FI58925B - FOERFARANDE FOER OMLAGRING AV EN 6-ACYLAMIDOPENICILLANSYRASULFOXIDE TILL EN 7-ACYLAMIDO-3-METHLCEF-3-EM-4-CARBOXYL SYRASE - Google Patents

Description

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j & T * (11) UTLÄGGNINGSSKAIPT 58925 fgft C i45) Patent ay tty II C5 1901 ^ '(51) K * .lk? /bn.CI.3 C O? D 501/10 FINLAND —FIN LAND (21) P * u <mlh »k.fmM-HuottMöknini 1294/72 (22) H * k * mlip» lY »- An * äknlr> *« d »j 08.05.72 ( 23) Alkspllvt — GIKlgh * t * d »| 08.05.72 (41) Tullut JulklMkil - Bllvit offentllj 22 U J2

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Paterrt- och ragisterstyralsan 'Amektn uti * jd och utukrtftm pubtkerad 30.01.8l (32) (33) (31) Aim of priority 11.05.71 usa (us) 143683 (71) Bristol-ifyers Company, 345 Park Avenue, New York, N.Y. 10022, USA (72) Raymond Urgel Lemieux, Edmonton, Alberta, Rintje Raap, Victoria, BC, Canada (CA), Joseph Rubinfeld, Northport, New York, USA (74) Oy Kolster Ab (54) Process for the conversion of 6-acylamidopenicillanic acid sulfoxide to 7-acylamido-3-methylcef-3-ene-4-carboxylic acid

The invention relates to a process for the preparation of 6-acylamidopenicillanic acid sulfoxide of the formula 0 "/ K /" 3 R-C-NH -, - S - 'CH3

J_N-L- CO H

wherein R is benzyl or phenoxymethyl, to convert 7-acylamido-3-methylcef-3-ene-4-carboxylic acid of formula 2,58925 0 s R-C-HN - | - N, N-N-N-CH3

C02H

wherein R is as defined above, by heating in the presence of an acid catalyst.

In the process according to the invention, the direct conversion of 6-acylamidopenicillanic acid sulfoxide to 7-acylamido-3-methylcef-3-em-4-carboxylic acid takes place without first having to esterify the 3-carboxyl group of penicillin. Much has been described in the literature for the conversion of penicillin-1-oxide esters to the corresponding 3-methylcef-3'-em-4-carboxylate esters, but according to the prior art, the 3-carboxyl group of penicillin must be in the form of a carboxylic acid ester to prevent decarboxylation. . The main prior art related to this reaction step is as follows: 1. U.S. Patent 3,275,626, issued September 27, 1966. This patent prescribes the rearrangement of 6/3-acylamidopenicillanic acid ester. It further teaches that if the penicillin sulfoxide used in the rearrangement is not in the 3-carboxylic acid ester form, then the reaction yields the decarboxylated 3-methyl-3-cephem product (column 5, lines 29-36 and column 7, lines 24-33).

2. GB Patent 1,204,394 teaches the rearrangement of 6-acylamidopenicillanic acid sulfoxide esters in a tertiary sulfonamide solvent system.

3. GB Patent 1,204,972 teaches the rearrangement of 6-acylamidopenicillanic acid sulfoxide esters in a tertiary carboxamide or tertiary urea solvent system.

4. U.S. Patent 3,507,861, issued April 21, 1970, further teaches the decarboxylation of a carboxyl group used as a "sulfoxide in conversion" as a free acid.

5. Morin, Jackson et al. further describe their findings in "Chemistry of Cephalosporin Antibiotics. XV. Transformation of Penicillin Sulfoxide", A Synthesis of Cephalosporin Compound, J. Ap. Chem.

Soc., 91 »1401, (March 12, 1969). This publication unequivocally discloses that the only product that can be separated and characterized from the acetic anhydrides of the free 3,58925 free penicillin sulfoxide acids and the acid-catalyzed secondary was 3-methyl-7- (2-phenoxyacetamido) -3-cephem.

6. Morin, Jackson et al. in J. Am. Chem. Soc. 85, 1896 (June 20, 1963) that rearrangement of penicillin sulfoxide acid results in decarboxylation.

7. That is to say, Lilly and Compan's ZA patent publication 68/2780 clearly shows that in all cases known penicillins must be esterified and converted into the corresponding sulfoxides before treatment, i. conversion to a 3-methyl-3-cephem-U-carboxylate derivative.

8. U.S. Patent 3,197 k66, issued July 27, 1965, teaches the preparation of penicillin sulfoxides.

9. Suddal, Morch, and Tybring teach the preparation of penicillin sulfoxide in their article "Penicillin Oxides, Tetrahedron Letters," 9 »Ρ · 38l (1962).

10. ZA Patent Publication 68/5889, Eli Lilly and Company, describes a process for preparing penicillin sulfoxide esters.

11. ZA Patent Publication 70/1627 to Glaxo Laboratories Limited describes the conversion of penicillin sulfoxide esters to 3-methylcef-3-ene-β-carboxylic acid esters using acid amine complexes and heat. Nothing has been shown that compounds other than penicillin sulfoxide esters can be reproduced without decarboxylation of the carboxyl group. All of the examples and claims set forth therein are directed to the secondary formation of penicillinic acid sulfoxide esters to 3-methyl-3-em-L-carboxylate esters.

In addition, it is known from FI patent application 1993/71 to subject N-nitroso or N-formylhetacillin sulfoxide in the free acid form to a rearrangement reaction to form N-nitroso or N-formylhetacalexin.

The process according to the invention is characterized in that the rearrangement reaction is carried out by heating 6-acylamidopenicillanic acid sulfoxide in the free acid form in a weakly basic solvent using either a strong acid alone or a nitrogen base having a pK 2 of at least U as catalyst.

The penicillanic acid sulfoxide used is derived from fermented penicillin.

By the term "fermented penicillin" is meant all known penicillins prepared by a fermentation process according to Behren's rule Medicinal Chemistry, 3rd Edition, p. 382, A. Burger, Wiley-Interscience (Pub.Ό) and in particular penicillins of the formula and 58925 "H / SV / CH3 RCN -IS CH3

0 ml_N - CO2H

wherein R is benzyl or phenoxymethyl. These penicillins are obtained more economically or more easily by fermentation methods. These preferred penicillins are 6-phenylacetamidopenicillanic acid (penicillin G) and 6-phenoxyacetamidopenicillanic acid (penicillin V).

U.S. Pat. No. 3,275,626 describes a general process for the preparation of antibiotics, including cephalosporins, in which the so-called penicillin sulfoxide ester is heated under acidic conditions to a temperature of about 100-175 ° C.

ZA patent 70/1627 describes a general process for the preparation of 3-methylcef-3-eme-U-carboxylate esters by heating a so-called penicillin sulfoxide ester with a "salt" formed by a nitrogen base and an acid. According to both of these prior patents, it is necessary to reproduce the penicillin sulfoxide esters in order to prevent decarboxylation in the resulting kef product.

According to the invention, it has been found that with certain catalysts, the conversion of penicillin sulfoxide-free acids can be carried out in good yield simply and economically.

According to the invention, 7- & ylamido-3-methylcef-3-em-U-carboxylic acid is prepared by reacting 6-acylamidopenicillanic acid sulfoxide in a weakly basic organic solvent such as dioxane, or diglyme, in the presence of a catalyst alone or in the presence of a strong acid alone. with a nitrogen base having a pK 2 value of at least 1+. The catalyst is preferably obtained from a nitrogen base and an acid which form salts or complexes, which salt may be formed in situ in the reaction mixture. The acid is preferably a polybasic acid, such as a phosphorus-containing acid.

The phosphorus-containing acid may be orthophosphoric, polyphosphoric, pyrophosphoric acid or phosphoric acid or it may be phosphonic acid. The phosphonic acid may be aliphatic, araliphatic or arylphosphonic acid; the aliphatic, araliphatic or aryl group of such a phosphonic acid may be a hydrocarbon group (e.g. a lower alkyl, phenyl-lower alkyl or phenyl group) or a hydrocarbon group substituted with e.g. a halogen atom or a nitro group. Examples of aliphatic phosphonic acids include lower alkyl and substituted (e.g. halogen) lower alkyl phosphonic acid such as methanephosphonic acid, ethanephosphonic acid, dichloromethanephosphonic acid, trichloromethanephosphonic acid and iodomethane-phosphonic acid. Examples of arylphosphonic acids are benzene and substituted (e.g. halogen or nitro) benzenephosphonic acid, e.g. bromobenzenephosphonic acid and nitrobenzenephosphonic acid. The definition of "phosphorus-containing acid" also includes anhydrides of the above-mentioned acids, e.g.

By the term "nitrogen base" is meant a basic substance that contains nitrogen, although it may contain other hetero differences and, e.g., oxygen. Preferably, however, weakly basic organic amines are used. The bases that can be used have a pK 2 value for protonation of at least U (measured in water at 25 ° C). The base may be a polyfunctional base having a nitrogen group with a pK 2 value for the first protonation step. The organic base may be primary, secondary or tertiary; preferably weak tertiary organic bases are used. Illustrative of these are unsaturated heterocyclic bases such as pyridine, quinoline, isoquinoline, benzimidazole and their homologues, e.g. alkyl-substituted pyridines and quinolines such as (f '', / 3 'and ^ "picolines and 2- and U- Other substituted heterocyclic bases that may be used include those substituted with halogen (e.g., chlorine or bromine), acyl (e.g., formyl or acetyl), acylamide (e.g., acetamido), cyano, carboxy, aldoxyimino, and the like.

Other organic bases that can be used include aniline and ring-substituted anilines such as haloanilines (e.g., o-chloroaniline, m-chloroaniline, and p-chloroaniline); anilines (e.g. o-methylaniline and m-methylaniline); hydroxy and (lower) alkoxyanilines (e.g. o-methoxyaniline and m-hydroxyaniline); nitroanilines (e.g. m-nitroaniline) and carboxyanilines (e.g. m-carboxyaniline) as well as N- (lower) alkylanilines (e.g. N-methylaniline) and N, N-di (lower) alkylanilines.

A preferred group of catalysts is obtained by reacting a phosphorus-containing acid with a nitrogen base. Advantageous results have been obtained in the process according to the invention when salts of orthophosphoric acid are used as catalysts. However, equally good advantageous results are obtained when the catalyst is formed in situ. Catalysts are obtained by reacting substantially molar equivalents of an acid with an aromatic, heterocyclic, tertiary organic nitrogen base in a weakly basic solvent system. Advantageous results have been obtained in the process according to the invention using complexes of lower alkyl, halogen, acyl, acylamide, cyano, carboxy or aldoxyimino-substituted pyridine, quinoline, isoquinoline or derivatives thereof as catalysts.

58925

Particularly preferred complexes of nitrogen bases are obtained by reacting a phosphorus-containing acid with an aromatic heterocyclic, tertiary organic nitrogen base. Advantageous results have been obtained in the process according to the invention by using salts of orthophosphoric or phoronic acid with pyridine, quinoline, isoquinoline or bases substituted by e.g. lower alkyl, halogen, acyl, acylamide, cyano, carboxy or genuineoxyimino. Thus, useful catalysts include pyridine; 2-methyl- and N-methyl-pyridine; quinoline and isoquinoline salts of orthophosphoric, methanephosphonic, ethanephosphonic, iodomethanephosphonic, dichloromethane-phosphonic, trichloromethanephosphonic, bromobenzene-phosphonic and nitrobenzene-phosphonic acids.

The catalysts used in the process according to the invention are obtained in such proportions of acid and base that the base and / or solvent partially neutralize one or more acidic groups. Generally, less than a molar amount of nitrogen base is used, so in addition to the salt, the catalyst also contains some free acid.

The optimal ratio of acid to base in the catalyst system depends on various factors, such as the nature of the acid and base as well as the nature of the penicillan acid sulfoxide. The optimal ratio can be determined by preliminary experiments.

A preferred catalyst system is obtained by reacting one mole of pyridine with 2 moles of orthophosphoric acid in dioxane.

Another preferred catalyst system consists of quinoline and orthophosphoric acid in a weakly basic solvent (e.g. dioxane). This is obtained by reacting substantially 1 molar equivalent of quinoline and 2 molar equivalents of orthophosphoric acid. A preferred catalyst system that can be used is obtained by combining P 2 O 2. * ^ a pyridine in a weakly basic solvent, e.g. dioxane.

The reproduction is preferably performed in a weakly basic organic solvent to control acidity, homogeneity and temperature. Usually penicillanic acid sulfoxide is in solution in an organic solvent. The solvent must be substantially inert to the penicillanic acid sulfoxide used in the process and to the 3-methylcef-3-enem * i-carboxylic acid prepared by the process.

Solvents that can be used are described in U.S. Patent No. 3,275,626 and other publications describing the rearrangement reaction. However, particularly suitable solvents are ketones boiling at 75-120 ° C to 7,58925 (e.g. 100-120 ° C), esters boiling at 75-120 ° C (e.g. 100-130 ° C), dioxane and diethylene glycol dimethyl ether ( Exemplary ketones and esters that can be used in the process of the invention include aliphatic ketones and esters having suitable boiling points, such as ethyl methyl ketone, isohutyl methyl ketone, methyl n-propyl ketone, n-propyl acetate, n- butyl acetate, iso-butyl acetate, sec-butyl acetate and diethyl carbonate These solvents are such that they can be prototyped by a strong acid and as such should be considered as "weakly basic organic solvents" The most preferred solvent is dioxane.

The time to obtain the optimum yields in the process according to the invention varies according to the solvent used and the temperature. The rearrangement is suitably carried out at the boiling point of the chosen solvent, and solvents boiling at the lower limit of the above range require correspondingly longer reaction times, e.g. up to U8 hours, than solvents boiling at higher temperatures. For example, rearrangement in dioxane usually requires 7-15 hours to achieve optimal results, while in methyl isobutyl ketone the reaction requires 1-8 hours. The recovery yields depend, albeit less, on the concentration of the catalyst in the solvent, requiring correspondingly longer reaction times when lower catalyst concentrations are used.

It is particularly advantageous to use dioxane as the organic solvent, since penicillanic acid sulfoxides can be dissolved in this solvent in high concentration and usually the yield is not reduced even if the concentration is increased to the order of 35%.

The amount of strong acid used in the conversion should generally not exceed 1.0 per mole of penicillanic acid sulfoxide; however, it is generally preferred to use Q, Q5 to 0.5 moles per 1 mole of penicillan sulfoxide.

The amount of nitrogen base used in the conversion should generally not exceed 1.0 mole per mole of penicillanic acid sulfoxide; however, it is generally preferred to use Q, Q25 to 0.25 moles per penicillanic acid sulfoxide.

The appropriate time for each reaction can be determined by examining the reaction solution by one of the following methods: 1. Thin layer chromatography, e.g., using silica gel, developing with a 3: 1: 1 n-butanol-acetic acid-water system, and visualizing the spots by treatment with a sulfuric acid jet.

2. Determination of circulating capacity after suitable dilution of the reaction mixture, e.g. with chloroform.

8 58925 3. Determination of the ultraviolet spectrum of a sample of the reaction mixture suitably diluted with ethyl alcohol. This assay is not applicable when ketone solvents are used as the reaction medium.

k. NMR (nuclear magnetic resonance).

Although satisfactory yields can be obtained by carrying out the reaction under normal conditions, it may be possible to improve the yields by adding a desiccant (e.g., alumina, calcium oxide, sodium hydroxide, or molecular sieves) inert to the solvent in the reflux condenser to remove water formed during the reaction. Alternatively, the water formed during the reaction can be removed using a separating column, whereby the water formed is removed by fractional distillation.

It will also be appreciated that the process of the invention may be carried out at elevated pressures. Low boiling point solvents can be used at temperatures above their boiling point. For example, when carrying out the reaction in a closed vessel, the process using tetrahydrofuran can be carried out, if desired, at 150 ° C, despite the fact that this temperature is above the reflux temperature of tetrahydrofuran at normal pressure. The invention also means carrying out said reaction using elevated pressures.

Upon completion of the reaction, the salt may be removed either before or after concentration of the reaction mixture. If the reaction solvent does not mix with water, the complex can be removed by ordinary washing. On the other hand, if the reaction medium is miscible with water, the reaction solvent is removed by a suitable purification technique (this can be done by distillation under reduced pressure) and then the residue is purified in a conventional manner, e.g., by chromatography on silica gel, etc.

It has been found that the degree of recurrence obtained by the process according to the invention can be such that a complex purification treatment can be omitted. The product can be extracted into a solvent and purified by crystallization from a suitable solvent.

According to a most preferred embodiment of the invention, 6-acylamidopenicillanic acid sulfoxide is reconstituted by heating 6-acylamidopenicillanic acid sulfoxide in the free acid form in dioxane at reflux for about 1-16 hours in the presence of a catalyst formed from pyride and 0.025 to 0.5 moles per 1 mole of penicillin sulfoxide.

According to the invention, it has been found, quite surprisingly, that, despite the teachings of the prior art, it is possible and practical to convert penicillanic acid sulfoxides to 3-methylcef-3-emem-U-carboxylic acids, with minimal decarboxylation. This finding offers a number of advantages for the rearrangement of penicillan sulfoxide esters in that it avoids the first esterification of penicillanic acid or penicillanic acid sulfoxide and the de-esterification of the 3-methylcef-3-em-ii-carboxylate ester after rearrangement.

The resulting 7-acylamido compound can be N-deacylated to the corresponding 7-amino compound, and the latter can then be silylated and acylated with an appropriate acylating agent.

Example 1 Preparation of 7- (phenoxyacetamido) -3-methylcef-3-em-k-carboxylic acid, i.e. 7- (phenoxyacetamido) deacetoxycephalosporanic acid (2) by conversion of penicillin V acid sulfoxide (1) Pyridine di (phosphoric acid) complex (PDPA) was prepared as follows: 7.8 g (0.10 mol) of pyridine was added portionwise to a stirred and ice-cooled solution of 23.0 g (0.20 mol) of 85 # orthophosphoric acid in 100 ml of tetrahydrofuran. The white solid precipitate was collected by filtration, washed with THF and ether and dried in vacuo over P 2 O 3. The yield was 25 g (92%).

A mixture of 18.3 g (0.050 mol) of penicillin V sulfoxide, 1.33 g (0.005 mol) of PDPA and 300 ml of anhydrous dioxane was heated under reflux (oil bath) for 8 hours. The recovered dioxane was passed through Linde i + A molecular sieves (100 g) in a Soxhlet before returning to the flask. The solvent was removed under reduced pressure, and the residue was treated with a mixture of 200 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer was extracted with 60 ml of 1N aqueous sodium bicarbonate solution. The bicarbonate extract was cooled and acidified with dilute hydrochloric acid. The semi-solid precipitate was extracted into 125 ml of ethyl acetate. This solution was dried (MgSO 4) and concentrated to dryness to give 1.0 g of a yellow solid foam. The amount of the desired product was determined to be 6.30 g (36%) by Nmr spectroscopy using o-toluic acid as an internal standard. To a cold solution of the crude product in 25 ml of methanol was added 7.9 g (0.010 mol) of benzylamine. After the addition of seed crystals, the dibenzylamine salt of compound (2) crystallized rapidly. The reaction mixture was cooled overnight at -15 ° C, after which the material was collected by filtration and washed successively with cold methanol and ether. 7.5 g (28%) of a white fluffy substance were obtained, m.p. 135-136 ° C (decomposes). The infrared spectrum of this salt was identical to the dibenzylamine salt of the authentic compound (2) (m.p. -1k-10 ° C (decomposed) after recrystallization from methanol.

10 5 8925

The dibenzylamine salt was shaken briefly with 75 ml of ethyl acetate and 30 ml of 1N hydrochloric acid. Dibenzylamine hydrochloride crystallized from this mixture and was collected by filtration and dried (2.5 g, 78%). The ethyl acetate layer was dried (MgSO 4) and concentrated to a volume of about 20 mL. The white material crystallized rapidly and, after cooling, was collected by filtration. Sanato: U, 1 g (2h%), m.p.

173-175 ° C (dec.); 3? 50 (NH), 1760 (β-lactam carbonyl), 1730 (amide carbonyl) and 1670 cm -1 (carboxy). The infrared and nmr spectra were identical to those of a sample of authentic compound (2), m.p. 177-178 ° C (decomposes), compound 2 was prepared from phenoxyacetyl chloride and 7-amino-deacetoxycephalosporanic acid.

Example 2

Conversion of Penicillin V Acid Sulfoxide (I) to 7- (Phenoxyacetamido) -desacetoxycephalosporanic Acid (2) Under Different Conditions Example 1 was repeated using varying conditions such as l) different proportions of sulfoxide and acid catalyst; 2) various solvents; 3) different reaction times; (k) possibly a desiccant; and 5) different reaction temperatures.

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Example 3

Conversion of compound 1 to the dibenzylamine salt of compound 2

A mixture of 18.3 g (0.05 moles) of penicillin V sulfoxide and 2.81+ g (0.02 moles) of P 2 O 2 was stirred with 300 ml of dioxane and heated under reflux for 8 hours. The reaction mixture was then filtered and the solid was washed with dioxane. The combined filtrates were concentrated and the residue was taken up in 100 mL of ethyl acetate and washed with water (2 x 50 mL). After drying the reaction mixture with> SO 2, the solvent was removed to give 15.3 g of a yellow-brown foam. A sample mixed with 0-toluic acid was analyzed by nmr spectroscopy to give a 22% yield of compound 2. The crude compound 2 was then converted to its pure dihenzylamine salt as follows: 1.0 g of foam was dissolved in 35 ml of methanol and 7.9 g (0, 0l + g) dibenzylamine. The reaction mixture was cooled overnight at -10 ° C, after which the resulting precipitate was filtered, washed with a small amount of cold methanol and dried to give 5.8 g (22%) of a pale material, m.p. 135 ~ 13β ° 0 (decomposes). The substance was found to be the dibenzylamine salt of 7- (phenoxyacetamido) deacetoxycephalosporanic acid.

Example ί

Conversion of Compound 1 to Compound 2

A mixture of 18.3 g (0.050 mol) of penicillin V sulfoxide, 1.38 g (0.005 mol) of PDPA and 300 ml of bis (2-methoxyethyl) ether (diglyme) was stirred at 110-115 ° C for 2 hours. . The reaction mixture was further treated according to Example 3 to give U, 75 g (17%) of the dibenzylamine salt, m.p. 130-13 ° C (decomposes), from which 1.75 g (10%) of 7-phenoxyacetamido) -desacetoxycephalosporanic acid were isolated, m.p. 168-70 ° C (decomposes).

Example 5

Conversion of Compound 1 to Compound 2

A mixture of 18.3 g (0.050 moles) of penicillin V sulfoxide, 0.9 g (0.001 + 3 moles) of $ 85 orthophosphoric acid and 300 ml of dioxane was heated at reflux for 16 hours. The reaction mixture was further treated as described in Example 3 to give 1.0 g (15%) of the dibenzyl brine salt, m.p.

130-132 ° C (decomposes), from which 1.13 g (6.5%) of 7- (phenoxyacetamido) -des-acetoxycephalosporanic acid were isolated, m.p. 172-173 ° C (dec).

Example 6

Conversion of Compound 1 to Compound 2

A mixture of 18.3 g (0.050 moles) of penicillin V sulfoxide, 0.65 g (0.0050 moles) of quinoline, 0.98 g (0.0085 moles) of 85 # orthophosphoric acid and 15,58925 300 ml of dioxane, heated to reflux for 8 hours. The reaction mixture was further treated according to Example 3 to give 6.3 g (23%) of the dibenzylamine salt, m.p. 135-136 ° C (decomposes), from which 3.5 g (20%) of 7- (phenoxyacetamido) desacetoxycephalosporanic acid were isolated, m.p. 17 ° + - 175 ° C (decomposes).

Example 7

Conversion of penicillin V acid sulfoxide to 7- (phenoxyacetamido) -desacetoxycephalosporanic acid 123.0 g (0.866 moles) of PgO 2 was added to 5.0 liters of dry dioxane followed by 1 + 7.0 ml (2.60 moles) of deionized water and 27.1 + ml pyridine. The slurry was stirred at reflux. The refluxed slurry was added to a solution of 1000 g (2.60 moles) of penicillin V sulfoxide monohydrate in 10 liters of dioxane at a steady rate over a period of 8 hours. Upon completion of the reaction (detected by T.L.C.), the slurry was cooled to 30-50 ° C and then filtered and washed with dioxane for complete removal. The filtrate and washings were combined and reduced in vacuo to remove dioxane. To the oil was added 10.0 liters of methylene chloride (MeCl 2) and the solution was stirred. To the MeCl 2 solution was added 15 liters of deionized water and the phases were mixed well. The pH was adjusted to 1.8 using HCl. The phases were separated and the aqueous phase was discarded. Rich MeCl 2 was stirred and 15.0 liters of deionized water was added. To the stirred mixture was added U60 g (5.5 moles)

The NaHCO 3 · pH was adjusted to 8.3-8.1+ using 10 # NaOH and the phases were stirred for 15-20 minutes (20 ° C) and the MeCl 2 phase was discarded. The aqueous phase was stirred and 10.0 liters of fresh MeCl 2 was added and the pH was adjusted to 1.8 using 6N HCl. The phases were stirred for 15 minutes and the rich MeCl 2 layer was separated and collected. A second extraction of the aqueous phase was performed using 5 liters of MeCl 2. The combined anhydrous MeCl 2 phases were dried. The MeCl 2 solution was liberated from MeCl 2 by vacuum distillation to give a glass. The yield was 1 + 00 g of the compound and analyzed by IR, NMR and iodometer analysis it was pure 7- (phenoxyacetamido) -desacetoxycephalosporanic acid.

Example 8

Conversion of penicillin V acid sulfoxide to 7- (phenoxyacetamido) -desacetoxycephalosporanic acid-dibenzylamine salt 1.3 g (0.05 moles) of penicillin V sulfoxide, 0.1 + 0 g (0.005 moles) of pyridine and 3 g (0.026 moles) of anhydrous dioxane, stirred and refluxed for 6 hours in an oil bath at about 135 ° C. The solvent was then removed, 100 ml of 58925 ι6 ethyl acetate was added to the residue and the solution was washed with water (2 x 50 ml). The organic layer was dried over MgSO 4 and the solvent was removed to give 17 g of a tan foam. The foam was dissolved in 35% methanol and 7.9 g (0.1 mol) of dibenzylamine was added and the resulting mixture was cooled for 1 hour at -5 ° C -15 ° C. The resulting precipitate was filtered, washed with cold methanol and dried to give 7.6 g (28.2%) of a light brown solid, m.p. 133-135 ° C (decomposes).

Claims (1)

17 58925 Claim: A process for the preparation of 6-acylamidopenicillanic acid sulfoxide of the formula 0 & CH_ • f q / J R-C-NH-j-f | CH3 NJ ^ CO H 0 wherein R is benzyl or phenoxymethyl to convert to 7-acylamido-3-methylcef-3-em-4-carboxylic acid of formula 0 RC-HN CH3 co2h in which R is as defined above, by heating in the presence of an acid catalyst, characterized in that the rearrangement reaction is carried out by heating 6-acylamidopenicillanic acid sulfoxide in the free acid form in a weakly basic solvent using either a strong acid alone or with a nitrogen base as catalyst