DE2011375A1 - Cephalosporin compounds - Google Patents

Description

Dr, F. Zumstein Sr. - Tue \ E. Assmann Dr. R. Koenigsberger - Dlpl.-Phys, R. Holzbauer - Dr. F. Zumstein Jun.

PATENT LAWYERS

TELEPHONE: COLLECTIVE NO. 22 83 * 1

TELEX 5E9979

TELEGRAMS! ZUMPAT POSTSCHECKKOr ^ TOi MÖNCHEN 91189

BANK ACCOUNT: BANKHAUS H. AUFHÄU3ER

θ MDNOH EN 2,

BRAÜHAUaSTRA83E

55 / Erlr Λ

Gases .; m 88-954

Cephalosporin 111 .. *. 1_ - -.

Glaxo laboratories Limited, Greenford, Middlesex, UK

Cephalosporin bonds.

The present invention is concerned with an improved Process for the preparation of cephalosporin compounds. In particular, see the invention dealt with 'the conversion of penicillin-like Compounds in cephalo3porin-like compounds.

The compounds of the present. Registration will be related to Denotes penicillanic acid and cepham,

Penicillanic acid has the following structure:

COOH

■■ I

and Cepham has the following structure?

009839

II

(see JACS 1962, £ 8, 3400 and J. Chem. Soc. 1965, 5031). The term ¹¹ C epheme "denotes the basic cepham skeleton with a single olefinic double bond.

Öephalosporin antibiotics are of great interest because a number of them have valuable properties in the treatment of infections caused by pathogenic bacteria If are and some of which are reslstent to other antibiotics. At present, penicillin compounds are manufactured in larger quantities than cephalosporin compounds on an industrial scale, and as interest in cephalodporin compounds gradually increases, it is of great value to develop processes for ^. To have available to make the latter, such as a simple process for converting penile-like compounds into cephalosporins.

The present invention is therefore mainly concerned with the conversion of ß-acylamidopenicillanic acid i-oxide esters into 7ß- Acy3 amido-3-methyl-ceph-3-em-4-carboxylic acid ester.

A general method is disclosed in U.S. Patent 3,275,626 ' for the production of antibiotic substances, including Cephalosporins, described in the so-called penioillin sulfoxide is heated under acidic conditions to a temperature of about 100 to about 175 ° 0.

It has now been found that yields of cephalosporin compounds, which are considerably higher than those who, after 'implementation as they' in U.S. Patent 3,275,626 can be achieved can, if one carefully (A) the solvent that is in the Reaction is used, (B) the acid catalyst and (0) the temperature and builder of the reaction selects. (0) depends, in part at least, on the particular choice of solvent and catalyst.

According to the present invention, "in process g" ar manufacturing

development of 7ß-acylamio-3-methyl-eeph-3-em-4-carboxylic acid esters supplied, which is characterized in that a 6β-acylamidopenicillanic acid i-oxide ester (which in the following for the sake of simplicity called penillin oxide) in the presence of an acidic catalyst, which is a hydrocarbon (e.g. alkyl,

Aralkyl or aryl) sulfonic acid (for example methanefonic acid or p-toluenesulfonic acid) or a phosphoric acid (for example orthophosphoric acid, polyphosphoric acid, pyrophosphoric acid, phosphorous or a phosphonic acid) and a solvent which is selected from ketones which are from 75 to 120 ° C (for example 100 to 120 * 0) boil, esters which boil from 75 to 140 ⁰ C (for example 100 to 130 ⁰ C), dioxane (in these solvents the reaction runs in a time of at least 2 hours at temperatures of about 75 to about 110 ⁰ C and within at least 45 minutes at higher temperatures from) and diethylene glycol dimethyl ether (diglyme) rearranged. The reaction is preferably carried out at the boiling point of the solvent.

The phosphonic acid can be an aliptic, araliphatic, or arylphosphonic acid; the aliphatic, araliphatic or aryl group of such a phosphonic acid can denote a hydrocarbon group (for example a lower alkyl, phenyl-alkyl or phenyl group) or a substituted hydrocarbon group, for example a group of hydrocarbons; a halogen atom or an ITitro group. Examples of aliphatic phosphonic acids include the lower alkyl and substituted (e.g. halogen) lower alkyl phosphonic acids such as methane phosphonic acid, ethane phosphonic acid, dichloromethane phosphonic acid, dichloromethane phosphonic acid and iodomethane phosphonic acid. Examples xou Arjlpiiosphansäuren include the B enzol- and substituted (for example with halogen oderUitro) benzene »phosphonic _r eg BrombenzolphoBphonsäuren and ^ itrobenzolphosphonsäuren.

-The amount of acid catalyst used should be preferred Do not exceed 1.0 mol / mol Panici 11 inoxide. It will

"... 009839/2289

preferred to use about 0.2 mole when using dioxane as the solvent and 0.05 to 0.1 mole when using a ketone or an ester is used as a solvent.

The time required to achieve optimal yields depends on various factors, such as the temperature used. The rearrangements are aptly carried out at the boiling point of the selected solvent, and accordingly can for the solvents in the lower Boiling part of the above range, correspondingly longer reaction times, for example up to 48 hours., Required than for those ketones and esters which boil at higher temperatures, the rearrangements in dioxane are in general It takes 10 to 15 hours for best results. The yields in the rearrangements also depend to a lesser extent on the concentration of the acid catalyst in the solvent away. So "~ are for lower concentrations of the acidic catalyst correspondingly longer response times are required.

Examples of ketones and esters which are used in the process according to the invention can be used are aliphatic ketones and esters that have suitable boiling points, including ethyl methyl ketone, Isobutyl methyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and diethyl carbonate.

The appropriate amount of time for a particular reaction can be determined by testing the reaction solution using one of the following methods :

(1) Investigation with thin layer chromatography, for example on silica gel, using a 2: 1 mixture of benzene and ethyl acetate for development and making the stains visible by treatment with an iodine / aside solution (Russell, Nature, 1960, 18b , Vöö) . Where, for example, as the starting material of the ü, *! _f 2-trichloroethyl üoü f.ss-PhenylacetamictopenicilianßUure-ISS-oxide comparable

OD9839 / 2269

is used, the product (R ™ 0.65) has an orange / tare une Color, whereas the starting material (R- ^ 0.5) shows a dark yellow color. -

(2) Determination of the rotation after suitable dilution of the Reaction mixture with, for example, chloroform. If the same starting material is used as in (1), the rotation is noticeable between 1/3 to 1/4 of the original value.

(3) Determination of the ultraviolet spectrum of a sample in the Reaction mixture, which has been diluted accordingly with ethyl alcohol. If the same starting material is used as in (1),

1 %

the value calculated for * ' at 264 nm increases to approx. 100 if the reaction is successful. Absorption maxima at higher wavelengths are preferably low or absent. This determination cannot be made when ketones are used as solvents in the reaction medium.

Although satisfactory yields can be achieved if one Carrying out the reaction under normal reflux, it may be possible be that the yields are improved by using a drying or dehydrating agents (e.g. aluminum oxide, - Calcium oxide, sodium hydroxide or molecular sieves) used, the is inert to the solvent at reflux temperature in order to remove the water formed during the reaction.

After the reaction is complete, it is desirable to remove the acid catalyst before concentrating the reaction mixture. If the reaction solvent is immiscible with water, the acids can be removed by simply washing with water. On the other hand, there is a convenient method for the removal of the acid catalyst in the reaction mixture when the Reale- tion medium 'is) miscible with water, to be treated with a finely divided neutralizing agent such as calcium carbonate or magnesium oxide and then erhilfβ in the presence of a EIIT to filter "The reaction solvent is then removed, conveniently

009839/2219

under reduced pressure and the residue through, either usual procedure, e.g. chromatography on silica gel, purified. It has been found, however, that the degree of conversion achieved by the process of the invention can be such that Complicated cleaning procedures can be omitted, and that the product is in an essentially pure form after a simple crystallization process is obtained. If so desired can be treated with animal charcoal to decolorize.

The reaction product can be isolated by mixing the reaction mixture in water, the product filtered off and, if desired by recrystallization from or slurrying with further cleaned with a suitable solvent.

The used as starting material in the process according to the invention Penicillin oxide can be obtained from a salt of 6ß-phenylacetamidopenicillanic acid or the öß-phenox-acetamidopenicillanic acid are made through a fermentation process, esterification the carboxyl group in the 3-position and oxidation of the Sulfur atom in the 1-position. Alternatively, the penicillin oxide can be derived from 6β-aminopenicillanic acid or the Ester by acylation of the amino group in the 6ß-position, esterification the carboxyl group in the 3-position and oxidation of the sulfur in the 1-position.

The oxidation can be carried out as described by Ohow, Hall and Hoover (J.Org.Chem. 1962, 22, 1381). The penicillin compound is mixed with the oxidizing agent in an amount sufficient to provide at least 1 atom of active oxygen is present per atom of thiazolidinaohulfur. Suitable oxidizing agents include metaperiodic acid, peracetic acid, Monoperephthalic acid, m-chloroperbenzoic acid and t-butyl hyperhydrite, the latter being preferably used in admixture with a weak base, e.g. pyridine. An excess of oxidizing agent can lead to the formation of the 1,1-

009839/2269

Dioxyds lead »The 1-oxide can either be in the ^ c - and / or ß-i'orm can be obtained.

The acyl group in the 6β-amino position of the penicillin oxide can be any desired acyl group, especially if it is reasonably stable under the rearrangement conditions. Suitable- * the acyl group is wise like that of penicillin is obtained in a fermentation process, for example Phenylacetyl or phenoxyacetyl. Such a group can be as follows: _oephalosppjrinend ^ r] odükt the desired group however

this can be achieved through subsequent conversions like them described below. Another acyl group which may suitably be used is the Sormyl group.

Alternatively, the acyl group in the 6β-position of the penicillin oxide can be that which is desired in the cephalosporin compound, for example a bisnylacetyl or phenylglyoxyl group, or it can be a precursor for the desired acyl group, for example an acyl group which has a protected functional component Group such as a protected amino group, An example of such an acyl group is a protected ¹ X -aminophenylacetyl group.

The amine protecting group is suitably one produced by hydrolysis can subsequently be removed without affecting the remainder of the molecule is attacked, especially the Iac camouflage and 7β-amido bonds the resulting cephalosporin connection. The same or a different protecting group can also be used as the esterifying group at the 3-CÜÜH position, and both groups can be removed immediately if desired. Si> x "preferred The method consists in that you have both groups in the last stage removed in the multi-stage process. .group include urethane, arylmethyl ~ (for example trityl) -amino, Arylmethyleneamino, sulfenyiamino and enamines. Such Groups can generally be formed by one or more reagents be removed, which are selected from among diluted minerals

009839/2289

8AÜ ORIGINAL

acids, for example dilute hydrochloric acid, concentrated organic acids, "for example concentrated acetic acid, trifluoroacetic acid and liquid hydrogen bromide" at very low temperatures, for example -80 ° 0. A suitable protective group is the tert-butozycarbonyl group, which can easily be removed by hydrolysis with dilute mineral acid, "for example dilute hydrochloric acid, or preferably with a strong organic acid (for example formic acid or trifluoroacetic acid), for example" at a temperature of 0 to 40 ⁰ C, preferably at room temperature door (15 to 25 ⁰ C) is removed. Another suitable protective group is the 2,2,2-'i ¹ richlorethoxy- ^ carbonyl group, which can be split off by an agent such as zinc in acetic acid, formic acid, lower alcohols or pyridine.

The ester of penicillanic acid is preferably formed with an alcohol or phenol that can be easily split off, for example by hydrolysis or reduction, in the later course of the synthesis, to subsequently the Ceph-3-em compound formed to be supplied as free acid. Alcohol and phenol residues, the that can be easily split off include those that attract electrons Substituents, for example sulfonic acid groups and contain esterified carboxyl groups, these groups • can subsequently be split off by alkaline reagents.

Benzyl and o-Benzyloxyphenoxyestergruppen can by hydrogenolysis be split off, although this can result in poisoning of the catalyst. A preferred method of removal includes cleavage with acid, and (troops passing through acidic cleavage can be removed include adamantyl, tert-butyl, Benzyl groups. like anisyl and the residues of alkanols, which contain electron donors in the X position, such as acyloxy, alkoxy, benzoyloxy, substituted benzoyloxy, halogen, alkylthio, Phenyl, alkoxyphenyl or aromatic heterocyclic G-rup- ■ pen. These groups can differ from benzyl alcohols, such as p-methoxybenzyl alcohol, di-p-methoxyphenylmethanol, triphenylmethanol, Diphenylmethanol, benzoyloxymethanol, benzoylmethanol, p-nitro-

009839/2269

■ benzyl alcohol and furfuryl alcohol.

Alcohol residues which can subsequently be readily cleaved by a reducing agent, are those which richloräthanol from 2,2,2-Trihalogenäthanol, for example 2,2,2-'i ^1, p-nitrobenzyl or 4-pyridylmethanol derived. 2,2,2-trihaloethyl groups can suitably be removed by zinc / acetic acid, zinc / formic acid, zinc / lower alcohol or zinc / syridine or by chromium-II reagents; p-Mtrobenzyl groups can suitably be removed by hydrogenolysis and 4-pyridylmethyl groups can suitably be removed by electrolytic reduction. . ·

If the ester group is subsequently removed by acid-catalyzed reaction, this can be achieved by adding formic acid or irifluoroacetic acid (preferably in combination with anisole) used, or alternatively by adding hydrochloric acid, for example in a mixture with acetic acid used. - ■ · - · -——-- · -

It is particularly preferred in the method according to the invention to use such penicillin oxides ^ which are a diphenylmethoxycarbonyl, a 2,2,2-trichloroethoxycarbonyl'-, a tert-butoxy carbonyl, a p-üFitrobenzyloxycarbonyl-, a benzoylmethoxycarbonyl- or a p-methoxybenzyloxycarbonyl group in the 3-position own as the ceph-3-em connections made by this Type of ester is formed (»n, no noticeable Δ * ^ ώ -isomerization are included in the saponification process.

If the Umlagerungspruuuki · wiue TiS Auylamidooeph-J-em-vcrbindung 1st who do not yet have the desired Aoylgruppe, can the 7.beta.-Aoylamido-connection are entaoetyliert on nitrogen desired to any other body of the molecule reactions w trden when, corresponding 7β-amino compound is formed, and the latter can be aoylated with a suitable aoylating agent.

0 0 9 8 3 9/22 6 9 originally inspected

Process for the N-deacylation of cephalosporin derivatives, the 7β-acylamido groups are known, and a suitable method "is that the 7β-acylamidoceph-3-em-4-carboxylic acid ester treated with an imide halide-forming compound, the imide halide thus obtained into the imino ether transferred and the latter decomposed. If desired, can the ester group can be split off by hydrolysis or hydrogenolysis, the 4-carboxylic acid being formed. Easily split off Ester groups are described above.

Suitable imide halide forming compounds include acid halides ones derived from phosphoric acids are preferred Compounds are the chlorides, such as phosphorus oxychloride or phosphorus pentachloride.

The process for N-deacylation is described in further detail in Belgian patent 719,712. The N-deformylation of a 7.beta.-i'ormamidogruppe can with mineral acid at a temperature of -15 to 100 ^0C, preferably +15 reached to 40 ⁰ C. A suitable reagent for N-deformylation is concentrated: ·· Hydrochloric acid in methanol or, preferably, in dioxane or tetrahydrofuran, since undesired transesterification reactions that ■ can occur in methanol are avoided.

The following examples illustrate the invention without, however, restricting it. In the examples, thin-layer chronography (TLC) was carried out on silica gel, unless otherwise stated, using a mixture of benzene and ethyl acetate (2: 1) as the developing agent and making the spots visible with iodine / azide solution .

example 1

2,2,2-i'rioaloräthyl-6ß-phenylaoetamidopenioillanat-1ß- oxide (4 ^ 82 g 10 mmol) was dissolved in dioxane (250 ml) , the methane

009839/2269

sulfonic acid (96 mg, tmol) and the solution was heated to reflux. The condensed steam was passed through a molecular sieve (Linde type; 4A, 1/16 "pellets, 40g) before. he was returned to the Reaktiönskorben. The reaction mixture was heated to reflux for 9 hours, additional portions of methanesulfonic acid (96 mg) being added after 3 and 6 hours. The reaction mixture was allowed to cool, the dioxane was removed in vacuo and the residue was taken up in ethyl acetate (200 ml) and then washed successively with water, 3% sodium bicarbonate solution and saturated brine (100 ml each). The solution was dried and evaporated to give a brown foam. This was dissolved in benzene; ethyl acetate (19: 1) and chromatographed on silica gel (200 g). The column was eluted first with the same solvent mixture and then a 9: 1 ratio and finally a 4: 1 ratio was used. A brown gel (3.35 g) was obtained from the latter fractions, which was crystallized from ether (100 ml), the 2,2,2-trichloroethyl-3-methyl-7βpheuylacetamidoceph-3-em-4 - received carboxylate (2.06 g, $ 40.5 of theory), m.p. 160 -162 * Γ £ <* 3ψ + 5ΐ ^ο (c 0.98 in.CHCl ₅ ); ^ (Ethanol) at 258 to 264 nm- (B] J ₁₁₁ * 125).

Example 2

2,2,2-Trichloroethyl-6ß-phenylacetamidopenlcillanat ^ 1ß ^ iyd (19.3 g) were dissolved in warm isobutyl methyl ketone (800 ml). A solution of orthophosphoric acid (i.e., 75-0.18 ml; 0.0725 molar equivalents) was added and the mixture was refluxed for 4 1/2 hours. Wax gentle cooling below the boiling point öalciumcarbonat were (Calofort'U ^1, 6 g) and activated carbon (SS 110, 6g) was added. The mixture was stirred for 20 minutes and cooled ^{to 35 ° C. at the same time.} The activated carbon and calcium salts were removed by filtration and washed with isobutyl methyl ketone (75 ml). The combined filtrates and wash water were evaporated to dryness and the residue was treated with warm, commercially available, denatured spirit (40 ml), whereby

009839/2269

a crystalline solid was obtained. The mixture was stored in the refrigerator overnight, and the solid was separated off by filtration, washed with commercially available denatured spirit (10 ml) and diethyl ether (20 ml) and dried in vacuo, the 2,2,2-trichloroethyl -3-methyl-7β-phenylacetamidoceph-3-em-4-carboxylate was obtained. (8.25 g, $ 44.4 of theory). IJiJ ₁ ) + 52.5 ° (c 1.0, OHOl ^), i ¹ . 161-162 °.

Example 3

2,2,2-'frichloroethyl-6ß-phenylacetamidopen5cillanate-1ß-oxide (4.82 g) was dissolved in warm isobutyl methyl ketone (100 ml). A solution (1.75; 0.06 ml, 0.097 molar equivalents) of orthophosphoric acid was added and the mixture was refluxed for 3 hours. The work-up was followed in a similar manner as described in Example 2, except that the isolation from isopropanol / diethyl ether was carried out to give the ^{2,2,2-trichloro>} ethyl-3-methyl-7.beta.-phenylacetamidoceph-3-em- 4-carboxylate received (1.81 g, 39 $ of theory) m.p. 159.5 ° to 160.5 °, a single spot on TIC.

Example 4

2,2,2-trichloroethyl-6ß-phenylacetamidopenicillanat-1ß-oxide ■ (4,82g) were dissolved in warm isobutyl methyl ketone (250 ml), V and methanesulfonic acid (d.1,48;. 0.064 ml, 0.1 molar equivalents)

were added. The mixture was heated to reflux for 2.2 hours, after which a second portion (0.064 ml) of methanesulfonic acid was added 1.5 hours added. The condensed vapors were in the reaction vessel returned after having them molecular sieves (Linde Type 4A 1/16 "pellets, 50 g).

After cooling, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution (2 × 100 ml) and water (100 ml). The organic phase was dried over anhydrous sodium sulfate and then with activated charcoal (1.5 g) 20 Minutes stirred. The activated carbon was filtered off and the lo-

009839/2269

' solvent removed under reduced pressure. The brown ... was triturated with hot ether (40 ml) until it solidified, and after cooling the 2,2,2-trichloroethyl-3-methyl-7β-phenylaceta.midQ-ceph-3-em-4 -carboxy.lat filtered off and washed with a little cold ether.

Yield 1.25 g (27% of theory); Pp, 159 to 160 ° Cj on TLO just a single spot.

Example 5

2,2,2-trichloroethyl-6ß-phenylacetamidopenicillanate-1ß-oxide (4.82g, 10 mmol) was dissolved in dioxane (200 ml), "and methanesulfonic acid (96 mg, 1 mmol) was added. The solution was heated to reflux, the condensate being returned to the reaction vessel through a column fitted with molecular sieves (Linde type 4A 1/16 " pellets, 20 g) was filled. More methanesulfonic acid (96 mg, ImMoI) was added after 1.5 and 3.5 hours. After half an hour With reflux, the reaction mixture was cooled somewhat and finely divided calcium carbonate (2 g) was added. the The mixture was refluxed for a few minutes, cooled to 60 ° and the solid is filtered off. The filter cake was washed with dioxane (2 × 15 ml), and the washing solutions were washed with the filtrate combined, and the solvent 3m vacuum at 65 °

θΐη /. ■ ~.

drawn, whereby / viscous 01 was obtained. This viscous UI was triturated with petroleum ether 60 ° to 80 ° (20 ml), the mother liquor was decanted off and the residue was dissolved in ethyl acetate (40 ml). Activated charcoal (1.7 g) was added and the mixture some. Stirred minutes at room temperature. The activated charcoal was filtered off and the residue was washed with ethyl acetate (2 × 20 ml). The filtrate and the water liquors were combined. and the solvent was stripped off in vacuo at 50 ^° C., a gel being obtained. Treatment of this gel with ether (25 ml) provided a colorless, crystalline solid. After cooling the mixture to 0 ° for 30 minutes, the product was filtered off, washed with ether (2 χ 15 ml) and always tempered in vacuo at Z

. * ■ - · ■ '■' 009839/22 * 9 '

Door dried to give the 2,2,2-trichloroethyl-3-methyl-7β-phenylacetamidoceph-3-em-4-carboxylate (1.58 g, 34.1 ^ of theory). Thin-layer chromatography only showed a single blotch, R- ^ ₁ 0.61. tfp. 161 to 165 ° P ³ Q ^ + 51.7 ° (c 1.14, CHCl ₃ ) Sf ^ _x (ethanol) at 264 nm (E ₁ ¹ ^ 139).

Example 6

2,2,2-'i ^l richlorethyl-6ß-phenylacetamidopenicillanate-1ß-oxide (2.41 g, 5 mmol) were refluxed in n-propyl acetate (100 ml), the oil> (weight / volume) orthophosphoric acid (0.065 ml, 0.2 molar equivalents), heated to boiling for 18 hours. The solution was neutralized with finely divided calcium carbonate (1 g) and the solvent was removed by distillation, uas remaining crude product was crystallized from ethanol (10 ml), the 2,2,2-i ¹ richloroethyl-3-methyl-7β -phenylacetamidoceph-3-em-4-carboxylate obtained (0.7 g, 30.3% of the theory) C ⁰ ^ J _n + 50.3 ° (c 0, ö, CHCl ₃ ) ϊρ. 161 to 162 °, Λ _mav (ethanol) at 264 nm (ü ^^ 135), TLC one spot, R ,, 0.65.

Kept JC · I C'XU JJ

Example 7

^{2.2,2-l l} rich chloroethyl-6ß-phenylacetamidopenicillanate-1ß-oxide (4.82 g, 10 mmol) was dissolved in isobutyl acetate (100 ml), the 80% (liter / vol.) Orthophosphoric acid (0.0325 ml , 0.05 mol equivalent), heated to boiling under reflux, the condensate being returned to the reaction vessel through a column filled with desiccant. After refluxing for 3½ hours, the reaction solution was neutralized with calcium carbonate (.1 g), decolorized with activated charcoal (1.5 g) and concentrated, leaving a foam. The residue was crystallized from ethanol (10 ml) to give 2,2,2-triohloroethyl-3-methyl-7β-phenylacetamido-oeph-3-em-4-oarboxylate (2.1 g) (45.3 % of theory) Γ ° ^ _Ώ + 52 ° (ο 0.5, CHOl ₃ ), ϊρ. 160 to 163 ° ^ _1n J _1x , (ethanol) at 264 nm

an I ¹ IeOk ₁ Rp 0.65.

009839/2269

Example · 8 · ■

Example 7 was repeated with the exception that sec-butyl acetate was used as the reaction solvent. Heating at reflux for 5 hours and working up in an analogous procedure as described in Example 7, gave 2,2,2-trichloroethyl-3-ynethyl- ^; · 7β-phenylacetaraidoceph-? 5-em-4-car "boxylate, 2.04 g (44 $ of theory). / JtJ ₁ ) + 51.8 ° (c 0.5, .OHOl ₃ ), pp. 160 to 162% / ^^ (ethanol) "at 264 nm (£ J £ _m 136) TLO a spot, R ^ 0.65.

Example 9

Example 7 was repeated except that n-butyl acetate was used as the reaction solvent. Ifech refluxing for 2 hours and working up in an analogous manner to that described in Example 7, the 2,2,2-trichloroethyr-3-methyl-7β-phenylacetamidoceph-3 ~ em-4- * carboxylate, 2, 33 g. (50.3% of theory) pp. 162 to 165 ° Z ^ A ₀ + 50.3 ° (c 0.8, CHCl ^) / l _v (ethanol) calc .; 264 nm. ($ Fl _m 136) TLO a KLeck,

0.65. . ■

Example 10

Example 7 was repeated except that diethyl carbonate was used as the reaction solvent. Heating at reflux for 2 hours and working up analogously to that described in Example 7 gave the 2,2,2-trichloroethyl-3-methyl-7β-phenylacetamidoceph-3-em-4-carboxylate, 2.17 g. (47 $ of theory), pp. 160 to 162 ° f ^ -JQ + 50.2 ° (e 0.8, CHOl ₃ )

(Ethanol) at 264 nm (E ^ _n , 134. TCL a pleck, R ^ 0.65.

Example 11

2,2,2-trichloroethyl-6ß ^ phenoxyacetamidopenieillanat-1ß-oxide (2.49 g, 5 mmol) were in liioxane (125 ml), the methanesulfonic acid (48 mg, 0.5 mmol) was dissolved and the solution became ■ heated to reflux. The condensed vapors were through Molecular sieves (Linde type 4A, 1/16 "pellets, 40g) directed,

009839/2269

before they were returned to the reaction vessel. The reaction mixture was heated to reflux for 9 hours with additional portions of methanesulfonic acid (48 mg) being added after 4 and 8 hours. The reaction mixture was cooled, the dioxane was removed in vacuo and the residue was taken up in ethyl acetate (100 ml) and washed successively with 3% sodium bicarbonate solution (2 × 100 ml) and water (100 ml). The solution was dried and evaporated to give the crude product (2.475 g). After washing, the crude product obtained was dissolved in methylene chloride (20 ml) and chromatographed on silica gel (200 g). The column was eluted with methylene chloride with a gradually increasing content of acetone, 100 ml fractions were collected, and fractions 9 to 11 (2 ^c /> acetone in methylene chloride) were evaporated and treated with ether, giving 0.72 g (29.8% of marriage theory) des

2,2,2-trichloroethyl-3-methyl-7β-phenoxyacetamidoceph-3-em-4-carboxylate was obtained; L ^ fψ + 57 ° (c 1.02 in CHCl ₅ ) (Ä) (PL) ^ A )

(Ethanol) at 265 nm (ePL 139) 268 nm ^ A _n 145), * 75 nm

4f ι CTIl ι CTH

(E «! __ 135). An analytically pure sample was obtained through 1 cm

Recrystallization from acetone / low-boiling petroleum ether, melting point 114 -5 °, £ <± 7 _± + 59 ° (c 1.12 in OHOl ₃ ).

Example 12

A solution of p-methoxybenzyl-eß-phenylaeetamidopenicillanate-1ß-oxide (2.35 g, 5 mmol) in dry dioxane (160 ml) containing methanesulfonic acid (48 mg, 0.5 mmol) was thus refluxed heated so that the condensed vapors passed through molecular sieves (Linde type 4A, 1/16 "; 40 g) before entering the Reaction vessels were returned. The reaction mixture will Heated under reflux for 7 1/2 hours, during which 2 and 4.5 hours additional amounts of methanesulfonic acid (48mg): added became. The dioxane was removed in vacuo and the remaining brown, gummy mass was dissolved in methylene chloride (15 ml) dissolved and on silica gel. (Merck, 0.05 to 0.2 mm; 100 g) chromatographed. Methylene chloride and 2-6 acetone in methylene chloride

009839/2269

eluted. essential oils; further ELutron with 5? , 32? Ό of theory), /? _Mov (ethanol)

at 267 ma. (EJr, 148).
ι ο cn

Example 13 . ^: ·

2u 2,2,2-trichloroethyl-6ß-phenylaeetaaiidopenicillanat-1ß-oxide (4.818 g, 0.1 mole) in dioxane (2GO ml) was added orthophosphoric acid (88? £ wt .- / tol ₁ 0.196 g, 0, 00196 moles) and heated the solution to reflux. The condensed vapors were passed through a column containing molecular sieves (Linde Type 4A); before they were poured back into the reaction vessel. The solution was refluxed for 18 hours. Finely divided calcium carbonate (2 g) was added to the warm solution and the mixture was stirred for a further 10 minutes, cooled and filtered. A work-up similar to that described in Example 1, with the exception that the final isolation from ether (25 ml) was carried out, gave 2,2,2- ^f i ¹ richlOratshyl-3-methyl-7ß-phenyl-acetamidoceph -3-em-4-carboxylate (2.6g, 56 $ of theory) Ep. 164-6 ^, £ <& 7 + 51.5 ° (c 0.8 in CHCl ₃ ); Jljyzx (ethanol) at 264 mn (E ¹ ^ _1n 145). one heck at TLC. ,

Example 14 ^ *

To 2,2,2-trichloroethyl-ß-phenylacetamidopenicillanate-iß-oxide (48.18 g, 0.1 mol) in dioxane (1 L) was added orthophosphoric acid ($ 88 w / v, 2.23 g, 0.02 mole) and warmed the solution at reflux. The "condensed vapors were through a column passed by calcium oxide before being returned to the tteatrtlönsgefäß became. The solution was refluxed for 15 1/2 hours. Finely divided calcium carbonate was added to the warm solution (5.4 g), stirred 10 minutes, cooled and filtered. The dioxane was distilled off under reduced pressure, and the remaining gummy mass was dissolved in ethyl acetate (500 ml) with Activated charcoal (15 g) 1 hour, stirred and filtered. The solution was

0 098 39/2289

un "he evaporated reduced pressure to dryness, and the partially solid gel was triturated with ethanol, cooled overnight, and the colorless solid was isolated by filtration to give the ^2,2,2-r i'richloräthyl-3-methyl '/ ß-phenylacetamido- cep! a-3-em-4-carboxylate received (25.88 g; 55 "8" of theory), up. 161-4 °: £ - * J + 51 "b ° ( o 0, ö in 'JHCU) A _108x (ethanol) at 2b4 nm (Ju ₁ ^ _n ,, 136); I'LL) a JTlecK.

ι Ο HX

Example 15

2,2,2-Trichloroethyl-6ß-phenylacetamidopenicillanate-1ß-oxide (2.41 g, 5 mmol) was dissolved in dioxane (bO ml; anhydrous ψ toluene-p-sulfonic acid (86.1 mg, 0.1 molar equivalents The mixture was heated to boiling under reflux, the condensate, before it was returned to the reaction flask, being passed through a column with molecular sieves (Linde type 4A 1/16 "pellets; 10 g). Further additions of anhydrous toluene -p-sulfonic acid (0.1 molar equivalents each) were made after 2 and 3 1/2 hours. After a total reaction time of 5 1/2 hours, the product was isolated as in Example 5, the 2 _? 2,2-Tricliloroethyl-3-methyl-7β-phenylacetamidoeeph-3-em-4carboxylate was obtained (0.54 g, 23.4% of theory); pp. 161-3 °, £ '* 3ψ + 51.8 ° (c 0.8 CHCl ₃ ); A ^ _x (ethanol) at 258-264 nm.

( ^E 3? L ¹ ^ O). A spot in TLC, R ₁ -, 0.65. ι cm JB

Example 16

A solution of diphenylmethyl-öß-phenylacetamido-penicillanate-1 β-oxide (5.16 g, 1CJmMoI; in dry diglyme (20 ml) was 7.U a solution of Wethansulfon acid (96 rag, 1 mmol) in dry Diglyme (~ 180 ml) was added, the latter solution distilling slightly. The distillation was continued for another 15 minutes, then the reaction mixture was cooled to room temperature and filtered through a column of silica gel (100 g). Elution with ethyl acetate was continued to give an eluate (500 ml) which was evaporated in vacuo a brown, gelatinous solid »

009839/2269

-.19 -

This solid substance was stirred with ether (approx. 20OmI), whereby the diphenylmethyl-I-methyl-Tß-phenylaeetsjaidoceph-I-em-4-carboxylate was obtained (1.48 g, 30% of theory) A _m (ethanol )

Λ at * HQaJi

■ at 258 nm. (EJi _n , 138).

I CUL

Examples 17 Ms 21

Using various catalysts, the 2,2,2-Srichloräthyl-öß-phenylacetaiiiidopenicillanat-iß-oxide in the -2,2,2-irichloroethyl-3-methyl-7ß-phenylacetaIIlidoceph.-3-em-4-. carboxylate converted under the conditions and in the yields, as given in Table I.

Table i

Ex. ._ solution concentration y ^ + yield

ffr. Catalyst -MoI-- _center f tration 5j ^xt der

5Jiir b.Siede- d.Penfcil- g theory

te "dot linoxyds ^SM

17 Metiianphos- 0.6 dioxane 5 $> 18.5 39.7 phonic acid

18 ethane phosphonic 0.6 »" 16 49.6 acid 'j

19 "Jodmethanphos- 0,2". · "16 54 * 2 'phonic acid

20 QJrichloromethane -

phosphonic acid 0.2 _t '- ■ "" 16 33

21 o-BrcciDGnsol- * phosphoic acid 0.25 "" 19 49

983 9-2269

Claims (1)

Patent claims 1. A process for the preparation of 7β-acylamido-3-methylceph-3-em-4-cartonic acid esters?. ·, Characterized in that an ß-acylamidopenicillanic acid i-oxide ester (hereinafter referred to as penicillin oxide) in the presence of an acidic catalyst such as a hydrocarbon sulfonic acid or a phosphoric acid and a solvent, such as ketones, VCN 75 to 120 ⁰ C, esters boiling from 75 to 140 ⁰ C, dioxane (where in these solvents, the reaction in a period of at least 2 h. at a Temperature of 75 to 11ü ° ö and at least 45 minutes at higher 'i' temperatures expires) and xiiäthylglycoldimethyläther rearranged. 2. The method according to claim 1, characterized in that the Hydrogen sulfonic acid is an alkyl, aralkyl or ArylEulfonic acid is 5. Traversed; according to claim 2, characterized in that the Koblenv / hydrogen sulfonic acid is methanesulfonic acid or pi ¹ oil and oil sulf cn acid. 4. The method according to claim 1, characterized in that the phosphoric acid o-phosphoric acid, polyphosphoric acid, Pyrophosphcrsäur-e, phosphorous nänre or a "phosphoric acid int. is. 5. Process according to one of the preceding claims, characterized in that the ketone boils ^{from 100 to 120 ° C.} 6. The method characterized according to one of claims 1 to 4, "the ester boils from 100 to 130 ⁰ C. 009839/2269 8AD T. The method according to any one of claims 4 to 6, characterized in that the phosphonic acid is an aliphatic, -araliphatic or arylphosphonic acid isi ' 8. "Method according to claim 7, characterized in that the aliphatic, araliphatic ^ or aryl group of the acid Is a hydrocarbon group or that such a group is substituted by a halogen atom or a metal group. 9. The method according to claim 8, characterized in that the. aliphatic phosphonic acid a lower alkyl or a by Is halogen substituted lower alkyl phosphonic acid. 10. The method according to claim 9, characterized in that the aliphatic phosphonic acid. Methane phosphonic acid, ethane phosphonic acid, dichloromethanephosphonic acid, jrichloromethanephosphonic acid or iodomethane phosphonic acid. 11. The method according to claim 8, characterized in that the arylphosphonic acid is benzene or "a halogen or nitrobenzene phosphonic acid is, 12. The method according to claim 11, characterized in that the Halobenzenephosphonic acid is a bromobenzenephosphonic acid. 13. The method according to any one of the preceding claims, characterized in that the concentration of the acidic catalyst does not exceed 1.0 mole / mole penicillin oxide. 14. The method according to claim 13, characterized in that the The proportion of the acidic catalyst is approximately 0.2 mol / mol psnicillin oxide when the solvent is dioxane. 15. The method according to claim 13, characterized in that the proportion of dea acidic catalyst from 0.05 to 0 _? 1 mole / mole. Penicillin oxide if the solvent is an ester or 009839/2269 is a ketone. 16. The method according to any one of the preceding claims, '' thereby characterized as being at the boiling point of the solvent is performed. 17. The method according to any one of the preceding claims, characterized characterized in that the solvent ethyl methyl ketone, isobutyl methyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate or diethyl carbonate. is. 18. The method according to any one of the preceding claims, wherein a dehydrating or drying agent, which under the Reaction conditions is inert, the backflow is interposed to that formed during the reaction Remove knife. 19. The method according to any one of the preceding claims, characterized in that after completion of the rearrangement of the acidic catalyst is removed by simple washing if the reaction solvent is immiscible with water is. 20. The method according to any one of claims 1 to 18, characterized in, that after completion of the rearrangement, the reaction solvent is removed if the reaction solvent is miscible with water, and the residue is purified by a usual Yöi'i'a.hreü pj. 21. The method according to any one of the preceding claims, characterized characterized in that the aoyl group is in the 6ß-position of a penioillin compound produced by a fermentation process was obtained. 009839/2269 8A £> OfWGlNAL 22. The method according to claim 21, characterized in that the penicillin oxide comes from a salt of 6ß-phenylacetamidopeniellanic acid, which was obtained by a Permentationsverfah-ren by esterification of the carboxyl group in the 3-position of penicillinic acid and oxidation of the sulfur atom in the 1-position . · 23. The method according to any one of claims 1 to 20, characterized in that the penicillin oxide from 6β ~ aminopenieil-xanoic acid is obtained by acylation of the amino group in the 6ß-position, if still present, esterification of Carboxyl group in the 3-position and oxidation of the sulfur | felatoms in the 1 position. 24. The method according to claim 22 or 23, characterized in that that the oxidation of the sulfur atom is carried out in the 1 position by mixing the penicillin compound with an oxidizing agent in an amount that at least 1 atom of active η oxygen per atom of thiazolidine sulfur is available. - Process according to Claim 24, characterized in that the oxidizing agent is methaperiodic acid, peracetic acid, monoperphthalic acid, m-chloroperbenzoic acid or tert-butyl hyperchlorite mixed with a weak base. 26. The method according to any one of the preceding claims, characterized in that the acyl group in the 6ß-Stel-Xung des i'enicillin oxide is that which is found in the oephalosporin compound is desired, or that it is a precursor for is the connection you want. 27. The method according to claim 26, characterized in that the acyl group contains a protected amino group. 009839/2269 28. The method according to any one of the preceding claims, characterized characterized in that the penicillin oxide is an ester which was formed with an alcohol or phenol, which in can easily be split off at a later stage in order to subsequently use the Qeph-3-em compound formed as free To deliver acid. 29. The method according to claim 23, characterized in that the ester is a 2,2,2-trichloroethyl-, a p-methoxybenzjrl-, a tert-butyl or a p-nitrobenzyl ester group contains. 30. The method according to any one of the preceding claims, characterized characterized in that if the rearrangement product is a 7ß-Acylamidoceph-3-em compound which does not contain the desired acyl group, the 7ß-acylamido compound li-deacylates is, if desired after reactions on others Position the molecule to form the corresponding 7β-amino compound, and the latter with an appropriate one Acylating agent is acylίert. 31 · The method according to claim 30, characterized in that N-deacylation by treatment of a 7β-acylamidoceph-3-em-4-carboxylic acid ester with an imide halide-forming agent, converting the imide halide thus formed into the imino ether and decomposition of the latter is effected. 32. 7β-Acylamido-3-methylceph-3-em-4-carboxylic acid ester tiach eiüSüi the Y & rXähreü & tüäß aea of the vcrhuriXG pending claims. 009839/226 «ba & original