz) 1.30 (3H, t, J=7Hz) (19) 7-[2-Allyloxyimino-2-(3-chloro-4-methoxyphenyl)acetamido]3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), pale yellow powder, mp 153 to 156°C (dec ).

I.R. spectrum (Nujol) 3250, 2600, 1780, 1720, 1670, 1645, 1630, 1600 cm1 N.M.R. spectrum (dg-DMSO, δ) 9.65 (IH, d, J=8Hz) 7.27 (IH, d, J=2Hz) 7.20 (IH, dd, J=Z,8Hz) 7.09 (IH, d, J=8Hz) •6.15 (2H, m) 5.15 (2H, t, J=9Hz) 5.05 (IH, d, J=5Hz) 4.60 (2H, d, J=5Hz) 4.15 (2H, AB , J-13Hz) 597 3.95 (3H, s) 3.90 (3H, s) 3.47 (ZH, ABq, J=18Hz) (20) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3450, 3250, 1765, 1710, 1655, 1530 cm1 N.M.R. spectrum (dg-DMSO, δ) 9.77 (IH, d, J=8Hz) 7.6 •7.1 (4H, m) 6.56 (2H, s) 5.83 (IH, dd, J=4,8Hz) 5.20 (IH, d, J=4Hz) 4.76 (2H, ΑΒς, J=13Hz) 3.94 (3H, s) 3.55 (2H, broad s) 2.28 (3H, s) (21) 7-[Z-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(l-methyl-lH-tetrazol-5-yI)thiomethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3300, 1760, 1660, 1600, 1580, 1520 cm1 N.M.R. spectrum (dg-DMSO, 6) ppm : 9.7 (111, d, J«=8Hz) 7.7 - 6.7 (9H, m) .8 - 5.4 (3H, broad s) .06 (IH, d, J=5Hz) 4.33 (2H, broad s) 3.9 (3H, s) 3.56 (2H, broad s) 43597 (2 2) 7- [Z-Methoxyimino-2-(3-mesylaminophenyl)acetamido]-3(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155° C (dec.).

I.R. spectrum (Nujol) 3300, 1780, 1730, 1670 cm'1 N.M.R. spectrum (dfi-DMSO, δ) ppm 9.98 9.81 9.62 .90 .24 4.49 3.98 3.77 2.96 (IH, s) (IH, d, J=9Hz) (IH, s) (IH, dd, J=5, 9Hz) (IH, d, J=5Hz) (2H, ABq, J=14Hz) (3H, s) (2H, broad s) (3H, s) (23) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3450, 3300, 3200, 1780, 1725, 1670 1590, 1520 cm A spectrum (dg· •DMSO, δ) 9.77 (IH, d, J=7Hz) 7.6 -6.8 (6H, m) 5.83 (IH, dd, J=4, 7Hz) 5.17 (IH, d, J=4Hz) 4.31 (2H, ABq, J=14Hz) 3.96 (6H, s) 3.72 (2H, broad s) 45S97 (24) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1735, 1675 cm*1 N.M.R. spectrum (dg-DMSO, δ) 81 (IH, d, J=8Hz) 62 (IH, s) 7 - 7.58 (4H, m) 87 (IH, dd, J=5, 8Hz) 2 (IH, d, J=5Hz) 25, 4.63 (2H, ABq, J=14Hz) 9 (3H, s) 7 (2H, broad s) (25) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1740, 1720, Γ680 cm'1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.86 (IH, d, J=8Hz) 9.61 (IH, s) 7.00 - - 7.65(4H, m) 5.84 (IH, dd, J«5, 8Hz) 25 5.2 (IH, d, J=5Hz) 4.25, 4.63 (2H, ABq, J=14Hz) 3.92 (3H, s) 3.53, 3.86 (2H, ABq, J=19Hz) 2.3 (3H, s) 78' 5 9 7 (26) [2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem4-carboxylic acid (syn isomer), mp 138 to 142°C (dec.) I.R. spectrum (Nujol) 3300 - 3400, 2600, 1780, 1720, 1665, 1600 cm1 spectrum (dg-DMSO, δ) 9.80 (IH, d, J=8Hz) 6.4 - 7.4 (11H, m) S.8S (IH, dd, J«5, 8Hz) 5.20 (IH, d, J=5Hz) 4.83 (2H, d, J=5Hz) 4.32 (2H, ABq, J=15Hz) 3.95 (3H, s) 3.68 (2H, ABq, J=18Hz) (27) 7[2-Methoxyimino-2-(4-dimethylaminophenyl)acetamido]3-(l-methyl-ΙΗ-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 88°C (dec.).

I.R. spectrum (Nujol) 1780, 1730, 1680, 1610 cm A spectrum (dg-DMSO, δ) 9.63 (IH, d, J=8Hz) 7.40 (2H, d, J=8Hz) 6.73 (2H, d, J=8Hz) 5.83 (IH, dd, J®5, 8Hz) 5.17 (IH, d, J=5Hz) 4.33 (2H, ABq, J=13Hz) 3.97 (3H, s) 3.87 (3H, s) 3.73 (2H, broad s) 3.00 (6H, s) -45597 (28) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)aeetamido]-3-[1-(2dimethylaminoethyl)-32-tetrazol-5-yl]thiomethyl-3-cephem-4carboxylic aoid (syn isomer), I» R* spectrum (Nujol) 1765 cm1 Ν. M, R. spectrum (dg-DMSO, 9.67 (12, d, J=9Hz) 6.72-7.36 (42, m) 5.78 (12, dd, J=5, 9 Hz) 5.12 (32, •a, J=5. Hz) 4.55 (2H, broad s) 4.30 (2H, broad s) 3.90 (3H, s) 3.40-3.80 (2H, ¢) 3.14 (2H, broad s) 2.48 (6H, s) (29) 7-[2~^2-(2-Hydroxyphenoxy)ethoxyiminoj-2-(3-hydroxyphenyl) acstamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic aeid (syn isomer).

I. R. spectrum (Nujol) 3270, 1780, 1725, 1670, 1560 cm-1 Ν, M. R. spectrum (dg-DMSO, δ ) ppm 6.5-7.4 (8H, m) .86(32, dd, J=5, 8Hz) .14(12, d, J=5Hz) 4.0-4.6 (6H, a) 3.92(3H, s) 3.52, 3.70(2H, ΑΒ^, J=7Hz) 46S97 Example a A mixture of dimethylformamide (0.73g) and phosphorus toxychloride (1.6g) was warmed for 30 minutes at 40°C. Benzene was added thereto and the mixture was concentrated. The residue was suspended in ethyl acetate (20 ml) and 2-methoxyimino2-(3-hydroxyphenyl) acetic acid (syn isomer) (1.95g) was added thereto at -15 to -5°C, after which the resulting mixture was stirred for 30 minutes at the same temperature. On the other hand, a solution of sodium hydroxide (0.9g) in water (5 ml) was dropwise added at 0 to S’C over 25 minutes to a suspension of 7-aminocepha.losporanic acid (2.7g) in water (12.5ml) and the mixture was stirred for 5 minutes, after which acetone (20 ml) was added thereto. To the resulting mixture containing sodium 7-amino-3-hydroxymethyl-3-cephem-4-carboxylate was dropwise added at 0 to 5°C over 3 minutes the above obtained ethyl acetate solution keeping the pH value at 7.5 to 8.5 by adding triethylamine. After stirring for 30 minutes, the organic solvents were distilled off. The aqueous layer was washed with ethyl acetate (20ml), adjusted to pH 2.0 with hydrochloric acid ar.d extracted with ethyl acetate (60ml) at 0 to 3°C. The aqueous layer was further extracted with ethyl acetate (30ml). The combined ethyl acetate extracts were washed with a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off and the residue was pulverized with diisopropyl ether to give a mixture of 7-[2-methoxyiminO-2(3-hydroxyphenyl)acetami do] - 3-hydroxyme thyl-3-cephem-4carboxylic acid(syn isomer)(I) and 6-[2-methoxyimino-2-(3hydroxypheny1)acetami do]-S a,6-dihydro- 3H, 7H - aze to [ 2,1 -b ] - f uro [3,4-d][l,3]thiazine-l,7(4H)-dione(synisomer)(II) (2.64 g). .45597 I.R. spectrum of (I) (Nujol) ' r' 3250, 1785, 1755, 1660, 1600, 1570, 1540 N.M.R. spectrum of (I)^d6-DM5O, 6) ppm 9.83 (IH, d, J=8Hz) 5 7^5 - 6 .75 (4H, m) 5.8 (IH, dd, J=5,8Hz) 5.21 (IH, d, J=5Hz) 4.3 (2H, broad s) 3.95 (3H, s) 10 3.63 (2H, broad s) I.R. spectrum of (II) (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540 N.M.R. spectrum of (II) (dg-DMSO, δ) ppm 9.83 (IH, d, J«=8Hz) .-1 7.5 - 6.75 (4H, m) 6.02 (IH, dd, J=5, 8Hz) .21 (IH, d, J=5Hz) .07 (2H, broad s) 3.95 (3H, s) 3.84 (2H, broad s) Example g 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.23 g) was dissolved in pyridine (1 ml) with stirring and ice-cooling, and acetyl chloride (0.082 g) was added thereto. The mixture was stirred for 40 minutes under ice-cooling.

The reaction mixture was poured·into ice-water, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After treating with activated 46S9? charcoal, it was filtered and the filtrate was concentrated.

The residue was pulverized with diisopropyl ether to give a mixture of 7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido]-3carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) and 7-[2-methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-carbamoyloxyaethyl-2-cephem-4-carboxylic acid ( syn isomer ) (0.18 g ).

N.M.R. spectrum (dg-DMSO, 6) ppm : 9.82 (IH, d, J=8Hz) 9.77 (IH, d, J=8Hz) 10 7.6-) 7.1 (8H, m) 6.60 (IH, s) 6.56 (2H, s) 5.83 (IH, dd, J=4, 8Hz) 5.60 (IH, dd, J=4,8Hz) 15 5.24 (IH, d, J=4Hz) 5.20 (IH, d, J=4Hz) 4.84 (IH, s) 4.76 (2H, ABq, J-13Hz) 4.56 (2H, broad s) 20 3.94 (6H, s) 3.55 (2H, broad s) 2.28 (6H, s} 42597 Example 10 The following compounds were obtained according to a similar manner to that of Example 9. (1) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3-(l,3,45 thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylrc acid (syn isomer) I.R. spectrum (Nujol) 3250, 1780, 1740, 1720, 1680 cm-1 N.M.R. spectrum (d6-DMSO, δ) ppm 9.86 (IH, d, J=8Hz) 9.61 (IH, s) 7.00 - 7.65 (4H, m) .84 (IH, dd, J«5, 8Hz) .2 (IH, d, Jc5Hz) 4.25,4.63 (2H, ABq, J=14Hz) 3.92 (3Hj. s) 3.S3, 3.86 (2H, ABq, J=19Hz) 2.3 (3H, s) (2) 7-[2-Me thoxyimino-2-(3-carb amoyloxypheny1) acetamido]3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3450, 3300, 3200, 1780, 1725, 1670, 1620, 1590, 1520 cm1 N.M.R, spectrum (d6-DMSO, δ) ppm · 9.77.(1H, d, J=7Hz) 7.6 - 6.8 (6H, m) .83 (IH, dd, J=4, 7Hz) .17 (IH, d, J=4Hz) 4.31 (2H, ABq, J=14Hz) 3.96 (6H, s) 4SS97 3.72 (2H, broad s) (3) 7-[2-Methoxyimino-2-(3-carbamoyl-oxyphenyl)acetamido]3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1735, 1675 cm*1 N.M.R. spectrum (d6-DMS0, δ) ppm 9.81 (IH, d, J=8Hz) 9.62 (IH, s) 6.7 - 7.58 (4H, m) .87 (IH, dd, J«S, 8Hz) .2 (IH, d, J=5Hz) 4.25, 4.63 (2H, ABq, J=14Hz) 3.9 (3H, s) 3.7 (2H, broad s) Example 11 Phosphorus oxychloride (0.26 g.) was added under icecooling to dimethylformamide (0.15 g.) and the mixture was warmed ·» at 40°C for 1 hour. Ethyl acetate (1.5 ml.) was added thereto and to the mixture was at a time added 2-methoxyimino-2-(2-methyll,3-thiazol-4-yl)acetic acid (syn isomer) (0.3 g.) with stirring and ice-cooling, after which the resulting mixture was stirred for 20 minutes· at 0 to 5°C. On the other hand, bis(trimethylsilyl)acetamide (1.2 g.) was added to a suspension of 7-amino3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.53 g.) in ethyl acetate (7 ml.) and the mixture was stirred at ambient temperature. To this solution was dropwise added the above obtained ethyl acetate solution at -20°C and the mixture was stirred for 2 hours at -10 to-20°C. Water (20 ml.) was added to the reaction mixture below -2S°C and „ 45S97 ethyl acetate (20 ml.) was added thereto, after which the mixture was stirred. An insoluble material was filtered off and the ethyl acetate layer was separated. Water (15 ml.) was added to the ethyl acetate layer and the mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with methylene chloride and methylene chloride in the aqueous layer was removed by bubbling of nitrogen gas. The aqueous solution was adjusted to pH 2.2 with 10% hydrochloric acid and precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-methyl-l,3thiazol-4-yl)acqtamido]-3-(l-methyl-lH-tetrazol-S-yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer) (0.28 g.).

I.R. spectrum (Nujol) 1780, 1710, 1675 cm'1 N.M.R. spectrum (dg-DMSO, δ) PPm · 9.65 7.66 .81 .15 4.31 3.93 3.90 3.70 2.65 (IH, d, J*10Hz) (IH, s) (IH, dd, J=5,10Hz) (IH, d, J=5Hz) (2H, ABq, J=13Hz) (3H, s) (3H, s) (2H, AB , J=16Hz) H (3H, S) 46597 Example 12 Phosphorus oxychloride (0.89 g.) and dry dimethylformamide (0.44 g.) were mixed under ice-cooling and then warmed for 30 minutes at 40'C. Dry methylene chloride (20 ml.) was added thereto and then distilled off. To the residue were added dry ethyl acetate (10 ml.) and then 2-methoxyimir.o-2[2-(2,2,2-tri£luoroacetamido)-l,3-thiazol-4-yl]acetic acid (syn isomer) (1.8 g.) with stirring and ice-cooling. The mixture was stirred for 40 minutes at the same temperature to give clear solution. On the other hand, trimethylsilylacetarnide (6.36 g.) was added to a suspension of 7-aminocephalosporanic acid (1.65 g.) in dry ethyl acetate (25 ml.) with stirring at ambient temperature, after which the mixture was stirred for 1 hour to give a clear solution. To this solution was at a time added the aboveobtained ethyl acetate solution with stirring at -20 to -25°C, and the resulting mixture was stirred for 2 hours at the same temperature. Water (30 ml.) was added to the reaction mixture at the same temperature, and then the mixture was stirred for 5 minutes at ambient temperature. The ethyl acetate layer was separated, and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined and water (SO ml.) was added thereto. The mixture was adjusted to pH 7.S with sodium bicarbonate, and the aqueous layer was separated.

Ethyl acetate (40 ml.) was added to the aqueous layer, and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid with stirring and ice-cooling. The ethyl acetate layer was separated, and the aqueous layer was further extracted twice with ethyl acetate (30 ml.). The ethyl acetate layers were combined, washed with an aqueous solution of sodium chloride and treated with activated charcoal. The solvent was distilled. off to 5.9 7give 7 -[2-methoxyimino-2-(2-(2,2,2-trifluoroacetamido)-1,3thiazol-4-yl}acetamido]cephalosporanic acid (syn isomer) (3.05 g.), mp 205°C· (dec.) .

I.R. spectrum (Nujol) 3250, 1790, 1735, 1680, 1650 N.M.R. spectrum (dg-DMSO, 6) ppm 9.8 (IH, d, J=8Hz) 7.55 (IH, s) 5.88 (IH, dd, J=5,8Hz) 10 5.25 (IH, d, J=5Hz) 4.8 (2H, AB , J=13Hz) H 3.95 (3H, s) 3.59 (2H, broad s) 2.03 (3H, s) Example 13 Phosphorus oxychloride (2.0 g.) was at a time added at 5 to lO^C to a suspension of 2-methoxyimino-2-(2-amino-l,3thiazol-4-yl)acetic acid (syn isomer) (2 g.) in dry ethyl acetate (20 ml.). A^teristirring for 20 minutes at 7 to 10°C, bis20 (trimethylsilyl) ac.etamide (0.4 g.) was added thereto at the same temperature. After stirring for 10 minutes at 7 to 10°C, phosphorus oxychloride (2.0 g.) was dropwise added thereto at the same temperature. ' The resulting mixture was stirred for 10 minutes at 7 to 10 °C, and dry dimethylformamide (0.8 g.) was dropwise added thereto at the same temperature. The mixture was stirred for.30 minutes at 7 to 10°C to give a clear solution. On the other hand, trimethylsilylacetamide (7.35 g.) was added to a suspension of 7-aminocephalosporanic acid (2.45 g.) in dry ethyl acetate (8 ml.), after which the mixture was stirred at 40°C to give a clear solution. To this solution was at a time 88. added the above-obtained ethyl acetate solution at -15°C, and the resulting mixture was stirred for 1 hour at -10 to -15’C. The reaction mixture was cooled to -30°C, and water (80 ml.) was added thereto. The aqueous layer was separated, adjusted to pH 4.5 with sodium bicarbonate and subjected to column chromatography on Diaion HP-20 resin (Trademark: prepared by Mitsubishi Chemical Industries Ltd.) using 25% aqueous solution of isopropyl alcohol as an eluent. The eluate was lyophilized to give 7-(2methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (1.8 g.), mp 227’C (dec.).

I.R. spectrum (Nujol) 3300-3350, 1780, 1740, 1670 N.M.R. spectrum (d6-DMSO, δ) ppm 9.6 (IH, d, J=8Hz) 6.8 (IH, S) 5.8 (IH, dd, J=5,8Hz) 5.2 (IH, d, J=5Hz) 4.87 (2H, ΑΒ^, J=13Hz) 3.89 (3H, s) 3.6 (2H, broad s) 2.08 (3H, s) Example 14 Phosphorus oxychloride (3.8 g.) was dropwise added at S to 8’C to a suspension of 2-methoxyimino-2-(2-amino-1,3thiazol-4-yl)acetic acid (syn isomer) (4.0 g.) in dry ethyl acetate (40 ml.). After stirring for 30 minutes around 5’C, bisftrimethylsilyl)acetamide (0.86 g.) was added thereto at the same temperature. After stirring for 10 minutes at the same temperature, phosphorus oxychloride (3.8 g.) was dropwise added thereto at 5 to 8’C, after which the mixture was stirred for 30 597 Dry dimethylformamide minutes at.the same temperature. (1.6 g.) was dropwise added thereto at 5 to 7°C, after which the resulting mixture was stirred for 30 minutes at the same temperature to give a clear solution. On the other hand, sodium acetate (3.3 g.) was added to a solution of 7-aminocephalosporanic acid (2.7 g.) in an aqueous solution (20 ml.) of sodium bicarbonate (1.7 g.), and then acetone (20 ml.) was added thereto. To this solution was dropwise added the aboveobtained ethyl acetate solution with stirring at 0 to 5°C keeping 10 · the pH of this solution at 7.0 to 7.5 by 20% aqueous solution of sodium carbonate. The mixture was stirred for 1 hour at the same temperature. An insoluble material was filtered off, and the Aqueous layer in the filtrate was separated. The aqueous layer was concentrated under reduced pressure to remove 15 the organic solvents, adjusted to pH 4.5. with sodium bicarbonate and subjected to column chromatography on Diaion HP-20 resin (Trademark: prepared by Mitsubishi Chemical Industries Ltd.) using 25% aqueous solution· of isopropyl alcohol as an eluent.

The eluate was lyophilized to give 7-[2-methoxyimino-2-(2-amino20 l,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (2.8 g.). This compound was identified with the compound obtained in Example 13 by I.R. and N.M.R. spectra.

Example 15 The following compounds were obtained according to similar manners to those of Examples 11 to 14 .

(D 7-[2-Methoxyimino-2-(2-mesylimino-3-methyl-2,35 dihydro-l,3-thiazol-4-yl)acetamido]-3-(1-methyl-IK-tetrazol-Syl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1718, 1675 cm1 N.M.R. spectrum (dg-DMSO, δ) 9.80 (IH, d, J=8Hz) 7.08 (IH, s) 5.80 (IH, dd, J=5,8Hz) 5.18 (IH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 3.99 (3H, s) 3.96 (3H, s) 3.72 (2H, AB , J=17Hz) H 3.66 (3H, s) 2.98 (3H, s) (2) 7-[2-Methoxyimino-2-(2-mesylamino-l,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3300-3150, 1780, 1710, 1670 cm N.M.R. spectrum (dg-DMSO, δ) ppm 9.84 (IH, d, J=8Hz) 6.97 (IH, s) .76 (IH, dd, J=5,8Hz) 5.12 (IH, d, J=5Hz) 4.33 (2H, ΑΒ^, J=13Hz) 4559·? 3.93 (6H, s) 3.74 (2H, ABq, J'=17Hz) 2.96 (3H, s) (3) 7-[2-Methoxyimino-2-(2-oxo-2,3-dihydro-l,3-thiazol-45 yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 1780, 1665 cm1 N.M.R.' spectrum (dg-DMSO, 6) 11.67 (IH, s) 9.83 (IH, d, j=8Hz) 6.61 (IH, s) 5.80 (IH, dd, J=5.5,8Hz) 5.17 (IH, d, J=5.5Hz) 4.37 (2H, broad s) 4.00 (3H, s) 3.96 (3H, s) 3.75 (2H, broad s) (4) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-l,320 thiazol-4-yl}acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiome;hyl3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 1790, 1730, 1660 cm1 N.M.R. spectrum (d6-DMSO, 6) 25 ppm 9.73 (IH, d, J=8Hz) 7.53 C1H, s) 5.83 (IH, dd, J=5,8Hz) S.1S (IH, d, J»5Hz) 4.33 (2H, broad s) 30 • 3.93 (6H, s) 3.72 (2H, broad s) '92. 45537 (IH, d, J=8Hz) (IH, s) (IH, dd, J=S,8Hz) (IH, d, J=5Hz) (2H, AB , J=13Hz) 4 (3H, s) (2H, AB , J-17Hz) 4 (3H, s) (2H, q, J-8Hz) (6H, s) (3H, t, J=8Hz) (5) 7[2-Methoxyimino-2-(2-t-pentyloxycarbonylamino-l,3thiazol-4-yl)acetamido]-3-(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3200, 1780, 1720, 1680 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.65 7.28 .80 .16 4.38 3.86 3.70 2.66 1.78 1.44 0.88 (6) 7-[2-Allyloxyimino-2-(2-mesylamino-l,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3100-3300, 1780, 1720, 1675 cm'1 N.M.R. spectrum (dg-DMSO, δ) 9.90 (IH, d, J=8Hz) 7.00 (IH, s) 6.07-5.63 (2H, m) 5.43 (2H, d, J=8Hz) 5.18 (IH, d, J=5Hz) 4.70 (2H, d, J=5Hz) 4.37 (2H, broad s) 5.9 7. 3.98 (3H, s) 3.75 (2H, broad s) 3.00 (3H, s) (7) 7-[2-Allyloxyimino-2-(2-t-pentyloxycarbonylamino-l,3thiazol-4-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1678, 1625 cm1 N.M.R. spectrum (dg-DMSO,6) 9.74 (IH, d, J“8Hz) 7.31 (IH, s) 6.28 - 5.76 (2H, m) 5.28 (2H, dd , J=8, 16Hz) S.18 (IH, d, J=5Hz) 4,66 (2H, d, J=5Hz) 4.36 (2H, AB, q, J-13Hz) 3.96 (3H, s) 3.74 (2H, ABi q, J“17Hz) 1,80 (2H, q, J=8Hz) 1.45 (6H, s) 0.89 (3H, t, J«=8Hz) (8) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]3-(l-aethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3200, 1765, 1600 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm : 9.51 (IH, d, J=8.SHz) 7.22 (2H, broad s) 6.72 (IH, s) .59 (IH, dd, J»5, 8.5Hz) .00 (IH, d, J«=5Hz) 4S597 4.35 (2H, ABq, J-12Hz) 3.90 (3H, s) 3.81 (3H, s) 3.55 (2H, ABq, J=18Hz) ( 9) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]3-(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. spectrum (Nujol) · 3400-3150, 1770, 1670, 1625 cm N.M.R. spectrum (dg-DMSO, δ) ppm 9.66 (IH, d, J=8Hz) 7.34 (2H, broad s) 6.76 (IH, s) 5.78 (2H, dd, J=Sj8Hz) 5.16 (IH, d, J=5Hz) 4.40 (ZH, ABq, J=l4Hz) 3.85 (3H, s) 3.70 (2H, ABq, >17Hz) 2.68 (3H, s) (10) 7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]3- (1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3100-3400, 1775, 1660, 1625 cm’ N.M.R. spectrum (dg-DMSO, δ) ppm : 9.70 (IH, d, J*8Hz) 6.80 (IH, s) 6.30-5.60 (2H, m) .24 (2H, dd, J-8,16Hz) .15 (IH, d, J=5Hz) 4559 7 4.63 (2H, d, J-SHz) • 4.32 (2H, ABcfy J»12Hz) 3.94 (3H, s) 3.70 (2H, ABq, J-17Hz) (Ll) 7-[2-Metlioxyimino-2-(2-£ormamido-l,3-thiazol-4-yl)acetamido33-(l,3,4-thiadiaz'ol-2-yl)thiomethyl-3-ceph.em-4-carboxylic acid (syn isomer), mp 145 to 147*C (dec.).

I.R. spectrum (Nujol) 3150 - 3400, 1780, 1725, 1680, 1640 cm'1 N.M.R. spectrum (d6-DMSO, δ) ppm 12.58 (IH, broad s) 9.70 (IH, d, J«8Hz) 9.58 (IH, s) 8.50 (IH, s) 7.40 (IH, s) 5,82 (IH, dd, J«5,8Hz) 5.17 (IH, d, JeSHz) 4.43 (2H, ABq, J«13Hz) 3.88 (3H, s) 3.70 (2H, broad s) (12) 7-[2-Methoxyimino-2-(2-acetamido-l,3-thiazol-4-yl)acetamido]•3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 171 to 173’C (dec.).

I.R. spectrum (Nujol) 3500, 3250, 1780, 1720, 1670 cm1 N.M.R. spectrum (d6-DMSO, 6) ppm 9.65 (IH, d, J=8Hz) 7.3 (IH, s) .8 (IH, dd, J»S, 8Hz) .IS (IH, d, J«5Hz) % £' S 8 7 4.35 (2H, broad s) 3.97 (3H, s) 3.9 (3H, s) 3.75 (2H, broad s) 2.15 (3H, s) 0-3 ) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido) -1,3thiazol-4-yl)acetamido]-cephalosporanic acid (syn isomer), mp 205°C (dec.), I.R. spectrum (Nujol) 3250, 1790, 1735, 1680, 1650 cm*1 N.M.R. spectrum (d6-DMSO, fi) 9.8 ι (IH, d, J«=8Hz) 7.55 (IH, s) 5.88 (IH, dd, J-5, 8Hz) 5.25 (IH, d, J«5HZ) 4.8 (2H, ABq, J-13Hz) 3.95 (3H, s) 3.59 (2H, broad s) 2.03 (3H, s) (14) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3 thiazol-4-yl}acetamido]-3-carbamoyloxyme thyl-3-eephem-4 carboxylic acid (syn isomer).

I.R, spectrum (Nujol) 3500, 3200 , 1785, 1700, N.M.R. spectrum (d6-DMSO, fi) ppm 9.75 (IH, d,· J»8Hz) 8.4 (2H, m) 7.53 (IH, s) 6.6 (IH, m) 6.20 (IH, d, J=5Hz) 45297 , 5.83 (IH, m) 4.77 (2H, ABq, J»14Hz) 3.91 (3H, s) 3.55 (2H, m) 5 (19 7-[2-Meth.oxyimino-2-{2-(2,2,2-trifluoroacetamido)-l,3thiazol-4-yl}acetamido]-3-(l,3,4-thiadiazol-2-yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3200, 1780, 1720, 1650 cm-1 ... N.M.R. spectrum (d6-DMSO, 6) 9.81 (IH, d, J-8Hz) 9.6 (IH, m) 9.57 (IH, s) 7.56 (IH, s) 5.83 (IH, dd, J-5, 8Hz) 5.20 (IH, d, J-5Hz) 4.47 (2H, ABq, J«3 4Hz) 3.96 (3H, s) 3.72 (2H, ABq, J-18Hz) (16) 7-[2-Meth.oxyiminO-2-(2-amino-1,3-thiazol-4-yl)acetamido}3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 260 to 270°C (dec.).

I.R. spectrum (Nujol) 3370, 3270, 1765, 1660, 1610, 1590, 1550 cm'1 N.M.R. spectrum (d6-DMSO, 6) ppm 9.58 (IH, d, J-8Hz) 6.76 (IH, s) .75 (IH, dd, J-5, 8Hz) 553 7 .12 (IH, d, J-5Hz) 4.27 (2H, broad s) 3.85 (3H, s) 3.57 (ZH, broad s) (17) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer), mp 227eC (dec.).

I.R. spectrum (Nujol) 3300 - 3350, 1780, 1740, 1670 cm'1 N.M.R. spec trum (d6-DMSO, δ) ppm 9.6 (IH, d, J»8Hz) 6.8 (IH, s) 5.8 (IH, dd, J-5, 8Hz) 5.2 (IH, d, J«5Hz) 4.87 (2H, ABq, J-13Hz) 3.89 (3H, s) 3.6 (2H, broad s) 2.08 (3H, s) (18) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 210 to 220°C (dec.).

I.R. spectTum (Nujol) 3250, 1765, 1650 cm'1 N.M.R. spectrum (d6-DMSO, 6) ppm 9.64 (IH, d, J-8Hz) 7.4 (2H, m) -, -.4 5 53 7 6.79 (IH, s) , 6.60 (2H, m) 5.77 (IH, dd, J=S, 8Hz) 5.16 (IH, d, J=5Hz) 4.75 (2H, ABq, J=12Hz) 3.87 (3H, s) 3.53 (2H, ABq, J=18Hz) (19) 7-[2-Methoxyimino-2-(2-amino-l,'3-thiazol-4-yl)acetamido]3-(1,3,4»thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172 to 175eC (dec.).

I.R. spectrum (Nujol) 3300, 1770, 1665 cm'1 N.M.R. spectrum (d6-DMSO, 6) ppm 9.80 (IH, d, J=8Hz) 15 9.63 (IH, s) 6.95 (IH, s) 6.8 (2H, m) 5.82 (IH, dd, J=5, 8Hz) 5.22 (IH, d, J=5Hz) 20 4.48 (2H, ABq, J«15Hz) 3.97 (3H, s) 3.76 (2H, ABq, J«18Hz) (20) 7-[2-Methoxyimino-2-(2-amino-l,3-tliiazol-4-yl)acetamido]3-(4-methyl-4H-l,2,4-triazol-3-yl)thiomethyl-3-cephem-425 carboxylic acid (syn isomer), mp 185’C (dec.).

I.R. spectrum (Nujol) 3150 - 3350, 1770, 1710, 1660, 1630 cm'1 N.M.R. spectrum (d6-DMSO, 6) ppm 9.61 (IH, d, J=8Hz) 8.69 (IH, s) ioo 537 6.73 (IH, s) .72 (IH, dd, J=4, 8Hz) .1 (IH, d, J=4Hz) 4.1 (2H, ABq, J=13Hz) 3.87 (3H, s) 3.65 (2H, broad s) 3.59 (3H, s) (2l) 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-1,3thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 155 to 160°C (dec.).

I.R. spectrum (Nujol) 3250, 1780, 1730, 1660, 1585, 1520 cm'1 N.M.R. spectrum (d6-DMSO, δ) ppm 9.76 (IH, d, J=8Hz) 7.57 (IH, s) 5.80 (IH, dd, J“4, 8Hz) 5.15 (IH, d, J=4Hz) 4.29 (2H, s) 3.93 (3H, s) 3.60 (2H, s) (22) 6-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]5a, 6-dihydro-3H,7H-azeto[2,l-b]furo[3,4-d](l,3]thiazine-l,7(4H)dione (syn isomer), mp 210 to 215°C (dec.).

I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 cm'1 N.M.R. spectrum (d6-DMSO, 6) ppm 9.70 (IH, d, J=8Hz) 7.26 (2H, broad s) 6.77 (IH, s) .93 (IH, dd, J=5, 8Hz) 101 .16 (IH, d, J-5Hz) ' 5.05 (2H, broad s) 3.85 (3H, s) 3.81 (2H, broad s) ί 02 43597 (gj) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]3- [l-(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem4- carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 1765 cm*1 N.M.R. spectrum (dg-DMSO, ¢) ppm 9.56 (IH, d, J=8Hz) 6.75 (IH, s) 5.75 (IH, m) 5.10 (IH, d, J=4Hz) 4.58 (2H, broad s) 4.32 (2H, broad s) 3.82 (3H, s) 3.68 (2H, broad s) 3.20 (2H, broad s) 2.50 (6H, s) (24) 7-[2-Methoxyimxno-2-(2-formamido-l,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer).

I.R. spectrum (Nujol) 3280, 1785, 1740, 1700, 1650 cm*1 N.M.R. spectrum (dg-DMSO, δ) ppm 12.68 (IH, broad s) 9.68 (IH, d, J=8Hz) 8.54 (IH, s) 7.45 (1H, s) .86 (IH, dd, J=5,8Hz) .20 (IH, d, J-5Hz) 4.90 (2H, ABq, J=8Hz) 3.61 (3H, broad s) 2.06 (3H, s) 103 (25) 7-[2-Methoxyimino-2-(2-ethoxycarbonylamino-l,3-thiazol4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4carboxylie acid (syn isomer).

I.R. specetum (Nujol) 3200, 1775, 1720, 1680, 1660 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm 11.9 (IH, m) 9.70 (1H, d, J=10Hz) 9.55 (IH, S) 7.31 (IH, s) .80 (IH, dd, J=5,10Hz) .18 (IH, d,J=5Hz) 4.44 (2H, ABq, J=16Hz) 4.22 (2H, q, J=7Hz) 3.89 (3H, s) 3.72 (2H, ABq, J=16Hz) 1.23 (3H, t, J=7Hz) (26) 7-[2-Methoxyimino-2-(2-(2,2,2-trifluoroacetamido)-1,3thiazol-4-yl}acetamido]-3-£ormyl-3-cephem-4-carboxylic acid (syn isomer) [or this compound can be represented as 3-hydroxy6-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)-l,3-thiazol-4yljacetamido]-5a,6-dihydro-3H,7H-azeto[2,l-b]furo[3,4-d][1,3] thiazine-l,7(4H)dione (syn isomer)].

I.R. spectrum (Nujol) 3150, 1790, 1720, 1655, 1560, 1500 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.88 (IH, d, J=8Hz) 7.60 (IH, s) 6.30 (IH, d, J=6Hz) W4 45537 (d6-DMSO, δ) (IH, broad s) (IH, d, J=8Hz) (IH, s) (IH, s) (IH, dd, J=5,8Hz) (IH, d, J«=SHz) (2H, ΑΒ^, J=13Hz) (3H, s) (3H, s) (2H, AB„, J=18Hz] 6.05 (IH, dd, J=5,8Hz) .23 (IH, d, J=5Hz) 3.96 (3H, s) 3.80 (2H, broad s) (27) 7 -[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-y1)acetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3200-3300, 1690, 1675 N.M.R. spectrum ppm 12.60 9.70 8.50 7.44 .88 .19 4.2S 3.95 3.85 3.65 (28) 7-[2-Methoxyimino-2-(2-£ormamido-l,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3300, 1780, 1705, 1680 cm'1 N.M.R. spectrum (d^-DMSO, 6) ppm 12.50 (IH, broad s) 9.67 (IH, d, J=8Hz) 8.50 (IH, s) (05 4S59’ 7.43 (IH,. s) ϊ 6.58 (2H, broad s) 5.80 (IH, dd, J“5,8Hz) 5.16 (IH, d, J=5Hz) 4.78 (2H, ABq, J=14Hz) 3.95 (3H, s) 3.57 (2H, ABq, J=18Hz) 106 43597 Example 16 A solution of 7-[2-methoxyimino-2-(2-(2,2,2-trifluoroacetamido)-l,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g.) S in a 0.1 N aqueous solution of sodium hydroxide (10.5 ml.) was warmed at 45°C for 6 hours. Water (15 ml.) and ethyl acetate (30 ml.) were added to the reaction mixture and the resulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid.

The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an.aqueous solution of sodium bicarbonate.

The aqueous solution was subjected to column chromatography on Amberlite XAD-2 (20 ml.^prepared by Rohm 5 Haas Co.) using 10% ethanol as developing solvent. The eluate containing object compound was collected and lyophilized to give 7-(2-methoxyimino15 2- (2-amino-l,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.12 g.).

I.R. spectrum (Nujol) 3200, 1765, 1600 cm1 N.M.R. spectrum (dg-DMSO, 6) 9.51 (IH, d, J=8.5Hz) 7.22 (2H, broad s) 6.72 (IH, s) 5.59 (IH, dd, J=5,8.5Hz) 5.00 (IH, d, J=SHz) 4.35 (2H, ΑΒς, J=12Hz) 3.90 (3H, s) 3.81 (3H, s) 3.55 (2H, AB , J=18Hz) IS .Example 17 ' . .

Trifluoroacetic acid (3 ml) was added under icecooling to 7-[2-methoxyimino-2-(2-t-pentyloxycarbonylamino-l,3thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added ether and precipitating powder was collected by filtration and dissolved in a mixture of water (20 ml) and an IN aqueous solution of sodium hydroxide to adjust to pH 12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and methylene chloride. Excess methylene chloride in the aqueous layeT was thoroughly removed by bubbling of nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and ice-cooling to precipitate powder. The powder was collected by filtration and dried to give 7-(2-methoxyiinino-2-(2-amino-l,3-thiazol-4yl)acetamido]-3-(5-methyl-1,3,4-thi.adiazol-2-yl)thiomethyl-3» cephem-4-carboxylic acid (syn isomer) (0.128 g) I.R. spectrum (Nuj ol) 3400-3150, 1770, 1670, 1625 cm”1 N.M.R. spectrum (dg-DMSO, S) 9.66 (IH, d, J-8Hz) 7.34 (2H, broad s) 6.76 (IH, s) 5.78 (2H, dd, J-5, 8Hz) 5.16 (IH, d, J-5Hz) 4,40 (2H, ABq, J-14Hz) 3.85 (3H, s) 3.70 (2H, ABq, J-17Hz) 2.68 (3H, s) 108 Example 18 Trifluoroacetic acid (4 ml.) and anisole (2 ml.) were added under ice-cooling to 7-[2-allyloxyimino -2-(2-t-pentyl'oxycarbonylamino-l,3-thiazol-4-yl)acetamido]-3-(1-methyl-1HS tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g.) and the mixture was stirred for 40 minutes at ambient temperature. The reaction mixture was post-treated according to a similar manner to that of Example 17 to give 7-[2-allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-310 (l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.425 g.).

I.R. spectrum (Nujol) . 3100-3400, 1775, 1660, 1625 cm'1 N.M.R. spectrum (dg-DMSO, ¢) 9.70 (IH, d, J=8Hz) 6.80 (IH, s) 6.30 » 5.i 60 (2H, m) 5.24 (2H, dd, J»8, 16Hz) 5.15 (IH, d, J=5Hz) 4.63 (2H, d, J=5Hz) 4.32 (2H, ABq, Ja12Hz) 3.94 (3H, s) 3.70 (2H, ABq, J=17Hz) Example 19 Disodium hydrogen phosphate (0.26 g) was added to a suspension of 7-[2-methoxyimino-2-(2-(2,2,2-trifluoroacetamido)-l,3-thiazol-4-yl)acetamido]cephalosporanic acid(syn isomer) (1 g) in water (15 ml). A saturated aqueous solution of disodium hydrogen phosphate was further added thereto to adjust the pH value of the mixture at 6. The resulting 109 42597 mixture was stirred for 23 hours at ambient temperature.

The reaction mixture was adjusted to pH 4 under ice-cooling with 10% hydrochloric acid, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid.

Precipitating crystals were collected by filtration, washed with cold water and dried to give 7-[2-methoxyimino-2-(2amino-l,3-thiazol-4-yl)acetamido]Cephalosporanic acid (syn isomer)(0.18 g), mp 227°C (dec.).

I.R. spectrum (Nujol) 3300 - 3350, 1780, 1740, 1670 cm'1 N.M.R. spectrum (dg -DMSO, d) ppm 9.6 (IH, d, J=8Hz) 6.8 (IH, s) . 5.8 (IH, dd, J=5, 8Hz) 5.2 (IH, d, J«=SHz) 4.87 (2H, ABq, J-13Hz) ’ 3.89 (3H, s) 3.6 (2H, broad s) 2.08 (3H, s) Example 20 7-[2-Methoxyimino-2-{2-(2,2,2-trifluoroacetamido)l,3-thiazol-4-yl}acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl3-cephem-4-carboxylic acid(syn isomer)(23g) was suspended in a solution of Sodium acetate trihydrate (74.8 g) in water (230 ml) and the suspension was stirred for 15 hours at ambient temperature.

The reaction mixture was adjusted to pH 5.0 with cone, hydrochloric acid and insoluble material was filtered off.

The filtrate was adjusted to pH 2.5 and precipitating crystals were collected by filtration and dried to give 7-. Π0 [2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1, 3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn Isomer) (14 g), mp 172 to 175°C (dec.). I.R. spectrum (Nujol) 3300, 1770, 1665 cm1 N.M.R. spectrum (dg· •DMSO, 5) ppm 9.80 (IH, d, J=8Hz) 9.63 (IH, s) 6.95 (IH, s) 10 6.8 (2H, m) 5.82 (IH, dd, J=S, 8Hz) 5.Z2 (IH, d, J=5Hz) 4.48 (2H, ABq, J=15Hz) 3.97 (3H, s) IS 3.76 (2H, ABq, J=18Hz) Example 21 -[2-Methoxyimino-2-(2-('2,2,2-trif luoroacetamido) -1,3thiazol-4-yl}acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (3.5 g.) was suspended in a solution of sodium acetate trihydrate (12.2 g.) in water (30 ml.). The mixture was· stirred for 15 hours at ambient temperature. The reaction mixture was saturated with sodium chloride and adjusted to pH 5.0 with cone, hydrochloric acid with stirring and ice-cooling. Precipitating insoluble material was filtered off. The filtrate was adjusted to pH 3.0 with cone, hydrochloric acid and further adjusted to pH l.S with 10% hydrochlorip acid. Precipitates were.collected by filtration and dried to give 7-[2-methoxyimino2-(2-amino-l,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (syn isomer) (2.1 g.), mp 210 to 220°C (dec.).

I.R. spectrum (Nujol) 3250, 1765, 1650 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.64 (IH, d, J=8Hz) 7.4 (2H, m) 6.79 (IH, s) 6.60 (2H, m) .77 (IH, dd, J=S,8Hz) .16 (IH, d, J=5Hz) 4.75 (2H, ABq, J=12Hz) 3.87 (3H, s) 3.53 (2H, ABq, J=18Hz) Example 22 Cone, hydrochloric acid (10.4 ml.) was added with stirring at ambient temperature to a suspension of 7-[2-methoxyΠ2 imino-2-(2-formamido-1,3-thiazol-4-yl)acetamido)cephalosporanic acid (syn isomer)’ (48.35 g.) in methanol (725 ml.). After stirring for 3 hours at ambient temperature, the reaction mixture was adjusted to pH 4.5 with aqueous solution of ammonia and methanol was distilled off. To the residue was added water (100 ml.). The mixture was adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, and insoluble material was collected by filtration to give 6-[2-methoxyimino-2-(2-amino-l,3-thiazol-4yl)acetamido]-5a,6 -dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]10 thiazine-1,7(4H)dione (syn isomer) (6.5 g.). The filtrate was adjusted to pH 4.5 with acetic acid, adsorbed by Diaion HP-20 resin (Trademark: prepered by Mitsubishi Chemical Industries Ltd.) (600 ml.), washed with water (2 A.) and then eluted with 25% aqueous solution of isopropyl alcohol. Eluates containing the object compounds were collected and cooled after addition of isopropyl alcohol (1/3 volume of the eluates). Precipitates were collected by filtration, washed with isopropyl alcohol and dried to give 7-[2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer) (10.4 g.). The mother liquor was concentrated under reduced pressure until crystals began to precipitate. To the residue was added isopropyl alcohol (2/3 volume of the residue). The mixture was cooled and precipitates were collected by filtration to give the same object compound (5.8 g.). Total yield (16.2 g.).

This compound was identified with the compound obtained in the foregoing Examples by I.R. and N.M.R. spectra.

Example 25 7-(2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-430 carboxylic acid (syn isomer) (10.8 g.) was added to methanol 113 4S597 (200 ml.), and phosphorus oxychloride (7.2 g.) was dropwise added thereto with stirring and ice-cooling at 2 to 9°C. After stirring for 1.5 hours at the same temperature, the reaction mixture was concentrated under reduced pressure on a water bath of 25 to 28°C to the volume of 100 ml. To the residue was added ether (300 ml.) with stirring and ice-cooling. Precipitates were collected by filtration and dried to give 7-[2-methoxy imir.o2 -(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (12.3 g.). This powder (12.3 g.) was suspended in water (100 ml.) and dissolved by adjusting pH of the suspension to 7.5 by addition of a saturated aqueous solution of sodium bicarbonate.

To the solution was added ethyl acetate (100 ml.), and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid.

Precipitates were collected by filtration, washed with cold water and dried to give 7-[2-methoxyimino-2-(2-amino-l,3-thiazol4-yl)acetamido]-3-(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer) (6,1 g.). The aqueous layer in the mother liquor was separated and stirred under cooling after addition of sodium chloride. Precipitates were collected by filtration to give the same object compound (3.8 g.). Total yield (9.9 g.). This compound was identified with the compound obtained in the foregoing Examples by I.R. and N.M.R. spectra. 114 Example 24 The following compounds were obtained according to similar manners to those of Examples I6to 25. (1) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]5 3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 260 to 270°C (dec.).

I.R. spectrum (Nujol) 3370, 3270, 1765 , 1660, 1610, 1590, 1550 cm'1 N.M.R. spectrum (dg-DMSO, 6) 10 ppm 9.58 (IH, d, J-8Hz) 6.76 (IH, S) 5.75 (IH, dd, J=5, 8Hz) S.12 (IH, d, J=5Hz) 4.27 (2H, broad s) 15 3.85 (3H, s) 3.57 (2H, broad s) 115 553 7 (2) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido] 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) mp 210 to 220° C (dec.).

I.R. spectrum (Nujol) 3250, 1765, 1650 cm-1 N.M.R. , spectrum (d6-DMSO, δ) ppm'1 9.64 (IH, d, J=8Hz) 7.4 (2H, m) 6.79 <1H, s) 10 6.60 (2H, m) 5.77 (IH, dd, J=5, 8Hz) ’ 5.16 (IH, d, J=5Hz) 4.75 (2H, ABq, J=12Hz) 3.87 (3H, s) 15 3.53 (2H, ABq, J=18Hz) ¢) 7- [2-Methoxyimin.o-2-‘(2-amino-ls3-thiazol-4-yl) acetamido] 3-(4-methyl-4H-l,2,4-triazol-3-yl)thiomethyl-3-cephem-4- carboxylic acid (syn isomer), mp 185°C (dec.). I.R. spectrum (Nujol) 20 3150 - 3350, 1770, N.M.R. spectrum (dg ppm 9.61 1710, 1660, 1630 cm’1 -DMSO, 6) (IH, d, J=8Hz) 8.69 (IH, s) 6.73 (IH. s) 25 5.72 (IH, dd, J=4, 8Hz) 5.1 (IH, d, J=4Hz) 4.1 (2H, ABq, J=13Hz) 3.87 (3H, s) 3.65 (2H, broad s) 30 3.59 (3H, s) Π6 A ’ ·*; <** ‘‘s hi Ai Ai bj B (4) 6- [2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]5a,6-dihydro-3H,7H-azeto[2,l-b]£uroi3,4-d][1,3]thiazine-1,7 (4H)-dione (syn isomer), mp 210 to 21S°C (dec.).

I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 cm'1 N.M.R. spectrum (d6-DMS0, 5) ppm 9.70 (IH, d, J=8Hz) 7.26 (2H, broad s) 6.77 (IH, s) 10 5.93 (IH, dd, J=5, 8Hz) .16 (IH, d, J=5Hz) .05 (2H, broad s) 3.85 (3H, s) 3.81 (2H, broad s) (5) 7-[2-Methoxyimino-2-(2~amino-l,3-thiazol-4-yl)acetamido3-3[ 1-(2-dimethylarninoethyl)-lff-tetfazol-5-yl3 thioraethy-l-'J-eephem4-carbOxylic acid (syn isomer).

I. R. spectrum (Nujol) 1765 cm”1 20 N, M. R, spectrum (dg-DMSO,δ ) ppm S.56 (iff, d, J=8Hz) 6.75 (Iff, s) 5.75 (IH, m) 5.10 (IH, d, J=4Hz) 25 4.58 (2H, broad s) 4.32 (2H, broad s) 3.82 (33, s) 3.68 (2H, broad s) 3.20 (2H, broad s) 30 2.50 (6H, s) //7 4SS9 7 Example 25 A suspension of 7-[2-methoxyimino-2-{2-(2,2,2trifluoroacetamido)-l,3-thiazol-4-yl}acetamido]cephalosporanic acid (syn isomer) (2.76 g) and 4-methyl-4H-l,2,4-triazole-35 thiol (0.63 g) in pH 6.4 phosphate buffer solution (SO ml) was adjusted to pH 6.4 with sodium bicarbonate and stirred for 6 hours at 65 to 706C. The reaction mixture was cooled and ethyl acetate was added thereto. The mixture was adjusted to pH 5 with 10% hydrochloric acid and washed with ethyl acetate.

The aqueous layer was treated with activated charcoal and adjusted to pH 2.7 with 10% hydrochloric acid with stirring ahd ice-cooling. Precipitating crystals were collected by filtration, washed with cold water and dried to give 7-[2methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido]-3-(425 methyl-4H-l,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g), mp 185°C (dec.).

I.R. spectrum (Nujol) 3150 - 3350, 1770, 1710, 1660, 1630 cm N.M.R. spectrum (dg -DMSO', 6) ppm 9.61 (IH, d, J=8Hz) 8.69 C1H, s) 6.73 (IH, s) 5.72 (IH, dd, J=4, 8Hz) 5.1 (IH, d, J=4Hz) 4.1 (2H, ABq, J=13Hz) 3.87 (3H, s) . 3.59 (3H, s) 3.65 (2H, broad s) Example 26 The following compounds were obtained according to a similar manner to that of Example 25, 118 55 9 7 (1) 7* [2-Methoxyimino-2-(2.-methyl-l,3-thiazol-4-yl)acetamido]3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 1780, 1710, 1675 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm ,65 (IH, d, J=10Hz) 66. (IH, s) ,81 (IH, dd, J=5, 10Hz) IS (IH, d, J=5Hz) 31 (2H, ABq, J=13Hz) 93 (3H, S) 90 (3H, s) 70 (2H, ABq, J=16Hz) 65 (3H, s) (2) 7-[2-Methoxyimino-2-(2-mesylimino-3-me thyl-2,3-dihydrol,3-thiazol-4-yl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carbcxylic acid (syn isomer).

I.R, spectrum (Nujol) 3250, 1780, 1718, 1675 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.80 (IH, d, J=8Hz) 7.08 (IH, s) 5.80 (IH, dd, J«5, 8Hz) 5.18 (IH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 3.99 (3H, s) 3.96 (3H, s) 3.72 (2H, ABq, J=17Hz) 3.66 (3H, s) 2.98 (3H, s) (3) 7-[2-Methoxyimino-2-(2-mesylamino-l,3-thiazol-4-yl)-acetamido] -3- (l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer),.

I 1 7 I.R. spectrum (Nujol) 3300 - 3150, 1780, 1710, 1670 cm1 N.M.R. spectrum (dg -DMSO, δ) ppm 9.84 (IH, d, J=8Hz) 6.97 (IH, s) 5.76 (IH, dd, J=5, 8Hz) 5.12 (IH, d, J=5Hz) 4.33 (2H, ABq, J=13Hz) 3.93 (6H, s) 3.74 (2H, ABq, J=17Hz) 2.96 (3H, s) (4) 7-[2-Methoxyimino-2-(2-oxO-2,3-dihydro-l,3-thiazol-4yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem 4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 1780, 1665 cm*1 N.M.R. spectrum (dg-DMSO, δ) 11.67 (IH, s) 9.83 (IH, d, J=8Hz) 6.61 (IH, s) 5.80 (IH, dd, J=5.5, 5.17 (IH, d, J=5.5Hz) 4.37 (2H, broad s) 4.00 (3H, s) 3.96 (3H, s) 3.75 (2H, broad s) (5) 7-[2-Allyloxyimino-2-(2-mesylamino-l,3-thiazol-4-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethy1-3-cephem4-carboxylic acid (syn isomer).

I.R. spectrum .(Nujol) tJ tai' I 3100 - 3300, 1780, 1720, 1675 cm N.M.R. spectrum (dgDMSO, 6) ppm 9.90 (IH, d, J=8Hz) 7.00 (IH, s) '6.07 • 5.63(2H, m) 5.43 (2H, d, J=8Hz) 5.18 (IH, d, J=5Hz) 4.70 (2H, d, J=5Hz) 4.37 (2H, broad s) 3.98 (3H, s) 3.75 (2H, broad s) 3.00 (3H, s) (6 J 7-[2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl)acetamido] 3-(l-methyl-lH-tetrazol-5- •yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). I.R. spectrum (Nujol) 3200, 1765, 160C I cm1 N.M.R. spectrum (d^-DMSO, 6) ppm : 9.51 (IH, d, J-8.5HZ) 7.22 (2H, broad s) 6.72 (IH, s) 5.59 (IH, dd, J»5, 8.5Hz) 5.00 (IH, d, J«=5Hz) 4.35 (2H, ABq, J»12Hz) 3.90 (3H, s) 3.81 (3H, s) 3.55 (2H„ ABq, J=18Hz) (7) 7-[2-Methoxyimino-2- (2-amino-l,3-thiazol-4-yl)acetamido] 3-(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4- carboxylic acid (syn isomer).

I2l I.R. spectrum (Nujol) 3400 - 3150, 1770, 1670, 1625 cm'1 N.M.R. spectrum (dfi -DMSO, 6) ppm : 9.66 (IH, d, J=8Hz) 7.34 (2H, broad s) 6.76 (IH, s) 5.78 (2H, dd, J-5, 8Hz) 5.16 (IH, d, J=5H2) '4.40 (2H, ABq, J=14Hz) 3.85 (3H, s) 3.70 (2H, ABq, J»17Hz) 2.68 (3H, s) (8) 7-[2-Allyloxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido33-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) .I.R. spectrum (Nujol) 3100 - 3400, 1775, 1660, 1625 cm'1 N.M.R. spectrum (dg-DMSO, 6) ppm : 9,70 (IH, d, J-8Hz) 6.80 (IH, S) 6.30 - S.60(2H, m) .24 (2H, dd, J=8, 16Hz) .15 (IH, d, J“5Hz) 4.63 (2H, d, J»5Hz) 4.32 (2H, ABq, J-12Hz) 3.94 (3H, s) 3.70 (2H, ABq, J«=17Hz) (9) 7-[2-Methoxyimino-2-(2-£ormamido-l,3-thiazol-4-yl)acetamido]3-(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 147°C (dec.). 122 I.R. spectrum (Nujol) 3150 - 3400, 1780, 1725, 1680, 1640 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 12.58 (IH, broad s) 9.70 (IH, d, J*8Hz) 9.58 (IH, s) 8.50 (IH, s) 7.40 (IH, s) 5.82 (IH, dd, J=5, 8Hz) 5.17 (IH, d, J=5Hz) 4.43 (2H, ABq, J=13Hz) 3.88 (3H, s) 3.70 (2H, broad s) (10) 7-[2-Methoxyimino-2-(2-acetamido-l,3-thiazol-4-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem4-carboxylic acid (syn isomer), mp 171 to 173°C (dec.).

I.R. spectrum (Nujol) 3250, 1780 , 1720, 1670 cm'·1 spectrum (dg-DMSO, δ) 9.65 (IH, d, J=8Hz) 7.3 (IH, s) 5.8 (IH, dd, J=S, 8Hz) 5.15 (IH, d, >5Hz) 4.35 (2H, broad s) 3.97 (3H, s) 3.9 (3H, s) 3.75 (2H, broad s) 2.15 (3H, s) 123 . 45397 (113 7-[2-Methoxyijnino-2-(2-amino-l,3-thiazol-4-yl)aeetamido]3-(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172 to 175°C (dec.).

I.R. spectrum (Nujol) 3300, 1770, 1663 cm1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.80 (IH, d, J=8Hz) 9.63 (IH, S) 6.95 (IH, s) 10 6.8 (2H, B) 5.82 (1H, dd, J=S, 8Hz) 5.22 (IH, d, J=5Hz) 4.48 (2H, ABq, J=15Hz) 3.97 (3H, s) 15 3.76 (2H, ABq, J=18Hz) 124 (12) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido] 3- [l-(2-dimethylarainoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem4- carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 1765 cm1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.56 (IH, d, J=8Hz) 6.75 (IH, s) .75 (IH, m) .10 (IH, d, J=4Hz) 4.58 (2H, broad s) 4.32 (2H, broad s) 3.82 (3H, s) 3.68 (2H, broad s) 3.20 (2H, broad s] 2.50 (6K, s) (13) 7-[2-Methoxyimino-2-(2-ethoxycarbonylamino-l,3-thiazol4-yl)acetamido]-3-(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3200, 1775, 1720, 1680, 1660cm1 N.M.R. spectrum (dg-DMSO, 6) ppm 11.9 (IH, m) 9.70 (IH, d, J-lOHz) 9.SS (IH, s) 7.31 (IH, s) .80 (IH, dd, J=5,10Hz) 4.44 (2H, AB , J=16Hz) H 4.22 (2H, q, J»7Hz) 3.89 (3H, s) 125 3.72 (2H, ABq, J=16Hz). ' 1.23 (3H, t, J=7Hz) (14) 7-[2-Methoxyimino-2-(2-formamido-l,3-thiazol-4-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4 carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3200-3300, 2600, 1780, 1720, 1690, 1675 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 12.60 (IH, broad s) 9.70 (IH, d, J=8Hz) 8.50 (IH, s) 7.44 (IH, s) ' 5.88 (IH, dd, J=5,8Hz) .19 (IH, d, J=5Hz) 4.25 (2H, ΑΒς, J=13Hz) 3.95 (3H, s) 3.85 (3H, s) 3.65 (2H, AB J-18Hz) H 126 S S 3 7 (15) 7-[2-Methoxyimino-2'(3-hydroxyphenyl)acetamido]-3(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) .

I.R. spectrum (Nujol) 3250, 1770, 1725, 1670 cm1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.76 6.7-7. 5.86 (IH, d, J=8Hz) 40 (4H, (IH, m) dd, J=5, 8Hz) 10 5.18 (IH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 3.92 (6H, s) 3.72 (2H, ABq, J=17Hz) (16) 7-[2-t-Butoxycarbonylmethoxyimino-2-(3-chloro-415 hydroxyphenyl)acetamido]-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder. 0-7) 7-[2 -Carboxy-me thoxyimino-2-(3-chloro-4-hydroxyphenyl)acet ami do]3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 148°C (dec.).

X. R. spectrum (Nujol) 3400, 3200 - 3300, 2500 - 2600, 1780, 1720, 1670, 1600 cm'1 N.M.R. spectrum (dg-DMSO, ¢) ppm 9.70 (IH, d, J«8Hz) 25 7.50 (IH, d, J=2Hz) 7.45 (IH, dd,J=2, 8Hz) 7.10 (IH, d, J=8Hz) 5.90 (IH, q, J=5Hz) 5.22 (IH, d, J=5Hz) 30 4.70 (2H, s) 127 2 a S 7 IS •30 J 4.35 (2H, ABq, J=13Hz) 3.95 (3H, s) 3.75 (2H, ABq, J=18Hz) (18)7-[2-(l-t-Butoxycarbonylethoxyimino )-2-(3-chloro-4hydroxyphenyl)acetamido]-3-(l-methyl-lH-tettazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder. Q.9) 7- [2^.(1-Carboxyethoxyimino) -2-(3-chloro-4-hydroxyphenyl) acetamido]-3-(1-methyl-ΙΗ-tetrazol-5-yl)thiomethyl-3-cephem4-carboxylic acid (syn isomer),mp 147 to 151°C (dec.).

I.R. spectrum (Nujol) 3250, 2500 r»-l cm - 2600, 1780, 1730, 1660 .. spectrum (dg-DMSO, δ) 9.62 (IH, d, J=8Hz) 7.46 (IH, d, J=2Hz) 7.34 (IH, dd, J=2, 8Hz) 7.04 (IH, d, J=8Hz) 5.90 (IH, q, J=SHz) 5.22 (IH, d, J=5Hz) 4.73 (IH, q, J=6Hz) 4.33 (2H, ABq, J=13Hz) 4.00 (3H, s) • 3.73 (2H, ABq, J=18Hz) 1.37 (3H, d, J=6Hz) 1630, (20) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3(4H-1,2,4-triazol-3-y1)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1775, 1710, 1665 cm1 128 i N.M.R. spectrum (dg-DMSO, δ) ppm 9.67 (IH, d, J=8Hz) 8.40 (IH, s) 6.70-7.43 (4H, m) 5.82 (IH, dd, J=S, 8Hz) 5.13 (IH, d, J=5Hz) 4.18 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.67 (2H, broad s) (21) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm1 N.M.R. spectrum (dg- -DMSO, δ) ppm 9.78 (IH, d, J=8Hz) 9.55 (IH, s) 6.70-7.40 (4H, m) 5.89 (IH, dd, J=5, 8Hz) 20 5.22 (IH, d, J=5Hz) 4^46 (2H, ABq, J=13Hz) 3.92 (3H, s) 3.76 (2H, ABq, Jc18Hz) (22) 7-[2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(52S methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.72 (IH, d, J=8Hz) 129 6 5 9 7 6.62-7.40 (4H, m) 5.94 (IH, dd, J=S, 8Hz) 5.18 (IH, d, J°5Hz) 4.18 (2H, ABq, J=13Hz) 3.89 (3H, s) 3.70 (2H, ABq, J=17Hz) 2.65 (3H, s) (230 7(2-Methoxyimino-2-(3-methoxyphenyl)acetamido]-3-(110 methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.78 (IH, d, J=8Hz) 6.95-7.54 (4H, m) .94 (IH, dd, J=5, 8Hz) no S S 7 18 (IH 12 (2H 92 (6H 76 (3H 72 (2H d, J=5Hz) ABq, J=13Hz) s) s) ABq, J=18Hz) (24) 7- [2-Methoxyimino-2-(4-hydroxyphenyl)acetamido]-3-(lmethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylie acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1720, 1670 cm'1 N.M.R. spectrum (dg-DMSO, 5) ppm 9.70 (IH, d, J=8Hz) 15 7.44 (2H, d, J=8Hz) 6.84 (2H, d, J=8Hz) 5.86 (IH, dd, J=5, 8Hz) 5.18 (IH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 20 3.93 (3H, s) 3.87 (3H, s) 3.74 (2H, ABq, J=18Hz) (25) 7-[2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetamido]3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145 to 148°C (dec.). /3/ 4S597 I.R. spectrum (Nujol) 350.0, 3250, 2500-2600, 1780, 1720, 1655, 1625, 1600 cm1 N.M.R. spectrum (dg- DMSO, 6) ppra 10.80 (IH, broad s) 9.68 (IH, d, J=2Hz) 7.46 (IH, d, J=2Hz) 7.32 (IH, q, J=2, 8Hz) 10 7.00 (IH, d, J=8Hz) 5.80 (IH, q, J=5Hz) 5.16 (IH, d, J=5Hz) 4.28 (2H, ABq, J=13Hz) 3.92 (3H, s) 15 3.87 (3H, s) 3.72 (2H, ABq, J=18Hz) 20 (26) 7-[2-Methoxyimino-2-(3-chloro-4-methoxyphenyl)acet amido]-3-(1-methyl-lH-tetrazol -5-yl)thiome thyl- 3-cephem-4 carboxylic acid (syn isomer), mp 143 to 145°C (dec.). I.R. spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 25 1630, 1600 cm1 N.M.R. spectrum (dg -DMSO, δ) ppm 9.76 (IH, d, J=8Hz) 7.56 (IH, d, J=2Hz) 7.48 (IH, dd, J=2, 8Hz) 132 7.22 (IH, d, J=8Hz) 5.84 (IH, q, J=5Hz) 5.18 (IH, d, J=5Hz) 4.27 (2H, ABq, J=13Hz) 3.90 (6H, s) 3.88 (3H, s) 3.70 (2H, ABq, J=18Hz) (27) 7-[2-Methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetamido]3-(l-methyl-lH-tet.razol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 149 to 152°C (dec.).

I.R. spectrum (Nujol) 3400 - 3450, 3200, 2500 - 2600, 1780, 1720, 1660, 1620, 1600, 1535, 1350 cm'1 N.M.R. spectrum (d6-DMSO, 6) ppm 9.72 (IH, d, J-8Hz) 7.97 (IH, d, J=2Hz) 7.72 (IH, dd, J=2, 8Hz) 7.21 (IH, d, J=8Hz) 5.82 (IH, q, J=5Hz) 5.16 (IH, d, J=5Hz) 4.3 (2H, ABq, J-13HZ) 3.92 (3H, s) 3.87 (3H, s) 3.72 (2H, ABq, J=18Hz) (28) 7-[2-Allyloxyimino-2-(3-chloro-4-hydroxyphenyl)ace tamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer), mp 163 to 165°C (dec.).

I.R. spectrum (Nujol) 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm'1 133 4S597' N.M.R. spectrum (dg -DMSO, δ) ppm 9.70 (IH, d, J=8Hz) 7.40 (IH, d, J=2Hz) 7.30 (IH, dd, J=2, 8Hz) 6.95 (IH, d, J=8Hz) 5.80 (2H, m) 5.30 (2H, d, J=8Hz) 5.10 (IH, d, j=5Hz) 4.60 (2H, d, J=5Hz) 4.27 (2H, ABq, J=13Hz) 3.85 (3H, s) 3.65 (2H, ABq, J=18Hz) (29) 7-[2-Allyloxyimino-2-(3-hydroxyphenyl)acetamido]-3- (I-methyl-lH-tetTazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 149 to : 152°C ( dec.), I.R. spectrum (Nujol) 3250 - 3350, 2550 - 2600, 1780, 1730, 1670, 1650, 1600 cm -1 N.M.R. spectrum (dg· -DMSO, δ) ppm 9.70 (IH, d, J=8Hz) 7.2 - 6.8 (4H, m) 6.1 - 5.8 (2H, m) 5.35 (2H, d, J=8Hz) 5.17 (IH, d, J=5Hz) 4.7 (2H, d, J=5Hz) 4.17 (2H, ABq, J=13Hz) 3.93 (3H, s) 3.75 (2H, ABq, J=18Hz) (30) 7-[2-(3-Hydroxy-4-bromobenzyloxyimino]-2-(4-hydroxyphenyl)acetamido]-3-(1-methyl-lH-tetrazol-S-yl)thiomethyl-3134 cephem-4-carboxylic acid (syn isomer), powder. I.R. spectrum (Nujol) 31S0, 1780, 1720, 1670 cm1 N.M.R. spectrum (dg -DMSO, 5) 5 ppm 9.60 (IH, d, J=8Hz) 6.72 - 7. 52 (7H, m) 5.80 (IH, dd, J=4, 8Hz) 5.15 (IH, d, J=4Hz) 5.00 (2H, s) 10 4.28 (2H, ABq, J=13Hz) 3.90 (3H, s) 3.65 (2H, ABq, J=18Hz) (31) 7-[2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyi)acetamido] -3-(l-methyl-lH-tetrazol-S-yl)thiomethyl-3-cephem-415 carboxylic acid (syn isomer), powder.

I.R. spectrum (Nujol) 3200 - 3300, 1780, 1720, 1660 cm'1 N.M.R. spectrum (dg· -DMSO, 6) ppm 9.77 (IH, d, J=8Hz) 20 6.7r7.7 (7H, m) 5.83 (IH, dd, J=5, 8Hz) 5.29 (2H, s) 5.15 (IH, d, J=5Hz) 4.3 (2H, ABq, J=13Hz) 25 3.92 (3H, s) 3.72 (2H, ABq, J=18Hz) (32 ) 7-[2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyi)acetamido]3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), colorless powder, mp 153 to 156°C (dec.) 135 HR. spectrum (Nujol) 3450, 3250, 2550 - 2600, 1780, 1725, 1665, 1630, 1600 cm'1 N.M.R. spectrum (dg-DMSO,δ) 5 ppm 9.71 (IH, d., J=8Hz) 7.50 (IH, d, J=2Hz) 7.36 (IH, dd, J=2, 8Hz) 7.03 (IH, d, J=8Hz) 5.83 (IH, q, J=5Hz) 10 5.17 (IH, d, J=5Hz) ‘ 4.33 (2H, ABq, J=13Hz) 4.17 (2H, q, J=7Hz) 3.97 (3H, s) 3.73 (2H, ABq, J=18Hz) IS 1.25 (3H, t, J=7Hz) ( 33) 7-(2-Allyloxyimino-2 -(3-me thoxypheny1)acetamido(-3-(1methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), powder, mp 135 to 138°C (dec.). I.R. spectrum (Nujol) 20 3300 , 2600, 1785, 1730, 1670 , 1645, 1600 cm N.M.R. spectrum (dg-DMSO, δ) ppm 9.82 (IH, d, Jc8Hz) 7.0 - 7.45 (4H, a) 5.8 - 6.2 (2H, m) 25 5.36 (2H, t, J«=10Hz) 5.21 (IH, d, J=5Hz) 4.72 (2H, d, J=SHz) 4.36 (2H, ABq, J=13Hz) 3.95, (3H, S) 30 3.91 (3H, s) 136 ο 5 9'7 3.87 (2Η, ABq, J=18Hz) (34) 7-[2-Ethoxyimino-2 -(3-hydroxyphenyl)acetami do ] - 3 - (1 methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), yellow powder, mp 145 to 148°C (dec.).

I.R. spectrum (Nujol) 3450, 3250, 2500 - 2600, 1775, 1720, 1665, 1620, 1600 cm-1 N.M.R. spectrum (d^-DMSO, 6) ppm 9.70 (IH, d, J*8Hz) 10 6.8-7.4 (4H, m) 5.90 (IH, q, J=5Hz) 5.20 (IH, d, J=5Hz) 4.36 (2H, ABq, J=13Hz) 4.20 (2H, q, J=7Hz) 15 4.00 (3H, s) 3.76 (2H, ABq, J=18Hz) 1.33 (3H, t, J=7Hz) (35) 7-[2-Ethoxyimino-2-(3-methoxyphenyl)acetamido]-3-(1methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), pale yellow powder, mp 140 to 143°C (dec.).

I.R. spectrum (Nujol) 3300, 2500 - 2600, 1785, 1730, 1670, 1630, 1600 cm'1 N.M.R. spectrum (dg-DMSO, 6) 25 ppm 9.71 (IH, d, J“8Hz) 6.9 - 7.5 (4H, m) 5.90 (IH, q, J=SHz) 5.17 (IH, d, J=5Hz) 4.33 (2H, ABq, J=13Hz) 30 4.20 (2H, q, Jc7Hz) 137 „ 45597 3.J95 (3H, s) 3.85 (3H, s) 3.75 (2H, ABq, J»18Hz) 1.30 (3H, t, J-=7Hz) (36) 7-[2-Allyi0xyimino-2-(3-chloro-4-methoxyphenyl)acetamido] 3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), pale yellow powder, mp 1S3 to 156°C (dec.).

I.R. spectrum (Nujol) 3250, 2600, 1780 , 1720, li S70, 1645, 10 1630, 1600 cm'1 N.M.R. . spectrum (dg-DMSO, δ) ppm , , 9.65 (IH, d, J=8Hz). 7.27 (IH, d, J=2Hz) 7.20 (IH, dd, J=2, 8Hz) 15 7.09 (IH, d, J=8Hz) 5.85 - 6.15(2H, m) ' 5.15 (2H,. t, J=9Hz) 5.05 (IB, d, J-SHz) 4.60 (2H, d, J=5Hz) 20 4.15 (2H, ABq, J=13Hz) 3.95 (3H,s) 3.90 (3H, s) 3.47 (2H, ABq, J-18HZ) (37) 7-[2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)25 acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3300, 1760, 1660, 1600, 1580, 1520 cm1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.7 (IH, d, J=8Hz) 138 4oSfl7 7.7 - 6.7 (9H, m) .8 - 5.4 (3H, broad s) .06 (IH, d, J»SHz) 4.33 (2H, broad s) 5 3.9 (3H, s) 3,56 (2H, broad s) (38) 7-[2-Methoxyimino-2-(3- mesylaminophenyl)acetamido] (l,3,4-thiadia20l-2-yl)thiomethyl-3-cephem-4-carboxylic (syn isomer), mp 155°C (dec.) - 10 I.R. spectrum (Nujol) 3300, 1780, 1730, 1670 cm*1 N.M.R. spectrum (d6 -DMSO, 6) ppm 9.98 (IH, s) 9.81 (IH, d, J=9Hz) IS 9.62 (IH, s) 5.90 (IH, dd, J=5,9Hz) 5.24 (IH, d, J=5Hz) 4.49 (2H, ABq, J-14HZ) 3.98 (3H, s) 20 3.77 (2H, broad s) 2.96 (3H, s) (39) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3450, 3300, 3200,- 1780, 1725, 1670, 1620, 1590, 1520 cm*1 N.M.R. spectrum (dgDMSO, ¢) ppm 9.77 (IH, d, J=7Hz) 30 7.6 - 6.8 (6H, m) /39 .83 (IH, dd, J=4, 7Hz) ! 5.17 (IH, d, J=4Hz) 4.31 (2H, ABq, J=14Hz) 3.96 (6H, s) 3.72 (2H, broad s) (40) 7-[2-Methoxyimino-2-(3-carbamoyloxyphenyl)acetamido]-3(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) .

I.R. spectrum (Nujol) 3250, 1780, 1735, 1675, cm*1 N.M.R. spectrum (d-DMSO, δ) 0 ppm 9.81 (IH, d, J=8Hz) 9.62 (IH, s) 6.7 - 7.58 (4H, m) 5.8 (IH, dd, J»5, 8Hz) 5.2 (IH, d, J=5Hz) 4.25, 4.63(2H, ABq, J=14Hz) 3.9 (3H, s) 3.7 (2H, broad s) ( 41) 7-[2-Methoxyimino-2-(3-acetoxyphenyl)acetamido]-3(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1780, 1740, 1720, 1680 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.86' (IH, d, J=8Hz) 9.61 (IH, s) 7.00-7.65 (4H, m) 5.84 (IH, dd, J=5, 8Hz) 5.2 (IH, d, J=5Hz) 4.25-4.63 (2H, ABq, J-14HZ) 3.92 (3H, s) HO 3.53, 3.86 (2H, ABq, J=19Hz) 2.3 (3H, s) (42) 7-(2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetamido)· 3-(1-methyl-ΙΗ-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 138 to 142°C (dec.).

I.R. spectrum (Nujol) 3300 - 3400, 2600, 1780, 1720, 1665, 1600 cm'1 N.M.R. spectrum (dg-DMSO, 6) ppm 9.80 (IH, d, J»8Hz) 6,4 - 7.4 (11H, m) 5.85 (IH, dd, J=S, 8Hz) 5.20 (IH, d, J=SHz) 4,83 (2H, d, J=5Hz) 4.32 (2H, ABq, J-lSHz) 3.95 (3H, s) 3.68 (2H, ABq, J=18Hz) (43)7-.[2-Methoxyimino-2- (4 -dimethylaminophenyl)a< (1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4 acid (syn isomer), mp 88°C (dec.). I.R. spectrum (Nujol) 3250, 1780, 1730 , 1680, 1610 cm'1 N.M.R. spectrum (d6-DMSO, 6) ppm 9,63 (IH, d, J=8Hz) 7.40 (2H, d, J=8Hz) 6.73 (2H, d, J=8Hz) 5.83 (IH, dd, J=5, 8Hz) 5.17 (IH, d, J=5Hz) 4.33 (2H, ABq, J=13Hz) 3.97 (3H, s) 141 3.87 (3H, s) 3.73 (2H, broad s) 3.00 (6H, s) (44) 7-(2-Methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-[1(2-dimethylaminoethyl)-IH-tetrazol-5-yl3thiomethyl-3-cephem4-carboxylic acid (syn isomer).

I. R, spectrum (Nujol) 1765 cm-3· Ν. M. R. spectrum (d&-DMS0, $) ppm 9.67 (IH, d, J=9Hz) 6.72-7.36 (4H, m) .78 (IH, dd, J==5, 9Hz) .12 (1H, d, J=5Hz) 4.55 (2H, broad s) 4.30 (2H, broad s) 3.90 (3H, s) . 3.40-3.80 (2H, m) . 3.14 (2H, broad s) 2.48 (6H, s) (45) 7-12-^2-(2-Hydroxyphenoxy)ethoxyiminoj-2-(3-hydroxyphenyl) acetamido]-3-(1-methyl-lH-t etrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer).

I. R. spectrum (Nujol) 3270, 1780, 1725, 1670, 1560 cm“1 Ν. M. R. spectrum (dg-DMSO,S ) ppm 6.5-7.4 (8H, m) .86(1H, dd, J=5, 8Hz) .14(1H, d, J=5Hz) 4.0-4.6 (6H, m) 3.92(3H, s) 3.52, 3.70(2H, ABq, J=7Hz) 142 5 2 7 Example 27 A solution of 7-[2-methoxyimino-2-(2-amino-l,3thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour. Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyiminc>-2-(2-amino-l,3-thiaZol4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,l-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione (syn isomer) (0.23g), mp 210 to 215°C(dec.).

I.R. spectrum (Nujol) 3270, 1780, 1740, 1655, 1610, 1525 cm'1 N.M.R. spectrum (dg ppm 9.70 7.26 6.77 .93 .16 .05 3.85 3.81 DMSO, 5) (IH, d, J=8Hz) (2H, broad s) (IH, s) (IH, dd, J=5, 8Hz) (IH, d, J=5Hz) (2H, broad s) (3H, s) (2H, broad s) 143 4i>S97 Example 28 The following compound was obtained according to a similar manner to that of Example 27 . 6-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido] -5a,65 dihydro-3H,7H-^zeto[2,l-b]furo[3,4-d][1,3]thiazine-1,7(4H)dione(syn isomer).

I.R. spectrum (Nujol) 3250, 1785, 1755, 1660, 1600, 1570, 1540 cm'1 N.M.R. spectrum (dg· -DMSO, δ) 10 ppm 9.83 (IH, d, J=8Hz) 7.5 - 6, .75 (4H, m) 6.02 (IH, dd, J=S, SHz) 5.21 (IH, d, J=5Hz) 5.07 (2H, broad s) 15 3.95 (3H, s) 3.84 (2H, broad s) 144 Example 29 -[2-Methoxyimino-2-{2-(2,2,2 -trifluoroacetamido)l,3-thiazol-4-yl}acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.0 g.) was dissolved in a mixture of dimethyl5 formamide (6 ml.) and acetone (30 ml.). Jones reagent (1.25 ml.), which was prepared from cone, sulfuric acid (0.28 ml.), chromium trioxide (0.33 g.) and water (0.9 ml.), was dropwise added thereto over 2 minutes with stirring and cooling at 0 to 2°C. After Stirring for 20 minutes at the same temperature, the reaction mixture was poured into ice-water (50 ml.). After acetone was distilled off, the residue was twice extracted with ethyl acetate (50 ml.). The extracts were washed with a saturated aqueous Solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diisopropyl ether to give 7-[2-methoxyimino-2(2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl)-acetamido]-3formyl-3-cephem-4-carboxylic acid (syn isomer) [or this compound can be represented as 3-hydroxy-6-[2-methoxyimino-2-{2-(2,2,2trifluoroacetamido)-l,3-thiazol-4-yllacetamido]-5a,6-dihydro-3K, 7H-azeto[2,l-b]furo[3,4-d][l,3]thiazine-l,7(4H)dione (syn isomer)] (0.56 g.).

I.R. spectrum (Nujol) 3150, 1790, 1720, 1655, 1560, 1500 cm'1 N.M.R. ppm spectrum (dg-DMSO, 5) 9.88 (IH, d, J-8Hz) 7.60 (IH, s) 6.30 (IH, d, J=6Hz) 6.05 (IH, dd, J=5,8Hz) 30 5.23 (IH, d, J=5Hz) 145 597 3.96 (3H, s) 3.80 (2H, broad s) Example 30 The following compounds were obtained by conducting elimination reaction of protective group of amino on carbamoyl group according to a similar manner to that of Example 3. (1) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido] 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 210 to 220°C (dec.).

I.R. spectrum (Nujol) 3250, 1765, 1650 cm*1 N.M.R. spectrum (dg-DMSO, δ) ppm 9.64 (IH, d, J=8Hz) 7.4 (2H, m) 6.79 (IH, s) 6.60 (2H, m) 5.77 (IH, dd, J=5,8Hz) 5.16 (IH, d, Ja5Hz) 4.75 (2H, ABq, J=12Hz) 3.87 (3H, s) 3.53 (2H, ABq, J=18Hz) (2) 7-[2-Methoxyimino-2-(2-formamido-l,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. spectrum (Nujol) 3300, 1780, 1705, 1680 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 12.50 (IH, broad s) 9.67 (IH, d, J=8Hz) 8.SO (IH, s) 146 A t ρ·; ο 'ΐ 4 ο ** < 7.43 (ΙΗ, s) 6.58 (2Η, broad s) 5.80 (ΙΗ, dd, J-5,8Hz) 5.16 (ΙΗ, d, J«5Kz) 4.78 (2Η, ABq, J«=14Hz) 3.95 (3Η, s) 3.57 (2Η, AB , J=18Hz) 147 Reference.1 Phosphorus pentachloride (3.3 g.) was added under iceCooling to a suspension of 2-methoxyimino-2-(2-amino-l,3-thiazol4-yl)acetic acid (syn isomer) (1.5 g.) in methylene chloride (30 ml.) and the mixture was stirred for 30 minutes at ambient temperature. Methylene chloride was distilled off under reduced pressure and acetone was added to the residue to give a suspension On the other hand, a suspension of 7-amino-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.) in an aqueous solution of sodium bicarbonate (0.76 g. in 50 ml. of water) was stirred for 10 minutes and acetone (50 ml.) was added thereto to give a solution. To the solution was dropwise added the above obtained suspension containing acid chloride with stirring and ice-cooling and keeping the solution at pH 7.5 to 8.5 with a 20%· aqueous solution of sodium carbonate. The mixture was stirred for 1 hour at 3 to 5°C and pH 8.0. Acetone was distilled off under reduced pressure and the residue was adjusted to pH 7.4 with a saturated aqueous solution of sodium bicarbonate and further adjusted to pH 4.5 with 10% hydrochloric acid with stirring and ice-cooling. Precipitates were filtered off and the filtrate was saturated with sodium chloride, adjusted to pH 2.5 with 104 hydrochloric acid and stiTred for 1 hour. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-amino-l,325 thiazol-4-yl)acetamido]-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl3-eephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.95 g.).

I.R. spectrum (Nujol) 3400, 1775, 1710, 1670, 1630 cm'1 148 N.M.R. spectrum (d0-DMSO, δ) ppm 9.85 (IH, d, J»8Hz) 9.50 (IH, d, J=8Hz) 7.58 (IH, s) 6.87 (IH, s) 6.65 (4H, broad s) 5.77 (2H, m) 5.15 (2H, d, J=5Hz) 4.35 (4H, broad s) 4.06 (6H, s) 3.97 (6H, s) 3.75 (4H, broad s) Reference 2 A suspension of phosphorus pentaehloride (1.7 g.) in IS methylene chloride (20 ml.) was changed to a solution by stirring for 2 hours at ambient temperature. 2-Methoxyimino2-(2-amino-l,3-thiazol-4-yl)acetic acid (syn isomer) (0.8 g.) was added thereto at a time at ambient temperature and the mixture was stirred. Methylene chloride was distilled off under reduced pressure and the residue was dissolved in acetone (20 ml.). On the other hand, 7-amino-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (1.0 g.) was suspended in a solution of sodium bicarbonate (0.59 g.) in water (20 ml.) and dissolved by adding acetone (10 ml.). To this solution was dropwise added the above obtained solution containing acid chloride with stirring and ice-cooling and keeping the solution at pH 7.5 to 8,5 with a 20% aqueous solution of sodium carbonate. After stirring for 1 hour at pH 8 under ice-cooling, an insoluble material was filtered off. Acetone was distilled off under reduced pressure from the filtrate and an insoluble material was 149 S ΰ 3 '7 filtered off. The filtrate was adjusted to pH 2.5 with 10¾ hydrochloric acid. Precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl) acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.4 g.). The filtrate was saturated with sodium chloride and 'stirred under ice-cooling to give precipitates. The precipitates were collected by filtration and dried to give the same object compound (0.3 g.). Total yield (0.7 g.).

I.R. spectrum (Nujol) 3400, 1775, 1705 cm 1 N.M.R. spectrum (dg-DMSO, 6) ppm '9.71 (IH, d, J=8Hz) 9.42 (IH, d, J'8Hz) 7.70 (IH, s) 7.40 (4H, broad s) 7.00 (IH, s) 6.61 (4H, s) 5.76 (2H, m) 5.16 (2H, d, J=4,5Hz) 4.76 (4H, AB , J=12Hz) H 3.98 (3H, s) 3.89 (3H, s) 3.53 (4H, ABq, J“18Hz) Reference g A mixture of dimethylformamide (0.22 g.) and phosphorus oxychloride (0.46 g.) was warmed for 1 hour at 40°C. The mixture was dissolved in dry methylene chloride.(20 ml.) and 2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol30 4-yl)acetic acid (anti isomer) (0.73 g.) was added thereto with 150 45537 stirring and ice-cooling, after which the resulting mixture was stirred for 1.5 hours under ice-cooling. On the other hand, 7-amino-3-(1-methy1-1H-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid (0.82 g.) was dissolved in a solution of bis(trimethylsilyl)acetamide (1.5 g.) in dry methylene chloride (20 ml.). To this solution was added at -30°C the above obtained methylene chloride solution, after which the mixture was stirred for 2 hours at -5 to -20°C. After distilling off methylene chloride at low temperature, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and water (50 ml.) was added thereto. The resulting mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the aqueous layer was separated. The aqueous layer was adjusted to pH 1.5, saturated with sodium chloride and extracted with ethyl acetate. The -extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate.

The solvent was distilled off and the residue was pulverized by a mixture of diisopropyl ether and ether. The powder was collected by filtration and dried to give 7-[2-methoxyifflino-2(2-mesylimino-3-methyl-2,3-dihydro-l,3-thiazol-4-yl)acetamido]5-(1-methy1-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.0 g.). This powder (1.0 g.) was suspended in water (30 ml.) and dissolved by adjusting to pH 6 by an aqueous solution of sodium bicarbonate. After removing the solvent by bubbling of nitrogen gas, the aqueous solution was lyophilized to give sodium 7-[2-methoxyimino-2-(2-mesylimino3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (anti isomer) (0.98 g.). 75/ I.R. spectrum (KBr) 1760, 1675 cm1 N.M.R. spectrum (D2°» 3) ppm ' 8.05 (IH, s) .76 (IH, d, J=5Hz) . 5.16 (IH, d, J=5Hz) 4.14 (2H, ΑΒ^, J=13Hz) 4.10 (3H, s) 4.02 (3H, s) 3.52 (2H, ABq, J=17Hz) 3.45 (3H, s) . . 3.24 (3H, s) Reference 4 The following compounds were obtained according to a similar manner to that of Reference 3. (1) 7-[2-Methoxyimino-2-(2-methyl-l,3-thiazol-4-yl)acetamido]3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer), I.R. spectrum (Nujol) 1790, 1720, 1680 rT1 cm N.M.R. spectrum (dg-DMSO, δ) ppm 9.53 (IH, d, J=8Hz) 8.27 (IH, s) 5.83 (IH, dd, J=5.5, 8Hz) 25 • 5.15 (IH, d, J=S.5Hz) 4.30 (2H, ABq, J=14Hz) 4.00 (3H, s) 3.93 (3H, s) 3.70 (2H, ABq, J=16Hz) 30 2.65 (3H, s) 152 (2) 7·[2-Methoxyimino-2 -(Z-amino-1,3-thiazol-4-yl)acetamido]3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer).

I.R. spectrum (Nujol) 3400, 1775, 1670 cm1 N.M.R. spectrum (d6-Dl MSO-, δ) ppm 9.44 (IH, d, J=SHz) 7.71 (IH, s) 6.40 (2H, broad s) 10 5.77 (IH, dd, J=5,8Kz) 5.13 (IH, d, J=5Hz) 4.31 (2H, broad s) 4.00 (3H, s) 3.95 (3H, s) 15 3.70 (2H, broad s) 153 4S597 f 3) 7-[2-Methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetamido] cephalosporanic acid (anti isomer).

I.R. spectrum (Nujol) 3400-3100, 1780, 1730, 1675 cm'1 N.M.R. spectrum (dg-DMSO, δ) 9.43 (IH, d, J=8Hz) 9.16 (2H, broad s) 7.73 (IH, s) 5.82 (IH, dd, J«S,8Hz) 5.18 (IH, d, J=5Hz) 4.90 (2H, AB , J=13Hz) H 4.03 (3H, s) 3.60 (2H, broad s) 2.07 (3H, s) (4) 7-[2-Methoxyimino-2-(2-formamido-l,3-thiazol-4-yl)acetamido] 3-(l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer), mp 1-52’C (dec.).

I.R. spectrum (Nujol) 3300 - 3100, 1775, 1720, 1670, 1630 cm'1 N.M.R. spectrum (d6-DMSO, δ) ppm 12.63 (IH, broad s) ' 9.66 (IH, s) 9.57 (IH, d, J=8Hz) 8.50 (IH, s) 8.07 (IH, s) 5.75 (IH, dd, J=5,8Hz) 5.15 (IH, d, J=5Hz) 4.27 (2H, ABq, J=13Hz) 4.00 (3H, s) 3.70 (2H, broad s) 154 (5) 7-[2-Methoxyimino-2 -(3-hydroxyphenyl)acetamido]-3-(1methyl-lH-tetrazol-5-yl)thiomet’nyl-3-eephem-4-carboxylic acid (anti isomer).

I.R. spectrum (Nujol) 3350, 1780, 1726, 1680 cm’1 N.M.R. spectrum (dg-DMSO, fi) ppm 9.24 (IH, d, J=8Hz) 7.36-7.10 ) (4H, m) 7.00-6.74 .70 (IH, dd, J-5,8Hz) .13 (IH, d, J=5Hz) 4.34 (2H, ABq, J=13Hz) 3.95 (6H, s) 3.72 (2H, AB , J=17Hz) n 155 £ S 3 '7 Preparation of the starting compounds to be used for the afore• .mentioned Examnl-ea-and.- References Preparation 1 A mixture of 3-chloro-4-hydroxyacetophenone (11.9 g.), benzyl chloride (9.35 g.), potassium carbonate (14.5 g.) and dimethylformamide (60 ml.) was stirred for 1 hour at 100°C.

The reaction mixture was poured into water (150 ml.) and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate.

After distilling off the solvent, the residue (18 g.) was recrystal lized from ethanol (160 ml.) to give 3-chloro-4-benzyloxyacetophenone (13.2 g.), mp 110 to 112°C.

Preparation 2 1) Selenium dioxide powder (12.6 g.) was added over 10 minutes to a solution of 3-chloro-4-benzyloxyacetophenone (19,7 g.) in dry pyridine (100 ml.) with stirring at 100°C, and the mixture was stirred for 3 hours at the same temperature. Precipitating selenium was filtered off and the filtrate was concentrated. The residue was dissolved in water (150 ml.) and the solution was washed with ether. The aqueous solution was acidified under cooling with cone, hydrochloric acid and extracted with ether. The extract was washed with a sodium chloride aqueous solution, dried over magnesium sulfate and concentrated to give 2-(3-chloro-4-benzyloxyphenyl)glyoxylic acid (15.9 g.), mp 134 to 13S°C. 2) The following compounds were obtained according to a similar manner to that of Preparation 2-1). (1) 2-(3-Nitro-4-benzyloxyphenyl)glyoxylic acid, mp 161 to 164°C. (2) 2-(3-Chloro-4-methoxyphenyl)glyoxylic acid, mp 81 to 82°C.

I.R. spectrum (Nujol) 2500-2600, 1715, 1670, 1600 cm1 156 2 5 3 7 (3) 2-(3-Mesylaminophenyl)glyoxylic acid, mp 66 to 68°C.

I.R. spectrum (Nujol) 356C, 3250, 1720, 1670 cm1 Preparation 3 1) A mixture of 2-(3-nitro-4-benzyloxyphenyl)glyoxylic acid (30 g.), cone, hydrochloric acid (90 ml.) and acetic acid (120 ml.) was stirred for 3 hours at 100°C. To the reaction mixture was added under cooling ice-water (600 ml.) and the mixture was extracted with ethyl acetate. The extract was washed with ice-water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from a mixture of benzene: ether: petroleum ether (2:1:4). The crystals were collected by filtration, washed with benzene and dried under reduced pressure to give 2-(3-nitro-4-hydroxyphenyl)glyoxylic acid (19.0 g.), mp 139 to 140.5°C. 2) The following compound was obtained according to a similar manner to that of Preparation 3-1). (1) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid, mp 114 to 116°C.

Preparation 4 2-(3-Hydroxyphenyl)glyoxylic acid (3.32 g.) and 1Nmethanol solution of hydroxylamine (45 ml.) were refluxed with stirring for 25 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1Naqueous solution of sodium hydroxide (70 ml.). An aqueous solution was washed with ether, acidified with dil. hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with an activated charcoal. The solvent was distilled off to give 2-hydroxyimino-2-(3-hydroxyphenyl) acetic acid (a mixture of syn and anti isomers) (2.9 g.). 157 4S597 1 I.R. spectrum (Nujol) 3200, 1700 cm’1 Preparation 5 1) (a) Phenolphthalein indicator (3 drops) was added to a 5 solution of O-methylhydroxylamine hydrochloride (5.5 g.) in dry methanol (60 ml.). To the solution was dropwise added with stirring at ambient temperature IN methanol solution of sodium methoxide (65 ml.) until the color of the solution was changed to purplish red. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(3-hydroxyphenyl)glyoxylic acid (9.85 g.) was added to the filtrate and the mixture was refluxed for 30 minutes. After methanol was distilled off at low temperature, a saturated sodium chloride aqueous solution was added to the residue. The mixture was adjusted to pH 1 with 10¾ hydrochloric acid and extracted with ether (300 ml.). The extract was dried over magnesium sulfate. Ether was distilled off at. low temperature to give 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers). (b) This material was dissolved in ether (60 ml.) and a solution of diazomethane in ether was gradually added thereto under ice-cooling until the color of the mixture was changed to yellow. Acetic acid was immediately added thereto and the mixture was washed with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give oily residue (10.8 g.), - The oily residue was subjected to column chromatograph^on silica gel (165 g.) using a mixture 'of benzene 158 5 £, γ and ethyl acetate (9 : 1) as developing solvent. Firstly the eluate containing syn isomer was eluted and the eluate was collected and concentrated to give oily methyl Z-methoxyimino2-(3-hydroxyphenyl)acetate (syn isomer) (7.9 g.). The oil was allowed to stand to give crystals, mp 39.5 to 40.5°C.

I.R. spectrum (Nujol) 3450, 1730 cm'1 N.M.R. spectrum (CDCZ^, 5) ppm 6.7 - 7.42 (4H, m) 10 3.98 (3H, s) 3.92 (3H, S) After the eluate containing syn isomer was eluted, then the eluate containing anti isomer was eluted. The eluate was collected and concentrated to give methyl 2-methoxyimino-215 (3-hydroxyphenyl)acetate (anti isomer) (1.5 g.). This material was recrystallized from a mixture of benzene and petroleum ether to give crystals, mp 96 to 98°C.

I.R. spectrum (Nujol) 3350, 1715 cm*1 N.M.R, spectrum (CDCAj, , δ) ppm 7.12 - 7.40 (IH, m) 6.96 - 7.02 (3H, m) 3.99 (3H, s) 3.84 (3H, s) (c) A 2N aqueous solution of sodium hydroxide (40 ml.) was added with stirring at ambient temperature to a suspension of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (syn isomer) (7.55 g.) in water (70 ml.) and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was adjusted to pH 6.5 with 10% hydrochloric acid, subjected to 159 salting-out and washed with ether (60 ml.). The aqueous , layer was adjusted to pH 1 with cone, hydrochloric acid and extracted once with 100 ml. of and twice with 60 ml. of ether. The extract was washed twice with a saturated sodium chloride aqueous solution (60 ml.) and dried over magnesium sulfate.

Ether was distilled off to give oil. Benzene was added thereto and removed (twice) to give crystals of 2-methoxyimino2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.44 g.), mp 98 to 101°C (dec.).

I.R. spectrum (Nujol) 3370, 1720 cm’1 An aqueous solution of 2N sodium hydroxide (8 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-hydroxyphenyl)acetate (anti isomer) (1.56 g.) in methanol (30 ml.). After stirring for 3 hours at the same temperature, methanol was distilled off. To the residue was added water and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, subjected to'salting-out and extracted with ether. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give crystals of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (anti isomer) (1.07 g.). The crystals were recrystallized from a mixture of petroleum ether and ether to give crystals (0.7 g.), mp 99 to 101°C (dec.).

I.R. spectrum (Nujol) 3350, 1690 cm’1 2)(a) Phenolphthalein indicator (3 drops) was added to a solution of O-methylhydroxylamine hydrochloride ( 3.7 g.) in dry methanol (45 ml.). To the solution was dropwise added 160 ώ' 5 3 7 with stirring at ambient temperature IN methanol solution of sodium methoxide (39 ml.) until the color of the solution was changed to purplish red. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(4-hydroxyphenyl)glyoxylic acid (6.56 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temperature. After methanol was distilled off at low temperature, a saturated sodium chloride aqueous solution was added to the residue. The mixture was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ether. The extract was dried over magnesium sulfate. Ether was distilled off at low temperature to give 2-methoxyimino-2-(4-hydroxyphenyl) acetic acid (syn isomer). (b) This material was dissolved in ether (50 ml.) and a solution of diazomethane in ether was gradually added thereto under ice-cooling until the color of the mixture was changed to yellow. Acetic acid was immediately added thereto and the mixture was washed with a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off to give oily residue (8 g.). The oily residue was subjected to column chromatography on silica gel using a mixture of benzene and ethyl acetate (9 : 1) as developing solvent to give methyl 2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (6.39 g.).

I.R. spectrum (Nujol) 3350, 1720 cm1 161 N.M.R- spectrum (CDCJ^, δ) ppm 7.40 (2Η, d, J=8Hz) ’ 6.80 (2H, d, J=8Hz) ’ ' 3.96 (3H, s) 3.92 (3H, s) (c) A 2N aqueous solution of sodium hydroxide (11 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(4-hydroxyphenyl)acetate (syn isomer) (2.1 g.) in methanol (30 ml.) and the mixture was stirred for 18 hours at ambient temperature. The reaction mixture was adjusted to pH 7 with 10% hydrochloric acid and methanol was removed. To the residue was added water and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, subjected to salting-out and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystals of 2-methoxyimino 2-(4-hydroxyphenyl)acetic acid (syn isomer) (1.5 g.).

I.R. spectrum (Nujol) 3150, 1700 cm'1 3)(a) Phenolphthalein indicator (2 drops) was added to a solution of O-methylhydroxylamine hydrochloride (2.74 g.) in dry methanol (30 ml.). To the solution was dropwise added with stirring at ambient temperature IN methanol solution of sodium methoxide until the color of the solution was changed to purplish red. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 1 hour at ambient temperature. After precipitating sodium chloride was filtered off, 2-(3-nitro-4-hydroxyphenyi)glyoxylic ac.id /62 2 5 3 7 (6.75 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temperature. After methanol was distilled off at 35°C, a saturated sodium chloride aqueous solution was added to the residue. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ether.

The extract was dried over magnesium sulfate. Ether was distilled off at 35°C under reduced pressure to give yellow crystals of 2-methoxyimino-2*(3-nitro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.). (b) This material was dissolved in a mixture of tetrahydrofuran (15 ml.) and ether (100 ml.) and a solution of diazomethane in ether was gradually added thereto at ambient temperature until the color of the mixture was changed to yellow. Acetic acid was immediately added thereto and the mixture was concentrated to dryness at 35°C under reduced pressure. The residue was dissolved in a mixed solvent of ethyl acetate and benzene (1 : 9) and subjected to column chromatography on silica gel using the same mixed solvent as developing solvent. The eluate containing syn isomer was collected and concentrated to give methyl 2-methoxyimino-2(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.7 g.), mp 93 to 95°C.

I.R. spectrum (Nujol) 3300, 1745, 1630, 1535, 1350 cm1 N.M.R. spectrum (CDCAj, 6) .87 (IH, s) 8.22 (IH, <3, J=2Hz) 7.86 (IH, dd. , J=2,8Hz) 7.20 (IH, d, J=8Hz) 4.03 (3H, s) 3.95 (3H, s) 163 S 5 9 7 (c) A 2N aqueous solution of sodium hydroxide (14 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetate (syn isomer) (3.5 g.) in methanol (70 ml.) and the mixture was stirred for 60 hours at ambient temperature. The reaction mixture was concentrated to dryness at 40°C under reduced pressure and the residue was dissolved in water. The solution was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was back-extracted with a saturated sodium bicarbonate aqueous solution. The aqueous extract was adjusted to pH 1 with cone, hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was washed with ice-water and dried Over magnesium sulfate. The solvent was concentrated to dryness at 40°C under reduced pressure to give -yellow crystals of 2-methoxyimino-2-(3-nitro-4-hydroxyphenyl)acetic acid (syn isomqr) (3.2 g.), mp 142 to 143°C (dec.).

I.R. spectrum (Nujol) 3300, 2500 - 2600, 1710, 1630, 1600, 1535, 1375 cm-1 N.M.R. spectrum (CDCAg, 6) ppm 10.67 (2H, s) 8.33 (IH, d, J=2Hz) 7.95 (IH, dd, J=2,8Hz) 7.22 (IH, d, J=8Hz) 4.13 (3H, s) 4)(a) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (6.45 g.) and O-methylhydroxylamine hydrochloride (2.74 g.) were reacted according to a similar manner to that of Preparation 5-3)(a) to give oil of 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.). (b) 2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.) and diazomethane (I.S g.) were reacted and the product was purified by column chromatography according to a similar manner to that of Prepa5 ration S-3)(b) to give crystals of methyl 2-methoxyiraino-2-(3chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0 g.).

I.R. spectrum (Film) 3450, 1735, 1605, 1600 cm'1 N.M.R. spectrum (CDCS.3, δ) 10 ppm 7.55 (IH, d, J=2Hz) 7.37 (IH, dd, J=2,8Hz) 6.95 (IH, d, J=8Hz) 6.12 (IH, s) 3.97 (3H, s)’ IS 3.91 (3H, s) (c) Methyl 2-methoxy ’imino >-2-(3-chloro-4-hydroxyphenyl)- acetate (syn isomer) (2.6 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation S-3)(c) to give 2-methoxyimino-220 (3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.4 g.), mp 147 to 150°C (dec.).

I.R. spectrum (Nujol) 3500, 2500 - 2600, 1745, 1610, 1600 cm'1 N.M.R. spectrum (CDClj, 6) ppm 8.40 (2H, broad s) 7.65 (IH, d, J=2Hz) 7.40 (IH, dd, J=2,8Hz) 7.00 (IH, d, J:8Hz) 4.07 (3H, s) 165 £53 7 ) 2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allylhydroxylamine hydrochloride (1.7 g.) were reacted according to a similar manner to that of Preparation 5-2)(a) to give oil of 2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (2.7 g.).

I.R. spectrum (Film) 3350, 2550-2600, 1720, 1645, 1600 cm’1 6) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2 g.) and O-allylhydroxylamine hydrochloride (1.1 g.) were reacted according to a similar manner to that of Preparation 5-2)(a) to give oil of 2-allyloxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.5 g.).

I.R. spectrum (Film) 3450, 2600, 1730, 1700, 1650, 1610, 1600 cm1 N.M.R. spectrum (dg-DMSO, 5) .5 (2H, .bri sad s) 7.52 (IH, d, J-2Hz) 7.42 (IH, dd , J=2,8Hz) 7.12 (IH, d, J»8Hz) 6.0 (IH, m) 5.40 (2H, J=8Hz) 4.70 (2H, d, J-5HZ) 7) A mixture of 2-(3-chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.), O-t-butoxycarbonylmethylhydroxylamine (1.62 g.) and methanol (20 ml.) was adjusted to pH 5 to 6 by adding an IN methanol solution of sodium methoxide and stirred for 3 hours at ambient temperature. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in an IN aqueous solution of sodium hydroxide to adjust to pH 7.0. The aqueous solution was washed with ether, adjusted to pH 2.0 166 537 with 10% hydrochloric acid under ice-cooling and extracted with ether. The extract was washed with water and dried over magnesium sulfate. The solution was concentrated to dryness under reduced pressure to give crystals of 2:t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 116 to 118°C (dec.).

I.R. spectrum (Nujol) 3250, 2600, 1735, 1690, 1670, 1610, 1590 cm'1 N.M.R. spectrum (dg-DMSO, 6) (2H, broad s) ppm 11.00 7.50 7.40 7.08 4.68 1.45 (IH, d, J=2Hz) (IH, dd, J=2,8Hz) (IH, d, J=8Hz) (2H, s) (9H, s) 8)(a)Potassium carbonate (49.7 g.) and dimethyl sulfate (45.4 g.) were added to a solution of 2-hydroxyimino-2-(3hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (18.1 g.) in dry acetone (250 ml.) and the mixture was refluxed with stirring for 8.5 hours. After acetone was distilled off, the residue was dissolved in water and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give oil (24 g.). The oil was subjected to column chromatography on silica gel using benzene as developing solvent. Firstly the eluate containing syn isomer was eluted and the eluate was collected and concentrated to give oil of methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (syn isomer) (9.2 g.). 167 4SS97 I.R. spectrum (Film) 1738 cm'1 M.R. spectrum (CDCAj, , d) ppm 7.47 - 6.77 (4H, m) 4.00 (3H, s) 3.92 (3H, s) 3.82 (3H, s) After the eluate containing syn isomer was eluted, then the eluate containing anti isomer was eluted. The eluate was collected and concentrated to give methyl 2-methoxyimino2-(3-methoxyphenyl)acetate (anti isomer) (3.9 g.), mp 66 to 68°C, This substance was recrystallized from petroleum ether to give prisms, mp 65 to 65.5°C.

I.R. spectrum (Nujol) 1720 cm1 N.M.R. spectrum ppm 7.14 6.80 CCDCAg, , d) - 7.44 (IH, m) - 7.04 (3H, m) 4.02 (3H, s) 3.84 (3H, s) 3.76 (3H, s) (b) Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (syn isomer) (1.6 g.) and a 2N aqueous solution of sodium hydroxide (4 ml.) were treated according to a similar manner to that of Preparation 5-3) (c) to give oil of 2-methoxyimino2-(3-methoxyphenyl)acetic acid (syn isomer) (1.23 g.).

I.R. spectrum (Film) 1735 cm'1 Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (anti isomer) (1.6 g.) and a 2N aqueous solution of sodium 168 hydroxide (4 ml.) were treated according to a similar manner to that of Preparation 5-3)(c) to give colorless prisms of 2-methoxyimino-2-(3-methoxyphenyl)acetic acid (anti isomer) (1.3 g.), mp 97 to 98°C.

I.R. spectrum (Nujol) 1695 cm'1 9)(a) A solution of diazomethane in ether was added at ambient temperature to a solution of 2-methoxyimino-2-(3-chloro-4hydroxyphenyl)acetic acid (syn isomer) (7 g.) in dry ether (50 ml.) until the color of the mixture was changed to yellow.

Acetic acid was immediately added thereto and the reaction mixture was concentrated to dryness at 35°C under reduced pressure. The residue was subjected to column chromatography on silica gel (120 g.) using a mixture of benzene and ethyl acetate (9 : 1) as a developing solvent. The first eluate was collected and concentrated at 40°C under reduced pressure to give oil of methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn isomer) (3.1 g.).

I.R. spectrum (Film) 2850, 1735, 1610, 1600, 1250 cm'1 N.M.R. spectrum (CDC;e3’ 6) ppm 7.57 (IH, d, J=2Hz) 7.37 (IH, dd. , J=2,8Hz) 6.87 (IH, d, J=8Hz) 3.97 (3H, s) 3.91 (3H, s) 3.88 (3H, s) (b) Methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn isomer) (2.7 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar 169 45S3 7 \manner to that of Preparation 5-3) (c) to give crystals of 2methoxyimino-2-(3-chloro-4-methoxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 133 to 135°C (dec.).

I.R. spectrum (Nujol) 2500-2600, 1745 , 1610, 1600 N.M.R. spectrum (cdca3, δ) ppm 9.95 (IH, broad s) 7.72 (1H, d, J=2Hz) 7.50 (IH, dd, J=2,8Hz) 6.92 (IH, d, J=8Hz) 4.08 (3H, s) 3.95 (3H, s) )(a)A solution of 2-bromopropionyl bromide (25 g.) in dry chloroform (50 ml.) was dropwise added with stirring and iceJ cooling to a solution of N,N-dimethylaniline (24 g.) in t-butanol (11 g.) and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into 6N sulfuric acid (150 ml.) and extracted with ether. The extract was in turn washed with 6N sulfuric acid, water, a 10% potassium carbonate aqueous solution and water and dried over magnesium sulfate.

The solvent was distilled off to give oil of t-butyl 2-bromopropionate (21 g.). (b) This oil (21 g.) was added with stirring at ambient temperature to a mixture of N-hydroxyphthalimide (16.3 g.), triethylamine (24 g.), dimethylformamide (20 ml.) and dimethylsulfoxide (20 ml.) and the resulting mixture was stirred for 4 hours at ambient temperature. The reaction mixture was poured into water (800 ml.) and precipitating materials were collected by filtration, washed with water and dried to give t-butyl 2-phthalimidoxypropionate (22.7 g.). /70 £c) This compound (22.7 g.) was dissolved in methylene chloride (200 ml.). A solution of 10% hydrazine hydrate (9 ml.) in methanol (20 ml.) was added thereto and the mixture was stirred for 2 hours at ambient temperature. Precipitating materials were dissolved by adding SN aqueous solution of ammonia and the aqueous layer was extracted with methylene chloride.

Two methylene chloride layers were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give oil of 0-(l-t-butoxycarbonylethyl)hydroxylamine (13.5 g.).

I.R. spectrum (Film) 3350, 3250, 1745 cm1 (d) 2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.) and 0-(1-t-butoxycarbonylethyl)hydroxylamine (3.2 g.) were reacted according'to a similar manner to that of Preparation 5-7) to give 2-£l-t-butoxycarbonylethoxyimino)-2-(3-chloro-4hydroxyphenyl)acetic acid (syn isomer) (3.3 g.), mp 148 to 151°C.

I.R. spectrum (Nujol) 3450, 2500-2600, 17ZS, 1690, 1620, 1600 cm*1 N.M.R. spectrum (dg-DMSO, δ) ppm 7.46 (IH, d, J=2Hz) 7.33 (IH, dd, J=2,8Hz) 7.07 (IH, d, J=8Hz) 4.67 (IH, q, J=6Hz) 1.50 (12H, s) 11) Phenolphthalein indicator (3 drops) was added to a solution of O-methylhydroxylamine hydrochloride (8.8 g.) in dry methanol (60 ml.). To the solution was dropwise added with stirring at ambient temperature IN methanol solution of sodium methoxide (105 ml.) until the color of the solution was changed 171 to pale pink. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The pH value of the solution was 8.0 to 8.5. The mixture was stirred for 30 minutes at ambient temperature.

·* After precipitating sodium chloride was filtered off, 2-(3hydroxyphenyl)glyoxylic acid (16.6 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temperature.

After methanol was distilled off at low temperature,water was added to the residue. The mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate, washed with ether, adjusted to pH 1 with 10¾ hydrochloric acid, subjected to salting-out and extracted with ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ether was distilled off and the operation that benzene was added to the residue and distilled off was repeated twice to give crystals of 2-methoxyimino-2-(3hydroxyphenyl)acetic acid (syn isomer) (14.8 g.). This compound was identified with the compound obtained in Preparation 5-1)(c) by I.R. spectrum. 12) A solution of 2-(3-methoxyphenyl)glyoxylic acid (1.8 g.) in an aqueous solution of sodium bicarbonate was adjusted to pH 7.0. On the other hand, a solution of O-ethylhydroxylamine hydrochloride (1.4 g.) in water (20 ml.) was adjusted to pH 7.0 with sodium bicarbonate. Two solutions were combined together, adjusted to pH 5.5 with 10¾ hydrochloric acid and stirred overnight at ambient temperature. The reaction mixture was adjusted to pH 7.5 with sodium bicarbonate and washed with ethyl acetate. The aqueous layer was adjusted to pH 1.0 with cone, hydrochloric acid under ice-cooling and extracted with ethyl acetate. The extract was washed with 172 5 3 7 ice-water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give oil of 2ethoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (2.2 g.).

I.R, spectrum (Film) 2600, 1735, 1700, 1610, 1600 cm1 13) The following compounds were obtained according to similar manners to those of Preparation 5-5) to 5-7) and 5-10) to 5-12). (1) 2-Ethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer), oil.

I.R. spectrum (Film) 3450, 2250-2600, 1700-1720, 1610, 1600 cm'1 (2) 2-Ethoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) oil.

I.R. spectrum (Film) 3400, 2600, 1700-1730, 1605, 1600 cm'1 (3) 2-(3-Hydroxy-4-bromobenzyloxyimino)-2 -(4-hydroxyphenyl)acetic acid (syn isomer), colorless powder.

I.R. spectrum (Nujol) 3500, 3200, 1700 cm'1 N.M.R. spectrum (dg-acetone, δ) ppm 6.68-8.05 (7H, m) .15 (2H, s) (4) 2-(2-Thienylmethoxyimino)-2-(4-hydroxyphenyl)acetic acid (syn isomer), powder.

I.R. spectrum (Nujol) 1705 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 6.7-7.7 (7H, m) .28 (2H, s) 173 (5) 2-Allyloxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer), oil.

I.R. spectrum. (Film) 3050-3100, 2600, 1730, 1645, 1610, 1600 cm'1 N.M.R. spectrum (d^DMSO, 6) 50 (4H, m) 30 (IH, m) 33 (2H, t, J=9Hz) 70 (2H, d, J=SHz) 82 (3H, s) (6) 2 -Allyloxyimino-2-(3-chloro-4-methoxyphenyl)acetic acid (syn isomer), pale yellow oil.

I.R. Spectrum (Film) 3100, 2600, 1710-1730, 1645, 1610, 1600 cm1 spectrum (dg-DMSO, 6) '7.63 (IH, d, J=2Hz) 7.50 (IH, dd , Jc2,8Hz) 7.23 (IH, d, J=8Hz) 5.9-6.3 (IH, ¢) 5.33 (2H, t, J=9Hz) 4.73 (2H, d, J=5Hz) 3.91 (3H, s) (7) 2-Phenylthiomethoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer), oil.

I.R. spectrum (.Film ) 3300, 1730 cm'1 N.M.R. spectrum (CDCAj, 6) ppm : 6.8 - 7.7 (9H, m) .54 (2H, s) 174 (8) 2-Methoxyimino-2-(3-mesylaminophenyl) acetic acid (syn isomer), mp 128eC (dec.).

I.R. spectrum (Nujol) 3300, 1740 cm1 (9) 2-(3-Phenylallyloxyimino)-2-(3-hydroxyphenyl)acetic acid (syn isomer), mp 115 to 116°C.

I.R. spectrum (Nujol) 3400, 1725 cm'1 (10) 2-Methoxyimino-2-(4~dimethylamino-phenyl)acetic acid (syn isomer), mp 88 to 89°C (dec.).

I.R. spectrum (Nujol) 2700 - 2100, 1720, 1660, 1612, 1590 cm'1 14) Acetyl chloride ¢4.1 g.) was added with stirring and ice-cooling to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (5 g.) in pyridine (20 ml.) and the mixture was stirred for 50 minutes at ambient temperature.

The reaction mixture was poured into ice-water, adjusted to pH 2.1 and extracted three times with ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was thoroughly removed under reduced pressure to give 2-methoxyimino-2-(3acetoxyphenyl)acetic acid (syn isomer) (6.1 g.).

I.R. spectrum (Film) 3500, 2950, 1760, 1735, 1605, 1575, 1485, 1440, 1425, 1370 cm1 N.M.R. spectrum (CDCfc^, δ) ppm 7.94 (1H, s) 7.6-7.0 (4H, m) 4.05 (3H, s) 2.30 (3H, s) 175 S597 IS) Trichloroacetyl isocyanate (70 ml) was dropwise added over 6 minutes at ambient temperature to a solution of 2methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40g) in dry dioxane (200 ml), and the'resulting mixture was stirred for 5 hours at ambient temperature. Dioxane was distilled off and to the residue were added ethyl acetate (200 ml) and by small portions water (200 ml) under ice-cooling. The mixture containing trichloroacetylcarbamoyl 2-methoxyimino-2-(3trichloroacetylcarbamoyloxyphenyl)acetate was stirred for 5 hours at ambient temperature keeping the pH value of the mixture at 6.0 to 6.4 by adding an aqueous solution of sodium bicarbonate. The resulting mixture was wahsed twice with ethyl acetate. The aqueous layer was adjusted to pH2 with a 10% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and precipitating crystals were collected by filtration to give colorless crystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl)acetic acid (syn isomer) (15g), mp 163*C (dec.). The same compound (5.4g) was obtained from the mother liquor.

I.R. spectrum (Nujol) 3480, 3360, 1730, 1660 cm'1 N.M.R. spectTum (d6-DMSO, 6) ppm 3.97 (3H, s), 7.16 (2H, broad s), 7.1 - 7.7 (4H, m), 9.7 (IH, broad s) ί 76 Preparation 6 1) A solution of sodium nitrite (12.4 g.) in water (150 ml.) was dropwise added with stirring at 5 to 7°C to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10°C. Water (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (500 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (32.6 g.).

I.R. spectrum (Film) 3350, 1740, 1710, 1620 cm'1 IS N.M.R. spectrum (CDCIj, 5) ppm 8.75 (2H, broad s) 4.35 (8H, m) 1.35 (6H, m) 2) Pulverized potassium carbonate (160 g.) was added to a solution of ethyl 2-hydroxyiminoacetoacetate (a mixture of 177 syn and anti isomers) (152 g.) in acetone (500 ml.). Dimethyl sulfate (130 g.) was dropwise added thereto with stirring over 1 hour at 45 to 50°C and the mixture was stirred for 2 hours.

An insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The filtered insoluble material was dissolved in water (500 ml.) and this solution was added to the residue. The mixture was extracted twice with ethyl acetate (300 ml.). The extract was washed twice with water (200 ml.) and with a saturated sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (145.3 g.), bp 55 to 64°C/0.5 mm Hg.

I.R. spectrum (Film) 1745, 1695, 1600 cm”1 N.M.R. spectrum (CDCi^, δ) ppm 4.33 (4H, q, J=8Hz) 4.08 (3H, s) 3.95 (3H, s) 2.40 (3H, s) 1.63 (3H, s) 1.33 (6H, t, J=8Hz) 3) Bromine (100 g.) was dropwise added over 40 minutes under reflux to a solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (100 g.) in a mixture of carbon tetrachloride (300 ml.) and acetic acid (300 ml.). The mixture was stirred at 70 to 80°C until the evolution of hydrogen bromide ceased. The reaction mixture was washed twice with water (300 ml.), a sodium bicarbonate aqueous solution 178 ύ ύ ΰ 9 ‘7 and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solution was treated with activated charcoal (2 g.) and concentrated under reduced pressure to give ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (120.8 g.).

I.R. spectrum (Film) 1740, 1705, 1600 cm N.M.R. spectrum (CDCitj, δ) ppm 4.17-4.54 (8H, m) 4.15 (3H, s) 4.13 (3H, s) 1.33 (6H, t, J=8!Iz) 4) A mixture of selenium dioxide (11.1 g.), dioxane (250 ml.) and water (5 ml.) was stirred for 15 minutes at 110 to 115°C to give yellow solution. Ethyl 2-(2-mesylaminol,3-thiazol-4-yl)acetate (26.4 g) was added thereto with stirring at the same temperature. After stirring for 1 hour, the reaction mixture was decanted with heating and cooled to precipitate yellow crystals. The crystals were collected by filtration, washed with dioxane and ether and dried to give ethyl 2-(2-mesylamino-l,3-thiazol-4-yl)glyoxylate (23.S g.).

I.R. spectrum (Nujol) 3300, 1718, 1682 cm-1 ) Ethyl 2-(2-mesylamino-l,3-thiazol-4-yl)glyoxylate (13.9 g.) was added with stirring at ambient temperature to a solution of sodium hydroxide (5.0 g.) in water (150 ml.). The mixture was stirred for 1 hour at ambient temperature, adjusted to pH 7 with cone, hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 0.5 with cone, hydrochloric acid to precipitate yellow crystals. The crystals 179 were collected by filtration, washed with water and dried to give 2-(2-mesylamino-l,3-thiazol-4-yl)glyoxylic acid (10.16 g.).

I.R. spectrum (Nujol) 3350, 1725, 1650 cm1 6) To a solution of ethyl 2-(2-amino-l,3-thiazol-4-yl)acetate (14 g.) in a mixture of pyridine (40 g.) and methylene chloride (300 ml.) was gradually added diethyl ether solution of t-pentyl chloroformate (70 ml.) containing 0.35 mole of tpentyl chloroformate over 10 minutes at -20°C with stirring, and the mixture was stirred for 2 hours at the same temperature and further stirred for 0.5 hour at 0°C. After the reaction, the reaction mixture was poured into water (200 ml.), and then the organic layer was separated. The organic layer was washed with 2N hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water in turn and then dried over magnesium sulfate.

The solvent was distilled off from the organic layer to give dark bTown oil of ethyl 2-(2-t-pentyloxycarbonylamino-l,3-thiazol 4-yl)acetate (12 g.).

I.R. spectrum (liquid) 1667, 1660 (CO) cm1 N.M.R. spectrum (CDCfj,5) ppm 3.75 (2H, s) 6.75 (IH, s) 7) Ethyl 2-(2-t-pentyloxycarbonylamino-l,3-thiazol-4-yl)25 acetate (0.3 g.) and selenium dioxide (0.11 g.) were treated according to a similar manner to that of Preparation 6-4) to give brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-l,3-thiazol 4-yl)glyoxylate (0.22 g.).

I.R. spectrum (liquid) 1720, 1090 [CO) cm'1 180 N.M.R. spectrum (CDCA3,6) ppm 8.3 (HI, s) 8) Ethyl 2-(2-t-pentyloxy.carbonylamino-l,3-thiazol-4-yl)glyoxylate (2.8 g.) and a solution of sodium'hydroxide (0.54 g.) in water (20 ml.) were treated according to a similar manner to that of Preparation 6-5) to give brown powder of 2-(2-t-pentyloxycarbonylamino-l, 3-thiazol-4-yl)glyoxylic acid (1.75 g.).

I.R. spectrum (Nujol) 1730, 1680 (CO) cm1 N.M.R. spectrum (dg-dimethylsulfoxide, 6) ppm 8.4 (IH, s) 9) A mixture of ethyl 2-hydroxyimino-2-(2-amino-l, 3thiazol-4-yl)acetate (a mixture of syn and anti isomers) (0.37g), ethanol (5 ml), water (5 ml) and sodium bisulfite (0.72 g) was stirred for 12 hours at 65 to 70°C. The reaction mixture was concentrated and water (10 ml) was added to the residue. The resulting mixture was subjected to salting-out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give · yellow crystals of ethyl 2-(2-amino-1,3-thiazol-4-yl)glyoxylate (0.18 g), mp 115 to 120°C.

I.R. spectrum (Nujol) 3420, 3250, 3120, 1730, 1665, 1612 cm'1 181 ) Sulfuryl chloride (235 ml.) was dropwise added over minutes with stirring and ice-cooling to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 A). After extracting with methylene chloride (500 ml.) and twice with methylene chloride (200 ml.), the ί extracts were combined. The combined extracts were washed 10 with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.) I.R. spectrum (Film) 1735, 1705'cm'1 182 Preparation Ί 1) A mixture of ethyl 2-hydroxyiminc-4-bromoacetoacetate (a mixture of syn and anti isomers) (22.0 g.), thioacetamide (7.5 g.) and benzene (100 ml.) was refluxed for 3 hours. After cooling triethylamine (10 g.) was added thereto and the mixture was stirred for 1 hour. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give ethyl 2-hydroxyimino-2-(2-methyl-l,3’thiazol-4-yl)acetate (a mixture of syn and anti isomers) (8.6 g.). This substance was subjected to column chromatography on silica gel (80 g.) using benzene as developing solvent. Firstly the eluate containing anti isomer was eluted, collected and concentrated to give ethyl 2-hydroxyimino-2-(2-methyl-l,3-thiazol-4-yl)acetate (anti isomer) (2.5 g.), mp 90 to 92°C.

I.R. spectrum (Nujol) 1720 cm1 N.M.R. spectrum (dg-DMSO, 6) ppm 12.55 (IH, s) 8.25 (IH, s) 183 $ $ 5 3 ‘7 4.27 (2Η, q, Ja7Hz) 2.63 (3H, s) 1.25 (3H, t, J=7Hz) After the eluate containing anti isomer was eluted, the eluate containing syn isomer was eluted, collected and concentrated to give ethyl 2-hydroxyimino-2-(2-methyl-1,3thiazol-4-yl)acetate (syn isomer) (0.5 g.), mp 134 to 136°C.

I.R. spectrum (Nujol) 1720 cm1 N.M.R. spectrum (dg-DMSO, 5) 11.81 (IH, s) 7.81 (IH, s) 4.35 (2H, q, J=7Hz) 2.70 (3H, s) 1.30 (3H, £ fl J=7Hz) 2) Phenolphthalein indicator (3 drops) was added to a solution of hydroxylamine hydrochloride (4.2 g.) in dry methanol (60 ml.). To the solution was dropwise added with stirring at ambient temperature IN methanol solution of sodium methoxide (60 ml.) until the color of the solution was changed to purplish red. Hydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(2-mesylamino-l,3-thiazol-4-yl)glyoxylic acid (12.5 g.) was added to the filtrate and the mixture was refluxed with stirring for 1.5 hours. The reaction mixture was cooled to precipitate crystals. The crystals were collected by filtration and dried to give crude 2-hydroxyimino-2-(2-mesylamino-l,3thiazol-4-yl)acetic acid (a mixture of syn and anti isomers) 184 b S 3 7 (5.5 g.). The filtrate was concentrated to the volume of 1/4 and ether was added thereto. Precipitating crystals were collected by filtration, washed with ether and dried to give the same compound (8.78 g.). Total yield (14.3 g.). 3) A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (2.4g) and thiourea (0.76 g) in ethanol (15 ml) was stirred for 1 hour at 60°C. Ethanol was distilled off under reduced pressure and water was added to the residue. The resultant mixture was adjusted to pH 1.0 and washed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and benzene (1:3) as developing solvent. The eluates containing syn isomer were collected and concentrated to give ethyl 2-hydroxyimino-2-(2-amino-l, 3-thiazol-4-yl)acetate (syn isomer) (0.3 g).

I.R. spectrum (Nujol) 3450, 3300, 3200, 1725, 1620 cm'1 N.M.R. spectrum (CDCAj, δ) ppm : 7.65 (IH, s) .33 (2H, broad s) 4.40 (2H, q, J=7.SHz) 1.38 (3H, t, J=7.5Hz) After the eluates containing syn isomerswere collected, the eluates containing a mixture of syn and anti isomers were collected and concentrated to give ethyl 2-hydroxyimino-2185 S 5 3 ‘7 (2-amino-1,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (0.3 g.).

I.R. spectrum (Nujol) 3400, 3300, 3200, 1715, 16?0 cm'1 N.M.R. spectrum (d6-DMSO, 6) : 12.42 (IH, broad s) 11.55 (IH, s) 7.52 (IH, s) 7.12 (4H, broad s) 6.83 (IH, s) 4.23 (4H, m) 1.26 (6H, m) 4) A solution of ethyl 2-hydroxyimino-2-(2-amino-l,3thiaz'ol-4-yl)acetate (a mixture of syn and anti isomers) (1.1 g) in an IN aqueous solution of sodium.hydroxide (15 ml) was allowed to stand for 2 hours at ambient temperature The reaction mixture was adjusted to pH 3.5 with 10% hydrochloric acid and precipitating crystals were collected by filtration, washed with acetone and dried to give 2hydroxyimino-2-(2-amino-l,3-thiazol-4-yl)acetic acid (a mixture of syn and anti isomers) (0.52 g), mp 184 to 186°C (dec.).

I.R. spectrum (Nujol) 3200, 1670, 1530 cm-1 186 Preparation 8 1) Thioacetamide (3.8 g.) was added to a solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (12.6 g.) in ethanol (50 ml.) and the mixture was stirred for 5 hours at 50°C. Ethanol was distilled off under reduced pressure and water was added to the residue.

The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to give ethyl 2-methoxyimino-2-(2methyl“l,3-thiazol-4-yl)acetate (a mixture of syn and anti isomers) (9,0 g.). 2) A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (7.6 g.), 0-ethyl thiocarbamate (3.0 g.) and dimethylacetamide (5 ml.) was stirred for 3 hours at 50°C. Ethyl acetate (50 ml.) was added to the reaction mixture and the resulting mixture was washed with water and with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystalline residue. The residue was washed with diisopropyl ether to give ethyl 2-methoxyimino-2-(2-oxo-2,3dihydro-l,3-thiazol-4-yl)acetate (syn isomer) (2.35 g.).

I.R. spectrum (Nujol) 3200, 1735, 1680, 1650 cm1 187 4S5S7 N.M.R. spectrum (CDCJl^o ppm 9.13 (IH, broad s) 6.37 (IH, s) 4.40 (2H, q, J»6Hz) 4.01 (3H, s) 1.38 (3H, t, J=6Hz) The mother liquor of diisopropyl ether was concentrated and the residue was subjected to column chromatography on silica gel (70 g.) using a mixture of benzene and ethyl acetate (9 : 1) as developing solvent. The eluate containing syn isomer was collected and concentrated to further give the above obtained syn isomer (0.65 g.). Total yield (3.0 g.). Thereafter a mixture of benzene and ethyl acetate (5:1) was used as developing solvent. The eluate containing anti isomer was collected and concentrated to give ethyl 2-methoxyimino-2-(2-oxo-2,3-dihydro-l, 3-thiazol-4-yl)acetate (anti isomer) (0.26 g.).

I.R. spectrum (Nujol) 3250, 3200, 1720, .1690 cm1 N.M.R. spectrum (CDCAj., δ) ppm 9.90 (IH, broad s) 7.30 (IH, s) 4.40 (2H, q, J=6Hz) 4.03 (3H, s) 1.38 (3H, t, J=6Hz) 3) A solution of ethyl 2-methoxyirnino-4-bromoacetoacetate (a mixture of syn and anti isomers) (17.4 g.) and thiourea (5.4 g.) in ethanol (100 ml.) was refluxed for 4 hours. The reaction mixture was allowed to stand and cooled in refrigerator to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-2-(2188 ε 5 Ξ '7 amino-1,3-thiazol-4-yl)acetate hydrobromide (anti isomer) (9.5 g.). The filtrate and the washings were put together and concentrated under reduced pressure. Water (100 ml.) was added to the residue and the mixture was washed with ether.

The aqueous layer was alkalized with a 28% aqueous solution of ammonia and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystalline substance of ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (5.2 g.).

I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm1 N.M.R. spectrum (CDCfj, 6) ppm 6.72 (IH, s) .91 (2H, broad s) 4.38 (2H, q, J=7Hz) 4.03 (3H, s) 1.38 (3H, t, J-7Hz) The above obtained ethyl 2-methoxyimino-2-(2-amino-l,3thiazol-4-yl)acetate hydrobromide (anti isomer) (9.5 g.) was suspended in ethyl acetate (200 ml.) and triethylamine (4.0 g.) was added thereto. After stirring for 1 hour at ambient temperature, an insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give crystalline substance of ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol4-yl)acetate (anti isomer) (6.15 g.).

I.R. spectrum (Nujol) 3450, 3250, 3150, 1730, 1620 cm1 189 42897 N.M.R. spectrum (CDC^, δ) ppm 7.50 (IH, s) .60 (2H, broad s) 4.35 (2H, q, J=7Hz) 4.08 (3H, s) 1.33 (3H, t, J=7Hz) 4) Phenolphthalein indicator (3 drops) was added to a solution of 0-methyl-hydroxylamine hydrochloride (1.2S g.) in dry methanol (15 ml.). To the solution was dropwise added with stirring at ambient temperature IN methanol solution of sodium methoxide (13 ml.) until the color of the solution was changed to purplish red. O-Methylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, ethyl 2-(2-mesylamino-l,3thiazol-4-yl)glyoxylate (3.8 g.) was added to the filtrate and the mixture was refluxed with stirring for 2 hours. After methanol was distilled off, the residue was dissolved in ethyl acetate. An insoluble material was filtered off and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel using a mixture of benzene and ethyl acetate (9:1) as developing solvent. The eluate containing syn isomer was collected and concentrated to give ethyl 2-methoxyimino-2-(2-mesylamino-1,3-thiazol-4-yl)acetate (syn isomer) (2.8 g.).

I.R. spectrum (Nujol) 1725 cm”1 N.M.R. spectrum (CDC£j,6) ppm 6.76 (IH, s) 190 4.44 (2H, q, J-7Hz) 4.04 (311, s) 3.04 (3H, s) 1.37 (311, t, J*?Hz) ) Pulverized potassium carbonate (0.33 g.) was suspended in a solution of ethyl 2-hydroxyimino-2-(2-methyl-l,3-thiazol4-yl)acetate (syn isomer) (0.5 g.) in acetone (20 ml.).

A solution of dimethyl sulfate (0.3 g.) in acetone (5 ml.) was dropwise added thereto with stirring at 40 to 4S°C. After stirring for 2 hours at the same temperature, an insoluble material was filtered off. The filtrate was concentrated and water -was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was in turn washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfafe. The solvent was distilled off under reduced pressure to give pale yellow oil of ethyl 2-methoxyimino2-(2-mcthyl-l,3-thiazol-4-yl)acetate (syn isomer) (0.5 g.).

I.R. spectrum (Film) 1740, 1710, 1595 cm'1 N.M.R. spectrum (CDCJU, •J ppm 7.40 (IH, s) 4.25 (2H, q, 4.03 (3H, s) 2.73 (311, s) 1.38 <3H, t. δ) J«7Hz) J«7Hz) 6) 2-Hydroxyimino-2-(2-mesylamino-l,3-thiazol-4-yl)acetic acid (a mixture of syn and anti isomers) (14.3 g.) obtained in Preparation 7-2) was suspended in dry acetone (300 ml.).

To the suspension were added potassium carbonate (22.8 g.) and 191 dimethyl sulfate (20.8 g.). The mixture was refluxed with stirring for 9 hours. Acetone was distilled off from the reaction mixture and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give oil (13 g.). The oil was subjected to column chromatography on silica gel using a mixture of benzene and ethyl acetate (9:1) as developing solvent. Firstly the eluate containing anti isomer was eluted, collected and concentrated. The residual oil (2.4 g.) was triturated under cooling to crystallize. The crystals were collected by filtration by adding petroleum ether to give methyl Z-methoxyimino-2-(2-mesylimino-3-methyl-2s3-dihydro-l,3’thiazol-4-yl)acetate (anti isomer) (2.1 g.).

I.R. spectrum (Nujol) 1740 cm'1 N.M.R. spectrum (CDC£3, δ) ppm 7.90 (IH, s) 4.10 (3H, S) 3.90 (3H, S) 3.47 (3H, s) 3.07 (3H, s) After the eluate containing anti isomer was eluted, the eluate containing syn isomer was eluted, collected and concentrated to give crystals of methyl 2-methoxyimino-2-(2mesylimino-3-methyl-2,3-dihydro-l,3-thiazol-4-yl)acetate (syn isomer) (5.5 g.).

I.R. spectrum (Nujol) 1740 cm'1 192 N.M.R. spectrum (CDCAj, δ) ppm 6.72 (IH, s) 4.05 (3H, s) 3.92 (3H, s) 3.72 (3H, s) 3.01 (3H, s) 7) The following compound was obtained according to a similar manner to that of Preparation 8-4).

Ethyl 2-methoxyimino-2“(2-amino-l,3-thiazol-4-yl)acetate (syn isomer).

I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm N.M.R. spectrum (CDCAj, δ) 6.72 (IH, s) 5.91 (2H, broad s) 4.58 (2H, q> J=7Hz) 4.03 (3H, s) 1.38 (3H, t, J“7Hz) 8) A mixture of acetic anhydride (6.1g) and formic acid (2.8g) was stirred for 2 hours at 50°C. The resulting mixture was cooled and ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (4.6g) was added thereto at 15°C. After the mixture was stirred for 3.5 hours at ambient temperature, cooled water (100 ml) was added thereto. The resulting mixture was extracted with ethyl acetate (200 ml). The extract was washed with water and then with a saturated aqueous solution of sodium bicarbonate until the washing was changed to weakly alkaline solution. The extract was further washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the 193 residue was washed with diisopropyl ether, collected by filtration and dried to give ethyl 2-methoxyimino-2-(2-formamido l,3-thiazol-4-yl)acetate (syn isomer) (4.22g), mp 122 to 124®C (dec.).

I.R. spectrum (Nujol) 3150, 1728, 1700 cm N.M.R. spectrum (CDCl^., d) ppm 12.58 (IH, broad s), 8.95(1H, s), 7.17 (IH, s), 4.42 (2H, q, J=8Hz), 4.00 (3H, s), 1.37 (3H, t, J=8Hz) 9) Pyridine (3g.) was added to a solution of ethyl 2methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (6.5 g.) in a mixture of ethyl acetate (60 ml.) and dimethylformamide (20 ml.). To the solution was dropwise added with stirring at 4®C ethyl chloroformate (8 g.). After adding water (50 ml.) to the reaction mixture, the organic layer was separated, washed with water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel ¢120 g.) using a mixture of ether and petroleum ether (5:2) as an eluent to give ethyl 2-methoxyimino-2-(2*ethoxycarbonylamino1,3-thiazol-4-yl)acetate (syn isomer) (5.4 g.).

N.M.R. spectrum (CDCJl ppm 9.36 (IH, 1 7.10 (IH, : 4.00-4.66 (4H, i 4.00 (3H, ! 1.20-1.60 (6H, 1 194 ) Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirring at ambient temperature to a solution of thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water (250 ml.).

After stirring for 35 minutes at 40 to 45°C, the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, washed with water (200 ml.) and then with diisopropyl ether (100 ml.), and dried to give colorless crystals of ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), mp 161 to 162eC.

I.R. spectrum (Nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm’115 N.M.R. spectrum (CDC2,, 6) ppm 6.72 (IH, s) .91 (2H, broad s) 4.38 (2H, q, J=7Hz) 4.03 (3H, s) 20 1.38 (3H, t, J=7Hz) 195 XI) Ethyl 2-hydroxyimino-2-(2-methyl-l,3-thiazol-4-yl)acetate (anti isomer) (0.3 g.) and dimethyl sulfate (0.18 g.) were reacted according to a similar manner to that of Preparation 8-5) to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyll,3-thiazol-4-yl)acetate (anti isomer) (0.27 g.).

I.R. spectrum (Film) 1750, 1605 cm”1 N.M.R. spectrum (CDCAj, S) ppm 8.07 (IH, s) 4.41 (2H, q, J»7Hz) 4.13 (3H, s) 2.75 (3H, s) 1.40 (3H, t, J-7Hz) 12) The following compound was obtained according to a similar manner to that of Preparation 8-8). ethyl 2-methoxyimino-2-(2-formamido-l,3-thiazol-4-yl)acetate (anti isomer), mp 96 to 99°C (dec.).

I.R. spectrum (Nujol) 3150, 1740, 1650, 1600 cm1 N.M.R. spectrum (CDClj, 6) ppm 11.20 (IH, broad s), 8.60 (IH, s), 7.90 (IH, s), 4.32 (2H, q, J=8Hz), 4.13 (3H, s), 1.32 (3H, ty J=8Hz) 196 Preparation 9 1) Ethanol (10 ml.) was added to a suspension of ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate (syn isomer) (2.2 g.) in a IN aqueous solution of sodium hydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 7.0 with 10¾ hydrochloric acid and ethanol was distilled off under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10¾ hydrochloric acid and stirred under ice-cooling to precipitate crystals. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol to give colorless needles of 2-methoxyimino-2-(2-amino-l,3thiazol-4-yl)acetic acid (syn isomer) (1.1 g.).

I.R. spectrum (Nujol) 3150, 1670, 1610, 1585 cm'1 N.M.R. spectrum (dg-DMSO, 5) ppm 7.20 (2H, broad s) 6.85 (IH, s) 3.83 (3H, s) 2) 1N-Aqueous solution of sodium hydroxide (1.5 ml.) was added to a solution of ethyl 2-methoxyimino-2-(2-methyl-l,3thiazol-4-yl)acetate (syn isomer) (0.3 g.) in ethanol (5 ml.) and the resulting mixture was stirred for 2 hours at 40°C.

The reaction mixture was adjusted to pH 7.0 with 10¾ hydrochloric acid, concentrated under reduced pressure, adjusted to pH 1.5 with 10¾ hydrochloric acid and extracted with ethyl acetate.

The extract was washed with water and a saturated sodium chloride 197 aqueous solution and dried over magnesium sulfate. The solvent was distilled off to give crystalline substance of 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (syn isomer) (0.14 g.).

I.R. spectrum (Nujol) 1730 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 7.80 (IH, s) 3,85 (3H, s) 2.62 (3H, s) ) The following compounds were obtained according to similar manners to those of Preparation 9-1) to 9*2). (1) 2-Methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl) acetic acid (syn isomer).

I.R. spectrum (Nujol) 3250, 1710, 1650 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 10,61 (IH, broad 6.73 (IH, s) 20 3.95 (3H, s) (2) 2-Methoxyimino-2-(2-mesylamino-l,3-thiazol-4-yl)acetic acid (syn isomer).

I.R. spectrum (Nujol) 3150, 1720 cm'1 N.M.R. spectrum.(dg-DMSO, δ) ppm 7.17 (IH, s) '3.93 (3H, s) 3.02 (3H, s) (5) 2-Methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro50 l,3-thiazol-4-yl)acetic acid (syn isomer).

I.R. Spectrum (Nujol) 1730 cm1 198 (4) 2-Methoxyimino-2-(2-formamido-l,3-thiazol-4-yl)acetic acid (syn isomer), mp 152eC (dec.).

I.R. spectrum (Nujol) 3200, 2800 - 2100, 1950, 1600 cm'1 N.M.R. spectrum (d6-DMSO, δ) ppm 8.60 (IH, s) 7.62 (IH, s) 3.98 (IH, s) (5) 2-Methoxyimino-2-(2-ethoxycarbonylamino-l,3-thiazol-4-yl)acetic acid (syn isomer).

I. R. spectrum (Nujol) 3200, 1730, 1710, 1690, 1570 cm1 Ν. M. R. spectrum (dg-DMSO, ft) 12.16 (Ui, bri xad s) 7-50 (IH, s) 7.20 (IH, bri iad s) 4.25 (2H, q, J=7Hz) 3.93 (3H, s) 1.25 (3H, t, J=7Hz) 199 4.) Pyridine (5 ml.) was added to a suspension of 2methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetic acid (syn isomer) (2.0 g.) in ethyl acetate (20 ml.). A solution of bis(2,2,2trifluoroacetic)anhydride (2.5 g.) in ethyl acetate (3 ml.) was dropwise added thereto with stirring at 5 to 7°C and the mixture was stirred for 30 minutes at 3 to 5°C. Water (30 ml.) was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate and two ethyl acetate layers were combined together, washed with·water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-methoxyimino-2-[2-(2,2,2tri£luoroacetamido)-l,3-thiazol-4-yl]acetic acid (syn isomer) (0.72 g.).

I.R. spectrum (Nujol) 1725, 1590 cm'1 N.M.R. spectrum (dg-DMSO, δ) ppm 7.68 (IH, s) 3.91 (3H,s) ) The following compound was obtained according to a similar manner to that of Preparation 9-4). 2-Methoxyimino-2-(2-acetamido-l,3-thiazol-4-yl)acetic acid (syn isomer), mp 184 to 185°C (dec.).

I.R. spectrum (Nujol) 3200, 3050, 1695, 1600 cm'1 6) Phenolphthalein indicator (3 drops) was added to a solution of O-allyl-hydroxylamine hydrochloride (0.84 g.) in dry methanol (10 ml.). To the solution was dropwise added with stirring at ambient temperature IN methanol solution of sodium methoxide (6 ml.) until the color of the solution was 200 4SS0T changed to pale pink. O-Allylhydroxylamine hydrochloride was added thereto by small portions until the solution was changed to colorless solution. The mixture was stirred for 30 minutes at ambient temperature. After precipitating sodium chloride was filtered off, 2-(2-t-pentyloxycarbonylamino-l,3thiazol»4-yl)glyoxylic acid (2.0 g.) was added to the filtrate and the mixture was stirred for 1 hour at ambient temperature. After methanol was distilled off at low temperature, the residue was dissolved in an IN aqueous solution of sodium hydroxide.

The solution was washed with ether and ethyl acetate was added thereto. The mixture was adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to give 2-allyloxyimino-2-(2-t-pentyloxycarbonylaroino-l,3-thiazol4-yl)acetic acid (syn isomer) (1.62 g.).

I.R. spectrum (Nujol) 3200, 1712 cm-1 N.M.R. Spectrum (dg-DMSO, 6) ppm 7.40 (IH, s) 6.24-5.76 (IH, m) S.26 (2H,dd, J=9, 10Hz) 4.65 (2H, d, J=SHz) 1.78 (2H, q, J»8Hz) 1.44 (6H, s) 0.88 (3H, t, J=8Hz) 7) The following compounds were obtained according to a similar manner to that of Preparation 9-6). (1) 2-Methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3201 • thiazol-4-yl)acetic acid (syn isomer).

I.R. spectrum (Nujol) 3200, 1712 cm'1 N.M.R. spectrum (dg-DMSO, 6) ppm 7.40 (IH, s) 3.88 (3H, s) 1.77 (2H, q, J=8Hz) 1.44 (6H, s) 0.88 (3H, t, J=8Hz) (2) 2-Allyloxyimino-2-(2-jnesylajaino-l,3-thiazol-4-yl)acetic acid (syn isomer).

I.R. spectrum (Nujol) 3150, 1710, 1605 cm'1 (3) 2-Methoxyimino“2--(2-amino“2,3-thiazol -4-yl)aoetic acid (syn isomer).

I.R. spectrum (Nujol) 3150, 1670, 1610, 1585 cm1 N.M.R. spectrum (dg-DMSO, 6) ppm 7.20 (2H, broad s) .85 (IN, s) 3.85 (3H, s) 8) Ethyl 2-methoxyimino-2-(2-amino-l,3-thiazol-4-yl)acetate hydrobromide (anti isomer) (15.5 g.) was dissolved in a solution of sodium hydroxide (4.4 g.) in water (150 ml.) and the resulting solution was stirred for 1 hour at ambient temperature. An insoluble material was filtered off and the filtrate was adjusted to pH 5.0 to precipitate crystals. The crystals were collected by filtration and dried to give 2-methoxyimino-2-(2-amino-l,3thiazol-4-yl)acetic acid (anti isomer) (8.0 g.).

I.R. spectrum (Nujol) 202 3150, 1655, 1595, 1550 cm Α N.M.R. spectrum (d6-DMS0, 6) ppm 7.53 (IH, s) 7.23 (2H, broad s) 3.99 (3H, s) 9) The following compounds were obtained according to similar manner to that· of Preparation 9-8). (1) 2-Methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetic acid (anti isomer) I.R. spectrum (Nujol) 1730, 1590 cm-1 N.M.R. spectrum (dg-DMSO, δ) ppm 8.10 (IH, s) 4.00 (3H, s) 2.65 (3H, s) (2) 2-Methoxyimiao-2-(2-mesylimino-3-methyl-2,3-dihydrol,3-thiazol-4-yl)acetic acid (anti isomer).

I.R. spectrum (Nujol) 1730 cm'1 (j) 2-Methoxyimino-2-(2-formamido-l,3-thiazol-4-yl)acetic acid (anti isomer), mp 156 to 158°C (dec.).

I.R. spectrum (Nujol) 3200, 2700 - 2100, 1690, 1590, 1560 cm'1 N.M.R. spectrum (dg-DMSO,S) ppm 8.05 (IB, s) 4.02 (5H, s)

Claims (2)

1. CLAIMS:1. Syn-isomer of 3,7-disubstituted-3-cephem-4carboxylic acid compounds of the formula: N-OR in which R 1 is a group of the formula: ID IS wherein R 3 is hydrogen, halogen, nitro, ** 6 hydroxy, lower alkoxy or acyloxy and R is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino; a group of the formula; r7 <> ° wherein R is amino, protected amino, hydroxy or lower alkyl; or a group of the formula: S 8 9 wherein R is lower alkyl and R is amino, protected imino or oxo; R is an aliphatic hydrocarbon group which may have suitable substituent (s); R is carboxy or protected carboxy; and R is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have suitable substituent(s); 3 4 or R and R are linked together to form -COOCH, -, with proviso that R is not acetoxymethyl, 1-methyltetrazolylthiomethyl or 2-methyl-l,3,4-thiadiazolylthiomethyl when R 1 is a group of the formula: » 7 ~q• 7 2 wherein R is amino or protected amino and R is an un30 substituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms, -2042. The compounds of claim 1, the formula: in which R is group of wherein is hydrogen, halogen or nitro and r6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino; a group of the formula: R—// wherein S is 5 amino, protected amino, hydroxy or lower alkyl; or a group of the IS formula: 8 9 wherein R is lower alkyl and R is protected imiho; R is lower alkyl or lower alkenyl, each of which may have 1 to-2 substituent(s) selected from , carboxy, protected carboxy, arylthio, aryloxy which may have one hydroxy, aryl which may have one halogen and one hydroxy, and thienyl; R 3 is carboxy; and R^ is acyloxymethyl, hydroxymethyl, formyl, or a heterocyclicthiomethyl group which may have 1 to 2 substituent (s) selected from lower alkyl and di (lower)-alkylamino-(lower)-alkyl; or R 3 and R 2 * are linked together to form -COOCH2-. 3. The .compounds of claim 2, in which R 1 is a group of the formula: wherein R 3 is hydrogen, halogen or nitro and is hydroxy, lower alkoxy, lower alkanoyloxy, carbamoyloxy, lower alkanesulfonylamino or di-(lower)-alkylamino; and is lower alkanoyloxymethyl, carbamoyloxymethyl which may have one trihalo(lower)-alkanoyl, hydroxymethyl, tetrazolylthiomethyl which may have one substituent, selected from 2054BSS' 7 lower alkyl and di(lower)alkylamino(lower)-alkyl, thiadiazolylthiomethyl which may have one lower alkyl, 3 4 or triazolylthiomethyl; or R and R are linked' together to form -COOCI^ - . 5 4. The compounds of claim 3, wherein R is lower alkyl which may have one substituent selected from carboxy, lower alkoxycarbonyl, phenylthio, phenoxy having one hydroxy, phenyl having one halogen ahd one hydroxy, and thienyl, or lower alkenyl which may have one phenyl. 1q 5. The compounds of claim 2, in which R 1 is a group of the formula: wherein R is amino, acylamino, hydroxy or lower alkyl; and R is lower alkyl or lower alkenyl. 15 6. The compounds of claim 5, wherein R is amino or 2. 4 acylamino, R is lower alkyl and R is acyloxymethyl. 7. The compounds of claim 6, wherein R^ is carbamoyl-oxymethyl. -2068. The compounds of claim 7, wherein R is amino. 9. 7- Qz-Methoxyimino -2-(2-amino-l, 3-thiazol-4-yl)- acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylie aeid (syn isomer). 7 . 10. The compounds of claim 7, wherein R is acylamino. 11. The compounds of claim 10, wherein R is lower alkanoylamino or halo (lower)- alkanoylamino. 12. The compounds of claim 11, wherein R is lower alkanoylamino. 13. The compounds of claim 12, wherein R is formamido. 14. 7- |j>-Methoxyimino-2(2-formamido-l, 3-thiazol-4-yl)- acetamido]-3-carbamoyloxymethyl3-cephem-4-earboxylic acid (syn isomer). 20 15. The compounds of claim 10, wherein R is halo(lower)alkanoylamino. 16. The compounds of claim 15, wherein R is trihalo-(lower)alkanoylamino. 17. The compounds of claim 16, wherein R^ is 2,2,2trifluoroaeetamido. 18. 7- [_2-Methoxyimino30 2—{ 2—(2,2,2-trifluoro-acetamido)-1,3-thiazol-4-yl}-acetamido!-207J- 45537' 3. -carbamoyloxymefchyl-3-cephem-4-carboxylic acid (syn isomer). 19. The compounds of claim 5, wherein R is amino or acyl· 2 4 . amino, R is lower alkyl and R is hydroxymethyl. 20. The compounds of claim 19, wherein R is ammo. 2i 7 —1_2 -Methoxyimino -2-(2-amino-l, 3-thiazol· cephem-4-carboxylic acid 22. The compounds of 23. The compounds of alkanoylamino. 24. The compounds of (lower)- alkanoylamino. 25. The compounds of 20 trifluoroacetamido. -4-yl)-acetamido]-3-hydroxymethyl-3(syn isomer). claim 19, wherein R is acylamino. , 7 claim 22, wnerein R is halo-(lower). 7 . claim 23, wherein R is trihalo7 claim 24, wherein R is 2,2,226. 7-[2-Methoxyimino -2-(2-(2,2,2-trifluoro-acetamido)-1, 3-thiazol-4-y1}acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn 25 isomer). 27. The compounds of claim 5, wherein R is acylamino, ? 4 R is lower alkyl and R is formyl. 7 . 30 28. The compounds of claim 27, wherein R is halo-(lower)alkanoylamino. -208 xt-5 53 7 29. The compounds of claim 28, wherein R? i s trihalo(lower)-alkanoylamino. 30. The compounds of claim 29, wherein R 1 is 2,2,2trifluoroacetamido. 5 31. 7-/T : -Methoxvimino-2-{ 2- (2,2,2-trif luoroacetamido) l,3-thiazol-4-yl}acetamido7-3-formyl-3-cephem-4-carboxylic acid (syn isomer), which can also be represented as 3hydroxy-6-/^methoxyimino-2-{ 2-(2,2,2-trifluoroacetamido)1, 3-thiazol-4-yl}-acetamido7-5a, 6-dihydro-3H, 7H-azeto 10 /2~, 1-H7-furo-JJ, tt-ef-fT, 37-thiazine-l, 7 — (4H) -dione (syn isomer) . 32. The compounds of claim 5, wherein R is a heterocyclicthiomethyl group which may have 1 to 2 substituent (s) selected from lower alkyl and di(lower)— 15 alkylamino-(lower)-alkyl. 33. The compounds of claim 32, wherein R 4 is an unsaturated 5-membered heteromonocyclic-thiomethyl group containing 3 or 4 nitrogen atoms which may have one substituent selected from lower alkyl and di-209(lower)-alkyl-amino-(lower)-alkyl, or an unsaturated 5-membe'red heteromonocyclic-thiomethyl group containing a sulfur atom and 2 nitrogen atoms which may have one lower alkyl substituent. 34. The compounds of claim 33, wherein R is tetrazolylthiomethyl which may have one substituent selected from lower alkyl and di(lower)-alkylamino(lower)-alkyl, triazolylthiomethyl which may have one lower alkyl, or thiadiazolylthiomethyl which may have one lower alkyl substituent. 35. The compounds of claim 34, wherein R is tetrazolylthiomethyl having one substituent selected from lower alkyl and di(lower)-alkylamino-(lower)alkyl. 36. The compounds of claim 35, Wherein R is tetrazolylthiomethyl having one lower alkyl substituent. -2107 2 37. The compounds o£ claim. 36, wherein R is hydroxy, R is lower alkyl and R 4 is tetrazolylthiomethyl having one methyl substituent. 38. 7-^2-MethoxyiminoS 2-(2-oxo-2,3-dihydro-l, 3-thiazol-4-yl)-acetamido]-3-(1methyl-lH-tetrazol-5-yl)- thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 39. The compounds of claim 36, wherein R is lower alkyl, 10 R 2 is lower alkyl and R 4 is tetrazolylthiomethyl having one methyl substituent. 40. 7-f2-Methoxyimino2-(2-methyl-l, 3-thiazol-4-yl)- acetamido]-3-(1-methyl-lH15 tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) . 41. The compounds of claim 35, wherein R is ammo, ? 4 . . R is lower alkyl and R is tetrazolylthiomethyl having 20 one dimethylaminoethyl substituent. 42. 7-£2-Methoxyimino2-(2-amino-l, 3-thiazol-4-yl)-acetamido]-3-[l -(2-dimethylaminoethyl)-lH-tetrazol-5-yl]- thio-methyl-3-cephem-4-carboxylic acid 25 (syn isomer). 7 . 2 43. The compounds of claim 34, wherein R is amino, R is lower alkyl and R 4 is triazolylthiomethyl having one lower alkyl substituent. -211V: 44. The compounds of claim 43, wherein R^ is triazolylthiomethyl having one methyl substituent. 45. 7-1~2-Methoxy imino -2-(2-amino-l, 3-thiazol-4-yl)- acetamido]-3-(4-methyl-4H-l, 5 2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 46. The compounds of claim 43, wherein R is ammo or 10 acylamino, R 2 is lower alkyl and R 4 is thiadiazolylthiomethyl« 47. The compounds of claim 46,wherein R is ammo and R^ is thiadiazolylthiomethyl. 48. 7-^2-Methoxyimino -2-(2-amino-l, 3-thiazol-4-yl)- acetamido]-3-(1,3,4-thiadiazol -2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 20 49. The compounds of claim 43, wherein R is acylamino. 50. The compounds .of claim 49-, wherein R is lower alkanoylamino, halo-(lower)-alkanoylamino or lower alkoxycarbonylamino. -212<2 £ £, Ο '7 51. The compounds of claim 50, wherein R is lower alkanoy4 lamino and R is thiadiazolylthiomethyl. 52. 7»[]2-Methoxy imino2-(2-formamido-l, 3-thiazol-4-yl)- acetamido]-3-(1,3,4-thiadiazol -2-yl)-thiomethyl-3-cephem-4-carboxylie acid (syn isomer). 53. The compounds of claim 50, wherein R is halo-(lower)4 alkanoy lamino and R is thiadiazolylthiomethyl. 54. The compounds of claim 53, wherein R is trihalo(lower)alkanoylamino. 5 5 _ 7 -jT 2 -Methoxyimino -2- {2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl}acetamido] -3-(1,3,4 -thiadiazol-2-yl)- thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 56. The compounds of claim 53, wherein R is lower alkoxycarbonylamino. 7 . 57. The compounds of claim 56, wherein R is ethoxycarbonylamino or t-pehtyloxycarbonylamino and R 4 is thiadiazolylthiomethyl 58. 7-^2-Methoxyimino -2-(2-ethoxycarbonyl-amino-l,3-thiazol-4-yl)- acetamido]-3(l,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer). -2134‘S5Q7 7 2 59. The compounds o£ claim 5,‘ wherein R is amino, R is lower alkyl and R 3 and R 4 are linked together to form-COOCH 2 -. 60. 7-^2-Methoxyimino -2-(2-amino-l, 3-thiazol-4-yl) acetamido]-5a, 6-dihydro-3H, 5 7H-azeto-[2,1-b]- furo-[3,4-d]~ [1,3]- thiazine-l,7(4K)- dione (syn isomer). compounds of claim 2, in which R 1 is a group of 8 9 wherein R is lower alkyl and R is acylimino, alkyl and R 4 is tetrazolylthiomethyl which may have one lower alkyl substituent. Q 62. The compounds of claim 61, wherein R is lower alkanesulfonylimino. 61. The the formula: R 2 is lower 63. A process for preparing syn-isomer of 3,7-disubstituted 15 -3-cephem-4-carboxylic acid compounds of the formula: -214in which R 1 is a group of the formula; wherein R is hydrogen, halogen, nitro, 6 hydroxy, lower alkoxy or acyloxy and R u is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino? a group of the formula: a’-TV'•S·' 7 wherein R hydroxy or lower alkyl; or a group of the formula: is amino, protected amino. ~~n—ι 8 9 wherein R is lower alkyl and R is imino, protected imino or oxo? R is an aliphatic hydrocarbon group which may have suitable substituent(s); R 3 is carboxy or protected carboxy; and R 4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have suitable sub3 4 stituent(s); or R and R are linked together to form 4 -CCOCHj-, with proviso that R is not acetoxymethyl, methyl-tetrazolylthiomethyl or 2-methyl-l,3,4-thiadiazolylthiomethyl when R 1 is a group of the formula: wherein R is amino or protected amino and R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula: R 3 3 4 wherein R and R are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a substituted acetic acid of the formula: R^-C-COOH ll 2 N-OR Z -2151 2 wherein R and R are each as defined above, or its reactive derivative at the carboxy group or a salt thereof. 64. A process of claim 63, wherein the reaction is carried out in the presence of a condensing agent. 65. A process of claim 64, wherein the condensing agent is a Vilsmeier reagent. 66. A process of claim 65, wherein the reaction is carried out in the presence of a Vilsmeier reagent produced by the reaction of phosphorus oxychloride with dimethylformamide, and under·, around neutral condition. 67. A process of claim 65, wherein R 1 is a group of the formula: and the reaction is carried out in the presence of a Vilsmeier reagent produced by the reaction of phosphorus oxychloride with dimethylformamide, and under around neutral condition, wherein phosphorus oxychloride is used more than two molar equivalents to each amount of the substituted acetic acid and dimethylformamide. 68. A process for preparing a compound of the formula: -216' 4. -SS97 in which R lb is a group of the formula: a group of the formula: Jky a HN’XgX in which R is lower alkyl? R is an aliphatic hydrocarbon group which may have 3 · suitable substituent(s); R is carboxy or protected carboxy; and R^ is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have suitable 3 4 substituent(s); or R and R are linked together to form 4 -COOCH 2 - , with proviso that R is not acetoxymethyl, 1-methyl-tetrazolylthiomethyl or 2-methyl-l,3,4-thiadia•j zr 2olylthiomethyl when R is a group of the formula: ξν ° 7 2 wherein R is amino and R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of is a group of the formula: S in which a group of the formula: ,9a/^ B Z in which R'“ is protected imino; or a reaction of the protective gr R 7a is protected amino; or R' -,9a Q R is as defined above and salt thereof, to elimination oup of the amino or imino. -21769. A process for preparing a compound of the formula: B Sa Sa wherein R is hydrogen, halogen, nitro, lower alkoxy or acyloxy; R^ a is acyloxy; R is an aliphatic hydrocarbon group which may have suitable substituent(s); 3 4 R is carboxy or protected carboxy; and R is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have suitable substituent(s); or R? and R^ are linked together to form-COOCH 2 -, or pharmaceutically acceptable salts thereof, which comprises acylating the hydroxy group of the compound of the formula: •V HO wherein R 2 , R 2 and R^ are each as defined above and R 5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy., or a salt thereof. 70. A process for preparing a compound of the formula: R-C-CONH It N-OR 2b -21810 in which R 1 is a group of the formula: 5. Wherein R 3 is hydrogen, halogen, alkoxy or acyloxy and R 3 is hydroxy, lower amino or di(lower)alkylamino; a group of the formula: nitro, hydroxy, lower alkoxy, acyloxy, acyl- is amino, protected amino, hydroxy or lower alkyl; or a group of the formula: o 9 wherein R is lower alkyl and R is imino, protected imino or oxo; R 2b is carboxy-(lower)- alkyl; R is carboxy or protected carboxy; and R 4 is acyloxymethyl, hydroxymethyl, formyl or a heterocyclicthiomethyl group which may have suitable substituent(s); or R 3 and R 4 are linked together to form-C00CH 2 -, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula: R -C-CONHN-0R Za ro j~ N \^ c =J~-R 4 wherein R 1 , R 3 and R 4 are each as defined above and R Za is protected carboxy-(lower)-alkyl, or a salt thereof, to elimination reaction of the protective group of the carboxy. -219^5597 71. A process R X -C-CONH « .

2 N-OR Z for preparing a compound of the formula: in which R 1 is a group of the formula: V- wherein R 5 is hydrogen, halogen, nitro, hydroxy, 6. ^= 7 lower alkoxy or acyloxy and R d is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower) alkylamino; a group of the formula: wherein R is amino, protected amino, hydroxy or lower alkyl; or a group of the formula: S' 8 9 wherein R is lower alkyl and R is imino, protected imino or oxo; R is an aliphatic hydrocarbon group which may have suitable substituent(s); and R is carboxy or protected carboxy; or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula: -2204S5S'7 wherein R 1 , R 2 and R 3 are each as defined above and R 4a is a protective group of amino, or a salt thereof, to elimination reaction of the protective group of the amino. 72. A process for preparing a compound of the formula: R-C-CONil-i— in which R 1 is a group of the formula: „5 XV wherein R S is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R is hydroxy, lower alkoxy, acyloxy, aeylamino or di(lower)alkyl amino; a group of the formula: wherein R is amino, protected amino, hydroxy or lower alkyl; or a group of the formula: 8 9 wherein R is lower alkyl and R is imino, protected imino or oxo; R is an aliphatic hydrocarbon group which may have suitable substituent(s); -22110 R is carboxy or protected carboxy; and 4 c R is a heterocyclic group which may have suitable substituent(s); with proviso that R* is not 1-methyl-tetrazolyl or 2-methyl-l,3,4-thiadiazolyl when R 1 is a group of the formulas 7 N _ R V wherein R is amino or protected amino and R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula: R 1 -C-CONH 5 — Ϊ-OR 2 J-N sJ~CH,-R 4b 1 13 R J 2 3 R and R are each as defined above and wherein R 4b R is a group which can be substituted by a group 4c 4c R —S- wherein R is as defined above, or a salt thereof, with a compound of the formula: ,4c SH 4c w wherein R is as defined above or its reactive derivative at the mercapto group. 20 73. A process for preparing a compound of the formula: R-C-CONH N-OR' in which R 1 is a group of the formula: „5 co—o wherein R is hydrogen, halogen, c nitro, hydroxy, lower alkoxy or acyloxy and R is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower)alkylamino; -222a group of the formula: wherein R is amino, protected amino, hydroxy or lower alkyl; or a group of the formula: wherein R is lower alkyl and R 9 is imino, protected imino or oxo; and R is an aliphatic hydrocarbon group which may have suitable substituent(s); or pharmaceutically acceptable salts thereof, which comprises treating a compound of tho formula: h-o r2 o^X R 3 CM OH 12 3 wherein R and R are each as defined above and R is carboxy or protected carboxy, or a salt thereof, with an acid. A process for preparing a compound of the formula: N-OR 2 R 3 CHO in which R 1 is a group of the formula: — wherein R S is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R 6 is hydroxy, lower alkoxy, acyloxy, acylamino or di(lower) alkylamino; -22345597 a group of the formulas *3 W—. 7 · R —-fr j)-wherein S is amino, protected amino, hydroxy or lower alkyl; or a group of the formula: g g wherein R is lower alkyl and R is imino, protected imino or oxo; R is an aliphatic hydrocarbon group which may have suitable substituent(s); and R is carboxy or protected carboxy; or pharmaceutically acceptable salts thereof, which comprises oxidizing a compound of the formula: CHgOH 12 3 wherein R , R and R are each as defined above or a salt there of. 75. A pharmaceutical composition comprising a compound of claim 1 in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. 76. A method for producing a pharmaceutical composition which comprises mixing a compound of claim 1 as an active ingredient with an inert carrier. -22477. A compound as claimed in Claim 1 and substantially as hereinbefore described. 78. A process as claimed in Claim 63 and substantially as hereinbefore described. 79. A process as claimed in Claim 68 and substantially as hereinbefore described. 80. A process as claimed in Claim 69 and substantially as hereinbefore described. 81. A process as claimed in Claim 70 and substantially as hereinbefore described. 82. A process as claimed in Claim 71 and substantially as hereinbefore described. 83. A process as claimed in Claim 72 and substantially as hereinbefore described. 84. A process as claimed in Claim 73 and substantially as hereinbefore described. 85. A process as claimed in Claim 74 and substantially as hereinbefore described. 86. A method of treating infectious diseases in non-human animals by administering a compound as claimed in Claim 1. 87. Syn-isomer of 3,7-disubstituted-3-cephem-4carboxylic acid compounds of the formula; in which r 1 is a group of the formula: -2254S597 ''Sz 4; Jr wherein R is amino, protected amino, hydroxy or lower alkyl; R is an aliphatic hydrocarbon group which may have suitable substituent(s); ' 3 R is carboxy or protected carboxy; and R 4 is carbamoyloxymethyl, hydroxymethyl, formyl, thiadiazolylthiomethyl, tetrazolylthiomethyl which may have lower alkyl, triazolylthiomethyl which may have lower alkyl, or R 3 and R* are linked together to form 4 -COOCH 2 -, with proviso that R is not acetoxymethyl1-methyl-tetrazolylthiomethyl or 2-methyl-l,3,4-thiadia7 zolylthiomethyl when R is amino or protected amino and 2 R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof. 88. The compounds of claim 87, wherein R is lower alkyl or lower alkenyl and R 4 is carbamoyloxymethyl, 20 hydroxymethyl, formyl, 1,3,4-thiadiazolylthiomethyl, 1Htetrazolylthiomethyl having a lower alkyl, 4h-1,2,4-triazolylthiomethyl having a lower alkyl, or R 3 and R 4 are 4 linked together to form -COOCHg-, with proviso that R is not acetoxymethyl, 1-methyl-tetrazolylthiomethyl or 225 methyl-1,3,4-thiadiazolylthiomethyl when R is amino or 2 protected amino and R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms, 89. A process of Claim 63, wherein R 1 is a group of the formula __„ and R* is carbamoyloxymethyl hydroxymethyl, formyl, thiadiazolylthiomethyl, tetrazolylthiomethyl which may have lower alkyl, triazolylthiomethyl which may have 3 4 lower alkyl, or R nnd R are linked together to form -COOCHj-, with proviso that R is -226not acetoxymethyl, 1-methyl-tetrazolylthiomethyl or 27 methyl-1,3,4-thiadiazolylthiomethyl when R is amino or 2 protected amino and R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms. 90. A process of Claim 89, wherein R is lower alkyl 4 or lower alkenyl and R is carbamoyloxymethyl, thiadiazolylthiomethyl Or tetrazolyithiomethyl having a lower alkyl, with proviso that R is not acetoxymethyl, 1methyl-tetrazolylthiomethyl or 2-methyl-l,3,4-thiadia7 2 zolylthio when R is amino or protected amino and R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms. 91. A process of Claim 68, wherein R is carbamoyloxymethyl, thiadiazolylthiomethyl or tetrazolyithiomethyl 4 , having a lower alkyl, with proviso that R is not acetoxymethyl, 1-methyl-tetrazolylthiomethyl or 2-methyl7 1,3,4-thiadiazolylthio when R is amino or protected amino 2 and R is an unsubstituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms. 92. A process of Claim 72 the formula: wherein R is a group of 4c and R is thiadiazolyl, tetrazolyl which may have lower alkyl or triazolyl which may have lower alkyl, with proviso that R is not acetoxymethyl, 1-methyltetrazolylthiomethyl or 2-methyl-l,3,4-thiadiazolylthio 7. 2 when R is amino or protected amino and R is an un-227-<1SSS7 substituted aliphatic hydrocarbon group containing 1 to 4 carbon atoms. 93. A process of.Claim 92,· wherein R is lower alkyl or lower alkenyl.