NO862107L - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CEPHALOSPORINE DERIVATIVES. - Google Patents

Description

The present invention relates to a process for the production of arylmalonamido 1-oxadethiacephalosporins with the general formula

wherein Ar is or (where acyl is organic or inorganic4cyl), COB 1 and COB<2> are each carboxy or protected carboxy,

(where COB^ is carboxy or protected carboxy),

and

Y is hydrogen or methoxy,

with the proviso that when Y is methoxy, Het

and pharmaceutically acceptable salts thereof, and the distinctive feature of the method according to the invention is that an amine with the general formula in which COB 2 , Het and Y have the above meaning is reacted with an arylmalonic acid with the general formula in which Ar and COB 1 have the above meaning, or reactive derivatives thereof, or for the preparation of a compound of the general formula in which COB 1 , COB 2 , Het and Y have the above meaning, the protecting group in Ar' is removed in a compound of formula

wherein Ar' is para-protected hydroxyphenyl and

COB 1 , COB 2 , Het and Y have the above meaning, but are not necessarily the same as in the starting material, or for the preparation of a compound of formula

wherein COB 1 , COB 2 , Het and Y have the above meaning, a compound of formula is acylated

in which COB 1 , COB 2 , Het and Y have the above-mentioned meaning, with an acylating reagent for the introduction of an acyl group, and optionally pharmaceutically acceptable salts thereof are prepared in a manner known per se.

These features of the invention appear from the patent claims.

Cephalosporin analogues with oxygen instead of sulfur atom in the core are described in Journal of Heterocyclic Chemistry, Volume 55

page 779 (1968) by J.C. Sheehan and M. Dadic; German Offenlegungsschrift No. 2,219,601 (1972); Canadian Journal of Chemistry, Volume 52, Page 3996 0 97^0 by Saul Wolfe et al; and Journal of American Chemical Society, Volume 96, Page 7582 (197<*>+) by B.G. Christensen et al.

Various 1-oxadethia cephalosporins have now been prepared which are closely related to known (1-thia) cephalosporins. Contrary to what is stated by B.G. Christensen and air. which assumed that racemic 1-oxacephalosporins exhibited approximately half the potency of (1-thia)cephalosporins, the optically active products prepared according to the invention were about <*>f to 8 times as active as the corresponding (1-thia)cephalosporins with regard to antibacterial properties. However, the B-lactam ring in 1-oxadethiacephalosporins was less stable than required for clinical drugs, in contrast to (1-thia)cephalosporins.

The compounds (I) selected from the optically active compounds prepared according to the invention overcame the aforementioned deficiency with 1-oxadethiacephalosporins.

Furthermore, the compounds (I) had the following properties in comparison with other 1-oxadethiacephalosporins: 1) more potent antibacterial action against gram-negative bacteria,

2) higher stability of the B-lactam ring,

3) closer to minimum inhibitory concentration between bacteria-producing and non-producing B-lactamase,

k) less dependence on inoculum size,

5) higher effectiveness against bacteria that are resistant to other cephalosporins, e.g. enterobacteria, Serratia, indole-positive proteus,

6) higher contributions of a bactericidal nature, and

7) higher blood level.

Furthermore, compounds (I) in which Y is methoxy have the following superior properties: a) wider antibacterial spectra (e.g. 3>6y/ml or more against pseudomonas sp. anaerobic bacteria (Bacteroid

fragilis),

b) higher potency against bacteria that produce B-lactamase

c) higher stability in blood, and

d) lower binding to serum proteins.

In formula (I), preferred are Ar 3_thienyl, p-hydroxyphenyl and

p-acyloxyphenyl, wherein acyl is 1-5C alkanoyl, carbamoyl, 2-6C N-alkylcarbamoyl, or ureinocarbonyl.

The group acyl in the definition of Ar can be inorganic or organic acyl groups containing up to 8 carbon atoms, in particular 1-5C alkanoyl, 8-12C aralkanoyl, 7-9C-aroyl, 2-5C alkoxycarbonyl, 8-20C aralkoxycarbonyl, carbamoyl, 2-6C N -alkylcarbamoyl, and ureidocarbonyl.

Specific examples of acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, enantoyl, phenylacetyl, phenyl-propionyl, benzoyl, toluoyl, carbethoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isobutylcarbamoyl, N ,N-dimethylcarbamoyl, carbamoylcarbamoyl, Na<->methylureidocarbonyl and similar acyl groups .

Group COB<1>, COB<2> and COB^ may be carboxy or protected carboxy as conventional in the chemistry of penicillins and cephalosporins, usually containing up to 15 carbon atoms. The protecting groups can be the same or different for each carboxyl group in the molecule. Generally, the protecting groups are removed to give free carboxy groups or salts in any step of the synthesis of the compounds (I). The structures of the carboxy protecting groups can therefore vary greatly without changing the scope of the invention. In other words, their structural properties can be determined on the basis of protection, removal and possibly by salt formation.

Specific examples of the protective groups mentioned are esters (including optionally substituted alkyl esters such as

t-butyl, mono-hydroxy-t-butyl, 2,2,2-trichloroethyl, and acyloxymethyl esters; aralkyl esters such as e.g. benzyl, p-tolylmethyl, p-nitrobenzyl, p-methoxybenzyl, phthalidyl, diphenylmethyl, trityl and phenacyl esters; metal esters such as e.g. trimethylsilyl, dimethylmethoxysilyl, trimethylstannyl esters and other readily removable aliphatic esters; and aromatic esters such as phenyl, tolyl, 3,^-dimethylphenyl, and 5-indanyl esters, and pharmaceutically acceptable salts (including alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium, calcium and acyloxycalcium salts; and salts with organic bases such as .eg procaine, triethylamine and dicyclohexylamine). Each carboxy group in the molecule can be free or protected by the same or different groups.

Preferably, COB<1>, COB<2> and COB^ can be free carboxy or

its pharmaceutically acceptable salts. Other preferred COB•i group is 5-indanyloxycarbonyl, phenoxycarbonyl or dimethylphenoxycarbonyl.

However, some carboxy protecting groups are useful for changing the nature of the products as drugs. In such cases, they can be specific, conventional, known groups for common drugs and these groups include the following pharmaceutically tolerable groups: phthalidyl, acyloxymethyl, indanyl, phenyl, tolyl, dimethylphenyl and carbethoxymethyl esters.

Preferred is Y methoxy, although the meaning of hydrogen for Y is also important.

Generally, the compounds (I) are administered as salts in human or veterinary medicine. The preferred salts are sodium or potassium salts, or salts with certain organic bases. They are chosen from the viewpoints of security, openability, stability, etc.

Specific examples of compounds (I) include the following: 7(3-[α-(2-thienyl)-α-carboxyacetamidec_7-3-(1-methyltetrazol-5-yD-thiomethyl-1-oxadethia-3-cef em- ^f-carboxylic acid,

7(3-[a-(2-thienyl)-a-carboxyacetamide 07-3-(1-carboxymethyltetra-zol-5-yl)thiomethyl-1-oxadethia-3-cef em-^f-carboxylic acid,

7(3-Za-(2-thienyl)-α-carboxyacetamide q7-3-(2-methyl-1,3,h-thiadiazol-5-yl)thio-methyl-1-oxad ethia-3-cephem-V-carboxylic acid,

7(3-/α-(3-thienyl)-α-carboxyacetamide q7-3_ (1-methyltetrazol-5-yD-thiometh<y>1- 1-oxadethia-3-cephem-^-carboxylic acid,

7-(3-^bc-(3-thienyl)-α-carboxyacetamido7-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylic acid,

7P-(3-thienyl)-α-carboxyacetamido7-3-(2-methyl-1,3,1+-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylic acid ,

7P-(α-phenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxad et ii α-3-cephem-^-carboxylic acid,

7-(3-(α-phenyl-α-carboxyacetamido)-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,

7-(3-(α-phenyl-α-carboxyacetamido)-3-(2-methyl-1,3,β-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylic acid,

7-(3-(α-β-Hydroxyphenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxade thia-3-cef em->+-carboxylic acid,

7P-(α-β-hydroxyphenyl-α-carboxyacetamido)-3-(1-carboxymethyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,

7P-(α-β-hydroxyphenyl-α-carboxyacetamido)-3-(2-methyl-1,3,<*>*-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cef em-k-carboxylic acid,

7P-(<x-p-acetoxyphenyl-oc-carboxyacetamido)-3-(1-methyltetrazol-5-yl}thiomethyl-1-oxadethia-3-cephem-lt-carboxylic acid,

7P-(α-β-acetoxyphenyl-α-carboxyacetamido)-3-(.1-carboxymethyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,

7P-(α-β-acetoxyphenyl-α-carboxyacetamido)-3-(2-methyl-1,3 thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,

,

7p-(a-p-pentanoyloxyphenyl-a-carboxyacetamido)-3-(2-methyl-1,3,N-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylic acid,

7P-(α-carbamoyloxyphenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,

7P-(oc-p-N-methylcarbamoyloxyphenyl-α-carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl- 1-oxadethia- 3- cef em-h-carboxylic acid,

7P-(α-p-N-pentylcarbamoyloxyphenyl-α-carboxyacetamido)-3-(2-methyl-1,3,β-thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid,

7P-(α-p-ureidocarbonyloxyphenyl-α-carboxyacetamido)-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,

7β-α-(2-thienyl)-α-carboxyacetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-α-carboxylic acid,

7P-Z«-(3-thienyl)-a-carboxyacetamido7-7a-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-1f-carboxylic acid,

7P-(α-phenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-lf-carboxylic acid,

7P- (*α-β-hydroxyenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-lf-carboxylic acid,

-

7P-((3e-p^)ropionyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-^f-carboxylic acid,

7β-(α-β-benzoyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid,

7β-(α-β-carbamoyloxygenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-β-carboxylic acid,

7P-(α-β-N-methylcarbamoyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-lf-carboxylic acid,

7P-(a-p-N-propylcarbamoyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em-^f-carboxylic acid,

7P-(α-p-ureidocarbonyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid,

7P-(a-p-Na<->methylureidocarbonyloxyphenyl-a-carboxyacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl- 1-oxadethia-3-cef em-h-carboxylic acid,

and their derivatives protected at the carboxy group with pharmaceutically acceptable groups or conventional protecting groups in the form of salts (salts with inorganic or organic bases such as sodium, calcium, magnesium, potassium, and other alkali metal or alkaline earth metal salts, triethylamine, dicyclohexylamine, morpholine or N-methylmorpholine salts) esters such as e.g. t-butyl, t-amyl, 2,2,2-trichloroethyl, acyloxymethyl, phthalidyl, diphenylmethyl, trityl, benzyl, p-nitrophenyl, p-methoxybenzyl, phenazyl, phenyl or indanyl esters and similar groups.

Compounds (I) with 1-methyltetrazol-5-ylthiomethyl in the 3-position are the strongest antibacterial compounds against gram-negative bacteria associated with less loss of activity at higher inoculum size.

Compounds (I) with 1-carboxymethyltetrazol-5-ylthiomethyl at the 3-position show stronger anti-infective activity in vivo than expected from in vitro data, due to their ability to achieve a high blood level.

Compounds (I) with phenylmalonamido, (2-thienyl)malonamido, or (3-thienyl)malonamido in the 7-position show strong anti-bacterial action especially against gram-negative bacteria.

Compounds (I) with p-hydroxyphenylmalonamido, p-acetoxyphenylmalonamido, p-carbamoyloxyphenylmalonamido, p-N-methylcarbamoyloxyphenylmalonamido, or p-ureidocarbonyloxyphenylmalonamido at the 7-position are potent antibacterial agents that are less deactivated due to their lower protein binding and their higher blood levels than for the corresponding unsubstituted arylmalonamido compounds. They also show greatly intensified activity against pseudomonas strains including those resistant to carbenicillin.

The compounds (I) with methoxy for Y in the 7a position are more stable against B-lactamase, more generally effective (e.g., improved activity against pseudomonas bacteria and other gram-negative bacteria), and more potent than compounds with hydrogen for Y.

All compounds (I) are new compounds that show strong anti-bacterial activity against gram-positive and gram-negative bacteria and are useful medicines, veterinary medicines and disinfectants. E.g. are they conventionally given orally or parenterally to humans or animals in a daily dose of e.g. 0.05 to 50 mg/kg body weight for the treatment or prevention of bacterial infections.

The compounds (I) are usually administered as capsules containing sterilized microcrystals or freeze-dried product and administered as solutions prepared for administration. Furthermore, an effective amount of the compounds can be conventionally administered orally or parenterally with pharmaceutically acceptable carrier additives, diluents or stabilizers, in the form of preparations such as e.g. capsules, injectable solutions, ointments, solutions, tablets, powders etc. They can take the form of unit doses. The salts including the alkali metal salts are mainly used for parenteral administration. Acyloxymethyl, indanyl, phenyl, phthalidyl, etc. esters are also suitable for oral administration. Furthermore, the compounds (I) are also useful for the preparation of other compounds of formula (I) by conversion.

The compounds (I) are prepared, e.g. by treating an amine (II) with an arylmalonic acid (III) or reactive derivatives thereof,

with respective structural formulas

in which Ar, COB 1 , COB 2, Het and Y have the previously indicated meaning.

Amino in the 7-position of the amine (II) can be activated with silyl or stannyl groups, or protected or activated with 1-haloalkylidine, 1-alkoxyalkylidene, alkylene, carbonyl, easily removable acyl, etc. groups for the acylation. Removal of these groups gives the desired compounds of formula (I).

When arylmalonic acid (III) is used as free acid, the acylation is carried out in a solvent, (especially nitriles, ethers, amides and halogenated hydrocarbons as solvent or mixtures thereof) in the presence of a condensing agent such as e.g. N,N'-dialkylcarbodiimides such as N,N'-dicyclohexylcarbodiimide, carbonyl compounds such as e.g. carbonyldiimidazole, acylamines such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, isoxazolinium salts such as N-ethyl-5-phenylisoxazolium-3-sulfonate, N-t-butyl-5-methylisoxazolium perchlorate, and other condensing agents at temperatures between -10°C and 70°C .

When arylmalonic acid (III) is used in the form of reactive derivatives for the acylation, these can be anhydrides such as mixed anhydrides with alkylcarboxylic acid, aralkylcarboxylic acid, hydrohalic acids, hydrogen azide, phosphoric acid, phosphoric acid, sulfuric acid,

sulfuric acid, hydrogen cyanide, symmetrical intermolecular anhydrides, mixed anhydrides with aliphatic or aromatic sulphonic or carboxylic acids, special intramolecular anhydrides such as ketene, isocyanate etc. reactive anhydrides, reactive esters such as e.g. enol esters, aryl esters such as pentachlorophenyl, p-nitrophenyl, 2,^-dinitrophenyl, benzotriazole esters, diacyliminoesters, reactive amides, e.g. amides with imidazole or triazole, reactive amides such as 2-ethoxy-1,2-dihydroquinolin-1-amide, and f or/raimino derivatives such as e.g. N,N-dialkyliminomethyl esters, N,N-diacylanilines.

If necessary, these acylating agents can be used in the presence of an acid receptor such as e.g. inorganic bases such as hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals, organic bases such as e.g. tertiary amines, aromatic bases, the alkylene oxide such as ethylene oxide, propylene oxide, amides such as N,N-dimethylformamide, hexamethylphosphorus triamide, and other acid receptors, or molecular sieves, preferably in a solvent, especially ketone, ester, ether, nitrile, amide, halogenated hydrocarbon solvents, or mixtures thereof.

Alternatively, the compounds (I) can be prepared from the corresponding azetidinones with an open ring by ring closure, e.g. using a Wittig reaction. E.g. the azetidinone (IV) is heated in an inert solvent such as ether, aromatic hydrocarbon, halogenated hydrocarbon, amide, sulfoxide and anhydride solvents to

give the compound (I) in high yield.

wherein Ar, COB 1 , COB 2 , Het, and Y have the above meaning,

and each of the three R's are the same or different, with optionally substituted alkyl or aryl.

When Ar is p-hydroxyphenyl, the compound (I) can be treated with an inorganic or organic acylating agent to give compounds (I) in which Ar is acyloxyphenyl. The acylating agent and reaction conditions are conventional.

When Ar is p-hydroxyphenyl, the compounds can first be protected at the hydroxy group with an easily removable protecting group and then the protecting group is removed to give the desired hydroxyphenyl compounds. Representative protecting groups may be groups that form esters, including C-j-C^ a-halo-alkanoyl such as trifluoroacetyl, trichloroacetyl, C-|-Cg alkanoyl such as acetyl, formyl, C^-Cg 3-ketocarboxyl-acyl such as acetoacetyl, C2~C12alkoicsycarbonyl such as t-butoxycarbonyl, cyclopropylmethoxycarbonyl, norbornyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, C8~C15aralkoxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitro- or p-methylbenzoyloxycarbonyl, diphenylmethoxycarbonyl and the like. acyl groups, and ethers including C^-Cg alkyl such as methyl, t-butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl, methoxymethyl, C^-C^ aralkyl such as benzyl, p-methoxy, p-methyl or p-nitrobenzyl, diphenylmethyl, triethyl,

and lying groups. The protecting group can preferably be introduced at the step for arylmalonic acid (III) or reactive derivatives thereof. The removal of the protective group is carried out by e.g. 1) cleavage of acylates or ethers with an acid, e.g. mineral acid, Lewis acid, strong carboxylic acid, sulphonic acid, or base. such as sodium potassium carbonate, hydroxide, organic base at room temperature or elevated temperature if necessary in the presence of a cation scavenger, or 2) hydrogenation of p-nitrobenzyloxycarbonyl or benzyloxycarbonyl with hydrogen or platinum or palladium in a conventional manner. When carboxy i

When the carboxy in the k-position or in the side chain in the 7-position or Het is protected, the protecting group can be removed to give the desired compounds (I) by conventional means for removing the protecting groups. E.g. are 1) highly reactive esters, amides and anhydrides easily hydrolysed with an acid or base, or 2) haloethyl, benzyl, methylbenzyl, nitrobenzyl and diarylmethyl esters are cleaved by mild reduction with e.g. tin, zinc, or 2-valent chromium salts in the presence of acids, sodium dithionite, catalytic hydrogenation with hydrogen over catalysts such as platinum, palladium, nickel, or 3) benzyl, methoxybenzyl, methylbenzyl, dimethoxybenzyl, t-alkyl, trityl, diarylmethyl and cyclopropylmethyl esters are split by the action of acids or by solvolysis such as e.g. with mineral acids such as hydrochloric acid, Lewis acid such as aluminum chloride, sulphonic acid such as e.g. toluene-p-sulfonic acid, strongly acidic carboxylic acids such as e.g. trifluoroacetic acid, formic acid, if necessary in the presence of a cation acceptor such as amizol, or h) phenacyl, ethynyl, p-hydroxy-3,5-di-t-butylbenzyl esters are decomposed by the action of bases such as alkali metal thiophenoxides, inorganic bases, basic salts beer. methods.

The compound (I) with one or more free carboxy groups can be converted into corresponding derivatives at the carboxy group by introducing protective groups or substituents, by conventional methods (e.g. -esters by reaction of corresponding alcohols with the aforementioned condensation agents, diazo compounds, halophormates, etc, and f^F salts by the action of the alkali metal hydroxide, carbonates, or alkanoate salts, or the action of organic bases, ion exchange resins, etc.

The following examples are given to illustrate the invention. Elemental analysis and physical constants of the products in each example are consistent with the given structure. In the following examples, the products usually contain an almost equal amount of isomers at the α-asymmetric carbon in the amide side chain.

Both isomers are included within the scope of the invention and can

orn must be separated using commonly known chromatographic techniques or other conventional methods. The nomenclature in the description is in accordance with that described in a Japanese patent application which has been made generally available, namely No. 1+9-1359l+

submitted by Merck Inc., USA.

Preparation 1: (Preparation of 7α-amino compounds)

(1) To a solution of diphenylmethyl 7P-phenylacetamido-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate

(955 mg) in methylene chloride (21+ ml) is added phosphorus pentachloride (666 mg) and pyridine (0.258 ml) under nitrogen gas at -20°C.

After incubating at -20°C for 30 min. and at room temperature for 30 min. the mixture is mixed with methanol (12 ml) at -20°C and stirred at room temperature for 30 min. The reaction mixture is diluted with water

(6 ml) is stirred for 30 min. and concentrated under reduced pressure. The residue is dissolved in a 3% aqueous solution of sodium bicarbonate under ice cooling and extracted with ethyl acetate. The extract is washed with water, washed over sodium sulphate and concentrated under reduced pressure. The separated crystals are collected by filtration and washed with ether to give diphenylmethyl 7(3-amino-3-(1-methyltetrazol-

5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate (661 mg).

Temp. 151 - 156°C. Dividend: 86.5$.

IR: v<CH>C133^<2>0, 33^5, 1790, 1718, 1630 cm"<1>,

max.

NMR: CDC131.75<b>rs2H, 3.8ls3H, lf.28brs2H, h. 50d (U-Hz) 1H,

*+.6^brs2H, k. 98d (ifHz) 1H, 6.90s1H, 7.20 - 7.70m10H.

(CHjoS000 <^nUV: >mak^2 286 nm (£=8695). /«^ _232>87'6

(c=0.360, (CH^)2S0)

(2) In a method similar to above (1), diphenylmethyl 7(3-phenylacetamido-3-(2-methyl-1,3,If-diadiazol-5-yl)-thiomethyl-1-oxadethia-3-cephem is treated -l+-carboxylate (381.5 mg) in methylene chloride (8 ml) with phosphorus pentachloride (259 mg) and pyridine (0.1 ml) at -20°C, with methanol (8 ml) and with water (h ml) to give diphenylmethyl 7(3-amino-3-(2-methyl-1,3,1+-thiadiazoI-5-yl)-thiomethyl-1-oxadethia-3-cephem-3-carboxylate (273.3 mg).

Dividend: 88.8$.

IR: vCHC13 3^20, 3350, 179^,1723 cm-<1>,

max.

NMR- 6CDCl3 1-88s2H' 2.67s3H, k. 2<j + If.55ABq(1^Hz)2H,

l+.52d(l+Hz)1H) ,<l>*.68s2E, 5.00d(töz)1H, 7.07s1H.

(3) In a method similar to the method above under (1), diphenylmethyl 7(3-phenylacetamido-3-(1-t-butoxycarbonyl-methyltetrazol-5-yl)thiomethyl-1-oxacetia-3-cephem-^- carboxylate (300 mg) in methylene chloride (10 mL) with phosphorus pentachloride (180 mg) and pyridine (0.07 mL) at -20°C, with methanol ( h mL), and with water ( k mL) to give diphenylmethyl 7 (3-Amino-3-(1-t-butoxycarbonyl-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (189 mg). Yield: 76$.

IR: y<CHC1>3 T753, 1795, 1722 cm<-1>,

max.

NMR: SpDC<1>3 1A5s9H, 1.60 - 2.00m2H,<l>+.30s2H, lf.1+0-

l+.60m1H,<l>+.65brs2H,<>>+.86s2H, 5.00d(l+Hz) 1H,

6.95s1H.

Preparation 2 (Introduction of 7oc-Methoxy)

(1) A solution of diphenylmethyl 7(3-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (600 mg) and 3,5-di-t- butyl-n-hydroxybenzaldehyde (353 mg) in a mixture of benzene (0.5 ml) and methylene chloride (5 ml) is refluxed for 1 hour while water is removed using a molecular sieve in a Dean Stark water separator. The resulting release of diphenylmethyl 7(3-(3,5-di-t-butyl-^-hydroxybenzal)amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-ceÉm- ^-carboxylate is cooled at -10°C to -15°C, mixed with anhydrous magnesium sulfate (1 g) and then with nickel peroxide (0.69 g) with stirring, and stirred at -10°C to -15°C for 30 min and then at room temperature for 15 min. The reaction mixture is filtered and the solid is washed with benzene. To the resulting solution of diphenylmethyl 7-(3,5-di-t-butyl-1+-oxo-2,5-cyclohexadienylidene-methyl) -imino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3~cephem-^-carboxylate is added to methanol (10 ml), and the solution is allowed to stand at room temperature for 1 hour and concentrated to dryness under reduced pressure The residue is chromatographed on silica gel (30 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (>+:1) to give diphenylmethyl 7(3-(3,5-di-t-butyl-^-- hydroxybenzal)amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxy lat (906 mg) as a practically pure yellow foam. Yield: 9937%. (2) To a solution of the above product in a mixture of methanol (10 ml) and tetrahydrofuran (5 ml) is added Girard T reagent (315 mg) and the mixture is stirred for 1 hour at room temperature, diluted with water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on xylica gel (30 g) containing ^0% water and eluted with a mixture of ethyl acetate:benzene:ethylene chloride (1:1:1) to give diphenylmethyl 7P-amino-7a-methoxy-3-(1- methyl terazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate C+69 mg). A total dividend in this example: 73.6%.

Temp. 160 - 162°C (decomposition).

IR: vCHC13 3if25, 3350, 1792, 1?2hcm"<1>,

max.

NMR: SCDC132.00brs2H, 3.38S3H, 3.87S3H, 1+.32s2H, *+.73s2H,

^.92s1H, 7-OOslH.

As can be seen from the above-mentioned preparation, nickel oxide has been found to be one of the best oxidizing agents for the phenolic intermediate for the introduction of methoxy in the 7a position of 1-oxa and also 1-thia ceferne rings.

I. Ring formation.

Example 1- 1

A solution of diphenylmethyl α-AP-(1-methyltetrazol-5-yl)-thioacetonyloxy-3β-(α-phenyl-α-diphenylmethoxycarbonylacetamido)-2-oxoacetidin-1-yl7-α-triphenylphosphoranylidene acetate (650 mg) in dioxane ( 5 ml) is refluxed under a nitrogen atmosphere for 16 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (20-g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (C+:1) to give diphenylmethyl 7(3-(α-phenyl-α-diphenyl-methoxycarbonylacetamido)-3 -(1-methyl-tetrazol-5-yl)thiomethyl-1-oxad e ti a-3-cef em-^--carboxy lat.

(1+32 mg). Temp. 107 - 109°C Yield: 80%.

IR: Vmax. 3<l>f10'1793'1719'l69<l>f'1630'1600 cm_1-

Example 1-2

By a method similar to that described in

example 1-1, diphenylmethyl a-/!+P-(1-methyltetrazol-5-yl)-thioacetonyloxy-3P~(a-phenyl-a-diphenylmethoxycarbonylacetamido)-3a-methoxy-2-oxo-azetidine-1- is boiled yl/-α-triphenylphosphoranylidene acetate (5^3 m§) under reflux in dioxane (5 ml) for 15 h under nitrogen gas, and purified by chromatography on silica gel (15 g) to give diphenylmethyl 76-(α-diphenylmethoxycarbonyl-α- phenylacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem-<1>+-carboxylate (5^-0 mg). Yield: 67%.

Example 1-^

In a method similar to that in example 1-2, diphenylmethyl a-/3P-(a-p-benzyloxyphenyl-a-diphenylmethoxycarbonylacetamido)-3a-methoxy-1+6-■[ 3-(1-methyltetrazol-5-yl)thiomethyl- 2-oxopropoxyj - 2- oxoazetidin-1-yl7-a-triphenylphosphoranylidene acetate under reflux in dioxane for 10 hours under nitrogen and purified by chromatography on silica gel to give diphenylmethyl 78-(a-diphenylmethoxycarbonyl-a-p-benzyloxyphenylacetamido)-7a-methoxy- 3-(1-Metylte trazol-5-yl)thiomethyl-1-oxade thia-3-cef em-^-carboxylate.

The starting material for this is prepared from diphenylmethyl α-(3B-benzamido-1+8-allyloxy-2-oxoazetidin-1-yl)-α-isopropylidene acetate using reactions comprising 1) peracid, 2) t-butyl hypochlorite, 3) lithium methoxide, •+) lithium 1-methyl-tetrazol-5-yl mercaptide and 5) chromium trioxide to give diphenylmethyl α-β-benzamido-3α-methoxy-1+β-7'3- ( 1-methyltriazol-5-yl)-thioronetyl-2-oxopropoxy/1-2-oxoazetidin-1-y]_7-a-isopropylidene acetate which is treated with 6) phosphorus pentachloride, 7) methanol, and 8) triethylamine to give diphenylmethyl α-/"38-amino-3α-methoxy-^P-{ 3"(1-methyltetrazol-5-yl)thiomethyl-2-oxopropoxy^-2oxo-azetidine-1- yl7-α-isopropylidene acetate, which is treated with 9) α-β-benzyloxyphenyl-α-benzyloxycarbonylacetyl chloride and triethylamine, 10) ozone, 11) zinc and acetic acid, 12) thionyl chloride and pyridine, and 13) triphenylphosphine.

II. Amide formation.

Example II- 1

To a stirred solution of diphenylmethyl 7B-amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate

(192 mg) in tetrahydrofuran (2 ml) and acetone (1 ml) are added mono-diphenylmethyl-phenylmalonate (208 mg) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (1^8 mg) at 0°C and the mixture is then allowed to stand overnight at room temperature. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, 5% aqueous solution of sodium bicarbonate and then water, dried over sodium salt and evaporated to dryness. The residue is purified by chromatography on silica gel (20 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (1+:1). The crystals obtained from the fraction are washed with a mixture of ether and n-pentane to give diphenylmethyl 7B-(α-phenyl-oc-diphenylmethoxycarbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia- 3-cef em-^-carboxylate, m.p. 100 - 105°C. Yield: k- 0%.

IR: y CHC131800, 1720, 1680 cm"<1>,

max.

NMR: & CDCl 37 -OOslH, 6.95s 1H, 5 . 80dd (^;9Hz) 1H, 5-06d (>+Hz) 1H,

i+.75s1H, ^f.65brs2H, ^.33s2H, 3.86s3H.

By using α-(diphenylmethoxycarbonyl-α-phenyl)acetyl chloride, triethylamine hydrochloride and pyridine instead of mono-diphenylmethyl-phenylmalonate and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, the reaction is carried out in an analogous manner for 25 min . to give the same product as mentioned above with 99% yield. Temp. 107-109°C

IR: V3^10,<1>793, 1719, 169A, 1630, 1600 cm<1>.

UV: (CH3)2<S0>281^ ( £_ 10136)_

max.

NMR: £(<CD>3)2<SO>3.8^s3H, >f.30brs2H,<l>+.58brs2H, lf.69s1H/2,

<i>+.71s1H/2, 5.02d(<>>+Hz)1H, 5-76dd ( h ;9Hz) 1H, 8.86brs1H, 6.90brs1H, 7.0-7.5m20H, 7.76d(9Hz)1H,

/o7p<3>- 1Mk2<±>8.1° (c = 0.226, (CH^SO)

Example II-2

Pyridine ( 0.1 ml) and a solution of α-(p-nitrobenzyloxycarbonyl)-α-phenylacetyl chloride (510 mg)

in methylene chloride (2 ml) under ice-cooling under a nitrogen atmosphere, and the mixture is stirred for 25 min. The reaction mixture is poured into water and extracted with methylene chloride. The extract is dried over sodium sulfate and evaporated to dryness to give a residue (1.0*+ g) which is chromatographed on silica gel (ho g) containing 10% water, eluted with a mixture of benzene and ethyl acetate (^:1), and crystallized from a mixture of ethyl acetate and ether to give diphenylmethyl 7B-(oc-p-nitrobenzyloxycarbonyl-cc-phenylacetamido)-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethyl a- 3_ cef em-!+-carboxylate (67O mg), m.p. 122 - 125°C. Yield: 83%.

UV: >((cH3)2S0 2?8 ^ ( i= ^ 8k90).

max.

IR:YSs. 3Lf00' 33<lf0>'1792'1?Lf2' 1718'1680'1631 ' l60<l>f'

1520, 131+5 cm<1>.

NMR: _g(<CD>3)2<SO>3.88s3H/2, 3.89s3H/2, 1+.21+brs2H, »+. 65 brs2H,

5.05s1H, 5.20dC+Hz)1H, 5.32brs2H, 5.75m1H, 6.86s1H, 7.20 - 7.70mUH, 7-50 - 8.0A2X2tø.

/o722-^ — 150.6 - 5A° (c = 0.350, (ch3)250).

Example II-^

To a stirred solution of diphenylmethyl 7(3-amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate

(100 mg) in methylene chloride in (11 ml) add pyridine (21 mg) and a solution of α-(indan-5-yl)oxycarbonyl-α-phenylacetyl chloride (prepared from the corresponding acid (77 mg)) in methylene chloride

(2 ml) under ice cooling, and the mixture is stirred for 30 min. The reaction mixture is poured into a mixture of ethyl acetate and water and the organic layer is isolated. This is washed with

dilute hydrochloric acid, an aqueous solution of sodium bicarbonate, . water, and an aqueous solution of sodium chloride, is washed over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel (5.5 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (C+:1) to give diphenylmethyl 7P~Za-(5-indanyl)oxycarbonyl-a-phenylacetamido.7 -3- (1-me tylte tr azol- 5-yD ti orne ty 1- 1-oxadethia-3- cef em- k- kar boxy-lat OM+ mg) as a pale yellow foam. Yield: 95.^%.

IR:V<CH>C131800, 1735, 1685 cm"<1>,

max.

Example II-^-

Pyridine (0 .0^8 ml) and a solution of phenylmalonyl hemichloride in methylene chloride (2 ml) (prepared by reaction between phenylmalonic acid (108 mg) and thionyl chloride (0.0^8 ml) in a mixture of ether (1 ml) and dimethylformamide (2 drops) at room temperature for 20 hours) and the mixture is kept at 0°C for 20 min. The reaction mixture is diluted with ethyl acetate, washed with dilute hydrochloric acid and water, washed over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel containing 10% water and eluted with a mixture of ethyl acetate and benzene (1:1 to 1:0) to give diphenylmethyl 7(3-(α-carboxy-α-phenylacetamido)-3-(1 -methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylate (107 mg) Yield: 61%.

Example II-5

To a solution of 7(3-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid (78 mg) and triethylamine (0.036 ml) in methylene chloride (1 ml) a solution of phenylmalonyl monochloride monobenzhydryl ester in methylene chloride (2 ml) is added

(prepared by reacting monobenzhydrylphenylmalonate (60 ml) with thionyl chloride (0.0^ ml) in a mixture of ether (1 ml) and dimethylformamide (1 drop) at room temperature for 10 hours), and the mixture is kept at 0°C for 1 hour . The reaction mixture is diluted with a mixture of ethyl acetate and acetic acid (9:1) to give 7(3-(α-diphenylmethoxycarbonyl-α-phenylacetamido)-3-(1-methyl-tetra azol-5-yl)thiomethyl-1- oxad e tia- 3- cef em- ^--carboxylic acid (60 mg).

Example II- 6

To a solution of 7(3-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V-carboxylic acid (78 mg) and triethylamine (0.036 ml) in methylene chloride (1 ral) is added a solution of phenylchloroformyl ketene (K5 mg) in methylene chloride (0.5 ml) and the mixture is kept at 0°C for 2 hours. The reaction mixture is washed with water, dried and evaporated. The residue is dissolved in ethyl acetate, purified by chromatography on silica gel (10 g) containing 10% water, and eluted with a mixture of ethyl acetate and acetic acid (9:1) to give 7(3-(oc-phenyl-α-carboxyacetamido)-3-(1-methyl-tetrazol-5-yl ) thiomethyl-1-oxad et ia-3-cef em-!+-carboxylic acid (88 mg).Yield: 7k%.

Example II-7

A solution of diphenylmethyl 7(3-amino-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (96 mg) in methylene chloride (3 ml) is added to a solution of a mixed anhydride (prepared by reacting mono-t-butyl-p-hydroxyphenylmalonate (76 mg) with i-butyl chloroformate (0.037 ml) in the presence of triethylamine (0.0^16 ml) in methylene chloride (h ml) at -30 °C for 30 min. and at 0 °C for 10 min.), and the mixture is stirred at -30 °C for 30 min., at 0 °C for 2 h, and at room temperature for 30 min. The reaction mixture is concentrated under reduced pressure The residue is dissolved in a mixture (2 ml) of pyridine and water (7:3) and stirred at room temperature for 1 hour. The reaction mixture is poured into ice-cold water and extracted with ethyl acetate. The extract is washed with water, 2N hydrochloric acid, water, 5 % aqueous solution of sodium hydrogen carbonate, and water, is washed over sodium sulfate, and evaporated under reduced pressure. The residue (1^+8 mg) is purified by chromatography on silica gel (0 5 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate C+:1). The eluate is treated with a mixture of ether and pentane to give diphenylmethyl 7B-(α-p-hydroxyphenyl-α-t-butoxycarbonylacetamido)-3-(1-methyltetrazol-5-yDthiomethyl-1-oxadethia-3-cephem-^-carboxylate (66 mg ).

Temp. 12<1>+ - 126°C. Yield: k6%.

IR: y CHC133<1>+10, 3320, 1800, 1717, 1679, 1510 cm-<1>,

max.

NMR-&CDC131A0s9H, 3.80s3H, ^+.27brs2H, 1+.38s1H/2,

1+.1+2S1H/2, ^+.62brs2H, 5 . 0*+d (*+Hz) 1H, 5.70dd(^+;

10Hz)1H, 6A6 - 8.31ml7H.

Example II- 8 •■ '

To a suspension of α-β-hydroxyenylmalonic acid monobenzhydryl ester (507 mg) in methylene chloride (3 ml) is added triethylamine

(139Pl) and oxalyl chloride (85 M-l) at 0°C. After conversion in

<!>+5 min. at 0°C, the mixture is added to a solution of diphenylmethyl 7β-amino-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (191 mg) in methylene chloride (3 ml ) and pyridine (80 µl) at 0°C. After stirring for 30 min. at 0°C the reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution,

and with water, washed over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel (15 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (9:1) to give diphenylmethyl 7S-/q<->p-hydroxyphenyl-oc-dif enylme toxycarbonylace tamido_7-3 - (1-methyltriazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-1+-carboxylate as a pale foam (137 mg). Yield: *f1 .6%.

IR: yCHC133325,<1>798, 1722, 1679 cm"<1>,

max.

NMT,. iCDCl, 3.73s3H, ^.20brs2H, l+.53brs2H, (*+.60s +

in rui.0j l+.63s)1H, l+.93brd(l+Hz)1H, 5.1+7 - 5.77m1H.

Example II-9

To; a solution of diphenylmethyl 7B-amino-3-(1-methyltetrazol-5-ylDthiomethyl-1-oxadethia-3-cephem-^-carboxylate (96 mg) in a mixture of tetrahydrofuran (1 ml) and acetone (0.5 ml ) mono-t-butyl α-(2-thienyl)malonate (129 mg) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (132 mg) are added in four equal portions at 1 hour intervals with stirring at room temperature in nitrogen gas, and the mixture is stirred for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate, and with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue (251 mg) is purified by chromatography on silica gel (10 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate C+:1). The eluate is treated with a mixture of ether and pentane to give diphenylmethyl 7α-/α-(2-thienyl)-α-t-butoxycarbonylacetamido/-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem- ^-carboxylate as an amorphous powder (1+9 mg). Temp. 97 - 99°C. Yield: 3h. 8%.

IR: V<CH>C133^-00, 1800, 1720, 1690, 1511cm"<1>,

max.

NMR: aCDC131A7s9H, 3-93s3H, 1+.32s2H, <1>+.69brs2H,

i+.SObrslH, 5.09d(<l>+Hz)1H, 5.75dd(10;<!>+Kz)1H,

6.90 - 7.73ml5H.

Example 11-10

To a solution of diphenylmethyl 7B-amino-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (96 mg) in a mixture of tetrahydrofuran (1 ml) and acetone (0 .5 ml) mono-t-butyl α-(3-thienyl)malonate (132 mg) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (132 mg) are added under ice-cooling, and the mixture is stirred at room temperature for h hours . The reaction mixture is diluted with ethyl acetate, washed with water, 1N hydrochloric acid, water, aqueous 5% solution of sodium bicarbonate, and saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue (198 mg) is purified by chromatography on silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (1:1) to give diphenylmethyl-76-/bc-(3-thienyl)-a-t -butoxycarbonylacetamide C17-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<1>+-carboxylate (56 mg) as a colorless powder. Temp. 85 - 90°C Yield: 39.7%.

IR: V<CHC1>3 1798, 1720, 1685, 1630 cm-<1>,

max.

jrørø.<5CDC131A5S9H, 3.85s3H, ^f.32s2H, lf.67m3H,

5.06d(l+Hz)1H, 5-86dd(10-, ^-Hz)1H, 7.00s1H,

7.1 - 7-65ml<l>+H.

Example 11- 11

To a solution of diphenylmethyl 7-(3-amino-3-(1-t-butoxy-carboxylmethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-h-carboxylate (102 mg) in a mixture of tetrahydrofuran ( 2 ml)

and acetone (1 ml) is added monobenzhydryl α-phenylmalonate

(186 mg) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (88 mg)

in two parts, and the mixture is stirred at room temperature for 3.5 hours. The reaction mixture is mixed with ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution and water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel (10 g) containing 10% water, eluted with a mixture of benzene and ethyl acetate

(9:1) and evaporated to give diphenylmethyl 7(3-(α-diphenylmethoxycarbonyl-α-phenylacetamido)-3-(1 -t-butoxycarbonylmethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem -'+-carboxylate (63 mg) as a colorless foam.Yield: 39%.

IR:YCHC131800, 1750, 1725, 1680cm"<1>,

max.

NMR: S<CD>C 136.96s1H, 6.93s1H, 5.75ddC+; 9Hz)1H, 5.03d(t+Hz) 1H,

l+.90s2H,<l>f.73s1H/2, U.71s1H/2,<>>+.60brs2H,

l+.30s2H, 1.I+0S9H.

Example 11-12

To a solution of diphenylmethyl 7B-amino-3-(1-t-butoxycarbonyl-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (87 mg) in acetonitrile (2 ml) is added /α-t-butoxycarbonyl-α-(2-thienyl)acetoxyj7succinimide (76 mg) and N-methylmorpholine (0.016 ml) under a nitrogen atmosphere, and the mixture is stirred for 90 min. The reaction mixture is mixed with ethyl acetate, washed with dilute hydrochloric acid, water, aqueous 5% sodium bicarbonate solution and water, dried over sodium sulfate, and evaporated. The residue is chromatographed on silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (9:1) to give diphenylmethyl 7(B-/a-t-butoxycarbonyl-a-(2-thienyl)-acetamido7- 3-(1-t-butoxycarbonylmethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<>>+ -carboxylate (96 mg) as a colorless foam.Yield: 80%.

IR: v<CHC1>3 1802, 1750, 1722, 1690 cm"<1>,

max.

NMR: δ<CD>C 136.93<s>1H, 5.72dd(<l>+; 9Hz)1H, 5.06d(<l>+Hz)1H,

^.83s2H,<l>+.75brs1K, *+.60brs2H, l+.30s2H,

1 .l+5sl8H.

Example 11-13

To a solution of diphenylmethyl 73-amino~3-(2-methyl-1 ,3 ,^f-thi^dlazol-5-yl) thiomethyl-1 - oxad e thia-3-cephem-1f-carboxylate (215 mg )" in a mixture of tetrahydrofuran (k ml) and acetone (2 ml) are added three portions of hemidiphenylmethyl α-phenylmalonate (131 mg x 3) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (107 mg x 3 ) at room temperature at 1.5 hour intervals. After 2 hours, the reaction mixture is diluted with ethyl acetate, washed with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate, and water, washed over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel (30 g) containing 10% water, eluted with a mixture of benzene and ethyl acetate (^:1) and the eluate treated with a mixture of ether and n-pentane to give diphenylmethyl 7(3-( a- ph enyl-oc-di enylme toxycarbonylace tamido) -3-(2-methyl-1, 3, ^-- thiadia^oT^-yl) thiomethyl-1-oxadethia-3-cef em-^-carboxylate (170 mg) as a colorless foam.Yield: *+ 7.5%

IR: VCHC13 3350,1799, 1715, l690sh cm"<1>,

max.

NMR: $CD<C1>3 2.67s3<H,>k. 22 + k. 53ABq(ll+Hz)2H,<!>+.57s2H,

<l>f.75s1H, 5.00d(<t>+Hz)1H, 5.73dd( k;9.5Hz) 1H, 6.92s1H, 6.97s1H.

Example II-A

Triethylamine (0.0^2 ml) and oxalyl chloride (0.0256 ml) are added to a solution of α-diphenylmethoxycarbonyl-α-phenylacetic acid (103.9 mg) in methylene chloride (2 ml) cooled to 0°C. After stirring at 0°C for 10 min. the mixture is poured into ': a solution of diphenylmethyl 7(3-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (101, 7 mg) and pyridine (0.059 ml) in methylene chloride (5 ml) at 0°C, stirred for 1 hour at 0°C, diluted with ethyl acetate, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate, and water, washed over sodium sulfate that and concentrated -under reduced pressure. The residue obtained is chromatographed on silica gel (20 g) containing 1.0% water and eluted with a mixture of benzene and ethyl acetate (1+:1) to give diphenylmethyl 7(3-(α-diphenylmethoxycarbonyl- α-fjmy_laLcetamido)-7α-methoxy-3-(1 - methyl 1te trazol-5-yl) thiomethyl-1 - oxadethia-3-cephem-^-carboxylate (121.2 mg) as a colorless foam. Yield: 72, k%.

IR:vCHCl33320, 1792, 1725, 1700cm"<1>,

max.

NMR:<S"CDC13(3.1+Os<+>3<A>2s)3H, 3-69s3H,<l>f.22s2H,<l>+A5s2H,

>+.75s1H, 5.00s1H, 6.92s2H, 7.85s1H.

Example II- 1^

A mixture of α-[indan-5-yl)oxycarbonyl-α-phenylacetic acid

( ikQ mg) and thienyl chloride (0.25 ml) are heated at 70°C for 1 hour and evaporated under reduced pressure. The residue is dissolved in benzene (2 ml) and re-evaporated to dryness. The residue is dissolved in methylene chloride (2 ml) and poured into a solution of diphenylmethyl-78-amino-7oc-methoxy-3-(1-methyltriazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem -^f-carboxylate (101.7 mg) and pyridine (0.016 ml) in methylene chloride (•+ ml) at 0°C After stirring for 30 min. at 0°C, the mixture is diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate, water, dilute hydrochloric acid, and water, washed over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel (20 g) containing 10% water to give diphenylmethyl 7B-[q-(indan-5-yl)oxycarbonyl-a-phenylacetamido7-mJ) 7a-methoxy-3-(1-methyltetrazol-5-yl )thiomethyl-1-oxadethia-3-cephem-^-carboxylate (116.1 mg) as a colorless foam. Yield: 73.8%.

IR: Y<CHC1>3 3390, 3320, 1730, 1727, 1700 cm"<1>,

max.

i... NMR:<£CDC132.05<qu>none(7Hz)2H, 2.87t(7Hz)<*>fH, 3A8S3H,

3.77s3H, lf.23s2H,<l>f.53s2H, lf.87s1H, 5-02s1H.

Example II- 16

To a solution of α-diphenylmethoxycarbonyl-α-β-acetoxyphenyl-acetic acid (1<*>+2 mg) in methylene chloride (2 ml) cooled to 0°C

triethylamine (0.0^6 ml) and oxalyl chloride (0.0256 ml) are added. After stirring for 15 min. at 0°C the mixture is gradually mixed with

A solution of diphenylmethyl 7β-amino-7α-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-3-carboxylate (101.7 mg) and pyridine (0 .02"+ ml) in methylene chloride (h ml) at 0°C, stirred for 15 min., diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, dilute hydrochloric acid, and water,

trub over sodium sulfate, and evaporate under reduced pressure. The residue obtained is chromatographed on silica gel (20 g) containing 10% water to give diphenylmethyl 76-(α-diphenylmethoxycarbonyl-α-p-

acetoxy enylacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-<>>+-carboxylate 0 33.^ mg) as a colorless foam from fractions eluted with a mixture of benzene and ethyl acetate (2:1). Dividend: 7^.5%.

IR: v<CHC1>3 3325, 1792, 1730, 1700sh cm"1,

max.

4

NMR: £<C>DC13 2.<1>+OS3H, 3AOS3H, 3.67S3H,<>>+._17s2H, 1+A2s2H,

^.73s1H, lf.98s1H.

Example 11-17

To a solution of α-diphenylmethoxycarbonyl-α-β-hydroxyphenyl-acetic acid (25<*>+ mg) in methylene chloride (3 ml) is added triethylamine (0.083 ml) and oxalyl chloride (0.051 ml) at 0°C. After stirring for 15 min. the mixture is added to a solution of diphenylmethyl-7B-amino7a-methoxy-3-(1-methyltetrazol-5-yl)thiol-1-oxadethia-3-cef emA-carboxylate (101.7 mg) and pyridine (0. 0^8 ml) in methylene chloride (h ml) at 0°C. After stirring for 30 min. at 0°C, the mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, hydrochloric acid and water, washed over sodium sulfate, and evaporated under reduced pressure. The residue obtained is chromatographed on silica gel (20 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (2:1) to give diphenylmethyl 7P-(α-diphenylmethoxycarbonyl-α-β-hydroxyphenyl-acetamido)-7α-methoxy- 3-(1-Methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem A-carboxylate (86.k mg) as a colorless foam. Yield: ^9.6%.

IR:Y<CE>C133585, 3315, 1790, 1722, 1700sh cm"<1>,

max.

NMR: S<CD>C13(3A5s<+>3A8s)3H, (3-72s<+>3-75s)3H, »+.18s2H,

l+A5s2H, ( k. 67s +<l>+.70s)1H, 5.02s1H.

Example II-18 \V'

J V ' i,.''/ ' i

To a suspension of α-(5-indanyl)oxycarbonyl-α-β-hydroxy-phenylacetic acid (370 mg) in methylene chloride (h ml) is added triethylamine (139 µl) and oxalyl chloride (85 µl) at 0°C under nitrogen to give a clear solution. After stirring for 20 min.

at 0°C, the mixture is added to a solution of diphenylmethyl-7S-aminoJ?a-methoxy-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (203 mg) in methylene chloride (5 ml) and pyridine (80 p. 1) and the mixture is stirred for 10 min. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid,

water, aqueous 5% sodium hydrogencarbonate solution, and water, washed over sodium sulfate, and evaporated under reduced pressure to

give a pale yellow foam, which is chromatographed on silica gel (50 g) containing 10% water, eluting with a mixture of benzene and acetic acid (1:1) to give diphenylmethyl 7P-/α-p-hydroxyphenyl-α-(5-indanyl) -oxycarbonylacetamidoJ7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate as a crystalline residue (230 mg; Yield•71.6%) which is recrystallized from a mixture of chloroform and ether to give pure crystals melting at 11<*>+ - 116°C.

UV: yCH 3 0 H .272 ( <f= 9500), 2&A ( £= 9260) nm.

max.

NMR: £CD3<C>OCD32.1m2H, 2.87t(7Hz)1fH, 3A3S3H, 3-91 s3H,

!+.31s2H, ^.65s2H, 5.07s1H, 5 .1 3s1H,

6.92brs3H.

IR: γ-CHC133590, 3335, 1789, 1736, 1722, 1700, 1601 cm"<1>,

max.

Example 11-19

To a solution of α-t-butoxycarbonyl-α-(3-thienyl)acetic acid

(97 mg) in methylene chloride (1 ml) is added triethylamine (0.0^2 ml)

and oxalyl chloride (0.026 mL) at 0°C under a nitrogen atmosphere.

After stirring for 30 min. at 0°C, the mixture is poured into a

solution of diphenylmethyl 7P-amino-7cc-methoxy-3-(1-methyltetrazol-

5-yl)thiomethyl-1-oxadethia-3-cef em-<>>+ -carboxylate (101 mg) and pyridine (0.02<*>+ ml) in methylene chloride (3 ml) at 0°C under nitrogen atmosphere. After stirring at 0°C for 90 min. the mixture is diluted with methylene chloride, washed with 5% sodium bicarbonate in water, water, 2N hydrochloric acid, and water, washed over sodium sulfate, evaporated under reduced pressure, chromatographed on silica gel (5 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (2:1) to give diphenylmethyl 7(3-[α-1-butoxycarbonyl-α-(3-thienyl)acetamido7-7α-methoxy-3-(1-methyl-tetrazol-5-yl) thiomethyl-1-oxad ethyl α-3-cef em-^f-carboxylate (1M+ mg) as a colorless foam Yield: quantitative.

IR: vCHC13 1795, 1720, ca. 1700 cm-1,

max.

NMR: δCDC136.96s1H, (5-07s + 5.05s)1H, ^.60brs3H, >+.30brs2H,

3-83s3H, (3-53S<+>3-50s)3H, 1Als9H.

Example 11-20

To a solution of 3-thienylmalonic acid indanyl ester (120 mg) in methylene chloride (1.5 ml) is added triethylamine (<1>+2 µl) and oxalyl chloride (26 µl) under ice cooling. After stirring for 15 min. the mixture is added to a solution of diphenylmethyl 7(3-amino-7ct-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-*+-carboxylate (116 mg ) in methylene chloride (3 ml) and pyridine (2<*>+ pl) and the mixture is stirred at 0° C. for 1 hour. The reaction mixture is poured into ethyl acetate, and washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water , washed over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1) to give diphenylmethyl-7(3-/a- (3 -thienyl)-α-(indan-5-yl)oxycarbonylacetamido7-7<x-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxad et ia-3-cephem-1+-carboxylate (l^+Omg).Yield: 78%.

IR:<yCHCl>3 3h0Q^ 332?^ 17g9j 1736^ 1?12 cm<-1>_

max.

NMR: δCDC132.07m2H, 2.87br-t(7Hz)<i>+H, 3-50s3H, 3.77s3H,

k. 2hs2R,<l>f.56s2H,<»>f.97s1H, (5-02s + 5-O<l>+s)1H, 6.88brs3H.

/a7p2'5 - 68.2 - 1.1° (c 1.023, CHCl3).

4

Example 11- 21 wV.

/v ' lb. I. Tl To a solution of 3-thienylmalonic acid monobenzhydryl ester (710 mg)

triethylamine (210 µl) and oxalyl chloride (130 µl) are added to methylene chloride (5 ml) under ice cooling. After stirring for 15 min. at the same temperature, the mixture is added to a solution of diphenylmethyl 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylate (510 mg) in methylene chloride (15 ml) and pyridine (120 µl) under ice-cooling.

After stirring for 30 min. the mixture is poured into ethyl acetate,

washed with 2N hydrochloric acid, water, 5% sodium bicarbonate and with water, washed over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel (100 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1 - ^:1)

to give diphenylmethyl 7β-[α-(3-thienyl)-α-diphenylmethoxycarbonyl-acetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate as a colorless foam (83<*>+ mg).

IR: y<CH>C13179<0,>1728, 1710sh cm"<1>,

max.

NMR: é°<DC1>3 3-30<S>3H, 3.60s3H, t+.09s2H,<l>+.37s2H, ^.79s1H,

*f.90s1H, 6.87s2H.

Example 11-22 (phenyl ester)

For a suspension of 3-thienylmalonic acid monophenyl ester (105 mg)

in methylene chloride (1.5 ml) add triethylamine (k2 pl) and oxalyl chloride (26 ml) under ice cooling.

After stirring for 15 min. the mixture is added to a solution of diphenylmethyl 7B-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-S-cephem-^-carboxylate (116 mg) in methylene chloride (3 ml) and pyridine (2h yl) at 0°C and the mixture is stirred at 0°C for 1 hour. The reaction mixture is poured into ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution, and water, dried over magnesium sulfate and evaporated.

The residue is chromatographed on silica gel (10 g) containing 10% water

and eluted with a mixture of benzene and ethyl acetate (8:1) to

give diphenylmethyl 7B-/a-(3-thienyl)-a-phenoxycarbonylacetamide Q7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate as a colorless foam ( 125 mg).j/ Yield: 76%.

IR:<VCHC1>3 3^06, 33"+1 , 1789, 17^0, 1711 cm"<1>,

max.

NMR: £CD<C1>3 3.<l>+9s3H, 3.78S3H, U.2>+s2H,<l>+.55's2H,<!>+.97s1H,

5.03s1H, 6.88s1H.

/"aj<22>,<5>-7^.8 - 1.1° (c = 1.005 CHCl 3 ).

Example 11- 23 »v,"

/ v V, r'7 To a solution of 3-thienylacetic acid mono~3,^-dimethylphenyl ester

(120 mg) in methylene chloride (1.5 ml) add triethylamine ( h2 ul)

and oxalyl chloride (26 µl) under cooling. After stirring for 15 min. the mixture is added to a solution of diphenylmethyl-7B-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem-^-carboxylate (116 mg) in methylene chloride ( 3 ml) and pyridine (2+ µl) and the mixture is stirred at 0°C for 1 hour. The reaction mixture is poured into ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution, and

water, washed over magnesium sulphate and evaporated. The residue is chromatographed over silica gel (10 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1) to give diphenylmethyl 7(3-/a-(3-thienyl)-a-(3,^ -dimethylphenyl)oxycarbonyl-acetamide 0.7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-

oxadethia-3-cephem-lf-carboxylate (128 mg). Yield: 72%.

IR: y CH<C1>3 3LK)5, 33^, 1790, 1737, 1712 cm'<1>,

max.

NMR: ε<C>DC132.22s6H, 3.50s3H, 3.76s3H, k. 2hs2R, ^.56s2H,

<>>+.95s1H, (5.00s + 5.02s)1H, 6.86s2H, 6.90s1H.

?p2'5 -68.1 - 1.1° (c = 1.002, CHCl 3 ).

Example H- 2^

For a solution of α-diphenylmethoxycarbonyl-α-(2-thienyl)-

To acetic acid (176 mg) in methylene chloride (1 ml) is added triethylamine (0.055 ml) and oxalyl chloride (0.03 ml) at 0°C under nitrogen.

After stirring for 15 min. at 0°C, the mixture is added to a

solution of diphenylmethyl 7(3-amino-7cc-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^f-carboxylate (101 mg) and pyridine in methylene chloride (3 ml) at 0° C. The mixture is stirred for 30 min., diluted with ethyl acetate, washed with aqueous 5% sodium bicarbonate solution, water, 2N hydrochloric acid, and water,

is washed over sodium sulfate, and concentrated under reduced pressure.

The obtained residue is chromatographed on silica gel (10 g)

containing 10% water, and eluted with a mixture of benzene and ethyl acetate C+:1) to give diphenylmethyl 7(3-/α-diphenylmethoxycarbonyl-α-(2-thienyl)acetamido7-7α-methoxy-3-(1-methyltetrazole -5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate (1^+0 mg) as a colorless foam.Yield: 85%.

IR: v<CH>Cl31785, 1720 approx. 1700 cm"<1>,

max.

NMR: £CDC136.93<s>2H, 5.00s2H, ^.50brs2H,<t>f.15brs2H,

3.80s3H, 3.>+Obrs3H.

Example 11- 25 ^ . ■_.

For a solution of α-(p-benzyloxyphenyl) malonic acid monobenzyl ester

(376 mg) in methylene chloride (k ml) is added triethylamine' (105 pl)

and oxalyl chloride (65^1) under ice cooling. After stirring for 15 min. under ice-cooling, the mixture is added to a solution of diphenylmethyl 7-(3-amino-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (25 mg) and pyridine (60 µl) in methylene chloride (7 ml) under ice-cooling. After stirring for 30 min at the same temperature, the mixture is poured into ethyl acetate, washed with 2N hydrochloric acid, water, aqueous 5% sodium bicarbonate solution, and water, dried over magnesium sulfate,

and evaporated. The residue is chromatographed on silica gel (20 g) containing 10% water, and eluted with a mixture of benzene and ethyl acetate (10:1) to give diphenylmethyl 7(3-/cc-(p-benzyloxy-phenyl)-oc-benzyloxycarbonylacetamido7 -7α-Methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-β-carboxylate as a colorless foam, (390 mg).

, CDC17

NMR: dJ 3-38s3H, 3.62s3H, >+.13s2H, 1+A5s2H, lf.56s1H,

<l>+.96s3H, 5.09s2H, 6.82d(9Hz)2H, 6.8>+s1H.

IR: v<CH>C133^11 , 3326, 1789, 1722, 1700shcm"<1>,

max.

/α?23 -72.0 - 2° (c 0.553, CHCl 3 ).

Example 11-26

To a solution of α-diphenylmethoxycarbonyl-p-(p-methoxybenzyl)-oxyphenylacetic acid (193 m§) in methylene chloride (2 ml) is added triethylamine (0.0^-16 ml) and oxalyl chloride (0.G$6 ml) at 0 °C and the mixture is stirred for 30 min. The resulting solution is added to a solution of diphenylmethyl 7B-amino-7a-methoxy-3-(1-methyl-\tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-'+-carboxylate (101.7 mg )

and pyridine (0.02l+ ml) in methylene chloride (h ml) at 0°C. After stirring for 30 min. at 0°C, the mixture is diluted with ethyl acetate, washed with water, washed over sodium sulfate and concentrated.

The residue is chromatographed on silica gel (20 g) containing 10% water

and eluted with a mixture of benzene and ethyl acetate (*+:1) to

give diphenylmethyl 7B-/a-p-(p-methoxybenzyl)oxyphenyl-a-diphenyl-

me toxycarbonylace tamido7-7cc-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-M-carboxylate (190.7 mg) as a colorless foam. Yield: 98%.

IR:Y<CHC1>3 3^20, 3325, 1792, 1730, 1700 sh cm"<1>,

max.

NMR-£CDCl3(3.38S<+>3.<l>+Os)3H, 3-70S3H, 3-77s3H,<>>+.20s2H,

<!>+.<l>f7s2H, >+.68s1H, l+.95s2H, 5.00s1H.

Example 11- 27 ;y,'

In a method similar to Example 11-26, diphenylmethyl 76-amino-7a-methoxy-3~(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate (800 mg) is treated with a-p- (p-Methoxybenzyl)oxyphenyl-a-p-methoxybenzyloxycarbonyl-acetyl chloride prepared from the corresponding free acid (1370 mg)

and oxalyl chloride in the presence of pyridine (190 mg) and triethylamine

(0.33 mL) in methylene chloride (k2 mL) to give diphenylmethyl 7(3-/α-p-(p-methoxybenzyl)oxyphenyl-α-p-methoxybenzyloxycarbonyl-,/acetamido7-7α-methoxy-3-(1-methyl tr azol-5-yl)-thiomethyl-1-oxadethia-3-cephem-i+-carboxylate (1.5 g).

Yield: almost quantitative.

IR:vCHC131792, 1725, 1700shcm"<1>.

max.

NMR: £CDCl3 3A5S3H/2, 3.i+8s3H/2, 3-78s6H, 3.82s3K,

lf.27 brs2H, l+.57brs3H,<!>+.98s2H, 5.03s1H,

5.13S2H.

Example 1 1- 28''

in

- - •• ) i To a stirred suspension of p-(p-methoxybenzyloxy)phenylmalon-

acid (125 mg) in methylene chloride (3 ml), triethylamine (55 ul) and oxalyl chloride (26 ul) are added at -15°C and the suspension / is stirred for kO min. at 0°G. The mixture is added to a solution of diphenylmethyl 7B-amino-7a-methoxy-3-(1-methyltetrazol-5-yD-thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (100 mg) in methylene-

chloride (3 ml) and pyridine (63 µl) and the mixture is stirred for 30 min. at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2N hydrochloric acid and water, triturated over sodium sulfate and concentrated to give a crude product (212 mg) which is chromatographed on silica gel (20 g) and eluted with a mixture of ethyl acetate and acetic acid (99:1) to to give diphenylmethyl 7|3-</>a-p-(p-methoxybenzyl-oxy)phenyl-a-carboxyacetamido7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem- ^-carboxylate as a foam (71 mg). Dividend: k5%.

IR: yCHC133385, 3300-2l+OObr, 1790, 1762, 1711+, 1612 cm<-1>,

max.

NMR: <$<CD>Cl33A3s3H/2, 3A6s3H/2, 3.7^s3H, 3-78s6H,

l+.22brs2H, >f.56brs3H, l+.96s2H, 5.05s1H.

The product obtained above (ho mg) gives 7P~(α-hydroxyphenyl-α-carboxyacetamido)-7<x-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-lf -carboxylic acid by the action of trifluoroacetic acid (0.2 ml) and anisole (0.<*>+ ml) at 0°C for 20 min.

III. Deprotection.

Example III-1

To a solution of diphenylmethyl-7|3-(α-phenylα-diphenylmethoxycarbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-α-carboxylate (120 mg ) in methylene chloride (3 ml), anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) are added in nitrogen-

atmosphere at 0°C and the mixture is stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (10 g) containing 10% water and eluted with a mixture of ethyl acetate and acetic acid (9:1) to give 7P-(α-phenyl-α-carboxyacetamido)-3-(1- methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid (57 mg) as powder.

Temp. 157 - 159°C, (decomposition). Yield: 81%.

IH: Vllll]1778, 1670, 1606cm"<1>.

IR:V^s. 3^+20, 2520br, 1775, 167^, 1606, 1528.5, 1376 cm"<1>.

UV: y1^ NaHCO3 265.5 nm (£ = 9^+2).

max.

NMR: g1^ NaHCO3i D2°l+.02s3H, h.05<+>)+.32ABq(1 3.5Hz)2H,

<l>+.55brs2H, 5.l6d(lfHz)1H/2, 5-21d AHz)m/2,

5A8d(l+Hz)1H, 7-37s5H, 5.08brs1H,

(the last peak gradually decreasing)

/α?<2>)<3>90.3~^.2° (c = 0:310, 1% NaHCO 3 ).

CD: A (e) (0.155% NaHCO 3 ) 305(0), 285(- 2500), 276.5(0),

258(+11700), 2<1>+9-5(0), 232(- 59100),

210 (- 3500).

Example III-2

To a solution of diphenylmethyl 76-/α-(5-indanyl)oxycarbonyl-α-phenylacetamido7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate O^Af mg) in methylene chloride (3 ml) anisole (0.2 ml) and trifluoroacetic acid (0.1 ml) are added under ice cooling and the mixture is stirred for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue is treated with ether and the resulting

final powder is collected by filtration to give sodium 7β-[(5-indanyl)oxycarbonyl-α-phenylacetamide O7-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-3-carboxylate (60mg).

IR: ^Sax1176°'l690sh, 1670 cm"<1>.

Example

To a solution of diphenylmethyl 7(3-(q-carboxy-a-phenylacetamido)-~/} 3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-k-carboxylate (57.6 mg ) in methylene chloride (10 ml), anisole (1 ml) and trifluoroacetic acid (1 ml) are added under a nitrogen atmosphere and ice cooling, and the mixture is stirred for 70 min. The reaction mixture is concentrated under reduced pressure to give 7(3-(a-phenyl-a- carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid Yield: almost quantitative.

Raw product.

IR: Vmax!1778'167°'16°^ cm~1'

Example III-W

To a solution of 7(3-(α-diphenylmethoxycarbonyl-α-phenyl-<K/?>acetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-carboxylic acid (72 mg) in methylene chloride 5 (2 ml), anisole (0.2 ml) and trifluoroacetic acid (0.2 ml) are added at 0° C. After 50 min.

during ice cooling, the reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (5 g) containing 10% water and eluted with a mixture of acetic

acid and ethyl acetate (1:9) to give 7P-(α-carboxyca-phenylacetamido)-3-(>methyltetrazol-5-yl)thiomethyl-1-oxadethia-3~cephem-^-carboxylic acid (<!> +1 mg). Temp. 165 - 170°C (decomposition).

Yield: 75%.

IR:Y<maxl>1778'16?0'1605 cm~1 '

Example III-5

A solution of diphenylmethyl 7(3-(α-p-nitrobenzyloxycarbonyl-α- /^ 5(phenylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (715 mg) in a mixture of methanol (ho ml)

and tetrahydrofuran (>+0 mL) is shaken in the presence of pre-reduced 5% palladium on charcoal (700 mg) and 10% hydrochloric acid (2 mL)

under hydrogen at one atmosphere and room temperature for 70 min.

The reaction mixture is filtered to remove the catalyst,

diluted with water (120 ml) containing 10% hydrochloric acid (2 ml), concentrated to remove the organic thickener, and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to

give diphenylmethyl 7(3-(α-carboxy-α-phenylacetamido)-3-(1-methyl-tetxazol-5-yl)thiomethyl-1-oxadethia-3~cephem-^-carboxylate (576 mg). Yield: 97 .6% (raw product).

Example III- 6

A mixture of diphenylmethyl 7(3-(oc-p-hydroxyphenyl-oc-t-butoxy-carbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (yh mg), thiophenol (0.075 mD°g trifluoroacetic acid (0.75 ml) is stirred for 1.5 hours under ice-

kidding The reaction mixture is evaporated under reduced pressure.

The residue is purified by chromatography on silica gel containing

10% water and eluted with a mixture of acetic acid and ethyl acetate

(1:9). The eluate is treated with a mixture of ether and pentane

to give 7P- (<*-p-hydroxyenyl-oc-carboxyacetamido)-3-(1-methyl-γ-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid

(30mg). Yield 58.9%.

Temp. 130 - 1<1>+'2°C (decomposition).

IR: V 3<1>+00'1787'1720 cm~<1>-

UV: V^s? 273 nm ( f = 7850)-

Example III- 7 r ) ■

'• Cl-, r 7 To a solution of diphenylmethyl 7(3- (a-p-hydroxyphenyl-a-diphenyl-methoxycarbonylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1 - oxadethia-3-cephem-V -carboxylate (137 mg) in methylene chloride (3 ml) is added anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) at 0° C. under nitrogen. After stirring for 1 hour at 0° C. the mixture is concentrated under reduced pressure, treated with ether, and washed with ether to give 7(3-(oc-p-hydroxy enyl-α-

carboxyacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylic acid as a colorless powder (81 mg) which decomposes at 130 - 1<l>f2°C. Yield: 59.6%. y~ H

IR: vs. 3<l>f00'1787'1720 cm"<1>'

UV:;YCH30H273nm ( £= 7850).

max.

Example III-8

To a solution of diphenylmethyl 7^-/ J*-~ (2-thienyl)-α-t-butoxy-carbonylacetamido7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-+-carboxylate (<1>+9 mg) in methylene chloride (1 ml) is added anisole (0.*+ ml) in trifluoroacetic acid (1 ml) at 0°C and the mixture ■./-(■ is stirred under ice cooling for h hours and at room temperature i'

kO min. The react ion mixture is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (5 g) containing

10% water, and eluted with a mixture of ethyl acetate and acetic acid (9:1). The eluate is treated with ether to give 76-(2-thienyl)-α-carboxyacetamido7-3-(1-methyltetrazol-5-yl)thiornetyl-1-oxadethia-3-cephem-if-carboxylic acid (23 mg ) as an amorphous powder.

Temp. 156 - 160°C (decomposition during foaming). Yield: 33.5%.

IR: VSks. 3390'1765'1670'16°8' 1520 cm"1'

/<*<723>- 62.0 - 3-7° (c = 0.279, 1% NaHCO 3 ).

CD: A (6) (0.279, 1% NaHCO 3 ) 300(0), 282(- 2600), 276(0),

259(+ 11100), 21+9(0) , 231 .5(-^7^00) , 210(- 9700).

Example III-9

A mixture of diphenylmethyl 7β-[α-(3-thienyl)-α-t-butoxycarbonyl-acetamido7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1f-carboxylate (56 mg), anisole (0.35 ml), and trifluoroacetic acid (0.35 ml) are stirred at 0°C for 2 hours. The reaction mixture

evaporated under reduced pressure. The rest is cleaned with wood

chromatography on silica gel (5 g) containing 10% water,

eluted with a mixture of ethyl acetate and acetic acid (9:1) and treated in a mixture of n-pentane and ether (2:1) to give ,/7P-/oc-(3-thienyl)-α-carboxyacetamido7-3 -(1-methyltetrazol-5-yl)-Y" thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid (37 mg) as colorless powder. M.p. 155 - 160°C. Yield: 96.8%.

IR: Vjj^g^ 3<>>+00, 1770, 1692, 1610 cm"<1>.

Example 111-10

To a solution of diphenylmethyl 76-(α-diphenylmethoxycarbonyl-α-phenylacetamido)-3-(1-t-butoxycarbonylmethyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylate (60 mg ) in anisole (0.5 ml), trifluoroacetic acid (1 ml) is added under ice-cooling under nitrogen, and the mixture is kept at 0°C overnight. The reaction mixture is concentrated under reduced pressure, the residue

treated with ethyl acetate to give crude 7S-(α-carboxy-α-phenyl- J acetamido)-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia- v 3-cephem-^f-carboxylic acid (22 mg) as powder. Yield: 6k%.

IR: xSSs. 1775'1725 cra"<1>-

Example III-11

To a solution of diphenylmethyl 76-Za-t-butoxycarbonyl-α-(2-thienyl)acetamide q7-3-(1-t-butoxycarbonylmethyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate ( 96 mg) in anisole (0.5 ml), trifluoroacetic acid (1.5 ml) is added under a nitrogen atmosphere under ice cooling and the mixture is allowed to stand overnight under ice cooling. The reaction mixture is concentrated under/reduced pressure. The residue is treated with a mixture of ether and 7 ethyl acetate to give crude 7β-β-(2-thienyl)-α-carboxyacetamido7-3-(1-carboxymethyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cef em - k-carboxylic acid (30 mg). Temp. with cleavage from 160°C

Yield: h8%.

IR: ^maL. 1780'172? cm"<1>'

Example 111-12

To a solution of diphenylmethyl 7(3-(α-phenyl-α-diphenylmethoxy-carbonylacetamido)-3-(2-methyl-1,3 A~thiadiazol-5-yl)thiomethyl-1-oxadethia-3-cephem-l+ -carboxylate (170 mg) in methylene chloride (3 ml), anisole (0.2 ml) and trifluoroacetic acid (0.1 ml) are added

at 0°C and the mixture is stirred at 0°C for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The residue is purified on silica gel (10 g) containing 10% water, eluted with a mixture of ethyl acetate and acetic acid (9:1) and treated with a mixture of A ethyl acetate and ether to give 7(3- (a-_pheny_l-a- carboxyacetamido)-3-£2^methyl-1,3,*+-thiadjUz_ol-_5-yl)thiomethyl-1-oxadethia-3-cef em-h-carboxylic acid C+5.8 mg) as a colorless powder. Dividend: >+5.1%.

Temp. 130 - 132°C.

IR:</>max. 3<l>f10'1772'1600 cm~<1>'

Example 111-13

To a solution of diphenylmethyl 7(3-(α-diphenylmethoxy-carbonyl-α-phenylacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem A-carboxylate (121, 2 mg) in methylene chloride (2 ml) add anisole (0.2 ml) and trifluoroacetic acid (0.1 ml) at 0°C.

After stirring at 0°C for 1 hour, the reaction mixture is concentrated under reduced pressure and treated with ether to give /uA 7(3-(α-carboxy-α-.-phenyl_lacetamido)-7α-methoxy-3-(1 -methyltetrazol-5-ylDithiomethyl-1-oxadethia-3-cephem-^-carboxylic acid A6.5 mg) as a colorless powder. Yield: 59.8%. M.p. 110 - 116°C.

UV:)fCH 3 OH 275.5 nm 9<l>+00). - 19 A - 2.8°(c=211,

max* CH30H).

IR: V^s. 178o>1717>1631 cm"<1>.

NMR: 5<D>2° +NaHCO3(3.<l>+6s + 3.53s)P, (3-99s +<>>+.02s)3H,

k. O -<l>+.2m2H,<l>+.<l>f8s2H,<l>+.53s1H, 5.13s1H,

7-38s5H.

Example III- A tcd?'^

To a solution of diphenylmethyl 78-(a-diphenylmethoxycarbonyl-a-p-acetoxyphenylacetamido)-7a-methoxy-3-(1 -methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate 033A mg) in methylene chloride (2 ml), anisole (0.2 ml) and trifluoroacetic acid (0.hml) are added at 0°C. The mixture is stirred for *+5 min., Nv is evaporated and treated with a mixture of ether and pentane, and ether to give 78-(α-carboxy-α-β-acetoxyphenylacetamido)-7α-j methoxy-3-(1-methyl tetrazol-5-yl)thiomethyl-1-oxad e thia-3-cef em- l+-carboxylic acid (77 mg) as a colorless foam. Temp. 110 - 115°C. Yield 91.9%.

UV: <CH>3<OH>275 nm ( 6=9300) .

max.•

[vj^ 27.5 - 2.6° (c = 0.258, CH 3 OH).

IR: V Ss. 1782'1728'1635 cm"<1->

NMR: £<D>2° + NaHC032.33s3H, (3Ms + 3-53s)3H,

(3.99s + lf.02s)3H, approx. l+.13brs2H,

*+A6brs2H, 5.13s1H, 7.12 + 7.*+7ABq(8Hz)>+H.

Example 111-<1>5^ . /

V

To a solution of diphenylmethyl 78-(a-diphenylmethoxycarbonyl-a-p-hydroxyphenylacetamido)r-7a-methoxy-3-(1-methyl trazol-5-yl)-rj thiomethyl-1-oxadethia-3-cephem-l+ -carboxylate (8^.6 mg) in methylene chloride (2 ml) is added anisole (0.1 ml) and trifluoroacetic acid (0.3 ml) at 0°C. After rotation for >5 min. at 0°C, the mixture is evaporated under reduced pressure and treated with a mixture of ether and n-pentane, and ether to give 7P-(α-carboxy-α-β-hydroxyphenylacetamido)-7<x-methoxy-3-(1 -me tylte tr azol-5-yl) thiomethyl-1 - oxadethia-3-cephem-<1>+-carboxylic acid (U- 6, h mg) as a colorless powder. Yield: 89.9%. Temp. 117 - 122°C (decomposition).

UV: J\CH30H276 nm ( 10200)

max.

fj<2>^15.3 2.6° (c = 0.216, CH^OH).

IR: Vmax. 1780'1719'1632 cm"1'

NMR: £<D>2° + NaCH03(3-^5s+3-53s)3H, (<l>+.00s+<l>+.02s)3-H,

(<!>+.08s ' l+.13m)2H, ( k. k5s + *f .*t8s)2-3H, 5.12s1H, 6.87 + 7.28ABq(8Hz)lfK.

Example III- 16 7c/:33

To a solution of diphenylmethyl 7(3-/oe-p-hydroxyphenyl-oc-(5-indanyl)oxycarbonylacetamido7-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-S-cephem- ^-carboxylate (150 mg) in methylene chloride (12 ml) is added anisole (0.5 ml) and trifluoroacetic acid (0.<*>+ ml) at 0° C. in nitrogen. After stirring for 20 min at 0° C, the reaction mixture is concentrated under reduced pressure, diluted with benzene and concentrated. The residue is treated with ether to give 7(3-/α-β-hydroxyphenyl-α-(5-indanyl)oxycarbonylacetamido7-7α-methoxy-3-(1-methyltetrazol-5 -yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid as a powder (91 mg) melting at 123-126°C with cleavage.Yield: 76.5%.

IR: Vmax. 3385' 1785' 1727' 1705' 1631' 1613' 1,595 cm"<1>'

UV: > CH30H271.5 ( £= 12950), 276.5 ( e= 12700) nm.

max.

foijf + 1.3- 0.8°, A7^<2>6- 25.1- 1.2°, Oti% ~ 5.2 1.2°

(c = 0.5>+1, CH 2 OH).

Example 111- 17 °^ ^ i'! ;,

To a solution of diphenylmethyl 7β-α-(p-benzyloxyphenyl)-α-/benzyloxycarbonylacetamide Q7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-α-carboxylate (100 mg) in methylene chloride (2 ml) is added anisole (0.2 ml) and a solution of q aluminum chloride (250 mg) in nitromethane (1.2 ml) under ice cooling. y'^' After stirring for 2 hours under ice cooling and for 1 hour at room temperature, the mixture is poured into a mixture of ethyl acetate and methanol (5:1), washed with 2N hydrochloric acid and saturated brine,

tbruk over sodium sul& and concentrate. The residue is washed with ether to give 7β-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-H-carboxyl-

acid (35 mg)•

IR: Vj^s. 1?80, 1719, 1632 cm<-1>.

Example 111-18 T. yjs l°( lJ $'"•

To a solution of diphenylmethyl 7β-[α-t-butoxycarbonyl-α-(3-thienyl)acetamido_7-7α-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-!+- carboxylate (1M+ mg) in anisole

(0.3 ml) is added trifluoroacetic acid (1.7 ml) at 0°C under nitrogen gas. After stirring for 3 hours, the mixture is concentrated

to dryness under reduced pressure, treated with ether, and washed

with ethyl acetate and ether to give 7β-α-carboxy-α-(3-thienyl)-acetamide 7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3 -cephem-^-carboxylic acid (61 mg) as a pale yellow powder. Yield: 61%. Temp. 118 - 125°C (decomposition) from acetone.

Δ7<25>12.8 - 2.5° (c 0.211, CH 2 OH).

UV: > CH3°<H>276 nm (£<=>10200).

max.

IR: V max. 1780'1^5 cm"<1.>

NMR: ^D2°+NaHC03lf.03s3H, (<l>+.11s + 1+.21m)2H, ( h. 51 s+ h. 53s) 2-3H, 5-15s1H, 7.05-7.25m1H, 7.27-7.52m2H .

Example 111-19

To a solution of diphenylmethyl 7P-[Joe-(3-thienyl)-a-diphenylme toxycarbonylacetamido7-7a-methoxy-3-(1-methyl trazol-5-yl)-thiomethyl-1-oxadethia-3-cephem -^-carboxylate (830 mg) in methylene chloride (15 ml) is added to anisole (2 ml) and trifluoroacetic acid (2 ml) under ice cooling. After stirring for 1 hour at the same temperature, the mixture is concentrated under reduced pressure. /Expression. The residue is washed with ether to give 7S-[α-(3-thienyl)-α-carboxyacetamido7-7o:-methoxy<y->3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3- cephem-^-carboxylic acid as a powder (383 mg) melting at 110-11^°C, identified with an authentic sample by comparison of IR spectra in KBr slice and thin-layer chromatogram.

Example 111- 20 ' J fJ^ ( t

To a solution of diphenylmethyl 7β-[α-(3-thienyl)-α-phenoxy-carbonylacetamido 7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (100 mg) in methylene chloride (2 ml) are added anisole (0.2 ml) and trifluoroacetic acid (0.2 ml) under ice cooling. After stirring for 1 hour, the mixture is concentrated

and treated in ether to give 7(3-[α-(3-thienyl)-α-phenoxycarbonyl-acetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-1-oxadethia-3-cephem -^-carboxylic acid as a powder (38 mg) melting at 108-111° C. Yield: 50%.

IR: yCH<C1>3 3<l>f00sh, 3325, 1788, 17^5, 1705 cm"<1>. ijU

max. yJj ^

/q7<23>- 61.3 in 2.0° (c = 0.517, CHCl3).

Example 111-21

To a solution of 7B-/α-(3-thienyl)-α-(3,<l>+-dimethylphenyl)oxy-carbonylacetamido_7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3-cephem-+-carboxylate (105 mg) in methylene chloride (2 ml) is added anisole (0.2 ml) and trifluoroacetic acid (0.2 ml)

during ice cooling. After stirring for 1 hour, the mixture is concentrated under reduced pressure, treated with ether, and filtered. The solid is washed with ether and dried to give 78-[cx-(3-thienyl)-a-(3,^-dimethylphenyl)oxycarbonylacetamido7-7a- / J j methoxy-3-(1-methyltetozol-5-yl) thiomethyl-1-oxadethia-3 cephem-^-' carboxylic acid as a powder (6^ mg) melting at 110-113°C. Yield: 77%.

IR: V<CHC1>3 3^00sh, 3325, 1787, 1737 cm"<1>,

max.

/«7d3 "53A - 1.9° (c 0.50<!>+, CHCl3).

Example 111- 22 years. (i'

To a solution of diphenylmethyl-73-/a-(3-thienyl)-ct-(lndan-5-yl)-oxycarbonylacetamide q7-7a-methoxy-3-(1 -methyltetrazol-5-yl)-thiomethyl-1- oxadethia-3-cephem-^-carboxylate (97 mg) in methylene-

chloride (2 ml), anisole (0.3 ml) and trifluoroacetic acid (0.3 ml) are added under ice cooling. After stirring for 1 hour, the mixture is concentrated under reduced pressure and the residue is treated with ether to give 7β-[α-(3-thienyl)-α-(5-indanyl)oxycarbonylacetamido/-7α-methoxy-3-(1-methyl te tr azol-5-yl) thiomethyl-1 - oxadethia- 3-cef em-^f- ^' carboxylic acid as powder (3^ mg) melting at 111-113°C j-Yield: h$%.

IR: V<CH>C133l+06sh, 3335, 1789, 17^+, 170^ cm"<1>,

max.

Æ*.7j53"57.5<1>2. k° (c = 0.^+02, CHC1

Example 111- 23 IA17

To a solution of diphenylmethyl 7β-/α-diphenylmethoxycarbonyl-α-(2-thienyl)acetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia-3-cephem-^-carboxylate ('[ ko mg) in methylene-

chloride, anisole (0.2 ml) and trifluoroacetic acid (0.1* ml) are added at 0°C under nitrogen gas. After stirring for 1 hour at 0°C, the mixture is evaporated under reduced pressure, treated with ether,

and washed with ether to give 7β-β-carboxy-α-(2-thienyl)acetamido<7->7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem -k-carboxylic acid (60 mg) as a colorless powder. Yield: 70%. , Smp. 10^ - 109°C (decomposition); \j

UV: ^<CH>3<OH>275 nm ( £= 8800). ! in \J

max.<1>

fij^ 7 15.0 - 1.5° (c 0.37^, ch3oh).

IR;<y>Ss,1?85> 1715 cm"<1>.

NMR: gD2°<+><NaH>C037_<0>Q _ 7>5m3Hj5 . t 5 s 1 h , l+.O^H,

(3.5^s + 3-1+8s)3H.

Example III - 2 + - ov- ^

To a solution of diphenylmethyl 7P~Za-(5-indanyl)oxycarbonyl-α-phenylacetamidoJ7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (116, 1 mg) in methylene chloride, anisole (0.1 ml) and trifluoroacetic acid (0.2 ml) are added. After j stirring for 30 min. at 0°C, the mixture is evaporated under reduced pressure, chromatographed on silica gel (10 g) containing 10% water, eluted with ethyl acetate containing 5% acetic acid, and

crystallized from a mixture of ether and pentane to give 7(3-/a-(indan-5-yl)oxycarbonyl-q^f e nylacetamido7-7a-methoxy-3-(1 -methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3-cephem-^-carboxylic acid (7^.5 mg) as colorless crystals.Yield: 81, h%.

Temp. 123 - 125°C (decomposition).

IR: VmSs. 177°>1702cra'<1>'

/o7<25>- 8A - 1A° (c = 0.286, CR^OH).

NMR: CDCl32.07s2H, 2.855. (3.32s + 3A3s)3H, 3-79s3H,

!f.25s2H,<l>f.50s2H,<1>+.69S1H, ^f.97s1H.

Example 111-25

To a solution of diphenylmethyl 7(3-(α-β-carbamoyloxyphenyl-α-diphenylmetoxycarbonylacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V -carboxylate (170.1 mg) in methylene chloride (2 ml) is added anisole (0.>+ ml) and trifluoro-

acetic acid (0.*+ ml) at 0°C and the mixture is stirred for 5 min., evaporated to dryness under reduced pressure, and treated with ■ ether to give 7P-(α-β-carbamoyloxyphenyl-α-carboxyacetamido) -7α-Methoxy-3-(1-methyl terazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V-carboxylic acid (98.2 mg) as a colorless powder.

Temp. 128 - 132°C.

IR: V^s. 1?8<1>+'1^(sh), cm"<1>.

UV:<CH>30H273nm (C=9500).

max.

/o/p<5>23-1<->0.7° (c 0.900, CH 3 OH).

Oak sample 111-26

In a method corresponding to example 111-25, diphenylmethyl 7(3-(q-p-N-methylcarbamoyloxyphenyl-a-diphenyl-methoxycarbonylacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxadethia is treated -3-cephem-1f-carboxylate (100 mg) with anisole (0.1 ml) and trifluoroacetic acid (0.1 ml) in methylene chloride (1 ml) at 0 O C for 1 hour to a ogi 7(3-(a-p-N- methylcarbamoyloxy enyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiorne ty1-1-oxadethia-3-cefear-3-carboxylic acid (52 mg) in high% yield.

Temp. 117 - 125°C

IR: Growth 3385'1786'1725 cm"<1>'

UV; <CH>3<OH>271 nm (£= 9532).

max.

Example 111-27 i"/

In a method similar to example 111-25, diphenylmethyl 78- (a-pjMir^i^pJtaxbjsnyloxyphenyl-a-diphenylmethoxy-carbonylacetamido)-7a-methoxy-3-(1-methyltetrazol-5-yl) is treated )thiomethyl-■ 1-oxadethia-3-cephem-U-carboxylate (213 mg) with anisole (0.k ml)

and trifluoroacetic acid (0.5 ml) in methylene chloride (3 ml) for 1 hour

at 0°C to give 7β-(α-β-ureidocarbonyloxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxα-dethia-3 -cephem-^-carboxylic acid (125 mg) in 91% yield.

Temp. 137 - -|<l>f2°C.

IR:<Y>max. 3^°'3330'1780'1712 crn"<1>'

NMR: ^<CD>3)2<SO>(3-25s + 3Als)3H, (3-90s + 3-93s)3H,

<»>+.21brs2H, +.98brs2H,<l>+.85brslH, 5.05s1H,

7.20 - 7.l5m2H, 7.13d(8Hz)2H, 7. *+2d(8Hz) 2H, (9-l5brs + 9.27 brs)1H, 10.25brs1H.

UV: <CH>3°H 276 nm ( £= 9105).

max.

Example 111-2.8 "V o"^ J

<■ - -; ;rTo a solution of diphenylmethyl 7?-/Ja-p-(p-methoxybenzyl)oxy-phenyl-a-diphenylmethoxycarbonylacetamido7-7a-methoxy-3-(1 - methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3- cephem->+-carboxylate y'

(170 mg) in methylene chloride (3.5 ml) is added anisole (0.35 ml) and trifluoroacetic acid (0.35 ml) at 0°C, and the mixture is stirred in | f\ kS min. at 0°C. After evaporation of the solvent, the product is treated with ether to give 7B~(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3"(1-methyltetrazol-5-yl)thiomethyl-1-oxa-dethia-3-cephem -^-carboxylic acid (91 mg) which is a colorless powder.

Yield: almost quantitative. Temp. 125 - 132°C (decomposition).

Example III- 29 f <n&-■ M

In a method similar to that in example 111-28, 3-r, diphenylmethyl 7P-/oc-p-(p-methoxybenzyl)oxyphenyl-a-p-metdoxybenzyloxycarbonylacetamido7-7a-methoxy-3-(1-methyl-\I tetrazol-5) is treated -yl)thiomethyl-1-oxadethia-3-cephem-l+-carboxylate (1.1+5 g) , ., with anisole (1+ ml) and trifluoroacetic acid (1+ ml) in methylene chloride j\J j (8 ml) at 0°C for 1+0 min. to give 70-(oc-p-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylic acid. Temp. 125 - 132°C

(cleavage). Yield: quantitative.

Example 111- 30 \ ^ i' .'; yw **y

1) To a solution of diphenylmethyl 7(3-/bc-p-(p-methoxybenzyl-oxy-phenyl-a-p-methoxybenzyloxycarbonyl-acetamido7-7a-methoxy-3-(1-methy 1te tr azol-5-yl) thiomethyl-1 - oxad eti a-3-cef em-l+-

carboxylate (1.20 g) in methylene chloride (2k ml) is added anisole (2.<1>+ ml) and a solution of aluminum chloride (2.58 g) in nitromethane (12 ml) at 0°C under nitrogen. After stirring for 15 min. at 0°C, the mixture is poured into cold aqueous 5% sodium bicarbonate solution (100 ml) and filtered to remove the precipitate formed. The filtrate is washed twice with methylene chloride (2 x 100 ml), acidified with 2N hydrochloric acid to pH 2.60 and poured into a column filled with hyperporous polymer "HP-20" (60 ml) (sold by Mitsubishi Chemical Industries Ltd.) . The column is washed with water, (300 ml)

and eluted with methanol. The eluate is concentrated under reduced pressure at room temperature. The residue is dissolved in methanol, treated with activated carbon and concentrated under reduced pressure to give 7B-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyl tetrazol-5-yl)thiomethyl -1 - ox ad eti a-3-cef em-lf-carboxylic acid as a powder (595 mg) which decomposes at 125 - 132°C.

Yield: 88.5%.

2) The same product can be produced by a method

corresponding to 1) above, in which

a) p-methoxy-benzyl ether is replaced by benzyl ether

b) the p-methoxybenzyloxycarbonyl group is replaced by the benzyloxycarbonyl group and/or

c) the diphenyl methyl ester is replaced by benzyl ester.

IV. O-acylation.

Example IV-1

To a solution of diphenylmethyl 7(3-(α-β-hydroxyf enyl-α-dif enylme toxycarbonylace tamido) ^7cc-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3_cephem-<!>+ -carboxylate (286 mg) in methylene chloride (2 ml) is added trichloroacetyl isocyanide (0.5 ml)

during cooling at -78°C. After incubating at -78°C for 30 min.

and at 0°C for 1 hour, the mixture is diluted with benzene (20 ml) and ethyl acetate (20 ml), washed with water, dried and concentrated. The obtained residue is chromatographed on silica gel (30 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate

(1:1) to give diphenylmethyl 7P-(oe-p-carbamoybxyphenyl-a-dipheny Ime toxycarbonylace tamido)-7a-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3 -cephem-^-carboxylate (179.9 mg) as a colorless foam. Yield: 59.5%.

IR: V<CH>C133530, 3^25, 3325, 1790, 1750, 1728, 1700sh cm<-1>,

max.

NMR: 6CDCl3(3A2s + 3A5s)3H, 3.73s3H, ^+.22s2H,<l>+A2s2H,

<t>+.80slH, 5.03s1H, 5-33s2H.

Ek sample IV- 2 ) :) ' ■

£ ■> i i By a method similar to that described above

under Example IV-1, diphenylmethyl 7(3-(α-β-hydroxy-

phenyl-α-diphenylmethoxycarbonylacetamido)-7α-methoxy-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cef ern-^--

carboxylate (100 mg) with methyl isocyanate (0.2 ml) in tetrahydro-

furan (1 ml) in the presence of 1,5-diazabicyclo/3,5p7undecene at 0°C * for h, 5 h to give diphenylmethyl 7(3-(a-p-N-methylcarbamoyloxy-/<*>Hf phenyl-a-diphenylImethoxycarbonylacetamido )-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate (52 mg).Yield: <1>+9%.

IR: V<CH>C133^60, 1785, 1725, 1700 cm'<1>,

max.

NMR: JCD<C1>3 2.87d(5Hz)3H', 3.<1>+5brs3H, 3.80s3H, 1+.23brs2H,

^A7brs2H, If.77brs1H, 5-00s1H, it.95 - 5.i+0m1H, 6.97s2H.

Example IV- 3

By a method similar to that described above

in Example IV-1, diphenylmethyl 7(3-(α-β-carbamoyloxy-phenyl-α-diphenyImethoxycarboxylacetamido)-7α-methoxy-3-(1-methyl-tetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem is treated -lf-carboxylate (1 75 mg)

with trichloroacetylisocyanide (0.k ml) at 0°C in methylene chloride (2 ml) and at room temperature for k hours to give the N<3->trichloro-acetylureidocarbonyloxyphenyl derivative, which is hydrolyzed with moist silica gel (10 g) for one hour in methylene chloride at , room temperature to give diphenylmethyl 7(3-(α-jD-ureidocarbonyloxy-[//jphenyl-α-diphenylmethoxycarbonylacetamido)-7α-methoxy~3-(1-methyl-tetrazol-5-yl)thiomethyl-1 -oxad etia-3-cef em->+-carboxylate (1*+5 mg). Colorless foam. Yield: 79%.

IR: yCHC133500, 1790, 1758, 1725, 1700sh cm"<1>,

max.-

NMR: g<CD>C133A3<s>3H, 3.68s3H,<l>+.21brs2H,<l>+.<l>+3brs2H, 1+.83brs1H,

5.03s1H, 5.80 - 6.70m2H, 6.95s2H, 8.23brs1H,

9.20brs1H, 6.95s2H.

V. Protection.

Example V-1

To a suspension of 7(3-(α-carboxy-α-phenylacetamido)-3-(1-methyl trazol-5-yl)thiomethyl-1-oxadethia-3-cef em-l+-

carboxylic acid (hOO mg) in methylene chloride (20 ml) is added to diphenyldiazomethane (700 mg) and the mixture is stirred at room

temperature for 30 min. The residue obtained by concentration under reduced pressure is chromatographed on silica gel (kO g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (1:1) to give diphenylmethyl 76(α-diphenylmethoxycarbonyl-α- //u^ phenylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (322 mg). Temp. 107 - 109°C. Yield: 1+7 A%.

(In another trial, a 95% yield of the product was achieved).

Example V-2

To a suspension of 76-(α-carboxy-α-phenylacetamido)~3-(1-methyltetrazol-5-yl)thiomethyl-1-oxad e thia-3-cef emA-carboxylic acid (50 mg) in a mixture of acetone (30 mL) and methanol (5 mL)

a solution of sodium acetate (1756 mg) in methanol (2 ml) is added

and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated under reduced pressure and the residue is washed with acetone to give disodium 7P-(α-carboxy-α-phenylacetamido)-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylate ( 57 mg).

IR: Vmax3lf25' 17^6' l66obr>1°10br, A10 cm"<1>.

Example V-3

The products from the above examples with free carboxy are resolved

in aqueous sodium bicarbonate solution to give the corresponding sodium salts which are tested with respect to antibacterial action.

These compounds are more active than the corresponding compounds

with a sulfur atom^instead of the oxygena empty in tilling one of the fr* ring system. The compounds with 7a-methoxy are stronger~" -^'^ antibiotics against gram-negative bacteria that are resistant^ to j<J>^ S"62*^/" common cephalosporins and also strongly active against pseudomonas j

aeruginosa strains.

Example V - k f ^ ,0jQ

To a solution of 70-Za-(3-thienyl)-α-carboxyacetamido7-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-h-carboxylic acid (2, 0^ g) in methanol (20 ml) is added to a solution of sodium 2-ethyl hexanoate in methanol (2 mol/l, 10 ml) at room temperature. After stirring for 10 min. dilute the reaction/mixture with ethyl acetate (100 ml) and stir for 5 min. and ^ is filtered to collect the separated solid, which is washed with ethyl acetate and used to give the disodium salt of 73-[α-(3-thienyl)-α-carboxyacetamido7-7cc-methoxy-3-(1-methyltetrazol-5-yl )-thiomethyl-1-oxadethia-3-cephem-<l>+-carboxylic acid (1.90 g)

Yield: 86.J%. Colorless powder that melts on cleavage from 150°C

IR:V^s. 1768'1680'1612 cm"<1>-

UV: ]\CH30H271 nm ( ε = 9>+20) .

max.

Example V-? ^ %{ j j p<\><p>^ ^.}.' tY

To a solution of 70-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-V-carboxylic acid (359 mg) in methanol (7 ml) is added to a solution of sodium 2-ethyl hexanoate in methanol (2 mol/l, 1.73 ml) at room temperature. After stirring for 10 min. dilute the reaction mixture with ethyl acetate, stir for 5 min. and filtered to collect the separated solid, which is washed with ethyl acetate and used to give the disodium salt of 7(3-(oc-p-hydroxyphenyl-a-carboxyacetamido)r7a-methoxy-3-(1-methyl-tetrazol-5- yl)-

thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid (3^2 mg).

Yield: 88.8%. Colorless powder that melts during cleavage

from 170°C.

IR: vH10s] 1768, 1675, 1608 cm<-1>.

UV: i>CH 3 O<H>273 nm (£= 11100).

max.

Example V- 6 fifdj- ■ ZZ '\

To a solution of 7-(3-[a-p-hydroxyphenyl-a-carboxyacetamidoy<7->7a-methoxy-3~(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-^-carboxylic acid (836 mg) in a mixture of methylene chloride (15 ml),

ethyl acetate 0 5 ml) and methanol (10 ml) are added to diphenyldiazo-

methane (950 mg) . After transfer 30 min. at room temperature

the mixture is concentrated under reduced pressure and washed with n-hexane. The product is chromatographed on silica gel (90 g)

containing 10% water and eluted with a mixture of benzene and ethyl acetate (1:1) to give diphenylmethyl 7(3-(α-β-hydroxyphenyl-α-diphenyImethoxycarbonylacetamido)-7α-methoxy-3-(1-methyltetrazole -5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylate (1.270 g).

Yield: 95%.

IR: yCHC133585, 3315, 1790, 1722, 1700sh cm*1,

max.

WE. Preparations and their use.

Example VI- 1 jOY\22-3 " in 1

The disodium salt of 70-(α-β-hydroxyphenyl-α-carboxyacetamido)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-1+-carboxylic acid (100 mg) in a 5 ml container is dissolved in sterile water for injection (1 ml) for use and given to an adult patient suffering from pyelitis by intravenous injection.

Example VI-2 ^y 2;.;. 7?

The freeze-fractured product from a solution of 7P-[oc-(3-thienyl)-oc-carboxyacetamide q7-7oc-methoxy-3-(1-methyl te trazol-5-yl)thiomethyl-l-oxadethia-3 -cephem-^-carboxylic acid (1 g) neutralized to pH 7.0 with sodium bicarbonate is placed in a 150 ml flask. - j The product is dissolved in sterilized water for injection (100 ml) and instilled intravenously to an adult patient immediately after or during a surgical operation for cancer to prevent and treat post-operative bacterial infection.

Example VI- 3 / " '

)-v. etc.

Micr ochrys tall insk 7(3-/a-carbamoyl oxyphenyl-oc-carboxyacet amide q7-7a-methoxy-3~(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem-.»^- carboxylic acid (200 mg) in a 5 ml container is suspended in sheltered sterilized water for injection containing 2 mg procaine (2 ml)

and is given intramuscularly to a patient suffering from matter-inflammation caused by staphylococcus aureus.

Example VI-^ '■ >'' y

r'y::Crystalline 7s-/a-(3~thienyl)-a-(5^indanyl)oxycarbonylacetamido.7-3-(1-methyltetrazol-5-yl)thiomethyl-1-oxadethia-3-cephem- ^-carboxylic acid (200 mg) is dissolved in sesame oil (0.25 ml) and filled

in a hard gelatin capsule. Each capsule is given orally with h hours

, space to a patient suffering from an upper respiratory tract infection caused by streptococcus pyogenes.

Example VI- 5 M v v . ■■7

Powdered 7-(3-β-hydroxyphenyl-α-(5-indanyl)oxycarbonyl-acetamide Q_7-7α-methoxy-3-(1-methyl trazol-5-yl)thiomethyl-1-oxa-dethia- 3-cephem-^-carboxylic acid (100 mg) is treated with corn starch (0 50 mg) and talc (10 mg), powdered and encapsulated in a hard gelatin capsule (250 mg) volume). Each capsule is administered orally at 3-hour intervals to an adult patient suffering from a urinary tract infection caused by Escherichia coli.

Example VI- 6 J ' '/£

Mixed powder of 7P-[g<->p-carbamoyloxyphenyl-a-(5-lndanyloxy)-carbonylacetamido7-7cx-methoxy-3-(1-methyltrazol-5-yl)thiomethyl-1-oxadethia-3-cephem -<>>+-carboxylic acid (10 g) lactose (50 g), corn starch (2 g), magnesium stearate (0.3 g) sucrose (10 g) and the required amount of acacia and talc are granulated. The granule

4

is mixed with water for use to obtain a suspension, and a teaspoonful of the suspension is given orally to a child suffering from pneumonia caused by Klebsiella pneumoniae.

Claims (1)

Analogous process for the preparation of therapeutically active 7-substituted malonamido-1-oxadethia-7cC-methoxy- 3(1-methyltetrazol-5-yl)-thiomethyl-cephalosporins of formula I in which COB 1 and COB <2> are carboxy or protected carboxy, as well as pharmaceutically acceptable salts thereof, characterized in that an amine of formula II in which COB 2 has the above meaning, is converted with a 2 or 3-thienyl-substituted malonic acid of formula III in which COB"'' has the above meaning, or a reactive derivative thereof, or by removing a protecting group B 1 or B 2 from an obtained compound of formula I in which B 1 and B 2 stand for protecting groups.