US3843637A - Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acyla mido-3-methyl-ceph-3-em-4-carboxylic acids - Google Patents

Abstract

6-Acylamidopenicillanic acid-1-oxides can unexpectedly be directly rearranged to 7-acylamido-3-methylceph-3-em-4-carboxylic acid without the necessity of first esterifying the 3-carboxyl function of the penicillin. For example, the rearrangement can be affected by treating 6-phenoxyacetamidopenicillanic acid sulfoxide with pyridine-di(phosphoric acid) complex (salt) to produce 7-phenoxy-acetamido-3-methylceph-3-em-4-carboxylic acid in 36 percent yield.

Description

United States Patent [191 lltniointeld et al.

[451 Oct. 22, 1974 [5 PROCESS FOR REARRANGING fi-ACYLAMIDOPENICILLANIC ACID-l-OXIDES TO 7-ACYLA MIDO-3-METHYL-CEPH-3-EM-4- cnn goxyuc Acrps [75] Inventors: Joseph Rubinfeld, Northport, N.Y.;

Raymond Urgel Lemiuex; Rintje Raap, both of Edmonton, Alberta,

Canada H V l [73] Assignee: Bristol-Myers Company, New York,

[22] Filed: May 11, 1971 [21] Appl. N0.: 143,683

[52] US. Cl. 260/243 C, 260/2391 [51] Int. Cl C07d 99/24 [58] Field of Search 260/243 C [56] References Cited UNITED STATES PATENTS 3,275.6-6 9/1966 Morin et a1. 260/243 C 3,668, 01 6/1972 Gutowski 260/243 C 6/1972 Foster et a1. 260/243 C 3,725,397 4/1973 Graham et a1. 260/243 C 3,725,399 4/1973 Ellerton et al. 260/243 C FOREIGN PATENTS OR APPLICATIONS 70/1627 2/1970 South Africa OTHER PUBLICATIONS Abstracts of ACS 160th National Meeting, Sept. l4-17, (1970), Division of Medicinal Chemistry.

Primary Examiner Nicholas S. Rizzo Attorney, Agent, or Firm-Robert E. Havranek [5 7] ABSTRACT 6-Acylamidopenicillanic acid-l-oxides can unexpectedly be directly rearranged to 7-acylamido-3- methylceph-3-em-4-carb0xylic acid without the neces sity of first esterifying the 3-carboxyl function of the penicillin. For example, the rearrangement can be al fected by treating 6-phen0xyacetamidopenicillanic acid sulfoxide with pyridine-di(phosphoric acid) complex (salt) to produce 7-phenoxy-acetamido-3- methylceph-3-em-4-carb0xylic acid in 36 percent yield.

1 Claim, N0 Drawings .1 PROCESS FOR REARRANGING 6-ACYLAMIDOPENICILLANIC ACID-l-OXIDES TO 7-ACYLA MIDO-3-METHYL-CEPH-3-EM-4- CARBOXYLIC ACIDS BACKGROUND OF THE INVENTION 1. Field of the Invention Due to the ever increasing importance of the cephalosporin antibiotics in medicine, it has become highly important to develop new and better methods of pro ducing the cephalosporin nucleus, 7-ACA and 7 ADCA (7-aminocephalosporanic acid and 7- aminodeacetoxycephalosporanic acid) in good yields. The present invention is directed to that effort.

2. Description of the Prior Art Thisinvention is directed to the preparation of 7- acylamido-3-methylceph-3-em-4-carboxylic acids by the sulfoxide rearrangement of corresponding 6- acylamidopenicillanic acid-l-oxides. There is much art in the literature relating to the rearrangement of penicillin-l-oxide esters to the corresponding 3- methylceph-3-em-4-carboxylate esters but all of this art teaches the necessity of the 3-carboxyl function of the penicillin being in the form of a carboxylic ester lest decarboxylation occur. The most pertinent art found is:

A. US. Pat. No. 3,275,626, issued Sept. 27, 1966 to Morin and Jackson. This patent teaches the rearrangement of 6B-acylamidopenicillanic acid ester.

cillin Sulfoxide, A synthesis of Cephalosporin Compound, J. Am. Chem. Soc., 9l, 1401 (Mar. 12, 1969). It was unequivocally stated in this publication that The only product which could be isolated and characterized from the acetic anhydride and acid-catalyzed rearrangement of penicillin sulfoxide free acids was 3-methyl-7-(2-phenoxyacetamido)-3-cephem."

4. Morin, Jackson et al., report in J. Am. Chem. Soc. 85, I896 (June 20, 1963) that the rearrangement of penicillin sulfoxide acid results in decarboxylation.

5. South African Pat. No. 68/2780 to Eli Lilly and Company clearly states that "In all cases, they (the prior art penicillins) must be esterified and con verted into the corresponding sulfoxide prior to treatment, i.e., rearranged to 3-methyl-3-cephem- 4-carboxylate derivative.

6. US. Pat. No. 3,l'97,466, issued July 27, 1965, to Chow et al. This patent teaches the preparation of penicillin sulfoxides.

7. Suddal, Morch and Tybring teach the preparation of penicillin sulfoxides in their article entitled Penicillin Oxides, Tetrahedron Letters, 9, p. 381 (1962).

8. South African Pat. No. 68/5889 to Eli Lilly and Company describes a process for the preparation of penicillin sulfoxide esters.

9. South African Pat. No. 70/ 1627 to Glaxo Laboratories Limited describes the rearrangement of penicillin sulfoxide esters into 3--methylceph-3-em-4- carboxylic acid esters using acid-amine complexes with the aid of heat. No teaching is found therein that compounds other than penicillin sulfoxide esters can be rearranged without the decarboxylation of the carboxyl group. All the examples shown therein and the claims thereto are directed to the rearrangement of penicillanic acid sulfoxide esters into 3-methylceph-3-em-4-carboxylate esters.

SUMMARY OF THE INVENTION This invention relates to a new and efficient process for the preparation of 7-acylamido-3methylceph-3- em-4-carboxylic acids having the formula ll H R-C-N----( CP 0 N wherein R is the side chain of a penicillin produced by fermentation, and M is H or a cation, said process comprising the rearrangement of the compound having the formula This invention relates to a new and unexpectedly successful process for the preparation of 7-acylamido-3- methylceph-3-em-4-carboxylic acids of the formula -iH S R-C-N amples in which R is the side chain ofa penicillin produced by fermentation, from 6-acylamidopenicillanic acid sulfoxides having the formula in which R is as above, and M is H or a cation, by the treatment of said penicillanic acid sulfoxide with a strong acid and a nitrogen base, with the aid of heat.

For the purpose of this disclosure, the term cation is meant to include those metallic cations such as sodium, potassium, calcium, aluminum, lithium and the like, and organic amine cations such as trialkylamines, e.g., triethylamine, trimethylamine, dibenzylamine, N-benzyl-B-phenethylamine, N-(lower)alkylpiperidines, e.g., N-ethylpiperidine, pyridine, and other amines which have been used to form salts with benzylpenicillin or the like.

The term penicillin produced by fermentation is meant to include all those penicillins known in the art to be prepared by a fermentation process according to Behrens Rule [Medicinal Chemistry, 3rd Edition, p. 382, A. Burger, Wiley-lnterscience (Pub.)] and most particularly include those penicillins having the forwherein R is phenyl, benzyl, phenoxymethyl, phenylmercaptomethyl, such phenyl, benzyl, phenoxymethyl, and phenylmercaptomethyl substituted with chlorine, methyl, methoxy, or nitro groups, as well as heptyl, and

thiophene-Z-methyl. Penicillins with these representative R groups are the more economically prepared or more readily obtainable by fermentation methods. Exof such penicillins and the 7- acylamidodesacetoxycephalosporanic acids which are obtained therefrom after sulfoxide formation and heat rearrangement by the above-referenced methods include:

Benzyl penicillin to form 7- (phenylacetamido)desacetoxycephalosporanic acid;

Phenoxymethyl penicillin to form 7- 3,4-Dimethoxybenzyl penicillin to form 7-(3,4- dimethoxyphenylacetamido)desacetoxycephalosporanic acid;

4-Methoxyphenoxymethyl penicillin to form 7-(4- methoxyphenoxyacetamido)desacetoxycephalosporanic acid;

4-Methylbenzyl penicillin to form 7-(4- methylphenylacetamido)-desacetoxycephalosporanic acid;

4-Nitrophenoxymethyl penicillin to form 7-[2-(4- nitrophenoxy)-acetamido]desacetoxycephalosporanic acid; and

3,5-Dimethylphenylmercaptomethyl penicillin to form 7-[2-3,5"-dimethylphenylmercapto)-aceta- L .9] l9a9qLQ1yP, sp ni a i The invention is thus principally concerned with the conversion of 6-acylamidopenicillanic acid-l-oxides into 7-acylamido-3-methylceph-3-em-4-carboxylic acids.

In US. Pat. No. 3,275,626 there is described a general method of preparing antibiotic substances, including cephalosporins, which comprises heating a socalled penicillin sulphoxide exter, under acid conditions, to a temperature of from about to about C.

- In South African Pat. No. 70/ 1627 there is described a general method of preparing 3-methylceph-3-em-4- carboxylate esters which comprises heating a so-called penicillin sulfoxide ester with a salt comprised of a nitrogen base and an acid. Both of the prior art patents teach the necessity of conducting the rearrangement on penicillin sulfoxide esters lest decarboxylation occur in the resulting ceph product.

It is an object of the invention to provide a novel process for the rearrangement of penicillin sulfoxide acid compounds to cephalosporin acid compounds. We have found that the rearrangement can be affected in good yields by means of certain catalytic systems.

In many instances the process can be effected with ease and economy of operation. The rearrangement is best performed under catalytic acid conditions using preferably polybasic acids such as ortho phosphoric acid, partially neutralized by basic solvents and more preferably by the addition of small amounts of a weakly basic substance such as pyridine or quinoline. For convenience we have described these catalysts as being complexes or salts although it should be understood that the term complex" is interchangeable with salts. Moreover, under the conditions of the reaction the salt or complex may exist in a dissociated form.

According to an embodiment of the present invention therefore there is provided a process for the preparation of 7-acylamido-3-methylceph-3-em-4-carboxylic acid comprising rearranging a 6-acylamidopenicillanic acid-l-oxide in a weakly basic organic solvent, such as dioxane or diglyme, in the presence of a nitrogen base having a pKb of not less than 4, and an acid, which will form salts or complexes, which salt may be formed in situ in the reaction mixture. The acid should preferably be a polybasic, for example, an organic acid such as a phosphonic or phosphoric acid.

The phosphorous containing acid may be orthophosphoric, polyphosphoric, pyrophosphoric or phosphorous acid or it may be a phosphonic acid. The phosphonic acid may be an aliphatic, araliphatic or aryl phosphonic 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 by, for example, a halogen atom or a nitro group. Examples of aliphatic phosphonic acids include the lower alkyl and substituted (e.g., halogeno) lower alkyl phosphonic acids such as methane phosphonic acid, ethane phosphonic acid,clichloromethane phosphonic acid, trichloromethane phosphonic acid and iodomethane phosphonic acid. Examples of aryl phosphonic acids include the benzene and substituted (e.g., halogeno or nitro) benzene phosphonic acids, e.g., bromobenzene phosphonic acids and nitro-benzenephosphonic acids.

The expression nitrogen base" is used herein as a convenient expression for a basic substance containing nitrogen although it may include other hetero atoms, e.g., oxygen. We prefer, however, to use weakly basic organic amines. Bases which may be used have a pKb for protonation of not less than 4 (i.e., as measured in water at 25 C.). The base may be a polyfunctional base having a nitrogen function with such a pKb for the first protonation step. The bases preferably have a pKb in water of not less than 7.

The organic base may be primary, secondary or tertiary; however, we prefer to employ weak tertiary organic bases. Illustrative of such tertiary organic bases are the unsaturated heterocyclic bases such as pyridine, quinoline, isoquinoline benzimidazole and homologues thereof, for example the alkyl substituted pyridines and quinolines such as a-, B- and y-picolines and 2- and 4- methylquinolines. Other substituted heterocyclic bases which may be used include those substituted by halogen (e.g., chlorine or bromine), acyl (e.g., formyl or acetyl), acylamido (e.g., acetamido), cyano, carboxy, aldoximino and the like.

Other organic bases which may be used include aniline and nuclear substituted anilines such as halogeno anilines (e.g., o-chloroaniline, m-chloroaniline and pchloroaniline); anilines (e.g., o-methylaniline and mmethylaniline); hydroxyand (lower)alkoxyanilines (e.g., o-methoxyaniline and m-hydroxy-aniline); nitroanilines (e.g., m-nitroaniline) and carboxyanilines (e.g., m-carboxyaniline) as well as N-(lower)alkyl anilines (e.g., N-methylaniline) and N,N-di(lower)alkyl anilines.

Preferred classes of catalytic systems are those obtained by the reaction of a phosphorus containing acid with a nitrogen base. Advantageous results have been obtained in the process according to the invention when salts of orthophosphoric are employed as catalysts. However, equally advantageous results are obtained when the catalyst is generated in situ. Catalyst systems 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 when complexes of pyridine, quinoline, isoquinoline or derivatives thereof substituted with lower alkyl, halogen, acyl, acylamido, cyano, carboxy, or aldoximino, are employed as catalysts.

Particularly preferred complexes of nitrogen bases are those obtained by reaction of a phosphorus containing acid with an aromatic heterocyclic, tertiary organic nitrogen base. Advantageous results have been obtained in the process according to the invention when salts of orthophosphoric or a phosphonic acid with pyridine, quinoline, isoquinoline, or such bases substituted by, for example, lower alkyl, halogen, acyl, acylamido, cyano, carboxy, or aldoximino are employed. Thus useful catalysts include pyridine; 2- methyl and 4-methyl-pyridine; quinoline and isoquinoline salts of orthophosphoric, methane phosphonic, ethane phosphonic, iodomethane phosphonic, dichloromethane phosphonic, trichloromethane phosphonic,

bromobenzene phosphonic and nitrobenzene phosphonic acids.

The catalytic system used in the process according to the invention may be derived from proportions of the acid and the base such that one or more of the acid function(s) are partially neutralized by the base and solvent. Generally, a less than molar quantity of nitrogen base is employed so that, in addition to the salt, the catalyst also comprises some free acid.

The optimal ratio of acid: base catalytic system will depend on various factors including the nature of the acid and the base as well as the nature of the penicillanic acid sulfoxide. The optimal ratio may be ascertained by preliminary trial and experiment.

One preferred catalytic system for use in the process according to the invention is that obtained by the reaction of 1 mole of pyridine and 2 moles of orthophosphoric acid in dioxane.

Another preferred catalytic system for use in the process according to the invention is formed from quinoline and orthophosphoric acid in a weakly basic solvent (i.e., dioxane). This is obtained by reaction of substantially one molar equivalent of quinoline and two molar equivalents of orthophosphoric acid.

The process according to the invention is preferably carried out in a weakly basic organic solvent to regulate acidity, homogeniety and temperature. Ordinarily, the penicillanic acid sulfoxide will be in a solution in the organic solvent. The solvent should be substantially inert to the penicillanic acid sulfoxide used in the process and to the 3-methylceph-3-em-4-carboxylic acid produced by the process.

Solvents which may be used include those described in US. Pat. No. 3,275,626 and other publications describing the rearrangement reaction. However, particu- 'larly suitable solvents include ketones boiling at from -l20 C. (e.g., l00-l20 C.), esters boiling at from 75l40 C. (e.g., lO0-l30 C.), dioxane and diethylene glycol dimethyl ether (diglyme). illustrative of those ketones and esters that may be used in the process according to the invention are aliphatic ketones and esters having appropriate 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. These solvents are capable of being protonated by a strong acid and as such are considered weakly basic organic solvents."

The time for achieving optimum yields by the process according to the invention varies according to the particular solvent and temperature employed. The rearrangements are conveniently carried out at the boiling point of the chosen solvent and, for those solvents boiling in the lower part of the ranges quoted above, correspondingly longer reaction times, e.g., up to 48 hours, may be required than for those solvent boiling at higher temperatures. For example, rearrangements in dioxane generally require times of 7-15 hours to achieve optimum results whereas those carried out in methyl isobutyl ketone generally require times of 1-8 hours. The

yields in the rearrangements are dependent, but to a lesser extent, on the concentration of the catalyst in the solvent, correspondingly longer reaction times being required for lower concentrations of catalyst.

We particularly prefer to use dioxane as the organic solventsince penicillanic acid sulfoxides can be dissolved in this solvent in high concentration and in general there is no falling off of yield with increase of concentration up to concentrations of the order of 35 percent.

The quantity of the strong acid used in the rearrangement should not generally exceed 1.0 mole per mole of the penicillanic acid sulfoxide, however, we generally prefer to use it in proportions of from 0.05 to 0.5 mole per mole of penicillanic acid sulfoxide.

The quantity of the nitrogenous base used in the rearrangement should not generally exceed 1.0 mole per mole of the penicillanic acid sulfoxide; however, we generally prefer to use it in proportions of from 0.025 to 0.25 mole per mole of penicillanic acid sulfoxide.

The appropriate time interval for any particular reaction may be determined by testing the reaction solution by one of more of the following procedures:

1. Thin layer chromatography, for example on silica gel, developing with 321:1 n-butanolacetic acid water system and rendering the spots visible by treatment with a sulfuric acid spray.

2. Determination of the rotation after suitable dilution of the reaction mixture with, for example,

chloroform.

3. Determination of the ultraviolet spectrum of a sample of the reaction mixture suitably diluted with ethyl alcohol. This determination cannot be adapted when ketonic solvents are used as the reaction media.

4. NMR (nuclear magnetic resonance).

Although satisfactory yields can be obtained by carrying out the reaction under normal reflux, it may be possible to improve the yields by inserting a desiccating agent (e.g., alumina, calcium oxide, sodium hydroxide or molecular sieves) which is inert to the solvent in the reflux return line to remove water formed during the reaction. Alternatively, the water formed during the reaction may be removed by the use of a fractionating column the water formed being removed by fractional distillation.

After completion of the reaction the salt may be removed either before or after concentrating the reaction mixture. If the reaction solvent is immiscible with water, the complex can be removed by a simple washing procedure. On the other hand, if the reaction medium is miscible with water a convenient purification technique is to remove the reaction solvent (this may be achieved by distillation under reduced pressure) and then to purify the residue by a convenient process, e.g., chromatography on silica gel, etc., or precipitation by salt formation, fractional crystallization, etc.

It has been found that the degree of conversion achieved by the process according to the invention may be such that complicated purification procedures can be dispensed with and the product isolated in a substantially pure condition after a simple crystallization process.

The product may be isolated by pouring the reaction mixture into water, filtering off the product and, if desired, further purifying by recrystallization from, or slurrying with, a suitable solvent.

The penicillanic acid sulfoxide used as the starting material in the rearrangement process according to the invention is derived from a fermentable penicillin or a salt thereof. The preferred penicillins used in this process are 6-phenylacetamidopenicillanic acid and 6- phenoxyacetamidopenicillanic acid or a salt thereof.

The oxidation may be carried out as described by Chow, Hall and Hoover (J. Org. Chem. 1962, 27, 1,381). The penicillin is mixed with the oxidizing agent in an amount such that at least one atom of active oxygen is present per atom of thiazolidine sulphur. Suitable oxidizing agents include hydrogen peroxide, metaperiodic acid, peracetic acid, monoperphthalic acid, mchloroperbenzoic acid and t-butyl hypochlorite, the latter being preferably used in admixture with a weak base, e.g., pyridine. An excess oxidizing agent may lead to the formation of l,l-dioxide. The l-oxide may be obtained in the R- and/or S-form.

Acyl groups at the 6-amino position of the penicillanic and sulfoxide may be any desired acyl group but should preferably be reasonably stable under the conditions of the rearrangement. Conveniently, the acyl group at the 6-position is that of a penicillin obtained by a fermentation process, e.g., phenylacetyl or phenoxyacetyl. Such a group may not be the desired group in the cephalosporin end-product but this can be obviated by subsequent transformations described below. Another acyl group which may conveniently be used is the formyl group.

Alternatively, the acyl group at the 6-position of the penicillanic acid sulfoxide may be that desired in the cephalosporin compound.

Where the product of the rearrangement is a 7- acylamidoceph-3-em-4-carboxylic acid not having the desired acyl group, the 7-acylamido compound may be N-deacylated, if desired after reactions elsewhere in the molecule, to yield the corresponding 7-amino compound and the latter then acylated with an appropriate acylating reagent.

Methods'of N-deacylating cephalosporin derivatives having 7-acylamido groups are known and one suitable method comprises treating a 7-acylamidoceph-3-em-4- carboxylic acid ester with an imide halide forming component, converting the imide halide so obtained into the imino ether and decomposing the latter. lf desired, the ester group may be split off by hydrolysis or hydrogenolysis to yield the 4-carboxylic acid.

Suitable imide halide forming components include acid halides derived from phosphorous, the preferred compounds being the chlorides such as, for example, phosphorus oxychloride or phosphorus pentachloride.

This method of N-deacylation is described in greater detail in Belgian Pat. No. 719,712. N-Deformylation of a 7-formamido group may be effected with a mineral acid at a temperature of l5 to C., preferably +l5 to 40 C. A convenient reagent for the N- deformylation is concentrated hydrochloric acid in methanol or, preferably, in dioxane or tetrahydrofuran since undesired transesterification reactions that tend to occur in methanol are thereby avoided. A most preferred deacylation process is described in U.S. Pat. No. 3,499,909 (see example 7 herein).

Applicants have found much to their surprise, that despite the teachings of the prior art, it is possible and practical to rearrange penicillanic acid sulfoxides to 3- methylceph-3-em-4-carboxylic acids with little decarboxylation occurring. This discovery offers a multitude of advantages over the process of rearranging the penicillanic acid sulfoxide esters in that it avoids the necessity of first esterifying said penicillanic acid or penicillanic acid sulfoxide and subsequent to the rearrangement, de-esterifying said 3-methylceph-3-em-4- carboxylate ester.

A preferred embodiment of the present invention is the process for the preparation of a compound having the formula in which R is the side chain of a penicillin produced by fermentation and M is H or a cation; which process comprises heating a compound having the formula in which R and M are as above; in a weakly basic organic solvent in the presence of a catalyst of a strong acid and a nitrogen base, said base having a pKb of not less than 4, or a strong acid alone, with the aid of heat.

Another preferred embodiment is the process for the preparation of a compound having the formula H s, a-carin which R is hexyl, thiophene-Z-methyl, phenylmethyl, phenyl, phenoxymethyl, phenylmercaptomethyl, said phenyl group having the formula in which R is H, Cl, CH CH O or N0 and M is hydrogen, sodium, potassium, calcium, aluminum, lithium, a cation derived from a tri-(lower)alkylamine, pyridine, benzylamine, or a N-(lower)alkylpiperidine; which process comprises heating a compound having the formula 2 H H v s 5, R-C'-N-- 3 o Nm- (10 M in which R and M are as above, in a weakly basic solvent with a catalytic amount of a strong acid and a nitrogen base, said base having a pKb of not less than 4.

Another preferred embodiment is the process for the preparation of a compound having the formula in which R is hexyl, thiophene-Z-methyl, phenylmethyl,

phenyl, phenoxymethyl, phenylmercaptomethyl, said phenyl group having the formula in which R is H, Cl, CH CH O or N0 and M is hydrogen, sodium, potassium, calcium, aluminum, lithium, a cation derived from a trialkylamine, pyridine, benzylamine, or a N-(lower)alkylpiperidine; which process comprises heating a compound having the formula in which R and M are as above, in a weakly basic solvent with a catalytic amount of a strong acid and a nitrogen base, said base having a pKb of ot less than 7.

A more preferred embodiment is the process for the preparation of a compound having the formula in which R is hexyl, thiophene-Z-methyl, phenylmethyl,

phenyl, phenoxymethyl, phenylmercaptomethyl, said phenyl group having the formula in which R is'l-l, Cl, CH CH O or N which process comprises heating a compound having the formula in which R is as defined as above, in a weakly basic organic solvent selected from the group comprising dioxane, tetrahydrofuran, ethyl methyl ketone, isobutyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, diethyl carbonate, or diethylene glycol dimethyl ether, at a temperature range of about 50 C. to about the reflux temperature of the solvent system, for a period of time of up to about 48 hours, said time partially determined by the temperature at which the process is conducted, in the presence of a catalytic amount of pyridinedi(phosphoric acid) complex.

A still more preferred embodiment is the process for the preparation of a compound having theformula g CH CH CO H II in which R is as above; in a'weakly basic organic solvent selected from the group comprising dioxane, tetrahydrofuran, ethyl methyl ketone, isobutyl acetate, secbutyl acetate, diethyl carbonate, or diethylene butyl acetate, sec-butyl acetate, diethyl carbonate, or diethylene glycol dimethyl ether, at a temperature range of about 50 C. to about the reflux temperature of the solvent system, for a period of time of up to about 48 hours, said time partially determined by the temperature at which the process is conducted, in the presence of pyridine-di(phosphoric acid) complex, said complex being present in a molar ratio of about 0.05 to 0.5 moles per mole of compound ll.

A most preferred embodiment is the process for the preparation of a compound having the formula in which R is benzyl or phenoxymethyl; which process comprises heating a compound having the formula in which R is as above; in dioxane at reflux temperature for a period of about 4 to about 12 hours, in the presence of pyridine-di(phosphoric acid) complex, said complex being present in a molar ratio of about 0.05 to 0.2 moles per mole of compound ll.

The 3-methylceph-3-em-4-carboxylic acids (l) produced by the instant invention can be readily converted to 7-ADCA according to the process described in US. Pat. No. 3,499,909 in excellent yield (see column 7, example 4), for example:

2.23 g. of the N-ethyl-piperidine salt of N- phenacetyl-3desacetoxy-7aminocephalosporanic acid were suspended in 18 ml. of methylene chloride, and after addition of 1.3 ml. of dimethylaniline, 1 ml. of trimethylchlorosilane was added thereto to form the corresponding trimethylsilyl ester. After 1 hour, the mixture was cooled to 50 C. and 1.1 g. of PCI was added. For 2% hours the temperature was held at 40 C. and then lowered to 65 C. A solution of 0.3 ml. of dimethylaniline and 12 ml. of butanol was added to the cooled mixture and then the temperature was held for 2% hours at 40 C. The reaction mixture was poured into a mixture of 35 ml. of water and 17 ml. of methanol, and brought at once to a pH of 3.5 with the aid of ammonium bicarbonate. After about 20 hours storage at 5 C., the precipitate was filtered off, washed with methanol-water l:l), methylene chloride and acetone, and dried to obtain 0.936 gm. (92 percent yield) of desacetoxy-7aminocephalosporanic acid.

The 7-ADCA so isolated can then be acylated to produce antibacterial cephalosporin compounds, for example:

7-( D-a-aminophenylacetamido )-3-methyl-A- cephem-4-carboxylic acid,

7-( dl-a-amino-m-chlorophenylacetamido )-3-methylcephem-4-carboxylic acid, 7-(dl-a-amino-p-chlorophenylacetamido)-3-methyl- A -cephem-4carboxylic acid, 7-(d1-a-amino-p-chlorophenylacetamido)-3-methyl- A -cephem-4-carboxylic acid trifluoroacetate, 7-(dl-a-amino-m-bromophenylacetamido)-3-methyl- A -cephem-4-carboxylic acid, 7-(dl-a-amino-m-bromophenylacetamido)-3-methyl- A -cephem-4-carboxylic acid trifluoroacetate,

7-(dl-a-amaino-m-fluorophenylacetamido)-3- methyl-A -cephem-4-carboxylic acid, 7-(dI-a-amino-m-methoxyphenylacetamido)-3- methy1-A -cephem-4-carboxy1ic. acid, 7-(d1-a-amino-m-methoxyphenylacetamido)3- methyl-A -cephem-4-carboxy1ic acid, 7-(dl-a-amino-m-methoxyphenylacetamido)-3- methyl-A -cephem-4-carboxylic acid trifluoroacetate, 7-(D-a-amino-m-hydroxyphenylacetamido)-3- methyl-A -cephem-4-carboxylic acid, 7-(p-chlorophenoxyacetamido)-3-methyl-A cephem-4-carboxylic acid potassium salt, 7-(m-nitrophenoxyacetamido)-3-methyl-A -cephem- 4-carboxylic acid potassium salt, 7-phenylmercaptoacetamido-3-methy1-A-cephem-4- carboxylic acid potassium salt, 7-(n-butylmercaptoacetamido)-3-methyl-A cephem-4 carboxylic acid potassium salt, and 7-(m-chlorophenylmercaptoacetamido)-3-methyl- A -cephem-4-carboxylic acid potassium salt. For the purpose of this disclosure, the term (lower) 1 alkyl is herein defined as an alkyl group comprised of from 1 to 8 carbons, said moiety being a straight or branched chain, saturated or monounsaturated hydrocarbon chain.

It is also to be understood for the purpose of this application that this process can be run at elevated pressures. As such, lower boiling solvents can be employed at temperatures above their boiling points. For example, if the reaction is conducted in a closed vessel, the process employing tetrahydrofuran could be conducted at 150 C. if so desired despite the fact that this temperature is above the reflux temperature of tetrahydrofuran at atmospheric pressure. The invention is meant to also embody said reaction conditions using elevated pressures.

EXAMPLE 1 Preparation of 7-(Phenoxyacetamido)desacetoxycephalosporanic Acid (2) by Rearrangement of Penicillin V Acid Sulfoxide (1) The pyridine-di(phosphoric acid) complex (PDPA) was prepared as follows: Pyridine (7.9 g., 0.10 mole) was added in portions to a stirred and ice-cooled solution of 85 percent orthosphosphoric acid (23.0 g., 0.20 mole) in 100ml. of tetrahydrofuran. The white solid precipitate was collected by filtration, washed with THF and ether and dried in vacuo over P yield: 25.4 g. (92 percent).

A mixture of penicillin V sulfoxide (18.3 g., 0.050 mole), PDPA (1.38 g., 0.005 mole) and anhydrous dioxane (300 ml.) was heated under reflux (oil bath) for 8 hours. The refluxing dioxane was passed through Linde 4A molecular sieves (-100 g.) in a Soxhlet apparatus before returning to the flask. The solvent was removed under reduced pressure and the residue treated with a mixture of ethyl acetate (200 ml.) and water (50 ml.). The ethyl acetate layer was extracted with l N aqueous sodium bicarbonate (-m1.). The bicarbonate extract was cooled and acidified with dilute hydrochloric acid. The semi-solid precipitate was extracted into ethyl acetate( 125 ml.). This solution was dried (MgSOQ and concentrated to dryness giving 14.0 g. of a yellow solid foam. By n.m.r. spectroscopy, using o-toluic acid as an internal standard, the amount of the desired product was estimated at 6.30 g. (36 percent). To a cold solution of the crude product in 25 ml. of methanol was added dibenzylamine (7.9 g., 0.040 mole). After the addition of some seed crystals the dibenzylamine salt of 2 crystallized readily. After cooling overnight at 15, the solid was collected by filtration and washed successively with cold methanol and ether. There was obtained 7.5 g. (28 percent) of white fluffy solid, mp. l35-136 (dec.). The infrared spectrum of this salt was superimposable with that of the dibenzylamine salt of authentic 2 (mp. 141-l42 (dec.), after recrystallization from methanol).

The dibenzylamine salt was briefly shaken with ml. of ethyl acetate and 30 ml. of l N hydrochloric acid. Dibenzylamine hydrochloride crystallized from this mixture and was collected by filtration and dried (2.5 g., 78 percent). The ethyl acetate layer was dried (MgSO and concentrated to a volume of approximately 20 ml. A white solid crystallized readily and, after cooling, was collected by filtration; yield: 4.1 g. (24 percent), m.p. 173l75 (dec.); -y,,,,, 3450 (NH), 1760 (B-Iactam carbonyl), 1730 (amide carbonyl) and 1670 cm (carboxyl). The infrared and n.m.r. spectra were superimposable with those of an authentic sample of 2, mp. l77l 78 (dec. prepared from phenoxyacetyl chloride and 7- aminodesacetoxycephalosporanic acid.

EXAMPLE 2 Rearrangement of Penicillin V Acid Sulfoxide (1) to 7-(Phenoxyacetamido)desacetoxycephalosporanic Acid (2) Under Various Conditions.

The essence of Example 1 was repeated using variable conditions such as (1 differing proportions of the sulfoxide and acid catalyst; (2) different solvents; (3) different reaction times; (4) with or without a desiccant; and (5) differing reaction temperatures to obtain the results reported below:

7-(PHENOXYACETAMIDOiDESACETOXYCEPHALOSPORANIC ACID BY REARRANGEMENT OF PENICILLIN V SULFOXIDE YIELD OF 2 REAC- REAC- ACTUAL ISOLATED AS ISOLATED EXP. MMOLES CATALYST TION ON (FROM (MHONH 5 PURE NO. OF 1 (MOLE EQUIV.) DESICCANT SOLVENT TEMP. TIME N.M.R.) SALT CRYST.)

I 10 DDP (0.05) M01. dioxane reflux 3 14 9 2 do. do. (0.2) do. 3 21 15 3 do. do. (0.1) do. 1 9 6 4 do. do. (0.1) do. 2 15 9 5 do. do. (0.1) do. 3 I7 11 6 do. do. (0.1 do. 4 18 I5 7 do. do. (0.1) do. 5,. 22 17 8 do. do. (0.1) do. 3 14 7 9 50 do. (0.1) do. 4 21 17 14 10 do. do. (0.1) MIBK 3 21 23 17 11 10 MDP (0.1) dioxane 3 24 l4 12 do. do. (0.1) do. 5 22 18 13 do. do. (0.1) MIBK 3,, 15 11 14 do. do. (0.1) dioxane 5,. 19 13 7-(PHENOXYACETAMIDO)DESACETOXYCEPHALOSPORANlC ACI D BY REARRANGEMENT OF PENlClLLlN V SULFOXIDE- Continued YIELD OF 2 REAC. REAC. ACTUAL ISOLATED AS ISOLATED EXP. MMOLES CATALYST TlON TlON (FROM b zlz PURE NO. OF 1 (MOLE EQUlV.) DESlCCANT SOLVENT TEMP. TIME N.M.R.) SALT CRYST.)

. 15 do. MDP(0.1)+

TMO'"(2.0) do. 5 l3 9 16 50 MDP (0.1) do. 4' 23 22 17 17 pyr.(0.1) do. 4 3.5 1 18 do. pyr. TsOH (0.1) do. 3 7 5.5 l9 l0 pyr. H=PO (0.1) do. 3 10 6 20 do. pyr H PO do.

(0.1 d0. 8 23 13 2| l0 PDPA (0.1) do. 8 28 23 22 50 PDPA (0.1) do. 8 36 28 24 23 10 H,PO (0.1) do. 8 12 8 24 2.7 none I do. 4 0 25 1O PDPA M01. sieves dioxane" reflux 2 12 10 26 10 do. 0. do. do. 4 25 19 27 50 do. none do. do. 8 22.5 20 28 10 do. Ac o do. do. 4 25 19.5 29 50 do. Ac O do. do. 6 27.5 22 30 50 do. Ac,0 do. do. 8 26 23.5 18 31 10 do. Ac O do. do. 8 22 20.5 32 10 do. none do. 130-35 1 20 14.5 33 10 do. Ac O do. 130-35 1 21 17 34 10 do. A'c,0 diglyme l0510 2.5 23 20 35 50 do. none do. l10l5 2 19.5 17 36 10 do. Ac o do. 125-30 1 27 25 37 10 do. A,o do. 125-30 1 18 12.5 38 10 do. none do. 125-30 1 22.5 14.5 39 10 do. A0 0 do. 135* 1 14 11.5 40 10 do. none do. 135 2 1 30 15.5 41 10 do. Ac o do. 140-45 0.5 23 23 42 10 pyr. H PO Mol. sieves dioxane reflux 5 10 7 43 50 H,PO none do. do. 16 l5 15 6.5 44 10 HJO, Mol. sieves do. do. 4 2 2 45 10 pyr. oxalic acid mol. sieves do. do. 8 3 3 46 10 pyr. o-NO,oOO,H mol. sieves do. do. 4 2 1.5 47 10 p-NH'SO,H none do. do. 16 5 48 10 PDPA none DMF IDS-10 2.25 3 49 10 PDPA none THF reflux 5O 50 PDPA none MlBK do. 3 l0 10 51 10 PDAC MgSO dioxane do. 4 8 5 52 l0 PDAC B 0: do. do. 4 5 3 53 I0 PDPA CuSO do. do. 4 54 10 N(CH ),.2H;,PO mol. sieves do. do. l0 16 ll 55 10 NH,2H,PO mol. sieves do. do. 8 15 9 56 10 Et,N.2H;,PO mol. 'eves do. do. 6 2 2 57 10 2-picoline.

2H PO mol. sieves do. do. 8 12.5 9.5 58 10 4-picoline.

- ZH PO, mol. sieves dioxane reflux 5 19.5 14 59 10 quinoline.

ZHJO, mol. sieves do. do. 8 26 19.5 60 10 quinoline.

ZH PO Ac O do. do. 8 21 18.5 61 50 I quinoline.

2H;,PO None do. do. 8 25 23 20 62 10 isoquinoline.

21-1,,PO Ac O do. do. 8 20.5 14 63 100 PDPA none do. do. 8 20 I8 PDPA: pyridine-di(phosphoric acid) complex; 0.1 mole equivalent of catalyst was used in all experiments. "In the experiments with molecular sieves (Linde 4A; -2 g. per m.mole of sull'nxitfe) the desiccant was placed in a Soxhlet; the other drying agents (2 mole equivalents) were part of the reaction mixture. 0.17 Molar solutions were employed, except Exp. 63 which was 0.20 molar.

'No desiccant.

'TMO=Trimethyl Orthoformate. Pyridine-di(phosphoric acid) (PDPA) Monopyridinium Dichloromcthylphosphonate (MDP) Dipyridinium Dichloromethylphosphonatc (DDP) Pyridinium p-toluenesulfonatc (PYR, TsOH) Pyridine (PYR) EXAMPLE 3 Rearrangement of 1 Into 2.

A mixture of penicillinV sulfoxide (1'8.3 g. 0.050

mole), PDPA (1.38 g., 0.005 mole) and dioxane 300 lution of this in 25 ml. of methanol was cooled and treated with dibenzylamine (7.9 g. 0.040 mole). After cooling at l5 overnight the white solid precipitate was filtered off and washed with cold methanol and ether. The dibenzylamine salt of the cephalosporanic acid amounted to 6.1 g. (22.5 percent), m.p. l37-l 38 (dec.). To liberate the eephalosporanic acid it was briefly shaken with a mixture of ethyl acetate ml.) and l N hydrochloric acid (30 ml.). The precipitated dibenzylamine hydrochloride (2.14 g., 82 percent) was removed by filtration. The ethyl acetate solution was dried (MgSO and concentrated to a volume of 15-20 ml. A white solid crystallized readily and, after cooling. was collected by filtration; yield: 3.45 g. (20 percent) desacetoxycephalosporanic of 7-(phenoxyacetamido)desacetoxycephalosporanic acid, m.p. 172-173 (dec.).

EXAMPLE 4 Rearrangement of 1 Into 2 A mixture of penicillin V sulfoxide (18.3 g., 0.050 mole), PDPA (1.38 g., 0.005 mole) and bis(2- methoxyethyl) ether (diglyme; 300 ml.) was stirred at 1l0-115 for 2 hours. The reaction mixture was worked-up as in Experiment 3 to give 4.75 g. (17 percent) of the dibenzylamine salt, m.p. 130-134 (dec.), from which 1.75 g. percent) of 7- (phenoxyacetamido)desocetoxycephalosporanic acid, m.p. l68-70 (dec.), was isolated.

EXAMPLE 5 Rearrangement of 1 Into 2 A mixture of penicillin V sulfoxide (18.3 g., 0.050 mole), quinoline (0.65 g., 0.0050 mole), 85 percent orthophosphoric acid (0.98 g., 0.0085 mole) and dioxane (300 ml.) was heated under reflux for 8 hours. The reaction mixture was worked-up as in Experiment 3 to give 6.3 g. (23 percent) of the dibenzylamine salt, m.p. 135l36 (dec.), from which 3.5 g. percent) of 7- (phenoxyacetamido)desacetoxycephalosporanic acid, m.p. 174175 (dec.) was isolated.

EXAMPLE 7 Preparation of 7aminodesacetoxycephalosporanic acid (7-amino-3-methylceph-3-em-4-carboxylic acid) (3) from 7-(phenoxyacetamido)desacetoxycephalos poranic acid (7-phenoxyacetamido)-3-methylceph-3- em-4-carboxylic acid) (2)- A solution of trimethylchlorosilane (0.65 g., 6.0 mmole) in 5 ml. of CH C1 was added dropwise in 3.5 minutes to a stirred mixture of 2 (1.74 g., 5.0 mmole), triethylamine (0.50 g., 5.0 mmole) and N,N- dimethylaniline (1.2 g., 10.0 mmole) in ml. of CH Cl at room temperature with stirring. The mixture was stirred an additional 30 minutes and then cooled to 55 C. Phosphorous pentachloride (1.15 g., 5.5 mmole) was added and the temperature maintained at stirring for 2 hours, then cooled again to 60 C. and 15 ml. of methyl alcohol and 0.3 g. of dimethy1aniline was added rapidly in 3 minutes (temperature rose to 50 C The resultant mixture was stirred at 40 i 4 C. for 2 hours and poured into an ice cold mixture of water (25 ml.) and methanol (12 ml.) with stirring. The pH of the stirred mixture was adjusted to 3.5 (initially l) with ammonium carbonate The mixture was cooled under refrigeration for 18 hot'irs and the solid precipitate was collected by filtration. The solid was washed with 15 ml. portions of ice water (2X) methanol (2X) and ether. The solid was dried in vacuo over P 0 to yield 0.83 g. (78 percent) of white crystalline solid that was determined to be identical with authentic 3.

EXAMPLE 8 Preparation of 7-(2,2-Dimethy1-4-oxo-4-phenyl-1- imidazolidinyl)3 methylceph-3em-4-carboxylic acid Place 0.10 mole of 7-ADCA in 300 ml. of anhydrous methylene chloride at 0l0 C. Add 28.0 ml. (0.204 ml.) of triethylamine and 15.0 ml. (0.118 mole) of dimethylaniline. Slowly add 25.4 ml. (0.2 mole) of trimethylchlorosilane while keeping the temperature at -10 C. Reflux the mixture for 30 minutes at 43 C. or stir for 2 hours at 510 C. Cool the mixture to 05 C. and slowly add 0.1 mole of phenylglycine chloride hydrochloride with stirring. Agetate for 1.5 to 2 hours at 05 C.

Add 30 ml. of triethylamine to the anhydrous acylation mixture. Immediatelv add ml. of acetone (chilled to 05 C.) followed by 300 ml. of 0-5 C. water. Agetate for 15 minutes and bring the pH into the range of 7.5 to 8.5 with 6N HCl or triethylamine if not in this range. Filter through filter aid and wash the cake with 75 ml. of cold water and 75 ml. of methylene chloride. Add the washer to the filtrate.

Separate the filtrates. Add to the water phase an additional ml. of methylene chloride. Stir five minutes and separate. Add 300 ml. of acetone to the aqueous phase and adjust the pH to 8.5-8.9 with 10 percent sodium hydroxide. Cool the reaction mixture for 16-20 hours at 05 C. Collect the resultant crystals which are determined to be 7-(2,2-dimethy1-5-oxo-4-phenyl- 1imidazolidinyl)-3methylceph-3-em-4-carboxylic acid.

EXAMPLE 9 Preparation of 7-(D-a-aminophenyacetamido)-3- methylceph-3-em-4-carboxylic acid V Suspend 10 gm. of 7-(2,2-dimethyl-5oxo-4-phenyll-imidazolidiny1)-3-methylceph-3em-4-carboxylic acid in about 0.75 ml. of water with rapid stirring at room temperature. Slowly add 1020 mole percent of 10 percent sodium hydroxide (based on the 10 gm. of cephem compound used) and continue to stir. The solid 7-( 2,2-dimethyl-5-oxo-4-phenyl- 1 imidazolidinyl)-3methylceph-3em-4-carboxylic acid slowly dissolves in the system and subsequently 7-( D-aaminophenylacetamido) 3-methylceph-3-em-4- carboxylic acid proceeds to crystallize. [f the pH rises, the pH is adjusted to pH 5.5-7. As a final pH, the mixture should be adjusted to pH 304 to obtain the maximum yield of material identified to be authentic V.

We claim:

1. The process for the preparation of a compound having the formula in which R is hexyl, thiophene-Z-methyl, phenylmethyl, phenyl, phenoxymethyl, phenylmercaptomethyl, said phenyl group having the formula in which R is H, Cl, CH CH O or N0 which process Comprises v 1.a Ha an ews! y nathrcwfor a h 82H II in which R is as defined as above, in a weakly basic organic solvent selected from the group comprised of dioxane, tetrahydrofuran, ethyl methyl ketone, isobutyl ketone, methyl n-propyl ketone, n-propylacetate, nbutyl acetate, isobutyl acetate, sec-butyl acetate, diethyl carbonate and diethylene glycol dimethyl ether, at a temperature range in the range of about 50 C to about the reflux temperature of the solvent system, for a period of time of up to about 48 hours, said time partially determined by the temperature at which the process is conducted, in the presence of a catalytic amount of pyridine-di-(phosphoric acid) complex, said complex being present in a molar ratio of about 0.05 to 0.5

moles per mole of compound II.

Claims (1)

1. THE PROCESS FOR THE PREPARATION OF A COMPOUND HAVING THE FORMULA