Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

• esters can be treated to remove or cleave the phenoxyacetamido or phenylacetamido group and to form the 7-aminodesacetoxy-cephalosporanic acid ester (the so-called 7ADCA nucleus ester), e.g., by treating the desacetoxy Cephalosporin V ester with phosphorous pentachloride or phosphorous oxychloride in the presence of an organic, non-hydroxylated solvent at a temperature of from about 40 C. to about C.
• the resulting 7-ADCA ester can be acylated with a selected acylating group to form a cephalosporin ester with more antibiotic potential, either as such, or after removal of the ester group.
• a selected acylating group for example, by reacting the 7-ADCA ester with D-u-aminophenylglycine in a form in which the amino group is protected under known conditions to form a 7-(protected amino D a-aminophenylacetamido)-3-methyl-3-cephem- 4-carboxylate ester, and then removing the amino-protecting group and the ester group by known methods there is formed free 7- D-a-phenylglycylamido desacetoxycephalosporanic acid.
• This acid is zwitterion (inner salt) or pharmaceutically acceptable cationic or anionic salt forms thereof is a useful antibiotic in combatting infections caused by Gram-positive and Gram-negative microorganisms, including penicillin G-resistant Staphylococcus aureus.
• This cephalosporin is known by the generic name, cephalexin, and is of special interest since it can be administered orally to obtain effective blood levels of the antibiotic.
• Daily doses of from about 1 to about 6 g. of cephalexin per day for a patient of about 70 kilogram weights are usually recommended for therapeutic administration. And all of this is accomplished without the necessity of using fermentation derived Cephalosporin C and 7-aminocephalosporanic acid.
• a further object of this invention is to provide a onestep process or method for esterifying penicillin and penicillin sulfoxide acid materials to form penicillin and penicillin sulfoxide ester products which are useful as intermediates in the heat-rearrangement of penicillins to desacetoxycephalosporin esters, which esters may be deesterified to corresponding desacetoxycephalosporanic acid antibiotics, or converted by known methods to more highly active desacetoxycephalosporin compounds.
• a further object of this invention is to contribute a process improvement for making penicillin and penicillin sulfoxide esters, which are valuable as intermediates in the overall process of converting penicillins to cephalosporin antibiotics, enabling the economical by-passing of the necessity for fermentation derived Cephalosporin C and the 7-aminocephalosporanic acid (7ACA) derived therefrom.
• phosgene is commingled with a liquid mixture of the selected penicillin or pencillin sulfoxide acid, the selected alcohol, and a tertiary amine or equivalent hydrogen halide absorber in an inert organic diluent at temperatures low enough to control the exothermic reaction which takes place and thus to avoid any substantial degradation of penicillin ester products, or reactants.
• the phosgene may be added to the penicillin acid or penicillin sulfoxide acid containing mixture, in solution of an organic solvent such as acetone, or the phosgene and the penicillin acid or penicillin sulfoxide acid mixture may be concurrently mixed in suitable plant scale equipment designed to quickly remove heat of reaction and/ or to Operate the process in a continuous manner.
• the penicillin acid or penicillin sulfoxide and alcohol and base should not be added to the phosgene in undiluted form, however.
• Conducting the process in this invention may involve an in situ formation of the carbonic acid anhydride or the pencillin acid chloride, but contrary to the disadvantages of some of the prior art methods, each of these two possible intermediates is desirable for penicillin ester formation, and in addition, as a result of this invention it becomes unnecessary to separately prepare haloformate reactants.
• Any excess phosgene used in the process is readily neutralized by the excess base present in the mixture, or destroyed by the water which is added after the phosgene addition is completed.
• the water or other separating medium which may be used precipitates the penicillin ester product, which crude precipitated product may be readily separated from the reaction mixture in conventional manner.
• phosgene In place of phosgene, carbonyl bromide, thiophosgene, carbonyl fluoride, or other equivalent reagents may be used, but for economical reasons phosgene is preferred.
• the esterification reaction is conducted in the presence of a hydrogen halide absorber or acid acceptor substance which is preferably an inexpensive tertiary amine which is soluble in the organic liquid diluent, but inexpensive alkali metal bicarbonates such as the lithium, sodium, and potassium bicarbonates could be used.
• a hydrogen halide absorber or acid acceptor substance which is preferably an inexpensive tertiary amine which is soluble in the organic liquid diluent, but inexpensive alkali metal bicarbonates such as the lithium, sodium, and potassium bicarbonates could be used.
• Examples of inexpensive hydrogen halide absorbers include the trialkylamines, such as the C to C trialkylamines, e.g., trimethylamine, tributylamine, dimethylbutylamine, and the heterocyclic amines such as pyridine, quinoline, the picolines, lutidines, and the like, the N,N-di-lower alkylanilines such as N,N-dimethylaniline, N,N-diethylaniline, and the like.
• the trialkylamines such as the C to C trialkylamines, e.g., trimethylamine, tributylamine, dimethylbutylamine, and the heterocyclic amines such as pyridine, quinoline, the picolines, lutidines, and the like
• the N,N-di-lower alkylanilines such as N,N-dimethylaniline, N,N-diethylaniline, and the like.
• Organic liquid diluents which may be used include the common aromatic solvents such as benzene, toluene, and the xylenes, the halogenated lower aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, lower alkanones such as acetone, methyl ethyl ketone, and the like, lower acyl nitriles such as acetonitrile, propionitrile, and the like, as well as lower dialkylsulfoxides such as dimethylsulfoxide, diethylsulfoxide, the lower dialkylacylamides such as dimethylformamide, diethylformamide, ethers such as dioxane, tetrahydrofuran, diethyl ether of diethylene glycol, lower nitro-hydrocarbons such as nitromethane, nitropropane, and the like, and alkyl acylates having up to about 7 carbon atoms,
• the organic liquid diluent is inert in that it does not interfere significantly with the esterification reaction.
• the diluent is also preferably water miscible so that the reaction mixture mixes nicely with the water which is added after phosgene addition is completed.
• a substantially anhydrous liquid medium is preferred for economic reasons but a small amount of water in the system can be tolerated without serious interference.
• Excess alcohol could be used as the organic liquid diluent but is not preferred since the excess alcohol competes for the added phosgene to form side-reaction products, thus involving waste of reactants.
• the common inert organic liquid diluent for the process of this invention will be selected by those skilled in the art primarily on the basis olflcost and availability. Numerous such diluents are availa e.
• penicillin and penicillin sulfoxide acid starting materials are those which have one of the following general formulas:
• penicillin sulfoxide acid where R is hydrogen or the residue of an acyl group of the particular penicillin.
• the alkali metal salts of these penicillins such as the sodium and potassium salts can also be used.
• phenoxymethyl penicillin, as such, or in its sulfoxide form are preferred.
• this process can also be applied to the penicillin nucleus (6-APA), if the 6-amino group is suitably protected by known methods.
• penicillins derived by fermentation methods known in the prior art can be esterified by the method of this invention or first converted to the sulfoxides and esterified by the method of this invention.
• the preferred penicillin and penicillin sulfoxide acids for use in the process of this invention are those of the formulas:
• penicillin esters prepared by the method of this invention are useful as intermediates to desacetoxycephalosporin antibiotics in that they can be oxidized by known methods, e.g., with 3-chloroperbenzoic acid, to form the corresponding penicillin sulfoxide esters which can be heat rearranged to the corresponding desacetoxycephalosporanate ester as described above.
• the ester products of the invention and desacetoxycephalosporins obtained therefrom are conveniently named by useing the penam and cepham nomenclature system.
• the penam nomenclature system for the penicillins is described by Sheehan, Henery-Logan, and Johnson in the J. Am. Chem. Soc., 75, p. 3293, footnote 2 (1953), and has been adapted to the cephalosporins by Morin, Jackson, Flynn and Roeske in the J. Am. Chem. Soc. 84, 3400 ,(1962).
• penam and cepham refer respectively to the following saturated ring system:
• penicillin V phenoxymethyl penicillin
• cepham refers to the same corresponding ring cepham structure but containing a double bond, the position of which is indicated by the lowest numbered carbon atom to which the double bond is connected, or by the word delta with a superscript for the same carbon atom number designation.
• penicillin V phenoxymethyl penicillin
• 6-(phenoxyacetamido)-2,2-dirnethylpenam-3-carboxylic acid a 2,2,2-trichloroethyl penicillin V sulfoxide ester obtained therefrom with 2,2,2-trichloroethanol
• 2,2,2-trichloroethyl 6-(phenoxyacetamido)-2,2- dimethylpenam-3-carboxylate examples of penicillin and penicillin sulfoxide ester products which can be prepared by the process of this invention include:
• Benzyl 6-(3',5'-dichlorophenylmercaptomethyl)-2,2- dimethylpenam-3-carboxylate-l-oxide from benzyl alcohol and 3,5 dichlorophenylmercaptomethyl penicillin sulfoxide;
• Phthalimidomethyl 6 (phenylacetamido) 2,2 dimethylpenam 3 carboxylate-l-oxide from phthalimidomethyl alcohol and penicillin G. sulfoxide;
• Succinimidomethyl 6 (3 chlorophenoxyacetamido), 2,2-dimethylpenam 3 carboxylate from succim'midomethanol and 3 chlorophenoxymethyl penicillin;
• the selected alcohol for penicillin or penicillin sulfoxide ester formation may be any alcohol which forms a readily cleavable penicillin ester group after the heat conversion step or one which forms an orally antibiotically active desacetoxycephalosporanate ester.
• Preferred easily cleaved esters are, for example, those obtained from 2,2,2-trichloroethanol, benzyl alcohol, benzyloxymethanol, the methoxy-substituted benzyl alcohols such as 4-methoxybenzyl alcohol, 3-methoxybenzyl alcohol, 3, S-dimethoxybenzyl alcohol, benzhydrol alcohol, bis(4- methoxyphenyl) methanol, and the hydroxmic alcohols such as N-hydroxysuccinimide, N-hydroxyphthalimide, as well as phthalimidomethyl alcohol and succinimidomethyl alcohol.
• the methoxy-substituted benzyl alcohols such as 4-methoxybenzyl alcohol, 3-methoxybenzyl alcohol, 3, S-dimethoxybenzyl alcohol, benzhydrol alcohol, bis(4- methoxyphenyl) methanol
• the hydroxmic alcohols such as N-hydroxysuccinimide, N-hydroxyphthalimide, as well as
• cephalosporin antibiotics in the acetoxymethyl ester form are orally absorbed, such as the acetoxymethyl 7-(2'-thienylacetamido) cephalosporinate.
• acetoxymethanol it will be desirable to use acetoxymethanol as the alcohol.
• Lower alkanols having from 1 to 6 carbon can also be used, but, in general, they form more difiicultly cleavable esters, and therefore are not preferred.
• the addition of phosgene or similar materials to the mixture of the selected penicillin or penicillin sulfoxide acid, or salt, alcohol, hydrogen halide absorber, and organic liquid solvent or diluent causes an exothermic reaction and evolution of carbon dioxide to occur.
• This exothermic reaction can be controlled to a desirable rate by a variety of known methods.
• the mixture is generally cooled and stirred or otherwise agitated to distribute the heat of reaction.
• the rate of addition of phosgene can be controlled to a slow rate to reduce the requirement for extensive cooling equipment.
• it is generally preferred to cool the mixture to which the phosgene is added to from --20 C. to about 40 C., depending upon the size of the reaction mixture and the rate of reaction desired.
• the low temperatures are generally maintained until all of the phosgene has been added, and the exothermic reaction has subsided.
• the penicillin or penicillin sulfoxide ester product can be removed from the reaction mixture by adding water in an amount to precipitate the ester product, and to destroy any excess phosgene in the mixture.
• the crude ester if it is an oil
• the crude ester can be removed by extraction with an appropriate organic solvent, filtration and purified, e.g., by crystallization of extracted ester, recrystallization of solids obtained from the process, or a slurry of the solids in the appropriate solvent or solvent mixture such as ethyl acetate and chloroform mixtures.
• the penicillin or penicillin sulfoxide acid or salt is preferably mixed with a slight molar excess of the selected alcohol in the organic solvent to insure complete reaction of the more expensive penicillin material.
• An excess of hydrogen halide absorber, such as a tertiary amine, is preferably used to insure complete reaction of the phosgene and its by-products. Care is taken in the equipment used to provide for the release of evolved gases such as carbon dioxide from the reaction mixture.
• the invention is further illustrated by the following detailed examples which show the preparation of a penicillin sulfoxide before esterification, and the esterification procedure. 'It is to be understood, however, that it is not required to form the sulfoxide before the esterification procedure, but is only the preferred practice.
• Penicillin V sulfoxide A suspension of 350 g. (1.0 mole) of penicillin V (phenoxymethyl penicillin) in 1 liter of acetic acid was cooled to to C. and 200 ml. of percent hydrogen peroxide in water (about 2 moles of H 0 was added dropwise at 15 to 20 C. over 90 minutes while stirring the mixture. The penicillin V slowly dissolved giving a clear, pale (light) yellow solution. After about 2 hours at 15 to 20 C. the penicillin V sulfoxide began to crystallize from the solution. Stirring was continued for a total reaction time of 4 hours. The mixture was cooled to about 0 C. and 1 liter of water was added dropwise in 60 minutes.
• Penicillin V sulfoxide, 2,2,2-trichloroethyl ester A stirred mixture of 366 g. (1 mole) of penicillin V sulfoxide and 166 g. (1.1 moles) of 2,2,2-trichloroethanol in 1 liter of acetone was cooled to 0 to 5 C. and 240 g. (3 moles) of pyridine was added at such a rate that the temperature did not exceed 10 C. Then ml. (about g., 1.4 moles) of phosgene was added dropwise in 30 minutes from a jacketed dropping funnel which was cooled to approximately 50 C. with a Dry Ice-acetone mixture. Carbon dioxide evolution was extremely rapid throughout the phosgene addition.
• a process for preparing an ester of a penicillin or pencillin sulfoxide which comprises commingling phosgene with a liquid mixture of (a) the penicillin or penicillin sulfoxide in the acid form or an alkali metal salt thereof,
• a process which comprises commingling phosgene with a liquid mixture of (a) a penicillin or penicillin sulfoxide in the acid form or an alkali metal salt form thereof, (b) the alcohol corresponding to the desired penicillin or penicillin sulfoxide ester, and (c) a hydrogen halide absorbing base, in an inert organic liquid diluting 10 medium at a temperature not above about 40 C.
• the penicillin or penicillin sulfoxide has a formula selected from the group consisting of where R is selected from the group consisting of phenyl, benzyl, phenoxymethyl, phenylmercaptomethyl, such phenyl, benzyl, phenoxymethyl, and phenylmercaptomethyl groups substituted with chlorine, methoxy, methyl, or nitro, and heptyl and thiophene-2-methyl, and the alcohol is selected from the group consisting of 2,2,2-trichloroethanol, benzyl alcohol, tert-butanol, benzyloxymethanol, methoxyphenol, methoxybenzyl alcohol, 3,5- dimethoxybenzyl alcohol, benzhydryl alcohol, and bis- (4-methoxyphenyl)methanol, the hydrogen halide absorbing base is a tertiary amine, and the inert organic liquid diluent is
• a method of preparing a penicillin or penicillin sulfoxide ester the improvement which comprises commingling phosgene with a mixture of the penicillin acid or penicillin sulfoxide acid, or an alkali metal salt thereof, the selected alcohol, a tertiary amine, in an inert organic liquid diluent at a temperature not above 40 C. to form the corresponding penicillin or penicillin sulfoxide ester.
• a process which comprises (a) forming a liquid mixture of a penicillin acid or a penicillin sulfoxide acid or an alkali metal salt thereof, the alcohol corresponding to the desired penicillin or penicillin sulfoxide ester, a hydrogen halide absorbing base, in an inert organic liquid diluting medium, (b) comrningling phosgene with the mixture from step (a), while (c) controlling the temperature of the liquid mixture not above about 40 C., to form a penicillin or penicillin sulfoxide ester.
• a process which comprises (a) forming a liquid mixture of a penicillin acid or penicillin sulfoxide acid or an alkali metal salt thereof, the alcohol corresponding to the desired penicillin or penicillin sulfoxide ester, a hydrogen halide absorbing base, in an inert organic liquid diluting medium, (b) commingling phosgene with the mixture from step (a), while (c) controlling the temperature of the liquid mixture not above about 40 C.
• a process which comprises forming a mixture of phenoxymethylpenicillin sulfoxide, pyridine, and 2,2,2-trichloroethanol in acetone, adding phosgene to the mixture while controlling the temperature below about 40 C. to form the 2,2,2-trichloroethyl phenoxymethylpenicillin sulfoxide ester.
• a process as defined in claim 14 which further includes the steps of adding water to the reaction mixture to precipitate the 2,2,2-trichloroethyl-phenoxymethylpenicillin sulfoxide ester.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1967
  • 1967-12-22 US US692678A patent/US3586667A/en not_active Expired - Lifetime
• 1968
  • 1968-09-18 IL IL30725A patent/IL30725A/en unknown
  • 1968-09-23 IE IE1137/68A patent/IE32440B1/xx unknown
  • 1968-09-23 FI FI2681/68A patent/FI54804C/fi active
  • 1968-09-24 SE SE12832/68A patent/SE366319B/xx unknown
  • 1968-09-24 FR FR1603296D patent/FR1603296A/fr not_active Expired
  • 1968-09-25 BE BE721348D patent/BE721348A/xx not_active IP Right Cessation
  • 1968-09-25 BR BR202603/68A patent/BR6802603D0/pt unknown
  • 1968-09-26 AT AT941868A patent/AT282061B/de not_active IP Right Cessation
  • 1968-09-26 NL NL686813822A patent/NL146169B/xx not_active IP Right Cessation
  • 1968-09-26 DK DK463668A patent/DK133107C/da not_active IP Right Cessation
  • 1968-09-26 GB GB4582868A patent/GB1231888A/en not_active Expired
  • 1968-09-27 ES ES358607A patent/ES358607A1/es not_active Expired
  • 1968-09-27 DE DE1795413A patent/DE1795413C3/de not_active Expired
  • 1968-09-27 CH CH1451268A patent/CH531538A/de not_active IP Right Cessation
• 1973
  • 1973-10-01 CY CY70773A patent/CY707A/xx unknown
  • 1973-12-30 MY MY491/73A patent/MY7300491A/xx unknown

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