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

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

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US3843637A
US3843637A US00143683A US14368371A US3843637A US 3843637 A US3843637 A US 3843637A US 00143683 A US00143683 A US 00143683A US 14368371 A US14368371 A US 14368371A US 3843637 A US3843637 A US 3843637A
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acid
methyl
penicillin
sulfoxide
mole
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J Rubinfeld
R Lemiuex
R Raap
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Bristol Myers Co
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Bristol Myers Co
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Priority to DK220672AA priority patent/DK140845B/da
Priority to AU41876/72A priority patent/AU461358B2/en
Priority to IE606/72A priority patent/IE36353B1/xx
Priority to AR241869A priority patent/AR194364A1/es
Priority to FI1294/72A priority patent/FI58925C/fi
Priority to IL39382A priority patent/IL39382A/xx
Priority to NL7206193A priority patent/NL7206193A/xx
Priority to ZA723119A priority patent/ZA723119B/xx
Priority to SE7206073A priority patent/SE411045B/xx
Priority to PL1972155264A priority patent/PL85195B1/pl
Priority to PL1972177894A priority patent/PL94030B1/pl
Priority to PL1972179917A priority patent/PL94780B1/pl
Priority to BE783222A priority patent/BE783222A/xx
Priority to NO1673/72A priority patent/NO146202C/no
Priority to FR7216878A priority patent/FR2143667B1/fr
Priority to DE19722222953 priority patent/DE2222953A1/de
Priority to CS723129A priority patent/CS190367B2/cs
Priority to CH695572A priority patent/CH578007A5/xx
Priority to CS76639A priority patent/CS190399B2/cs
Priority to HUBI457A priority patent/HU166186B/hu
Priority to JP4554772A priority patent/JPS565229B1/ja
Priority to SU721783307A priority patent/SU626704A3/ru
Priority to HUBI442A priority patent/HU165177B/hu
Priority to CS76640A priority patent/CS190400B2/cs
Priority to YU01226/72A priority patent/YU122672A/xx
Priority to DD162907A priority patent/DD99584A5/xx
Priority to GB2216472A priority patent/GB1391838A/en
Priority to AT419272A priority patent/AT325201B/de
Priority to AT223774A priority patent/AT329752B/de
Priority to ES402672A priority patent/ES402672A1/es
Priority to AT223674A priority patent/AT329751B/de
Priority to NO4188/72A priority patent/NO146241C/no
Priority to NO4187/72A priority patent/NO146203C/no
Priority to AR245351A priority patent/AR200720A1/es
Priority to AR245352A priority patent/AR197310A1/es
Priority to SU731963857A priority patent/SU662013A3/ru
Priority to ES430116A priority patent/ES430116A1/es
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Priority to IN2509/CAL/74A priority patent/IN139912B/en
Priority to IN2508/CAL/74A priority patent/IN139911B/en
Priority to SE7414728A priority patent/SE414177B/xx
Priority to SE7414727A priority patent/SE414176B/xx
Priority to IN1965/CAL/75A priority patent/IN138944B/en
Priority to DK200677A priority patent/DK144096C/da
Priority to DK200577A priority patent/DK144095C/da
Priority to FI790906A priority patent/FI790906A/fi
Priority to FI790905A priority patent/FI790905A/fi
Priority to YU01749/79A priority patent/YU174979A/xx
Priority to YU01748/79A priority patent/YU174879A/xx
Priority to JP15446479A priority patent/JPS55108876A/ja
Priority to JP15446579A priority patent/JPS55108875A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/08—Preparation by forming the ring or condensed ring systems
    • C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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:
  • 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.
  • polybasic acids such as ortho phosphoric acid
  • a weakly basic substance such as pyridine or quinoline.
  • these catalysts as being complexes or salts although it should be understood that the term complex" is interchangeable with salts.
  • the salt or complex may exist in a dissociated form.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • halogen e.g., chlorine or bromine
  • acyl e.g., formyl or acetyl
  • acylamido e.g., acetamido
  • cyano carboxy, aldoximino and the like.
  • 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.
  • halogeno anilines e.g., o-chloroaniline, m-chloroaniline and pchloroaniline
  • anilines e.g., o-methylaniline and mmethylaniline
  • 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.
  • 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,
  • 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.
  • a weakly basic solvent i.e., dioxane
  • the process according to the invention is preferably carried out in a weakly basic organic solvent to regulate acidity, homogeniety and temperature.
  • a weakly basic organic solvent to regulate acidity, homogeniety and temperature.
  • 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.
  • 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).
  • 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.
  • ethyl methyl ketone isobutyl methyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and diethyl carbonate.
  • 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.
  • reaction times e.g., up to 48 hours
  • rearrangements in dioxane generally require times of 7-15 hours to achieve optimum results
  • those carried out in methyl isobutyl ketone generally require times of 1-8 hours.
  • dioxane as the organic solvent since 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:
  • a desiccating agent e.g., alumina, calcium oxide, sodium hydroxide or molecular sieves
  • the water formed during the reaction may be removed by the use of a fractionating column the water formed being removed by fractional distillation.
  • 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.
  • 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.
  • the acyl group at the 6-position is that of a penicillin obtained by a fermentation process, e.g., phenylacetyl or phenoxyacetyl.
  • 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.
  • the acyl group at the 6-position of the penicillanic acid sulfoxide may be that desired in the cephalosporin compound.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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
  • 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:
  • the 7-ADCA so isolated can then be acylated to produce antibacterial cephalosporin compounds, for example:
  • this process can be run at elevated pressures.
  • lower boiling solvents can be employed at temperatures above their boiling points.
  • 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).
  • 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.
  • 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).
  • dibenzylamine 7.9 g., 0.040 mole
  • 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.
  • Example 1 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:
  • 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.
  • 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.
  • PDPA Pyridine-di(phosphoric acid)
  • MDP Monopyridinium Dichloromcthylphosphonate
  • DDP Dipyridinium Dichloromethylphosphonatc
  • PYR, TsOH Pyridine
  • EXAMPLE 3 Rearrangement of 1 Into 2.
  • 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.
  • 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.
  • 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

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  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
US00143683A 1971-05-11 1971-05-11 Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acyla mido-3-methyl-ceph-3-em-4-carboxylic acids Expired - Lifetime US3843637A (en)

Priority Applications (54)

Application Number Priority Date Filing Date Title
US00143683A US3843637A (en) 1971-05-11 1971-05-11 Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acyla mido-3-methyl-ceph-3-em-4-carboxylic acids
CA139,912A CA986096A (en) 1971-05-11 1972-04-18 Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acylamido-3-methylceph-3-em-4-carboxylic acids
PH13501A PH13518A (en) 1971-05-11 1972-04-28 Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acylamido-3-methyceph-3-em-4-carboxylic acids
DK220672AA DK140845B (da) 1971-05-11 1972-05-04 Fremgangsmåde til omlejring af et 6-acylamidopenicillansyresulfoxid til en 7-acylamido-3-methylceph-3-em-4-carboxylsyre.
AU41876/72A AU461358B2 (en) 1971-05-11 1972-05-04 Methods of preparatin for cephalexin and hetacephalexin
IE606/72A IE36353B1 (en) 1971-05-11 1972-05-08 Rearrangement of 6-acylamidopenicillanic acid sulfoxides and production fo cephalexin or hetacephalexin
AR241869A AR194364A1 (es) 1971-05-11 1972-05-08 Procedimiento para la redisposicion de un sulfoxido de acido 6-amino-penicilanico en acido 7-acilamido-3-metilcef-3-em-4-carboxilico
FI1294/72A FI58925C (fi) 1971-05-11 1972-05-08 Foerfarande foer omlagring av en 6-acylamidopenicillansyrasulfoxid till en 7-acylamido-3-metylcef-3-em-4-karboxylsyra
IL39382A IL39382A (en) 1971-05-11 1972-05-08 Process for the preparation of cephalexin and hetacephalexin
NL7206193A NL7206193A (no) 1971-05-11 1972-05-08
ZA723119A ZA723119B (en) 1971-05-11 1972-05-08 Process for the preaparation of antibacterial agents
SE7206073A SE411045B (sv) 1971-05-11 1972-05-09 Sett att omlagra en 6-acylamidopenicillansyra-sulfoxid till motsvarande 7-acylamido-3-metylcef-3-em-4-karboxylsyra
PL1972155264A PL85195B1 (no) 1971-05-11 1972-05-09
PL1972177894A PL94030B1 (no) 1971-05-11 1972-05-09
PL1972179917A PL94780B1 (pl) 1971-05-11 1972-05-09 Sposob wytwarzania cefaleksyny
BE783222A BE783222A (fr) 1971-05-11 1972-05-09 Procede de production d'agents antibacteriens
NO1673/72A NO146202C (no) 1971-05-11 1972-05-10 Fremgangsmaate for omleiring av et 6-acylamidopenicillansyresulfoksyd til en 7-acylamido-3-metylceph-3-em-4-karboksylsyre
FR7216878A FR2143667B1 (no) 1971-05-11 1972-05-10
DE19722222953 DE2222953A1 (de) 1971-05-11 1972-05-10 Verfahren zur herstellung antibakterieller mittel
CS723129A CS190367B2 (en) 1971-05-11 1972-05-10 Process for preparing derivatives of cephalosporine
CH695572A CH578007A5 (no) 1971-05-11 1972-05-10
CS76639A CS190399B2 (en) 1971-05-11 1972-05-10 Process for preparing caphalexine
HUBI457A HU166186B (no) 1971-05-11 1972-05-10
JP4554772A JPS565229B1 (no) 1971-05-11 1972-05-10
SU721783307A SU626704A3 (ru) 1971-05-11 1972-05-10 Способ получени 7-феноксиацетамидо-3метилцеф-3-ем-4-карбоновой ксилоты
HUBI442A HU165177B (no) 1971-05-11 1972-05-10
CS76640A CS190400B2 (en) 1971-05-11 1972-05-10 Process for preparing hetacephalexine
YU01226/72A YU122672A (en) 1971-05-11 1972-05-10 Process for producing antibacterial agents
DD162907A DD99584A5 (no) 1971-05-11 1972-05-11
GB2216472A GB1391838A (en) 1971-05-11 1972-05-11 Rearrangement of 6-acylamidopenicillanic acid sulphoxides and production of cephalexin or hetacephalexin
AT419272A AT325201B (de) 1971-05-11 1972-05-12 Verfahren zur herstellung von 7-acylamidocephalosporamsäuren
AT223774A AT329752B (de) 1971-05-11 1972-05-12 Verfahren zur herstellung von hetacephalexin
ES402672A ES402672A1 (es) 1971-05-11 1972-05-12 Un procedimiento para la transposicion de un sulfoxido de acido 6-acilamidopenicilanico a acido 7-acilamido-3-metilcef-3-em-4-carboxilico.
AT223674A AT329751B (de) 1971-05-11 1972-05-12 Verfahren zur herstellung von cephalexin
NO4188/72A NO146241C (no) 1971-05-11 1972-11-16 Fremgangsmaate til fremstilling av hetacephalexin eller salter derav
NO4187/72A NO146203C (no) 1971-05-11 1972-11-16 Fremgangsmaate til fremstilling av cephalexin eller salter derav
AR245351A AR200720A1 (es) 1971-05-11 1972-11-28 Procedimiento para la produccion de cefalexina
AR245352A AR197310A1 (es) 1971-05-11 1972-11-28 Procedimiento para la produccion de hetacefalexina
SU731963857A SU662013A3 (ru) 1971-05-11 1973-10-16 Способ получени гетацефалексина или его солей
ES430116A ES430116A1 (es) 1971-05-11 1974-09-16 Un procedimiento mejorado para la preparacion de cefalexinay sales no toxicas y farmaceuticamente aceptables de la mis-ma.
ES430117A ES430117A1 (es) 1971-05-11 1974-09-16 Un procedimiento mejorado para la preparacion de hetacefa- lexina.
IN2509/CAL/74A IN139912B (no) 1971-05-11 1974-11-14
IN2508/CAL/74A IN139911B (no) 1971-05-11 1974-11-14
SE7414728A SE414177B (sv) 1971-05-11 1974-11-22 Forfarande for framstellning av hetacefalexin
SE7414727A SE414176B (sv) 1971-05-11 1974-11-22 Forfarande for framstellning av cefalexin
IN1965/CAL/75A IN138944B (no) 1971-05-11 1975-10-10
DK200677A DK144096C (da) 1971-05-11 1977-05-05 Fremgangsmaade til fremstilling af hetacephalexin eller salte deraf
DK200577A DK144095C (da) 1971-05-11 1977-05-05 Fremgangsmaade til fremstilling af cephalexin eller salte deraf
FI790906A FI790906A (fi) 1971-05-11 1979-03-16 Foerfarande foer framstaellning av hetakefalexin och dess salter
FI790905A FI790905A (fi) 1971-05-11 1979-03-16 Foerfarande foer framstaellning av kefalexin och dess salter
YU01749/79A YU174979A (en) 1971-05-11 1979-07-18 Process for producing antibacterial agents
YU01748/79A YU174879A (en) 1971-05-11 1979-07-18 Process for producing antibacterial agents
JP15446479A JPS55108876A (en) 1971-05-11 1979-11-30 Manufacture of antibacterial
JP15446579A JPS55108875A (en) 1971-05-11 1979-11-30 Manufacture of antibacterial

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US00143683A US3843637A (en) 1971-05-11 1971-05-11 Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acyla mido-3-methyl-ceph-3-em-4-carboxylic acids

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JP (3) JPS565229B1 (no)
AR (3) AR194364A1 (no)
AT (1) AT325201B (no)
AU (1) AU461358B2 (no)
BE (1) BE783222A (no)
CA (1) CA986096A (no)
CH (1) CH578007A5 (no)
CS (3) CS190399B2 (no)
DD (1) DD99584A5 (no)
DE (1) DE2222953A1 (no)
DK (1) DK140845B (no)
ES (3) ES402672A1 (no)
FI (1) FI58925C (no)
FR (1) FR2143667B1 (no)
GB (1) GB1391838A (no)
HU (2) HU166186B (no)
IE (1) IE36353B1 (no)
IL (1) IL39382A (no)
NL (1) NL7206193A (no)
NO (3) NO146202C (no)
PH (1) PH13518A (no)
PL (3) PL94780B1 (no)
SE (3) SE411045B (no)
SU (2) SU626704A3 (no)
YU (3) YU122672A (no)
ZA (1) ZA723119B (no)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3953440A (en) * 1974-12-13 1976-04-27 Eli Lilly And Company Deacetoxycephalosporins via penicillin sulfoxide rearrangement
US3960851A (en) * 1972-05-15 1976-06-01 Eli Lilly And Company Preparation of desacetoxy-cephalosporin sulfoxides from penicillin sulfoxides
US3966720A (en) * 1972-12-09 1976-06-29 Nikken Chemicals Co., Ltd. Process for producing desacetoxy cephalosporanic acid compound
US3978053A (en) * 1973-11-29 1976-08-31 Sumitomo Chemical Company, Limited Process for producing cephalosporins
US3993646A (en) * 1971-06-24 1976-11-23 Fujisawa Pharmaceutical Co., Ltd. Process for the ring expansion of penicillins to cephalosporin compounds
US4010156A (en) * 1973-04-19 1977-03-01 American Home Products Corporation Process for the rearrangement of penicillins to cephalosporins and intermediate compounds thereof
US4061862A (en) * 1975-10-06 1977-12-06 Bristol-Myers Company Derivatives of 7-(cyclized)phenylglycyl-3-triazolo-thio methyl cephalosporin
US4091213A (en) * 1975-12-12 1978-05-23 Bristol-Myers Company 7-Cyclizedamino-3-heterothiomethyl cephalosporin derivatives
US4122258A (en) * 1972-03-23 1978-10-24 Takeda Chemical Industries, Ltd. Process for producing desacetoxycephalosporin derivatives by heating a penicillin-1-oxide in presence of an organic sulfide
US4282145A (en) * 1973-02-09 1981-08-04 Gist-Brocades N.V. Process for the preparation of azetidines

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1441587A (en) * 1972-07-14 1976-07-07 Glaxo Lab Ltd Cephalosporin compounds
US4182709A (en) * 1976-01-15 1980-01-08 Glaxo Group Limited Manufacture of semi-synthetic penicillin antibiotics
NO2451643T3 (no) 2009-07-08 2018-01-20

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH565809A5 (no) * 1969-03-11 1975-08-29 Glaxo Lab Ltd

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993646A (en) * 1971-06-24 1976-11-23 Fujisawa Pharmaceutical Co., Ltd. Process for the ring expansion of penicillins to cephalosporin compounds
US4122258A (en) * 1972-03-23 1978-10-24 Takeda Chemical Industries, Ltd. Process for producing desacetoxycephalosporin derivatives by heating a penicillin-1-oxide in presence of an organic sulfide
US3960851A (en) * 1972-05-15 1976-06-01 Eli Lilly And Company Preparation of desacetoxy-cephalosporin sulfoxides from penicillin sulfoxides
US3966720A (en) * 1972-12-09 1976-06-29 Nikken Chemicals Co., Ltd. Process for producing desacetoxy cephalosporanic acid compound
US4282145A (en) * 1973-02-09 1981-08-04 Gist-Brocades N.V. Process for the preparation of azetidines
US4010156A (en) * 1973-04-19 1977-03-01 American Home Products Corporation Process for the rearrangement of penicillins to cephalosporins and intermediate compounds thereof
US3978053A (en) * 1973-11-29 1976-08-31 Sumitomo Chemical Company, Limited Process for producing cephalosporins
US3953440A (en) * 1974-12-13 1976-04-27 Eli Lilly And Company Deacetoxycephalosporins via penicillin sulfoxide rearrangement
US4061862A (en) * 1975-10-06 1977-12-06 Bristol-Myers Company Derivatives of 7-(cyclized)phenylglycyl-3-triazolo-thio methyl cephalosporin
US4091213A (en) * 1975-12-12 1978-05-23 Bristol-Myers Company 7-Cyclizedamino-3-heterothiomethyl cephalosporin derivatives

Also Published As

Publication number Publication date
CS190400B2 (en) 1979-05-31
YU174979A (en) 1983-01-21
FR2143667B1 (no) 1977-01-28
SE414177B (sv) 1980-07-14
SE414176B (sv) 1980-07-14
NO146241B (no) 1982-05-18
AR200720A1 (es) 1974-12-13
AR194364A1 (es) 1973-07-13
BE783222A (fr) 1972-11-09
ZA723119B (en) 1973-05-30
YU174879A (en) 1983-02-28
CS190399B2 (en) 1979-05-31
NO146203B (no) 1982-05-10
FI58925C (fi) 1981-05-11
PH13518A (en) 1980-06-03
NO146241C (no) 1982-08-25
FR2143667A1 (no) 1973-02-09
AR197310A1 (es) 1974-03-29
NL7206193A (no) 1972-11-14
JPS565758B2 (no) 1981-02-06
PL85195B1 (no) 1976-04-30
YU122672A (en) 1982-02-28
PL94780B1 (pl) 1977-08-31
CA986096A (en) 1976-03-23
IL39382A0 (en) 1972-07-26
JPS565759B2 (no) 1981-02-06
AT325201B (de) 1975-10-10
DK140845B (da) 1979-11-26
NO146203C (no) 1982-08-18
CS190367B2 (en) 1979-05-31
DD99584A5 (no) 1973-08-12
NO146202C (no) 1982-08-18
FI58925B (fi) 1981-01-30
SU626704A3 (ru) 1978-09-30
SE7414727L (no) 1974-11-22
HU166186B (no) 1975-02-28
HU165177B (no) 1974-07-27
ES402672A1 (es) 1975-10-16
JPS55108875A (en) 1980-08-21
CH578007A5 (no) 1976-07-30
AU4187672A (en) 1973-11-08
PL94030B1 (no) 1977-07-30
ES430117A1 (es) 1976-10-16
GB1391838A (en) 1975-04-23
DE2222953A1 (de) 1973-03-01
AU461358B2 (en) 1975-05-22
ES430116A1 (es) 1976-10-16
SU662013A3 (ru) 1979-05-05
SE411045B (sv) 1979-11-26
IE36353L (en) 1972-11-11
SE7414728L (no) 1974-11-22
JPS565229B1 (no) 1981-02-04
DK140845C (no) 1980-05-12
NO146202B (no) 1982-05-10
IE36353B1 (en) 1976-10-13
IL39382A (en) 1975-07-28
JPS55108876A (en) 1980-08-21

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