SE408424B - PROCEDURE FOR THE PREPARATION OF 7-ACYLAMIDO-7-ALCOXIC PHALOSPORINES - Google Patents

Description

. Ä 7313930-5 2 . ocnš S Hooc-cH (cH2) 3coNH 7 É / '1 2 H NH 5-N --c 'ocNH 2 _O¿47 5 \% / 5 2 2 coon These antibiotics are called 7- (5-amino-5-carboxivaleramido) -7-methyl- toxicephalosporanic acid resp. 7- (5-amino-5-carboxivaleramido) -7-methoxy- -3-carbamoyloxymethyl »B-cephem-4-carboxylic acid. Alternatively, these are called : 65 n u antibiotics also Al688Ä resp. Al6886I; see Belgian patents 754 424 and 754 693. The latter antibiotic is also called anti- Biotic 842A in Belgian Patent Specification 76H 160.

Furthermore, Belgian Patent Specification 764 160 discloses an anti- biotic 810A with the following formula: ' AND; S Hooc-cH (cH2) 3coNH \\ o \ HRS NH2 O4¿, -¿N \ W;, i- cu2oc-o = cH - / 2 :::>) - ou COOH OCH3 This antibiotic is called 7- (5-aminoecarboxivaleramido% 7- -methoxy-34 (α-methoxy-p-hydroxycinnamoyloxymethyl) -3-cephem-H-carboxylic acid. É - Like other cephalosporins, these antibiotics can be treated according to the PCI5 method for removal of the acyl group in the 7-position below formation of a nucleus. This core may optionally be re-acylated for another 7-acyl group. However, one has now been discovered improved method for cleavage and formation of the then-mentioned anti- The biotic substances and other 5 derivatives thereof. The process may additionally used to 1 the said antibiotic substances or other 3-derivatives thereof introduce another 7-alkoxy group or a 7-methoxy- -d group instead of the original? -methoxy group. The present invention thus relates to a process for producing 1. »- position of compounds of the formula ffva fi vwmzxw ~ m; ~ »- 0 H OR i "q _ RE *" Ål - 1 ¿___N mn-R ; I I 0%; \\ 1 / ”_ ° coon? 7313930-sp where Ro represents a primary lower alkyl group containing 1-carbon atoms or a methyl die group; B1 represents acetoxy, carbamoyloxy, 1-methyl- - w-awfu- -1,2,4}, 4-tetrazol-5-ylthio or 5-methyl-1,1,5-thiadiazol-2-ylthio; H2 represents hydrogen, alkyl containing 1-6 carbon atoms or diphenylmethyl And R5 represents hydrogen, alkanoyl containing 1-8 carbon atoms more, phenoxyacetyl, mandeloyl or thienylacetyl. This procedure is known according to the invention that an iminohalide of the formula ' . X OC Rzooc-cx fl cneß-èair-. .län / s \, than O 1 / -..__) .. cH2-R \ where X represents bromine or chlorine; Rloch 32 has the meanings given above; and R 4 represents an acylamido group in which the acyl group is alkanoyl containing 1-4 carbon atoms, optionally substituted with halogen, or phthaloyl; is reacted with an alcohol of the formula RO-OH, where Ro has the above specified meaning, under substantially anhydrous conditions at a temperature between -7000 and + 50 ° C, the molar ratio between xønoien een iminonaiiaen är mins 2: 1, - '_' ". '' i after which the product formed (R5 = H) is reacted in situ with a compound having any of the following formulas: Y-RS, - o- (R5) 2 where Y represents bromine or chlorine; and R 5 has any of the above meanings in addition to a hydrogen atom.

The unacylated compounds in which R 2 represents hydrogen show / antibacterial effect. The unacylated compounds in which H2 any of the specified ester groups or in which other protecting groups present, can be deesterified and the other protecting groups can be removed, so that products with antibacterial action are obtained.

The imino halide used as starting material is prepared stepwise in situ by a compound of the formula and S_ R3o-cH (cH2) 5coNH _, .___. / "4 t ... Ill I cH -Rl R O¿ø7W \\ _ // 2 óoone * reacted with PCl5 or with another acid halide. 7313930-5 4 The compounds of the formula 2? CH5 fs * R ooc-cH (cH2) 3-CONH. r, _í. e L4,; - N, QL __. CH2-nl O,. , iprl coona prepared according to known methods. The antibiotic substances Al6884, Al6886I and 81A are thus reacted in such a way as to protect the amino acid. no group, protects the acid groups, and in the case of the antibiotic 81OA also protects the OH group.

The amino group is suitably protected by reacting antibiotics. Al6884, Al6886I or 81A with a suitable acyl halide, anhydride or the chain to form an acylamido group. The identity of the in the acylamido group formed is not critical. IN The carboxyl groups are protected by esterification. The identity of the ester the group is not critical. Suitable groups are those that can be easily split. when the protection function is no longer required.

When using the antibiotic 810A, the OH group can be easily protected according to known methods, e.g. by reaction with chloromethyl methyl ether or with p-bromophenacyl bromide (see Fieser & Fieser, Organic Reagent nic Synthesis, John Wiley & Sons, New York 1968, vol. I pp. 133 resp. vol. III, p.54).

The starting materials in which B1 represents 1-methyl-1,2,3,4-tetra- zol-5-ylthio or 5-methyl-1,3,4-thiadiazol-2-ylthio, is prepared on the method described in Belgian Patent Specification 768,528. The associations can then be treated in the manner described above to protect the amino group and the acid groups.

Whatever protecting groups you use, you turn over the resulting protected association and S aeooc-cH (cH2) 5-coNH..l- ~ w ~ ï / '\ W I l .___ iN .__. cH -R H4 _ 0.7 \\, f ** 2 coonz ( with a substance that can form an iminohalide. Although phosphorus pentachloride other acid halides can also be used. Other suitable substances is thus phosphorus oxychloride. phosphorus trichloride, thionyl chloride, phosgene, oxalic 7313930-5 yl chloride, and the complex compound formed by o-dihydroxybenzene and phosphorus trichloride.

The starting compound and the iminohalide-forming substance are reacted with each other in a conventional manner. Usually good results are obtained, when the reactants were used in amounts corresponding to 1 mole of the starting material. compound and 2-5 moles of iminohalide-forming substance. The reaction can be carried out at temperatures between -SOOC and + 50oC, but it is carried out preferably at room temperature. The reaction is preferably carried out in the presence of a tertiary amine, e.g. triethylamine, pyridine or di- methylaniline.

By this reaction an iminohalide of the formula is obtained C? X AND; I I, ' Rgooc-cmcng) 3-c = N_L -__._. Í \. ' 4 5 g_ "N ï__, 1 a »R ,,,» \ _ // 'f / Hgf * o 'I' coong which compound is then reacted in the critical without isolation the step of the present invention.

It has been found that when the iminohalide is treated with an alcohol in accordance with the present invention, the desired is obtained directly the core of the formula .O 9 "s H2N_, _ |. iWll.ü, _lcH nl O rf; -. R * (M / 2 coonâ fw By using an alcohol in accordance with the invention elimi ~ the need for water, which has been used in those previously described procedures, thereby eliminating the risk of degradation of the which has poorer stability under aqueous conditions. 7313930-5 6 In addition to the mentioned advantages, by using an alcohol -hol according to the invention introduce another 7-alkoxy group or introduce one metoki-d group. The exact mechanism is not clear, but the treatment with an alcohol in accordance with the present invention results in a core containing a 7-alkoxy group derived from the one used alkanols. When it is desired to maintain a 7-methoxy group, the method used is nol. The introduction of the 7-alkoxy group derived from the alcohol used the hole is accompanied by a certain epimerization in the 7-position. The antibiotic substances Al6884, Al6886I and 81A (and other 3-derivatives thereof) assumed to exist in the 7-α-methoxy configuration, while 7- (5-amino- -5-carboxivaleramido) group is in the β-configuration. Omacylera- the compounds prepared in accordance with the present invention exists in the form of a mixture of ε- and β-alkoxy compounds. The the exact ratio varies with the particular acyl group.

The alcohol used in this step is a primary lower alkanol containing 1-4 carbon atoms, i.e. methanol, ethanol, n-propanol, n-butanol or isobutanol, or methan-d -ol. In the implementation of the reaction, the alcohol is added to a solution containing intermediate ten iminohalide. It is essential for obtaining good yields that the solution is substantially anhydrous and that it is kept substantially water free until the core has been unacylated. The reaction can be carried over a wide temperature range, namely between -70 ° C and + 50 ° C. Preferably, however, the reaction is started at 0 ° C, after warming to room temperature for a few minutes and then acer cools to o ° c.

The proportions of iminohalide and alcohol are not critical and may vary with the reaction conditions and components.

It is believed that the reaction between iminohalide and alcohol consumes 2 moles of alcohol per mole of iminohalide. Additional alcohol is consumed leritd of excess PCl or other acid halide. In practice, has it has been shown that good results are obtained by using alcohol the hole in large excess, such as 5-10 moles of alcohol per mole of iminohalide.

The product obtained with the formula t 7313939-5 U N- »2, e L 1 I 6%? \\ ”/ coona can be separated from the reaction mixture if desired. Dyllk insulation should, however, be carried out under weakly basic conditions. Better re- results are obtained when the product is unacylated in situ. Omacylation is obtained by reaction with a compound of any of the formulas Y-R5 and 0 (R5) 2. The acylation reaction is carried out in a conventional manner.

The resulting compounds of the formula 000112 are useful in that the compounds in which R 2 represents an ester group, can be hydrolyzed to the corresponding free acids, in which draws hydrogen. The free acids with the ORO group 1a configuration are useful as antibacterial agents; see Belgian patent specification 768 528. In ß-ORO-epimeric form the esters can be treated according to present invention to form a mixture of α- and β- alkoxy esters, of which the α-alkoxlopimores are useful as described in ves above.

The invention is illustrated by the following example. In the theses of these examples, compounds: lnncnallando deuterium have been used as solvents and as reaction components in order to facilitate the identification of the products by NMH spectroscopy. An- use of such compounds containing doutcrium is therefore not criticism for carrying out the method according to the invention. _ Example 1. Preparation of 7-amino-7-motoxicephalosporanic acid L several of the methyl ester. 60.4 mg '(0.1 mmol) 7- (5-phenylimido-5-carhoxivaleramide) -7-methoxy- Cephalosporanic acid dimethyl esters were mixed at room temperature with 0.5 ml methylene chloride-da, 21 mg (0.25 mmol) pyridine-d5 and H2 mg (0.2 mmol) phosphorus pentachloride. The reaction mixture was kept at room temperature for about 1 hour, after which it was cooled to 0 ° C and kept at this . -_.-.._- -. .P ...., .. t ...... z ._ .. z .._ fh, _v ...... v »v.. ,,,, ._, ____, _ D _ Lin-_ i -. 1313930-s 8 ', _ __ ._ .._ "ill ..i_. temperature for another 1 hour. 50 mg (1, Hü mmol) methanol-d was added, and the reaction mixture was allowed to stand for 0.5 hours, whereupon the desired 7-amino-7-methoxycephalosporanic acid methyl ester was formed aitu.

In a representative such preparation, the reaction was monitored using NMR spectroscopy. The addition of the phosphorus pentachloride resulted in a downward shift of the signal for the α-methylene group Before the addition of the phosphorus pentachloride After to in the valeramido side chain. there was a broad prot proton resonance centered around 2.55 ppm. new- the addition of the phosphorus pentachloride but before the addition of the methanol l there was a 2-proton triplet at 2.74 ppm (J ^ f7 Hz) ¿indicating imaging iminochloride. After the addition of the methanol disappeared restore the triplet and a 4-proton resonance centered at 2.35 Ppm des. I - Example 2. Preparation of 7-phenoxyethoamido-7-methoxycephalo- sporanoic acid methyl ester. . IN To the reaction mixture described in Example 1 containing 7-Amino-7-methoxycephalosporanic acid methyl ester was added at 0 ° C 0.5 ml chloroform-d, 127 mg (1.52 mmol) pyridine-d5 and 131 mg (0.77 mmol) phenoxyacetyl chloride. The reaction mixture was kept at 0 ° C for 15 minutes. and then warmed to room temperature for 10 minutes. Reactive The mixture was then prepared according to conventional methods.

These methods were essentially the same as the methods described below. is shown in Example 9, starting with the addition of dry methanol.

The exception was that methylene chloride was used in the present case in for the chloroform used in Example 9. The resulting method The chlorine chloride phase is chromatographed on thick layer plates using of a mixture of benzene and ether (7th) as developer and acetone such as eluent. The mass spectrum showed a parent peak at Ä450, which was consistent with the calculated molecular shape (450, U) for the expected compound 7-phenoxyacetamido-Y-methoxycephalosporanic acid -metvlester.

The compound was also subjected to high resolution mass spectroscopy. This analysis showed a parent ion with mass U50, 1106 (the risk values for ogorxgzngoßs are 45o, 1o97), _ A representative sample of the product was subjected to NMR spectra. skopi-i CDCI3. The following values were obtained: J 2.05 (s, BH,} -CH 2 - OCOCH3); 3.31 (two kv, 2H, 2-CH2); 5.51 and}, 54 (two S, BH, T-OCH) two epimers); 3.87 (s, 3H, N-COOCH 2); N, 08 (broad, 2H, øOCH2CONH); 4.96 (two kv, m, j-cnzococnjh 5.12 (s, ~ o, _15r-1, 641 of 'z-a-ocnj - -._ ... ,,. ä. - v -..-_ --- .... . 7313930-5 1 9 I 7 W _> epimer); and 5.25 ppm (s, 0,0.85H, 6H of Y-β -OCH 2 epimer).

Example 3. Preparation of 7-amino-γ-methoxylcephalosporanic acid. 57.6 mg (0.1 mmol) of 8- (5-phthalimido-5-carboxivaleramido) -7-methoxy- cephalosporanic acid was mixed with 0.5 ml of methylene chloride-d2, and the mixture cooled to 0 ° C. 80.5 mg (0.52 mmol) of dimethylaniline and 28.5 mg (0.55 mmol) of acetyl chloride was then added, and the reaction mixture was maintained 000 and stirred. 'Within 15 minutes, all the issues had been resolved. One hour Later, 75 mg (0.35 mmol) of phosphorus pentachloride was added, and the reaction the mixture was stirred. Within 25 minutes, the phosphorus pentachloride had dissolved and the reaction mixture was allowed to stand for several hours. Reactional the mixture was then stored in dry ice for 2 hours, after which it was heated to 0 ° C. 96 mg (5.0 mmol) of methanol-d were added, and reaction-1 the mixture was stirred and warmed to room temperature 5 minutes later.

The desired 7-amino-7-methoxycephalosporanic acid was obtained in situ.

Example U. Preparation of 7-phenoxyacetamido-7-methoxycephalo- sporanic acid. : To the final reaction mixture of Example 5 was added 0 ° C 0.5 ml Chloroform-d, 276 * mg (5.5 mmol) pyridine-d5 and 275 mg (1.6 mmol) phenoxyacetyl chloride, and the resulting reaction mixture was stirred. Twenty minutes later, 0.5 ml of Chloroform and 96 mg were added (5.0 mmol) methanol. The reaction mixture was diluted to 10 ml with chloroform, was extracted with sodium bicarbonate solution in two portions of 15 ml, and the sodium bicarbonate solutions were washed with 20 ml of chlorine. form. The chloroform layer and the sodium bicarbonate layer were separated, and 50 ml of chloroform was added to the sodium bicarbonate layer, which was then was acidified to pH 2.5 with phosphoric acid, after which the chloroform layer was removed. separated. The solution was re-extracted with 20 ml of chloroform. The last two chloroform layers, obtained from the acidified bicarbonate solution The mixture was combined and evaporated to give a total of 55.2 mg 7-phenoxyacetamido-7-methoxycephalosporanic acid.

Example gel 5. Preparation of 7-phenoxyacetamido-7-methoxyphalosposin rancid. 7-Phenoxyacetamide-7-methoxycephalosporanic acid was prepared on the same as in Examples 5-4 except that 52.2 mg (0.1 mmol) of 7- (5-chloroacetate) amido-5-carboxivaleramido) -7-methoxycephalosporanic acid was used as starting material. The other reactants in the initial stages gene was 0.5 ml of methylene chloride, 80.5 mg (0.1 mmol) of N, N-dimethylaniline, 28.5 mg (0.55 mmol) of acetyl chloride and 7.7 mg (0.55 mmol) of phosphorus penta chloride. The reactants and amounts then used were the same as in Examples 5 and N. After processing, üßü mg was obtained e e. ~ §55,1277 (the theoretical value for c2OD¿nl9N2o8s of 45;, 1285). Losporanoic acid dibenzhydryl ester was dissolved in 5 ml of methylene chloride, and dissolved - 7313930-5 7-phenoxyacetamido-7-methoxycephalosporanic acid.

Example 6. Preparation of 7-amino-7-methoxy-da-cephalosporan acid methyl ester. f 60.4 mg (0.1 mmol) of 7- (5-phthalimido-5-carboxivaleramido) -7-methoxy- cephalosporanic acid dimethyl ester, 0.5 ml of methylene chloride-d2 and 21 mg (0.51 mmol) pyridine-d5 was mixed at room temperature, then H2 mg (0.2 mmol) phosphorus pentachloride was added. The reaction mixture was allowed to stand during eza 5 hours. Then the reaction mixture was cooled to 0 ° C. and 52 mg (1.44 mmol) of methan-da-ol-d were added. This was obtained in situ the desired product 7-amino-7-methoxy-β-cephalosporanic acid methyl ester.

Example 7. Preparation of 7-phenoxyacetamido-T-methoxy-d3-ephalalone sporanoic acid ~ methyl ester. ¿' To the reaction mixture obtained in Example 6 was added 0.5 ml chloroform-d, 127 mg (1.52 mmol) pyridine-ds and 131 mg (0.77 mmol): phenoxyethyl ethyl chloride. The reaction mixture was then treated on the same method as in Example 9. After conventional work-up, 18 mg was obtained of the starting compound 7- (5-phthalimido-5-carboxyvaleramido) -7-methoxycepha- losporanoic acid dimethyl ester, 6.2 mg 7- (5-phthalimido-5-carbomethoxy-d3- -valeramido) -7-methoxycephalosporanic acid methyl ester, 11 mg mg phenoxyacetic acid acid-methyl-dj-ester, and 19 ml of the desired product ¶-phenoxyacet- amido-7-methoxy-da-cephalosporanic acid methyl ester. Mass spectroscopy with high resolution of this final product showed a mother peak with the mass NMH spectroscopy in CDCl3 gave the following values: ¿í2.09 (s, BH, 3-CHQOCOCH); 3.45 (m, 2H, 2-CH 2); 3.91 (t, BH, 4-COOCH 3); 4.61 and 4.62 (2 sharp peaks, total 2H, øOCH2CONH); 4.98 (kv, 2H, 5-CH2 OCOCH3) f and 5.15 and 5.26 ppm (2 sharp peaks, 0.5H and 0.7H, respectively 6-H of 7-α-OCH 3 - resp. 7- B-OCH; -epimers). x ¿ Example 8. Preparation of 7-amino-7-methexicephalosporanic acid ~., ....., _...- ... ._ -benzhydryl ester. ¿ 910 mg (1 mmol) 7- (5-phthalimido-5-carboxivaleramido) -7-methoxicepha- The mixture is stirred at 0 ° C. Then 0.198 U (0.2 ml; 2.5, mmol fl rpyridine and then 0.1 H2 g (2.0 mmol) of phosphorus pentachloride. Reactive The mixture was stirred at room temperature for 1.5 hours. There- f after, 0.46 g (0.59 ml; 14, H_mmol) anhydrous methanol was added, after the reaction mixture was stirred for 10 minutes at 0 ° C and se- 3 for 5 minutes at room temperature. The resulting reaction the mixture containing the desired product Y-amino-7-methoxycephalo- sporanic acid-benzhydryl ester, recooled to 0 ° C and partitioned i ”13930-5 portions.

Example 9. Preparation of 7-phenoxyacetamido-7-methoxyphalalone sporanoic acid-benzhydryl ester. .

To one of the portions of the reaction medium prepared in Example 8 the mixture containing 7-amino-7-methoxycphalosporanic acid benzhydryl ester was added 2.5 ml of chloroform containing 0.60 g (7.6 mmol) of pyridine.

The reaction mixture was stirred for 5 minutes, then 0.68 g (5.85) mmol) phenoxyacetyl chloride was added. The reaction mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 10 minutes. 0.5 ml of dry methanol was added, and the reaction mixture was stirred at room temperature for another 5 minutes. Then the reaction was poured. mixture in ice water, and the chloroform phase was washed with diluent HCl and then with several volumes of water, after which it was dried, first over sodium chloride and then over magnesium sulphate. The chloroform was removed in a rotary evaporator to give 1.14 g T of an oil.

This oil was chromatographed, and the fraction containing 7- -phenoxyacetamido-7-methoxycephalosporanic acid benzhydryl ester was separated and was subjected to NMR spectroscopy in CDCl 3: 1.1.97, 1.98 (two s, EH ) 3-CH2OCOCH3); 5.4 (two kv, 2H, 2-CH2); 3.54 (broad, BH, 7-OCH 3); 4.56 (two s, 2H, ø0CH2CONH); 4.9 (two kv, 2H, 3-CH 2 OCOCH 3); 5.11 (s, 0.4H), 6-H of 7-α-OCH 2 -epimer); and 5.24 ppm (s, 0.6H, 6-H of 7- @ -OCH7-epi- J J. ~ more).

The same fraction was chromatographed in two parts, one of which contained? contained 7-β-methoxystereoisomer (32 mg) and the other contained both 7-α- -methoxy- and 7-β-methoxy-epimer (57 mg).

Example 10 Preparation of 7β-phenoxyacetamido-7-α-methoxy- cephalosporanic acid. The fraction described in Example 9 containing 7-d-methoxy- and 7-β anethoxy epimer were then treated to remove benzhydric rylestern. The fraction was dissolved in 0.2 ml of a mixture of equal parts trifluoroacetic acid and formic acid, and after 5 minutes at room temperature 4 ml of methylene chloride were added, after which the mixture was evaporated to dry at room temperature in a rotary evaporator. Ethyl- acetate was added, and the mixture was extracted with dilute sodium bicarbonate. carbonate solution. The sodium bicarbonate extract is washed with ethyl acetate and then acidified to pH 1.5 under ethyl acetate. Then separate phases, and the ethyl acetate extract was dried over magnesium sulfate, filtered and evaporated to dryness.

There was thus obtained the α-apimer, 7-β -phenoxyacetamido-7-α-methoxy-

Claims (1)

7313930-5 -. 12 12 »m - e f, cephalosporanic acid. When the product was subjected to NM spectroscopy in CD01, the following results were obtained: 2.06 (s, BH, 3-CH 2 OCOCH); 3.56 (kv, an, 24:12), - 3.54 (s, 3H, 7-ocH3) -, 4.61 (broad, an, øocH2coNH), - 5.04 (kv, 2H, 3 -CH 2 OCOCH 3); and 5.12 ppm (s, 1H, 6-H). Exemgel ll. Preparation of 7-acetamido-7-methoxycephalosporan crude benzhydryl ester. The second portion of the reaction mixture prepared in Example 8 containing 7-amino-7-methoxycephalosporanic acid benzhydryl ester was acylated with acetyl chloride. With the exception of the acyl halide, the reactants and reaction conditions were the same as in Example 9. As a final product, 7-acetamido-7-methoxycephalosporanic acid benzhydryl ester was obtained. When the product was subjected to NMR spectroscopy in CDCl 3, the following results were obtained: 1.96 and 1.97 (i.e., 6H, 5-CH 2 OCOCH and L 7 -CH 3 CONH); 3.38 (kv, 2H, 2-CH 2); 3.50 (broad, EH, 7-0CH 3); 4.81 (two kv, 2H, 3-CH 2 OCOCH 3); 5.10 (s from another signal, 6-H of 7-α-OCH 3 epimer); and 5.20 ppm (s, 0.6H, 6-H of 7-f? -OCH -epimer). Example Gel 12. In the same manner as in Examples 3 and 4, the following compounds were also prepared: 7-Mandelamido-7-mezoxy-5- (s-meth-1-yl-1,3,8-thiaziaz-2-z-thiomenyl) - 3-cephem-4-carboxylic acid, UV (EtOH): λ = 270 nm, λ = 4000. 7-Mandelamido-7-methoxy-3- (1-methyl-1,2,3,4-tetrazol-5-yl-thiomethyl) -3-, - cephem-IL-carboxylic acid, UV (EtOH): δ = 270 nm, E = 4000. 7- [§- (2-thienyl) acetamide] -7-methoxy-5-acetoxymethyl-§-cephem-4-carboxylic acid, U.V. (MeOH): λ = 260 nm, δ = 8000. »7- [α1 (2-thienyl) acetamide] -7-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, U.v. (Ebony / e = = 265 nm, E = 7000. e 7- [§ ~ (2-thienyl) -acetamide§7-7 ~ methoxy-3- (5-methyl-1,3,4-thiadiazole-2 -yl-thiomethyl) -3-cephem-4-carboxylic acid, UV (EtOH): δ = 265 nm, E = 6000. 7- [2- (2-thienyl) acetamide] 7-7-methoxy-5- (1-methylyl, 2,5,4-tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid; UV (EtOH): λ 2 270 nm, 6'6 6000. preparation of 7-acylamido-7-alkoxycephalosporins of the formula É ORO s I 1 R5_N ___ ïf ____ | / ^ \ š I-CH -R 0 / k. ä '2 ......., .. .., \., .. ß in 7313920-5 where Ro represents a primary lower alkyl group containing 1-4 carbon atoms or a methyl-d- group, _R1 represents acetoxy, carbamoyloxy, i-methgl-1,2,3,4-tetrazole-5 -ylthio or 5-methyl-1,3,4-thiadiazol-2--ylthio; H2 represents hydrogen, alkyl containing 1-6 carbon atoms or diphenylmethyl (benzhydryD; and R5 represents hydrogen, alkanoyl containing 1-8 carbon atoms, phenoxyacetyl , mandeloyl or thienylacetyl, characterized in that an iminohalide of the formula X OCH; S 32000-cH (cH2) 3-Å = Nl _, ____ T / ”H4 J; ç, il__N / , - ena-H10 cooR2 where X represents bromine or chlorine; R1 and H2 have the meanings given above; and Ru represents an acylamido group, in which the acyl group is alkanoyl containing 1-5 carbon atoms, optionally substituted by halogen, or phthaloyl; is reacted with an alcohol of the formula RO-OH, where RO has the meaning given above, under substantially anhydrous conditions at a temperature between -70 ° C and + 50 ° C, the molar ratio of the alcohol to the imino ion being at least 2: 1; then optionally the product formed (R5 = H) is reacted in situ with a compound of any of the following formulas o_4n5> 2 where Y represents bromine or chlorine, and R5 has any of the above meanings other than a hydrogen atom. Y - R5; STATED PUBLICATIONS: a. Wet, x Äm-.Fffwa i n. -Feß-e .fa-ru _. ._ _ m ", .l-q ... e-fwf. -a - U