IE41799B1 - Process for preparing 3-methyl-4-(5-tetrazolyl)- 3-cephem compounds - Google Patents
Process for preparing 3-methyl-4-(5-tetrazolyl)- 3-cephem compoundsInfo
- Publication number
- IE41799B1 IE41799B1 IE2059/75A IE205975A IE41799B1 IE 41799 B1 IE41799 B1 IE 41799B1 IE 2059/75 A IE2059/75 A IE 2059/75A IE 205975 A IE205975 A IE 205975A IE 41799 B1 IE41799 B1 IE 41799B1
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- penam
- tetrazolyl
- acid
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- dimethyl
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- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam sulfoxides, 6-(N-protected amino)-2,2-dimethyl-3-(5-tetrazolyl)penam sulfoxides and their direct conversion to 7-amino-3-methyl-4-(5-tetra-zolyl)-.DELTA.3-cephems and 7-(N-protected amino)-3-methyl-4-(5-tetra-zolyl)-.DELTA.3-cephems, useful antibacterial agents or intermediates for antibacterial agents, by heating under acid conditions, desirably in a liquid medium and especially one derived from a tertiary carboxamide, a tertiary urea derivative or a tertiary sulfonamide. The preparation of the tetrazolylpenam sulfoxide reactants is described.
Description
This invention relates to antibiotic compounds. More particularly, it relates to 6-amino-2,2-dimethyl3-(5-tetrazolyl)penam sulphoxides, 6*-(Unprotected amino) 2,2-dimethyl-3-(5-tetrazolyl)penam sulphoxides and their direct conversion to 7-amino-3-methyl-4-(5-tetrazolyl)0?-cephems and 7-(N-protected amino)-3-methyl-4-(53 tetrazolyl)-Δ -cephems, useful antibacterial agents or intermediates for antibacterial agents, by heating under acid conditions, desirably in a liquid medium and especially one derived from a tertiary carboxamide, a tertiary urea derivative or a tertiary sulphonamide.
The invention is also concerned with the preparation of the tetrazolylpenam sulphoxides.
The oxidation of 6-aminopenicillanic acid or a penicillin, especially a penicillin ester, to a sulphoxide has been known for many years, and a great variety of oxidizing agents have been used for the oxidation (Sykes et al, The Chemistry of Penicillin, Η. T. Clarke et al, Ed, Princeton University Press, Princeton, NJ
1949, pp 156, 927, 946, 1008; Chow et al, J Org Chem
27, 1381 (1965); Essery et al, J Org Chem 30, 4388 (1965); Spry, J Org Chem 37, 793, (1972); and United States Patent Specification No. 3,275,626.
The conversion of penicillin ester sulphoxides into desacetoxy cephalosporin esters by heating a penicillin ester sulphoxide under acid conditions, generally in a solvent or liquid medium at a temperature
- 3 of from 80°C to 175°C is described in a number of publications and patent specifications: Morin et al, J Am Chem Soc 91, 1401 (1969); Cooper et al, J Am Chem Soc 92,
2575 (1970); Cooper, J Am Chem Soc 92, 5010 (1920);
United States Patent Specifications No. 3,275,626; 3,591,585; 3,632,850; 3,647,787; 3,725,797 and
3,725,799. The last two cited specifications disclose the use as acid catalyst, of salts or complexes of a nitrogen base having a PKb of not less than four with a mono- or disubstituted orthophosphoric acid or an organic sulphonic acid, respectively.
6- Amino-2,2-dimethyl-3-(5-tetrazolyl)penams have been found to be valuable intermediates and/or antibacterial agents. Such compounds are described and claimed in Patent Specification No. 4θ53τ.
7- Acylamino-3-methyl-4-(5-tetrazolyl)-4?-cephems and salts thereof are useful as antibacterial agents and as intermediates for the production of antibacterial agents. Additionally, 7-amino-3-methyl-4-(5-tetrazolyl)A^-cephems and certain 7-(substituted amino)-3-methyl-3(5-tetrazolyl-A -cephems wherein the substituent on the
7-amino group is other than an acyl group are also valuable intermediates leading to the preparation of 3
7-acylamino-3-substituted-4-(5-tetrazolyl)-A -cephems. These compounds and their methods of manufacture are the subject of Patent Specification No. and Patent
Specification Nos. if Ο Ί 4«· fe and
The biological and non-biological uses of tetrazoles has recently been reviewed by Benson, Heterocyclic Compounds, Elderfield, Ed, Vol. 8, John Wiley + Sons,
Inc. New York, United States of America, 1967, Chapter 1 while a compilation of cephem references is noted in United States Patent Specifications Nos. 3,766,175 and 3,766,176.
In accordance with the present invention there is provided a process for preparing a 3-methyl-4-(5-tetrazolylJ-Δ -cephem which comprises heating a 2,2-dimethyl3-(5-tetrazolyl)penam sulphoxide in the presence of an acid reacting substance at a temperature of from 80°C to 175°C for a time sufficient to effect the conversion thereof.
The process of the invention may be illustrated, in part, by the following equation:10
(I) (II) wherein
R is a hydrogen or an amino protecting group, and Y is a tetrazolyl group of the formula;-
(i) (ii) wherein is Ej or a tetrazolylpenam or tetrazolylcephem nitrogen protecting group, the nature of which is defined hereinafter, R2 is a hydrogen atom or an alkanoyloxymethyl group having from three to eight
- 5 carbon atoms, a 1-alkanoyloxyethyl group having from four to seven carbon atoms, a methoxymethyl group or a phthalidyl group.
Patent Specification No. / ί 20/^divided out of this one provides penam oompounds of the general formula (I) as defined above. Since the tetrazolylcephem nitrogen protecting group occurs in the penam compound of formula (I), also may be defined as a tetrazolylpenam nitrogen protecting group.
The nature of such a protecting group is not critical to this invention. It is its ability to perform a specific function rather than its structure which is important. The selection and identification Of appropriate protecting groups readily and easily may be made by one skilled in the art. The suitability and effectiveness of a group such as a tetrazolylcephem nitrogen protecting group in this invention are determined by employing a compound of formula (I) wherein is the (R^-substituted)-5-tetrazolyl-group in question as reactant in the herein-described process for preparing compounds of formula (XI). In view of this, the tetrazolylcephem nitrogen protecting group clearly is also a tetrazolylpenam nitrogen protecting group. It therefore becomes convenient to refep to R^ as a tetrazolyl nitrogen protecting group.
The term amino-protecting group as used herein is intended to include any group which will permit synthesis of compounds of formula (II) under the conditions e.g. of acidity and temperature, of the process of this invention and which may be removed under conditions wherein the β-lactam ring remains substantially intact. The nature of the amino-protecting group is not critical
- 6 to this invention. The R group is not involved in formation of the tetrazolyl group or in the ring enlargement reaction. Its function is to protect the amino group in the penam and cephem ring systems during the process described in detail below for formation of compounds of formula (II). It is subsequently removed at an appropriate point, generally at the ultimate or penultimate step, of the process of this invention at which point its protective function is no longer required. In some instances, e.g., where ft is a triphenylmethyl or substituted triphenylmethyl group it may be removed during the course of the process of this invention. However, such a group may be said to have fulfilled its protective function. The selection and identification of individual protecting groups is readily accomplished by one skilled in the art. The suitability and effectiveness of a group as an amino-protecting group in this invention is simply determined by subjecting the 6-(Nprotected-amino)-2,2-dimethyl-3-(5-tetrazolyl)penam sulphoxide (formula I) or desoxy precursor thereof wherein the protecting group is the group in question to the process of the present invention. All such groups are to be considered within the scope of this invention.
In general, groups known in the art as amino25 protecting groups in peptide syntheses are operative in the process of this invention. Particular interest resides in the amino-protecting groups enumerated below because of their effectiveness in protecting the 6-amino group and their ease of removal under conditions wherein the β-lactam ring remains substantially intact namely,
2,2,2-trihaloethoxycarbonyl, (e.g. 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl), benzyloxycarbonyl and triphenylmethyl (trityl) groups, especially those of formula (III) below:-
wherein each of R^, R^, and R^ is a hydrogen, chlorine, bromine or fluorine atom, an alkyl group having from one to four carbon atoms, an alkoxy group having from one to four carbon atoms, or a phenyl group.
When R of formula (I) is a hydrogen atom, the amino group becomes under the acid conditions of the processes of the invention, an ammonium ion, and is thus protected.
Additionally, in a broad sense amino-protecting group'1 as used herein also embraces acyl groups of organic carboxylic acids. The products of formula (II) wherein R is an acyl group produced by the process of this invention are antibacterial agents per se or are readily converted to antibacterial agents. Preferred acyl groups include 2-phenylacetyl, 2-phenoxyacetyl and
2-phenyl-2-aminoacetyl groups.
The term tetrazolyl nitrogen protecting group is intended, in the most general sense, to cover those groups which protect the tetrazole ring during or after formation thereof and during reaction of the so-protected tetrazolylpenam or tetrazolylcephem compound. A group, therefore, may be regarded as a tetrazolyl nitrogen protecting group when it (a) may be attached to the tetrazolyl group during or after formation thereof; (b) will permit the ring enlargement reaction of this invention even though it may be removed during the said reaction; and (c) then may be removed from the tetrazolyl group without substantial degradation of the tetrazolylcephem ring system. Illustrative of such groups, in addition to those specifically enumerated herein as tetrazolyl nitrogen protecting groups are trialkylsilyl, triphenylmethyl and substituted triphenylmethyl groups.
Particularly preferred penam compounds include those where R is a hydrogen atom or 2,2,2-trihalo-, preferably trichloro- or tribromo-, ethoxycarbonyl, benzyloxycarbonyl or trityl of formula III above and Y is a tetrazolyl group of the formula (i) above where R^ is a tetrazolyl penam nitrogen protecting group, preferably a group of formula V or formula VI, and when R is hydrogen or an acyl group, and R2 are hydrogen or alkanoyloxymethyl, alkanoyloxyethyl or phthalidyl groups.
As one skilled in the art will recognise, the variables R.j and R2 when defined as alkanoyloxymethyl, 1alkanoyloxyethyl, methoxymethyl and phthalidyl are, in a sense, tetrazolyl nitrogen-protecting groups, HOwever, suoh groups, with the exception of methoxymethyl, can not be removed without substantial degradation of the β-lactam ring and, thus fail to meet the criteria set forth above for a tetrazolyl nitrogen-protecting group'1.
- 9 41799
For the sake of convenience, the compounds described herein are identified as derivatives of penam and cephem. The term penam has been defined in the J Am Chem Soc 75, 3293 (1953), as referring to the structural formula: 1
Using this terminology, the well-known antibiotic penicillin G is designated as 6-(2-phenylacetamido)-2,2dimethyl-penam-3-carboxylic acid. The 3-tetrazolyl derivative of penicillin G, formula (1) above wherein R is 2-phenylacetyl and Y is 5-tetrazolyl, is designated as 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam.
The term cepham has been defined in the J Am Chem Soc 84, 3400 (1962) as referring to the saturated structural formulas 1
Cepham
The term cephem refers to the same structure with a double bond, the position of which is indicated by a prefixed A with superscript denoting the carbon atom of lowest number to which the double bond is connected;
β
e.g. A . Thus, the compound of formula (II) wherein R is 2-phenylacetyl and Y is 5-tetrazolyl is designated as 7-(2-phenylacetamido)-3-methyl-4-(5-tetrazolyl) A -cephem.
Many of the 5-substituted tetrazoles can exist in two isomeric forms, viz:
and (i) ;N (ii) when or R£ is a hydrogen atom, the two forms co-exist in a dynamic tautomeric, equilibrium mixture. However, when R^ or represent a substituent other than hydrogen, the two forms represent different chemical entities which do not spontaneously interconvert.
The process of the present invention is broadly applicable to a great variety of precursors, e.g., desoxy compounds, of formula (I) compounds. Any compound of formula (I), or desoxy precursor thereof, the β-lactam structure thereof which is not substantially destroyed under the conditions of the process of this invention may be used as reactant in the conversion process described herein.
As noted above, R in formula (I) may be a hydrogen atom or an amino nitrogen protecting group, including an acyl group, which will protect the amino nitrogen atom and the β-lactam ring to which it is attached from degradative attack under the conditions of acidity and temperature of the process of the invention.
Preferred amino protecting groups are 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl.
Such groups permit satisfactory conversion of the thus protected penamtetrazole compound of formula (I) to the corresponding cephemtetrazole of formula (II) and relatively easy removal of the amino protecting group. Furthermore, the presence of such a protecting group is sometimes desirable as when the tetrazolyl nitrogen protecting group is one removable under acid conditions. These amino protecting groups are not removed under acid conditions alone and serve to protect the β-lactam.
They are subsequently removed by a reductive deblocking step.
Especially preferred as amino protecting groups are acyl groups of organic carboxylic acids and particularly those acyl groups which correspond to or which are convertible to, the acyl group desired in the tetrazolylcephem product. The 7-acylamino-3-methyl-4-(5-tetrazolyl) A-cephems thus obtained, if not antibacterial agents per se, are readily converted into antibacterial agents, as for example, by removal of the tetrazolyl nitrogen protecting group.
Particularly valuable acyl groups are those having the formulasH
Q
II
C- (IV) wherein n is 0 or 1, R' is a hydrogen atom, an alkyl group having from one to twelve carbon atoms, an alkenyl group having from two to twelve carbon atoms, a cycloalkyl group having from three to seven carbon atoms, a cyclohexenyl or 1,4-cyclohexdienyl group, 1-amino-cycloalkyl group having from four to seven carbon atoms, a cyanomethyl, 5-methyl-3-phenyl-4-isoxazolyl, 5-methyl-3-(ochlorophenyl)-4-isoxazolyl, 5-methyl-3-(2,6-dichloro41799 phenyl)-4-isoxazolyl or 5-methyl-3-(2-chloro-6-fluorophenyl)-4-isoxazolyl group, a 2-alkoxy-1-naphthyl group having from one to four carbon atoms in the alkoxy group, or a phenyl, phenoxy, phenylthio, pyridylthio, benzyl, sydnonyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, pyrazolyl, substituted phenyl, substituted phenoxy, substituted phenylthio, substituted pyridylthio, substituted benzyl, substituted thienyl, substituted furyl, substituted pyridyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrimidinyl, substituted triazolyl, substituted tetrazolyl, substituted imidazolyl or substituted pyrazolyl group, each substituted group being substituted by one or two fluorine, chlorine or bromine atoms or hydroxy, amino, N-alkylamino having from one to four carbon atoms, Ν,Ν-dialkylaraino having from one to four carbon atoms in each alkyl group, alkyl having from one to four carbon atoms, aminomethyl, alkoxy having from one to four carbon atoms, alkylthio having from one to four carbon atoms or 2-aminoethoxy groups, and Q is a hydrogen atom, or a hydroxy, amino azido, carboxy, pyridyl, thiazolyl, isothiazolyl, pyrimidinyl, triazolyl, imidazolyl, pyrazolyl, substituted phenoxy, substituted phenylthio, substituted pyridylthio, substituted thienyl, substituted furyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted isothiazolyl, substituted pyrimidinyl, substituted triazolyl, substituted imidazolyl or substituted pyrazolyl group, each substituted group being substituted by one or two fluorine, chlorine or bromine atoms, or hydroxy, hydroxymethyl, amino, N,N-dialkylamino having from one to four carbon atoms in each alkyl group.
alkyl having from one to four carbon atoms, aminomethyl, aminoethyl, alkoxy having from one to four carbon atoms, alkylthio having from one to four carbon atoms, 2-aminoethoxy or N-alkylamino having from one to four carbon atoms.
The α-carbon atom of the antibacterial cephem side chain to which the amino or hydroxy, (Q) group is attached is an asymmetric carbon atom allowing for the existence of two optically active isomers, the D- and L-diastereoisomers, as well as the racemate, DL, form.
In accord with previous findings concerning the activity of such cephems possessing asymmetric α-carbon atoms, the compounds of the present invention possessing the D-configuration are more active than those of the Lconfiguration and are the preferred compounds, although the L and DL forms of the compounds are also considered within the scope of the present invention.
Of the acyl groups enumerated above, those wherein R’ is a phenyl, mono- or disuhstituted phenyl group and Q is a hydrogen atom or a hydroxy, amino, azido or carboxy group represent a preferred class of derivatives. Preferred tetrazolyl nitrogen protecting groups (R^) are those having formula (V) and (VI)
wherein
Rg is a hydrogen atom, an alkyl group having from one to three carbon atoms or a phenyl group, is a hydroxy, methoxy, alkanoyloxy having from two to four carbon atoms or benzyloxy group and Rg is a hydrogen.
fluorine, chlorine, bromine or iodine atom or a hydroxy, methyl, methoxy, alkanoyloxy having from two to four carbon atoms, phenyl, or benzyloxy group and ‘9
X —CH
R,
R.
‘10 (VI) wherein each of Rg and R^ is a hydrogen atom or a methyl group and X is an oxygen or sulphur atom. DeOxy derivatives of Compounds of formula (I) having such tetrazole nitrogen protecting groups conveniently may be prepared as described in Patent Specification No. N-oSil,,
Furthermore, such protecting groups are readily removed from formula (II) compounds without substantial degradation of the β-lactam ring.
Especially preferred compounds of formula (II), particularly when R, the amino protecting group, is an acyl group, are those wherein the tetrazolyl group is unsubstituted, i.e. R^ and R2 are hydrogen atoms, and those wherein R^ and Rj ate alkanoyloxymethyl, alkanoyloxyethyl or phthalidyl groups. Such tetrazolyl cephems (formula (II)) produced by the conversion process of this invention are antibacterial agents per se.
The sulphoxide compound of formula (l) may be prepared by reacting an appropriate 6-amino- or 6-(Nprotected amino )-2,2-dimethyl-3-(5-tetrazolyl)-penam precursor, preferably in a reaction-inert solvent, with an oxidising agent, i.e. a substance which provides active oxygen, such as hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, or any other organic per acid or a salt thereof; metaperiodic acid, iodoso30 benzene or ozone. The oxidising agent is used in an amount sufficient to provide one atom of active oxygen per thiazolidine sulphur atom. The reaction is generally conducted at a temperature within the range of 10°C to 30°C, and preferably for reasons of convenience, at room temperature. The reaction temperature is, however, not critical.
Suitable reaction-inert solvents when each of Rj and R2 is hydrogen are water and aqueous organic solvents, especially mixtures of water and organic solvents which are miscible with water such as dioxane, tetrahydrofuran, acetone and diethyleneglycol dimethyl ether.
The sulphoxide is recovered by concentration of the solvent and precipitation of the product from the concentrate, or by evaporation of the solvent and recrystallization of the product.
When Rj and R2 on the tetrazolyl group are other than hydrogen, suitable solvents are halogenated hydrocarbons especially chlorinated hydrocarbons such as chloroform, methylene chloride, ethylene dichloride, ethylidene chloride or chlorobenzene? aromatic hydrocarbons such as benzene, xylene or toluene; ethers such as dioxane, tetrahydrofuran, or diethyleneglycol dimethyl ether; alkanoic acid amides such as Ν,Ν-dimethylformamide or N,N-dimethylacetaijiide.
The sulfoxide compound of formula (I) is then converted by the process of this invention to a corresponding 3-methyl-4-(5-tetrazolyl )-^-cephem compound of formula (II). The process comprises heating the appropriate sulphoxide of formula (I), desirably in a medium which is liquid at the temperature of the reaction, in the presence of an acid reacting substance (acid catalyst), i.e. under acid conditions, at from 80°C to 175°C until
41789
- 16 the conversion to the desired 3-methyl-4-(5-tetrazolyl)^3-cephem occurs.
Representative acid catalysts are mineral acids such as sulphuric, hydrochloric or phosphoric acid; sulphonic acids such as faenzenesulphonic acid, p-toluenesulphonic acid, naphthalenesulphonic acid or methanesulphonic acid; organic acid anhydrides such as acetic anhydride, propionic anhydride, or benzoic anhydride; Lewis acids such as aluminium chloride, boron trifluoride, or boron trichloride; acyl chlorides such as acetyl chloride, butyryl chloride, benzoyl chloride; thionyl chloride, phosgene, or nitrosyl chloride.
Alternatively, and preferably, in place of one of the acid catalysts enumerated above, the conversion is accomplished by treating the appropriate sulphoxide of formula (I) in the presence of certain acid salts or complexes as catalysts. These substances, the exact nature of which is not known, comprise the combination of a strong acid and a weak organic base. While any of the mineral acids disclosed above may be used as the acid component, favoured acid substances are phosphoric acid and certain primary and secondary phosphates; i.e. monoand diesters of phosphoric acid which are strong di- and mono basic acids, respectively. Representative of suitable primary phosphates are those wherein the ester group is an alkyl group of from 1 to 6 carbon atoms; an aralkyl group such as benzyl or phenethyl; an aryl group, such as a phenyl group or a phenyl group substituted with one or more halogen atoms or nitro groups such as 2-chloro-4nitrophenyl, 4-nitrophenyl; and halo substituted alkyl groups such as 2,2,2-trichloroethyl.
Representative of secondary phosphates are diaryl esters wherein aryl is as defined above.
Phosphoric acid is the preferred acid because of its availability relative to that of the above-mentioned esters and the satisfactory yields which it affords.
The weak organic base component of the catalyst may be any nitrogenous base having a pKb greater than 4.
As such it may be a primary, secondary or tertiary amine. Representative of such bases are aniline, o-chloroaniline, m-methylaniline, g-methoxyaniline, g-hydroxyaniline, mnitroaniline, picolines, pyridine, lutidine, quinoline, isoquinoline, N-methylaniline, benzimidazole, and others described in United States Patent Specification No. 3,725,397. Tertiary amines are, in general favoured; and heterocyclic tertiary amines are preferred bases.
The salt (or complex) catalyst may be performed or prepared in situ. It is generally more convenient to add the acid and base components to the reaction vessel to permit formation of the catalyst in situ.
The amount of acid catalyst or the acid salt (or complex) catalyst system used is not critical but may vary widely. In general, an amount ranging from 10% to 20% by weight of the sulphoxide reactant is used.
However, when the amino protecting group on the tetrazolylpenam is hydrogen or a basic substituted acyl group (e.g., 2-amino-2-phenylacetyl), at least an equivalent of acid is normally used, generally from 1% to 20% by weight in excess of the equimolar amount of acid.
The conversion may be conducted in the absence of a liquid medium but it is generally desirable to use a reaction-inert medium which is liquid at the reaction temperature of the process to moderate and facilitate the reaction. A wide variety of liquid media are thus available. The only criteria apart from that of being inert under the conditions of the conversion process are
- 18 sufficiently high enough boiling point to permit the use of a temperature of from 80°C to 175°C and that it be liquid within this temperature range. Suitable media are aliphatic hydrocarbons, ketones, ethers, alkanoic acid anhydrides, and esters; acetonitrile, propionitrile and tertiary carboxamides. Representative of such media are alkanes of 5 to 8 carbon atoms, benzene, toluene, xylenes, methylene chloride, carbon tetrachloride, 1,2dichloroethylene, methyl ethyl ketone, methyl isobutyl ketone, ethylacetate, acetate and propionic anhydrides, dioxane, tetrahydrofuran, diethyleneglycol dimethyl ether, Ν,Ν-dialkyl formamides and acetamides especially those Wherein the alkyl groups have from 1 to 5 carbon atoms, N-methyl-2-pyrrolidone, and other tertiary carboxamides such as enumerated in United States Patent Specification No. 3,688,202. The tertiary carboxamides may be used as the liquid medium but are generally used in admixture with one of the other reaction-inert media enumerated above to optimize the yield of the Δ^-cephem compound of formula (ll).
Furthermore, tertiary urea derivatives and/or tertiary sulphonamides which fulfil the criteria set forth above also may be used as the liquid medium in this conversion process. Examples of such media are tetra25 methyl urea, tetraethyl urea, N,N-dimethylcarbanilide,
1,3-dimethyl-2-imidazolidone, 1,3-dimethyl-2-hexahydropyrimidone, N,N-dialkylmethane sulphonamides wherein the alkyl groups have from 1 to 4 carbon atoms, and other such, compounds as are described in United States Patent
Specification No. 3,647,787.
As an alternative to using a completely reactioninert solvent, it can be particularly convenient to use a material which can act as the acid reacting substance as well as at least in part the liquid reaction medium.
Still further, any water present, especially byproduct water if desired, may be removed by using a liquid medium which permits effective removal of the water.
This is accomplished by using a liquid which forms an azeotropic system with water and permits its removal by azeotropic distillation or by using a liquid which reacts with water and permits its inactivation and, hence, effective removal from the reaotion zone. Representative of liquids which permit azeotropic removal of water are benzene, carbon tetrachloride, methyl ethyl ketone, ethylacetate, hexane and other water-azeotrope forming liquids such as set forth in Lange's Handbook of Chemistry, ninth edition (1956), pages 1484-1486 and 1493, published by Handbook Publishers Inc, Sandusky, Ohio, United States of America.
Illustrative of the second category of liquids; i.e., those which remove the water by chemical reaction are alkanoic acid anhydrides, sultones, and sulphonic acid esters. Examples of such chemical water inactivators are acetic and propionic anhydrides, p-toluenesulphonic acid anhydride, C-^-C^ esters of methane sulphonic, benzene and ^.-toluenesulphonic acids, propanesultone and butanesultone, and others are as disclosed in United States Patent Specification No. 3,591,585.
The above-mentioned liquids which effectively remove water may be used alone or in admixture with one or more of the reaction-inert liquids enumerated above.
Alternatively, the by-product water is effectively removed through the use of molecular sieves as adsorbents for the water. Suitable adsorbents are the natural and synthetic crystalline aluminosilicates. The latter adsorbents are favoured because of their greater water41799 loading capacity relative to the natural crystalline aluminosilicates. Included among such adsorbents are chabazite, gemlinite and analcite, naturally occurring materials, the synthetic Lind Molecular Sieves produced and distributed by the Linde Company, such as Types 4A,
5A and 13X, and the Microtraps produced by the Davison Chemical Company. Such materials adsorb and thus effectively remove water from the reaction medium. The molecular sieve may be added directly to the reaction mixture or, preferably, the water containing condensate from the reaction mixture contacted with such material to remove the water. A further useful adsorbent is neutral activated alumina.
The conversion is conducted at a temperature within the range of from 80°C to 175°C and preferably from 100°C to 150°C for periods of from 1 to 24 hours. The lower temperature values require more time than do the higher temperatures. The conversion in general, is carried out at the lower rather than the higher values cited above.
The product is isolated by removal of the liquid medium under reduced pressure and purification of the crude product thus obtained by recrystallization from an appropriate solvent, or by chromatography over silica gel, cellulose, or silicata-alumina.
The 7-amino-3-methyl-4-(5-tetrazolyl-cephem compounds of formula (II) are valuable intermediates for the preparation, by acylation, of antibacterial 7-acylq amino-3-methyl-4-(5-tetrazolyl)-A -cephems. Certain of
A the 7-(N-protected amino)-3-methyl-4-(5-tetraZolyl)-& 30 cephem compounds, i.e., those wherein the protecting group is other than an acyl group, also serve as intermediates for preparation of 7-acylamino-3-methyl-4-(5tetrazolyl)-A-cephems by procedures known to those skilled in the art.
The desoxy precursors of formula (I) compounds which serve as reactants in the conversion process of this invention are prepared from the N-triphenylmethyl or N(substituted)triphenylmethyl derivatives of 6-aminopenicillanic acid by the reaction sequence discussed below.
In the first step, 6-(triphenylmethylamino)penicillanic acid (Sheehan et al J Am Chem Soc 81, 5838, 1959) is converted into an amide of formula (VII).
<c6h5)3nh
C— N \CHW1W2 (VII) wherein
W^ is a phenyl, substituted phenyl, furyl, substituted furyl, thienyl or substituted thienyl group, and W2 is a hydrogen atom or an alkyl, phenyl, substituted phenyl, furyl, substituted furyl, thienyl, or substituted thienyl group. When is a phenyl or substituted phenyl group, and ia a hydrogen atom or an alkyl, phenyl or substituted phenyl group, the protecting group may be removed by hydrogenolysis. This group also may be removed by solvolysis in trifluoroacetic acid, when the combined effect of W^ and W2 is sufficient to offer the requisite degree of stability to the incipient carbonium ion.
+CH
Particularly preferred configurations for this protecting group which afford satisfactory yields of desoxy precursors of formula (I) are those of formula (V) and (VI) above.
The amide is prepared by activation of the 3-carboxy group of 6-(triphenylmethylamino)penicillanic acid, e.g. by mixed anhydride formation, followed by reaction with an equimolar proportion of an amine of the formula
Thus, formation of the mixed anhydride involves reacting an appropriate carboxylate salt of 6triphenylmethylaminopenicillanic acid in a reaction-inert organic solvent, with an approximately equimolar proportion of pivaloyl chloride or a lower-alkyl chloroformate.
Appropriate salts are, for example, alkali metal salts, such as sodium or potassium salts, and amine salts, such as triethylammonium, pyridinium, N-ethylpiperidinium or Ν,Ν-dimethylanilinium salts. Appropriate solvents are those which serve to dissolve at least one of the reactants and the mixed anhydride product. Examples of such sol20 vents are chlorinated hydrocarbons, such as chloroform, or methylene chloride; aromatic hydrocarbons, such as benzene, toluene, or xylene; and ethers, such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane. The reaction is usually carried out at a temperature in the range from -50°C to 30°C and preferably at 0°C. The reaction commonly requires about one hour. The product is isolated simply by filtering off the insoluble materials, and then evaporating the solvent in vacuo to give the crude product. The latter may be used directly, or purified further by methods known in the art. If desired, however, the mixed anhydride product need not be isolated. It may be used in situ for reaction with the amine simply by contacting the reactants in an inert solvent, for 0.5 to 2.0 hours, at a temperature in the range from -30°C to 30° C and preferably at 0°C. The same solvents identified above for mixed anhydride formation are useful for the reaction.
In the case where the reaction is conducted in a water-immiscible solvent, the product is usually isolated by washing the reaction mixture with water and then concentrating the organic solvent to dryness in vacuo, to give the crude product. The latter product may be used immediately for Step 2, or, if desired, it may be purified further by well-known methods. It is sometimes convenient simply to wash the reaction mixture with water, and then use the so-produced solution of amide directly in Step 2. In the case where the reaction is conducted in a water-miscible solvent, the product is usually isolated by first removing the water-miscible solvent by evaporation in vacuo, replacing it by a water-immiscible solvent, and then proceeding as described above.
Other values of R^ which, according to the criteria set forth herein, are not tetrazolyl nitrogen protecting groups may be introduced onto the carbamoyl group of 6triphenylmethylaminopenicillanic acid in like manner.
This includes such values as alkanoyloxymethyl, 1-alkanoxyloxyethyl and phthalidyl.
In Step 2, the product from Step 1, or a simple transformation product thereof in which any phenolic hydroxy groups are protected by conversion to formyloxy, alkanoyloxy or alkoxymethyl groups, is converted into an imidoyl chloride by reacting the said amide in a reaction-inert organic solvent with phosgene and a tertiary amine. About one molar equivalent of phosgene is usually used, but amounts up to two or three molar equivalents are sometimes employed. The tertiary amine is preferably present in an amount equal to or greater than the amount of phosgene. The reaction is carried out at a temperature in the range from -20°C to 30°C, and preferably at 25°C, and it usually requires a few hours to reach completion. A variety of tertiary amines may be used in this process, for example trimethylamine, triethylamine, Ν,Ν-dimethylaniline, N-methylmorpholine or pyridine. Typical solvents which may be used are chlorinated hydrocarbons such as chloroform, methylene chloride or 1,2-dichloroethane, and ethers such as tetrahydrofuran, or 1,2-dimethoxyethane. If desired, the imidoyl chloride may be isolated by evaporation of the filtered reaction mixture, but in many instances it is convenient to use the imino chloride in situ.
Several other reagents, for example, thionyl chloride or a phosphorus halide such as phosphorus pentaehloride are operative in the imidoyl chloride forming reaction.
Moreover, if desired, use may be made of the corresponding imidoyl bromide.
In Step 3 of the sequence, the above imidoyl chloride is Converted into a tetrazolylpenam compound of formula:-
wherein
-CHW^W^ is as previously defined. This transformation comprises treating the said imidoyl chloride in a reaction-inert solvent with about one molar equivalent, or sometimes a small excess, of azide ion. The reaction mixture is then stored at ambient temperature for several hours, for example, overnight, until conversion into tetrazole is substantially complete. A wide variety of azide ion sources are operative in this process, and examples of those which are particularly valuable are trialkylsilyl azides having from one to four carbon atoms in each of the alkyl groups, such as trimethylsilyl azide and triethylsilyl azide; metal salts of hydrozoic acid, such as potassium and sodium azide; tributylammonium azide, Ν,Ν-dimethylanilinium azide, N-methylmorpholinium azide and pyridinium azide; and tetramethylguanidinium azide. Appropriate solvents when the azide ion source is a trialkylsilyl azide or a trisubstituted ammonium azide are chlorinated hydrocarbon solvents, such as chloroform, methylene chloride and 1,2-dichloroethane. Dipolar aprotic solvents such as N-methylpyrollidone also may be used. In reactions where a metal salt of hydrazoic acid constitutes the azide ion source these dipolar aprotic solvents become the solvent-type of choice. Product isolation is achieved using standard methods. When a low boiling chlorinated hydrocarbon is the solvent, the reaction solution is washed with dilute alkali and then the organic solvent is evaporated off. When a dipolar aprotic solvent is the solvent the reaction mixture is usually first diluted with a large excess of dilute alkali, and then, after appropriate adjustment of the pH, the product is isolated by solvent extraction.
When a substituted triphenylmethyl group (formula
III) is desired as the amino-protecting group, the appropriate 6-(substituted triphenylmethylamino)penicillanic acid is readily prepared by alkylation of 6-aminopenicill5 anic aoid with the appropriate substituted triphenylmethyl chloride (or bromide).
The procedure comprises reacting 6-aminopenicillanic acid in chloroform or methylene chloride solution with the appropriate RCl or RBr and an equivalent amount of an acid acceptor. The reaction is initially conducted at 0° to 5°C for 0.5 to 2.0 hours and then at ambient temperature for up to 72 hours. The product, if desired, is isolated by standard procedures (e.g. evaporation of solvent).
When 2,2,2-trichloro (or tribromo) ethoxycarbonyl or benzyloxycarbonyl is desired as the amino-protecting group, the appropriate 6-substituted.aminopenicillanic acid is prepared by reaction of 6-aminopenicillanic acid with 2,2,2-trichloro(or tribromo)ethylchloroformate or benzyloxychloroformate in a reaction-inert solvent such as dioxane at -20°c to +25°C in a Schotten-Baumann reaction.
The N-triphenylmethyl derivative thus obtained is converted to the desoxy compound of formula (X) (R=H) by treatment of the triphenylmethyl derivative with acid.
A wide variety of acidic reagents such as methanesulphonic acid, benzenesulphonic acid or g_-toluenesulphonie acid? an anhydrous hydrohalic acid; such as hydrogen chloride or hydrogen bromide; or an alkanoic acid, such as acetic, propionic, chloroacetic or trifluoro aeetic acid, may be used. The reaction is normally carried out by dissolving the starting material in an appropriate solvent and adding two molar equivalents of the acid reagent, at ambient temperature. Reaction is complete within about one hour, and the product is present in the reaction medium in the form of the acid-addition salt corresponding to the acid reagent used. A solvent should be chosen which will dissolve the starting penam compound and the examples of suitable solvents are:- ethers, such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; chlorinated hydrocarbons, such as chloroform, methylene chloride and 1,2-dichloroethane; lower aliphatic ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters, such as ethyl acetate and butyl acetate; hydrocarbons, such as hexane, cyclohexane and benzene; and lower alkanols, such as methanol, ethanol,, and butanol. Although it is common to use about two molar equivalents of acid in this process, only one molar equivalent is necessary when either the reaction is carried out in the presence of one molar equivalent of water, or the acid is introduced as a monohydrate. A favoured procedure comprises the use of ^-toluenesulphonic acid in acetone since the ptoluenesulphonate salt of the product often precipitates.
The 2,2,2-trichloro (or bromo) ethoxycarbonyl protecting group is removed using acetic acid-zinc dust, formic acid-zinc dust or a zinc-copper couple in formic acid diluted with acetonitrile in the manner described by Chauvette et al J Org Chem 36, 1259-67 (1971) . The benzyloxycarbonyl protecting group is removed by treatment of the so-protected compound with a mixture of trifluoroacetic acid/anisole (4:1, v/v) and trifluoromethylsulphonic acid. It is advantageous that this procedure be conducted at ice-bath temperature (about 0°) and for a limited period of time, usually for four to six minutes. If a higher temperature, e.g, 25°C to 40°C, is used, or a longer reaction time, such as 1 to 3 hours, simultaneous removal of the tetrazole nitrogen protecting group is possible. This may, of course, be desirable in certain instances such as when a compound of formula (II) carries benzyloxycarbonyl as an amino protecting group and a tetrazolylcephem nitrogen protecting group of formula (V) and (VI).
The precursor compound of formula (I) wherein R is an organic acyl group, is prepared by acylation of the appropriate 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with an activated derivative of a carboxylic acid, such as an acid chloride, a mixed anhydride, an activated ester (e.g., p-nitrophenyl) or the reactive intermediate formed by the acid and dicyclohexylcarbodiimide or ether peptide bond forming reagent. A typical acylation procedure comprises reacting the compound in a reactioninert solvent, e.g. methylene chloride, chloroform, tetrahydrofuran, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone or N,N-dimethylformamide, with an equimolar amount of an appropriate acid chloride, and preferably of phenacetyl chloride or phenoxyacetyl chloride, at a temperature of from -40°C to 30°C and preferably from -10°C to 10°C. The product is isolated by standard methods as by evaporation of the reaction mixture to dryness and treatment of the residue with a water-immiscible solvent and water. The acylated product if insoluble, is filtered off? otherwise the pH of the aqueous phase is adjusted to an appropriate value and the phase containing the product separated and evaporated.
In like manner, formula (II) compounds wherein R is hydrogen are acylated.
417 9 9
The methods described above for removing aminoprotecting groups from 6-(protected amino)-2,2-dimethyl3-(5-tetrazolyl)penams,precursors of formula (I) compounds, also apply to removal of such groups from compounds of formula (II).
The tetrazolecephem nitrogen protecting group of compounds of formula (II) is removed in the manner described above and comprises contacting the compounds with trifluoroacetic acid acid/anisole at a temperature of 30° to 50° C for several hours.
Alternatively, when R^ or R2 is alkanoyloxymethyl, 1-alkanoyloxyethyl, phthalidyl or methoxymethyl, such groups may be introduced into a compound of formula (II) or a precursor desoxy compound of formula (I) (R^, R2=H) by alkylation of the tetrazolyl group with an appropriate alkylating agent? an alkanoyloxy methyl halide or 1alkanoyloxyethyl halide (Ulich et al, J Am Chem Soc 43, 660, 1921 and Euranto et al, Acta Chem Scand 20, 1273, 1966), phthalidyl halide or chloromethyl ether.
The phthalidyl, alkanoyloxymethyl and 1-(alkanoyloxy) ethyl substituted tetrazoles of the final products are pro-drug forms of the final products, and although inactive or of relatively low activity against microorganisms per se are metabolized to the free tetrazole (R^=H) when injected parenterally to animals, including man. The rate of metabolic conversion of the compounds to the free tetrazole occurs at such a rate as to provide an effective and prolonged concentration of the free tetrazole in the animal body. In effect, such compounds act as depot sources for the free tetrazole antibacterial agent.
The tetrazolyl cephems described herein wherein the substituent on the tetrazolyl moiety is R2 exhibit in
1799
- 30 vitro activity against a variety of microorganisms, including both gram-positive and gram-negative bacteria. Their useful activity can readily be demonstrated by in vitro tests against various microorganisms in a brainheart infusion medium by the usual two-fold serial dilution technique. The in vitro activity of the herein described compounds renders them useful for topical application in the form of ointments or creams, or for sterilization purposes, e.g., sick-room utensils.
They are also effective antibacterial agents in vivo in animals including man, not only via the parenteral route of administration, but also by the oral route of administration.
Obviously, the physician will ultimately determine the dosage which will be most suitable for a particular individual person, and it will vary with the age, weight, and response of the particular patient as Well as with the nature and extent of the symptoms, the nature of the bacterial infection being treated and the pharmacodynamic characteristics of the particular agent to be administered. It will often be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a smaller quantity administered parenterally.
Having full regard for the foregoing factors it is considered that an effective daily oral dose of the compounds of the present invention in humans of approximately 50 to 1000 mg/kg per day, with a preferred range of 250 to 750 mg/kg per day, in single or divided doses, and a parenteral dose of 25 to 500 mg/kg per day, with a preferred range of 125 to 400 mg/kg per day will effectively alleviate the symptoms of the infection.
These values are illustrative, and there may, of course, be individual cases where higher or lower dose ranges are warranted.
The tetrazolylcephems of formula (II) wherein the substituent on the tetrazolyl group is are remarkably effective in treating a number of infections caused by susceptible gram-negative and gram-positive bacteria in poultry and animals including man. For such purposes, the pure compounds of mixtures thereof with other antibiotics may be employed. They may be administered alone or in admixture with a pharmaceutical carrier on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch, milk, sugar or certain types of clay, or in capsules alone or in admixture with the same or equivalent excipients. They also may be administered orally in the form of elixirs or oral suspensions which may contain flavouring or colouring agents, or be injected parenterally, that is, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may be either aqueous such as water, isotonic saline, isotonic dextrose, Ringer's solution or non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, or sesame) and other non-aqueous vehicles which will not interfere with the therapeutic efficiency of the preparation and are nontoxic in the volume or proportion used (glycerol, propylene glycol, or sorbitol). Additionally, compositions suitable for extemporaneous preparation of solutions prior to administration may advantageously be made. Such compositions may include liquid diluents, for example propylene glycol, diethyl carbonate, glycerol or sorbitol, buffering agents, as well as local anesthetics and inorganic salts to afford desirable pharmacological properties.
Illustrative Examples of the process of this invention and representative preparations for making the necessary starting materials are as follows.
EXAMPLE 1.
7-(2-phenylacetamido-3-Methyl-4-(2-[Pivaloyloxymethylq tetrazol-5-yl)-<Δ -cephem
A. ) 6-(2-phenylacetamido)-2,2-dimethyl-3-(210 [pivaloyloxymethyl]-tetrazol-5-yl)penam sulfoxide.
To a solution of 6-(2-phenylacetamido)-2,2-dimethyl3-(2-[pivaloyloxymethyl] tetrazol-5-yl)penam (472 mg.,
1.0 mmole) in methylene chloride (15 ml.) is added mchloroperbenzoic acid (203 mg., 1.0 mmole) and the mixture stirred at room temperature for forty minutes.
The reaction mixture is transferred to a separatory funnel and washed twice with dilute aqueous sodium bicarbonate, once with distilled water and once with saturated brine. It is then dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The white foamy residue is taken up in methylene chloride (25 ml.) in a round-bottomed flask and the solution boiled on a steam bath. As the methylene chloride is boiled off it is replaced by hexane so as to maintain a constant volume. This is continued until the solution becomes cloudy. It is then cooled, stirred, and the walls of the flask scratched to induce crystallisation. The precipitate is granulated for 1.5 hours and then recovered by filtration, washed with hexane and air dried. Yield =
233 mg., (47.8%) as white crystals; m.p. 139.5°-140.5°C.
B. ) Conversions of A to corresponding Λ -cephem.
A Soxhlet apparatus is flame dried, placed under a positive nitrogen atmosphere and charged with sulfoxide (123 mg. 0.25 mmole) prepared in A above and anhydrous dioxane (20 ml., distilled from LiAlH^). Pyridine (3 drops) is added to the colourless solution, followed by phosphoric acid (1 drop of 85%). A white precipitate is formed. The reaction mixture is stirred and heated to gentle reflux and the condensate passed into a thimble filled with an adsorbent comprising a 1:1 mixture of alumina and Linde Molecular Sieve Type 4A (available from the Linde Company). The white precipitate dissolved after a few minutes of heating, leaving a slightly cloudy solution. The reaction mixture is refluxed for a total of 15 hours and is then evaporated under reduced pressure. The yellow, oily residue is taken up in methylene chloride (25 ml.) and water (25 ml.), thoroughly mixed and washed successively with 10 ml each of dilute hydrochloric acid, dilute sodium bicarbonate solution, water and saturated brine. The methylene chloride solution is dried with magnesium sulphate and evaporated to dryness under reduced pressure to give 110 mg (94%) yield of the title product.
EXAMPLE 2.
The procedure of Example 1 is repeated but using the appropriate 6-(N-protected amino)-2,2-dimethyl-3-(5tetrazolyl)penams of formula (I) to produce corresponding 4^-cephems of formula (II). (The dotted lines represent unsaturation, only one of which is present).
(I) (II)
-(pivaloyloxymethyl) phenylacetyl l-(p-methoxybenzyl)
-(p-methoxybenzyl) phenylacetyl 1-(^-benzyloxybenzyl)
-(o-methoxybenzyl) phenylacetyl 1-(acetoxymethyl)
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Φ rP fr fr
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EXAMPLE 3.
7-(2-Phenylacetamido)-3-Methyl-4-(l-[p-Methoxybenzyl]3 ** tetrazol-5-yl)-A -Cephem
A solution of 6-(2-phenylacetamido)-2,2-dimethyl-35 (l-[p.-methoxybenzyl]tetrazol-5-yl)penam sulfoxide (478 mg., 1.0 mmole) and ρ,-toluenesulfonic aoid (50 mg.) in xylene (20 ml.) is heated at reflux for five hours and then evaporated to dryness under reduced pressure. The residue is taken up in methylene chloride (25 ml.) and water (25 ml.), thoroughly mixed and washed successively with 10 ml. each of dilute hydrochloric acid, dilute sodium bicarbonate solution, water and saturated brine. The methylene chloride solution is dried (MgSO^) and evaporated under reduced pressure to give the title compound.
EXAMPLE 4.
7-Amino-3-Methyl-4-(l-[p-Methoxybenzyl]tetrazol-5-yl)-Cephem.
A. 6-Amino-2,2-dimethyl-3-(l-[p-methoxybenzyl]20 tetrazol-5-yl)penam sulfoxide.
Ozone is bubbled into a slurry of 6-amino-2,2dimethyl-3-(1-[p-methoxybenzyl]tetrazol-5-yl)penam (1.80 g., 0.005 mole) in methylene chloride (100 ml.) at 5°C for three hours. Lyophilization of the reaction mixture affords the sulfoxide.
. 3
B. Conversion of A to corresponding A -Cephem.
A mixture of the sulfoxide from A above (0.376 g., 0.005 mole), phenyl dihydrogen phosphate (0.174 g., 0.001 mole) and pyridine (0.091 g., 0.001 mole) in dioxane (50 ml. of anhydrous, peroxide-free) is refluxed for eight hours and the condensation passed through a column of neutral activated alumina before being returned to the reaction flask. The reaction mixture is evaporated to dryness in vacuo and the residue taken up in methylene chloride (50 ml.) and water (50 ml.) and thoroughly mixed The mixture is washed successively with dilute aqueous sodium bicarbonate (20 ml.), water (1 x 20 ml.) and saturated brine. The methylene chloride solution is dried (MgS04) and evaporated under reduced pressure to give the desired product.
When the above procedure is repeated, but the 6amino-2,2-dimethyl-3-(l-[p-methoxybenzyl]tetrazol-5-yl)penam used therein is replaced by an equimolar amount of the appropriate 6-amino-2,2-dimethyl-3-(substituted)tetrazol-5-yl)penam, there are produced the following compounds:-
o
R R
Ο trityl trityl
H
H
H
H
H phenacetyl phenylacetyl phenylacetyl
1-(p-methoxybenzyl 1-furfuryl 1-(p-acetoxybenzyl)
1-(p-hydroxybenzyl)
1-(p-hydroxybenzyl)
1- (p-benzyloxybenzyl)
2- (pivaloyloxymethyl) 1-(ac etoxymethyl)
1-(p-benzyloxybenzyl) 1-methoxymethyl
EXAMPLE 5.
7-(2-Phenylacetamido)-3-Methyl-4-(5-Tetrazolyl)-4 -Cephem
A. 6-(2-Phenylaeetamido)-2,2-dimethyl-3-(5-tetrazolyl )penam sulfoxide.
A solution of 5.3 g., 0.0148 mole) 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam acetic acid (15 ml.) and 30% hydrogen peroxide (3 ml.) is stirred at room temperature for 90 minutes. The reaction mixture is diluted to 200 ml. with water to give a cloudy solution which is filtered through diatomaceous earth.
The thus obtained clear aqueous solution is freeze-dried to furnish an amorphous solid which is extracted with dichloromethane. Insoluble matter is filtered. The dichloromethane solution is evaporated under reduced pressure; the residue is slurried in diethyl ether, filtered, and the filtrate evaporated to give the title compoundi Yield = 1.6 gm. (29%); ir (KBr) 1784, 1675 cm-1; nmr (DjO-NaHCOj) 7.35 ppm (s, 5H), 6.00 (d, IH), 5.5-5.3 (m, 2H), 3.65 (s, 2H), 1.60 (s, 3H0, 0.80 (s, 3H).
B. The product of procedure A above is converted to the title 4 -cephem compound by the procedure of Example 1.
PREPARATION A.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl] tetrazol-5-yl)penam (A). 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N[4-methoxybenzyl]carbamoyl)penam.
To a stirred slurry of 86.4 g. (0.8 mole) of 6-aminopenicillanie acid in 600 ml. of anhydrous chloroform is added 11.2 ml. (0.4 mole) of triethylamine, and the mixture is stirred at ambient temperature until a clear solution is obtained (ca. 15 minutes), To this solution
417 9 9 is then added, portionwise over about 25 minutes, 134.9 g. (0.44 mole) of 90% pure triphenylmethyl chloride, at ambient temperature. Stirring is continued for a further 64 hours, and then 5.6 ml. of triethylamine is added.
The solution is cooled to 0-5°C., and then an ice-cold solution of 38 ml. (0.4 mole) of ethyl chloroformate in 80 ml. of chloroform is added dropwise during 30 minutes with the reaction temperature being maintained between 4 and 9°C. After a further 15 minutes of stirring, 52.4 ml, (0.4 mole) of 4-methoxybenzylamine is injected into the reaction medium, below the surface of the solvent, at 4 to 9°C., and over a period of 30 minutes. Stirring is continued for a further 30 minutes at 3 to 6°C. for 20 minutes while the reaction medium warms to 20°C.
The reaction mixture is then washed with water, followed by brine. Finally, it is dried using magnesium sulfate to give a chloroform solution of 6-(triphenylmethylamino)2,2-dimethyl-3-(N-[4-methylbenzyl]carbamoyl)penam.
(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(l4-methoxybenzyl]tetrazoi-5-yl)penam.
To a chloroform solution containing 69,4 g. (0.120 mole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4methoxybenzyl]carbamoyl)penam, and having a volume of 133.3 ml., prepared by the method described in (A) above, is added a further 132.7 ml. of chloroform, followed by
29.1 ml. (0.360 mole) of pyridine. This solution is cooled to 10°C., and then 26.22 g. (0.126 mole) of phosphorus pentaehloride is added during 15 minutes, with stirring. Stirring is continued at ca. 1O°C. for 10 minutes, and then at ambient temperature for a further
1.5 hours, giving a solution of the imino chloride.
To a one-sixth aliquot of this imino chloride solution is added 4,85 ml. (Ο.ΟδΟ mole) of pyridine, followed by 2.42 ml. (0.060 mole) of methanol at ca. 25°C., with stirring. After a further 15 minutes of stirring 2.03 g. (0.038 mole) of ammonium chloride, followed by 2.59 g. (0.039 mole) of 95% pure sodium azide is added. The reaction mixture is then stirred at ambient temperature for a further 4 hours. At this point, 400 ml. of water and 200 ml. of chloroform are added, and then the layers are separated. The organic phase is washed with water, dried using magnesium sulfate, and then concentrated to a small volume in vacuo. This final chloroform solution is added dropwise with stirring to a large volume of diisopropylether, and, after 30 minutes, the precipitate which has formed is filtered off. This affords 6.1 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(l-[4-methoxybenzyl]tetrazol-5-yl)penam. The infrared spectrum of the product (KBr disc) shows an absorption band at 1790 cm-l (β-laetam); and the NMR spectrum (in CDClg) shows absorptions at 7.25 ppm (multiplet, aromatic hydrogens), 5.40 ppm (broad singlet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 4.50-4.30 ppm (multiplet, C-5 and C-6 hydrogens), 3.70 ppm (singlet, methoxy hydrogens), and 3.50-3.10 ppm (broad peak, NH), 1.50 ppm (singlet,
C-2 methyl hydrogens) and 0.75 ppm (singlet, C-2 methyl hydrogens).
PREPARATION B.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-[4-benzyloxybenzyl] tetrazol-5-yl)penam.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[4benzyloxybenzyl]carbamoyl)penam - To a stirred solution of 20.0 g. of 6-triphenylmethalamino-penicillanic acid (Sheehan and Henery-Logan, Journal of the American Chemical Society, 81, 5836 [1959]) in 140 ml. of acetone, at 0-5 C., is added 6.08 ml. of triethylamine followed by 5.78 ml. of isobutyl chloroformate. After a further 10 minutes, the mixture is filtered directly into a stirred solution of 9.28 g. of 4-benzyloxybenzylamine in 1,000 ml. of water and 300 ml. of acetone at ambient temperature.
The mixture so obtained is stirred for 4 minutes, and then an additional 500 ml. of water is added. Stirring is continued for a further 7 minutes, and then the reaction mixture is extracted with ether. The ether is dried using anhydrous magnesium sulfate, and then evaporated to dryness in vacuo. The crude product so obtained is re-dissolved in 200 ml. of ether, which is then added dropwise over 10 minutes to 2,500 ml. of hexane. The solid which precipitates is filtered off, giving 21.5 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-benzyloxybenzyl]carbamoyl)penam.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(chloro[N-(4-benzyloxybenzyl)imino]methyl)penam - To a stirred solution of 2.0 g. of the above-described amide in 10 ml. of dry chloroform, at 0-5°C., is added 0,99 ml. of pyridine, followed by 5.42 ml. of a 2.26 M solution of phosgene in chloroform. The reaction mixture is then stirred at ambient temperature overnight. At this point, it is evaporated to dryness in vacuo, yielding a viscous gum, Which is extracted with 100 ml. of ether. The ether is filtered, and evaporation of the filtrate affords the imino chloride as a yellow foam.
6-{Tr iphenyImethylamino)-2,2-dimethyl-3-(l-[4benzyloxybenzyl]tetrazol-5-yl)penam - The above-described imino chloride is re-dissolved in 8 ml. of dry Ν,Νdimethylformamide. To this solution is added 249 mg. of potassium azide, and the turbid solution is stirred at ambient temperature for 2.25 hours. The solvent is evaporated at ambient temperature, under high vacuum, leaving a brown gum. This residue is partitioned between 60 ml. of water and 150 ml. of ether. The ether phase is separated off, washed with saturated brine, dried using anhydrous sodium sulfate, and finally evaporated to dryness in vaeuo. The residue is 980 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl] tetr azol -5 -yl) penam. its nmr spectrum (in CDCl·^) shows absorption bands at 7.30 ppm (multiplet, aromatic hydrogens), 5.45 ppm (quartet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 5.00 ppm (singlet, benzyl hydrogens), 4.40 ppm (multiplet, C-5 and C-6 hydrogens), 1.40 ppm (singlet, C-2 hydrogen) and 0.70 ppm (singlet,
C-2 hydrogen).
PREPARATION C.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam (A) 6-(triphenylmethylamino)-2,2-dimethyl-3-(Nfurfurylcarbamoyl)penam
To a stirred slurry of 216 g. (1 mole) of 6-aminopenicillanic acid in 1500 ml. of chloroform, is added, at 25-3O°C., 278 ml. (2 mole) of triethylamine. . To the solution thus obtained is added, portionwise during 25 minutes, 306 g. (1.1 mole) of triphenylmethyl chloride, at 25-3O°C. Stirring is then continued for 44 hours at ambient temperature.
A 522-ml. portion (0.25 mole) of the above 6(triphenylmethylamino)penicillanic acid solution is cooled to 4°C., and then 3.5 ml. of triethylamine is added. With vigorous stirring is then added 23.75 ml. of ethyl chloroformate at 5-10°C. Stirring is continued for a further 30 minutes at ca. 6°C. at the end of the addition, and then.8.43 ml. of furfurylamine is injected into the reaction medium below the surface of the solvent. At 10 minute intervals, three further portions of furfurylamine (5.90 ml., 4.22 ml. and 3.54 ml.) are then injected into the reaction medium in similar fashion. The total volume of furfurylamine added is 22.09 ml. (0.25 mole), and the temperature is maintained at ca. 6°C. throughout the addition of the amine. When the addition of the amine is complete, the cooling bath is removed and the reaction medium is stirred at ca. 25°C. for 45 minutes.
It is then washed successively with three portions of water, and one portion of brine. Finally, it is dried using anhydrous magnesium sulfate. This affords 610 ml. of a chloroform solution of 6-(triphenylmethylamino)-2,2dimethyl-3-(N-furfurylcarbamoyl)penam. The NMR spectrum of this solution showed absorptions at 7.3 ppm (17R, m),
6.2 ppm (IH, m), 4.35 ppm (3H, m), 4.05 ppm (2H, s), 1.6 ppm (3H, s) and 1.35 (3H, s).
(B) 6-(triphenylmethylamino)-2,2-dimethyl-3-(1furfuryltetrazol-5-yl)penam.
To a stirred solution of 3.05 g. (5.7 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam, in 8 ml. of chloroform at 0°C., is added 1.35 ml. (17 mmole) of pyridine, followed by 2.64 ml. of a 4.33 M solution of phosgene in chloroform.
Stirring is then continued for 1 hour at 25°C. The chloroform, and excess phosgene and pyridine, are then removed by evaporation in vacuo, and the residue is redissolved in 5 ml. of chloroform. The solution is cooled to 0°C., and then 2.25 g, (14.4 mmole) of tetramethylguanidinium azide is added in several small portions. Stirring is continued for 15 minutes at ambient temperature, and then 20 ml. of chloroform, followed by 30 ml. of water, are added and the pH is adjusted to 6.5. The chloroform layer is separated off, washed with water, followed by brine, and then dried (MgSO^). Removal of the solvent by evaporation in vacuo leaves 3.37 g. of a dark-red foam. The foam is redissolved in a small volume of chloroform and absorbed onto a column of chromatographic silica gel. Elution Of the column with chloroform, followed by evaporation of the appropriate fractions in vacuo, affords 6-(triphenylmethylamino) -2, 2-dimethyl-3-(l-furfuryltetrazol-5-yl)penam. The NMR spectrum of the product (CDCl^) shows absorptions at 7.40 ppm (m, 16H), 6.40 ppm (m, 2H), 5.50 ppm (s, 2H), 5.20 ppm (s, IH), 4.90 ppm (m, 2H), 1.60 ppm (s, 3H), and 0.80 ppm (s, 3H).
PREPARATION D.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-^4-hydroxybenzylj tetrazol-5-yl)penam.
(A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N20 [4-hydroxybenzyl]carbamoyl)penam.
To a stirred slurry of 43.2 g. (0.20 mole) of 6aminopenicillanic acid in 300 ml. of chloroform is added
55.6 ml. (0.40 mole) of triethylamine, followed by 61.2 g. (0.22 mole) of triphenylmethyl chloride, at ambient temperature. Stirring is then continued for a further 48 hours at ambient temperature.
A 120-ml. portion (containing 0.060 mole of triethylammonium 6-(triphenylmethylamino]penicillanate) of the above chloroform solution is withdrawn. It is diluted with a further 40 ml. of chloroform, and then 1.67 ml. (0.012 mole) of triethylamine is added. The mixture is cooled to ca. 4°C., in an ice-bath, and then 6,84 ml.
of ethyl chloroformate is added all at once, with stirring. Stirring is continued for 30 minutes with ice-bath cooling, and then 7.5 g. (0.060 mole) of 4-hydroxybenzylamine is added. Stirring is continued for 10 minutes with icebath cooling, and then for a further 1 hour without cooling. At this point, the chloroform solution is washed with water, followed by brine, and then dried using anhydrous sodium sulfate. Removal of the solvent by evaporation in vacuo affords the crude amide. The crude amide is re-dissolved in 50 ml. of chloroform and absorbed on a column of chromatographic grade silica gel. The column is eluted with chloroform, taking 400 ml. fractions. Fractions 9 to 15 are combined and concentrated to an oil, which solidifies on trituration with methylene chloride. After further trituration with ether, there is obtained 12.63 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N[4-hydroxybenzyl] carbamoyl)penam, m.p. 166-168°C. (dec.).
The infrared spectrum of the product (CDC1, solution)
-1 J -1 shows absorptions at 1785 cm (β-lactam) and 1675 cm (amide I). The NMR spectrum of the product (CDClg) shows absorptions at 7.60-6.40 ppm (multiplet, 20H, aromatic hydrogens and amide hydrogen), 4.70-4.10 ppm (multiplet, 5H, C-5 and C-6 hydrogens, benzyl methylene hydrogens and C-3 hydrogen), 2.98 ppm (doublet, 1H, amine nitrogen), 1.64 ppm (singlet, 3H, C-2 methyl hydrogens) and 1.31 ppm (singlet, 3H, C-2 methyl hydrogens).
(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1[4-hydroxybenzyl] tetrazol-5-yl)penam.
To a stirred solution of 1.69 g. (3 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl] carbamoyl )penam (prepared as described in A) in 9 ml. of chloroform is added 1 ml. (12 mmole) of pyridine.
The solution is cooled to ca. 4°C. in an ice-bath and 0.80 ml. of chlorotrimethylsilane is added. The solution is stirred for 40 minutes at ambient temperature, and then it is again cooled to eg. 4°C. Phosgene (1.5 ml. of a 4.3M solution in chloroform (6.45 mmole)) is added and the cooling bath is removed. Stirring is continued for a further 1.5 hours, and then all the volatile components are removed by evaporation in vacuo.
The oily residue is redissolved in 6 ml. of chloroform and the solution is cooled to ca. 4°C. in an icebath, To the stirred solution is added 0.95 g. (6 mmole) of tetramethylguanidinium azide, and then stirring is continued for a further 1 hour at ambient temperature.
At this point, 25 ml. of water is added, followed by sufficient 1 N sodium hydroxide to bring the pH of the aqueous phase to 10. The chloroform layer is separated off, washed with water, dried using sodium sulfate and evaporated to dryness in vacuo. The oily residue (2.3 g.) is dissolved in a small volume of chloroform and absorbed on a column of 30 g. of chromatographic silica gel. The column is eluted with chloroform, taking 50-ml. fractions. Fractions 13 to 19 are combined and concentrated in vacuo to give 0.71 g. of 6-(triphenylmethylamino)-2,2-dimethyl3-(l-[4-hydroxybenzyl]tetrazol-5-yl)penam. The infrared spectrum of the product (in CHC1,) shows an absorption at -1 J
1780 cm (β-lactam). The NMR spectrum (CDCl^) shows absorptions at 7.80-6.67 ppm (multiplet, 20H, aromatic hydrogens and phenolic hydrogen), 5.66-5.10 ppm (quartet, 2H, benzyl methylene hydrogens), 5.02 ppm (singlet, IH,
C-3 hydrogen), 4.60-4.20 ppm (multiplet, 2H, C-5 and C-6 hydrogen), 3.10 ppm (doublet, IH, amine hydrogen), 1.44 ppm (singlet, 3H, C-2 methyl hydrogens) and 0.71 ppm (singlet, 3H, C-2 methyl hydrogens).
417 9 9
PREPARATION Ε.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-[4-acetoxybenzylj tetrazol-5-yl)penam
To a stirred solution 1.69 g. (3 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl] carbamoyl)penam in 9 ml. of chloroform is added 1 ml.
(12 mmole) of pyridine. The solution is cooled to ca. 4°C. in an ice-bath and 235 mg. of acetyl chloride is added slowly. The solution is stirred for 2 hours at ambient temperature, and then it is again cooled to ca. 4°C. Phosgene (1.5 ml of a 4.3 M solution in chloroform 6.45 mmole) is added and the cooling bath is removed. Stirring is continued for a further 1.5 hours, and then all the volatile components are removed by evaporation in vacuo. The residue is redissolved in 6 ml. of chloroform and the solution is cooled to ca. 4°C. in an icebath. To the stirred solution is added 0.95 g. (6 mmole) of tetramethylguanidinium azide, and then stirring is continued for a further 1 hour at ambient temperature.
At this point, 25 ml. of water is added, followed by sufficient IN sodium hydroxide to bring the pH of the aqueous phase to 10. The chloroform layer is separated off, washed with water, dried using sodium sulfate, and evaporated to dryness in vacuo. This affords crude 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-acetoxybenzyl] tetrazol-5-yl)penam, which is purified further by chromatography.
When the above procedure is repeated, except that the acetyl chloride is replaced by an equimolar amount of formic-acetic anhydride and chloromethyl methyl ether, respectively, the product is 6-(triphenylmethylamino) 2,2-dimethyl-3-(l-[4-formyloxybenzyl]tetrazol-5-yl)penam and 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxy41799 methoxy)benzyl]tetrazoi-5-yl)penam, respectively.
PREPARATION F.
6-Amino-2,2-dimethyl-3-(l-[4-methoxybenzyl] tetrazoi-5-yl) penam p-toluenesulfonate
To a stirred slurry of 143 g. of 6-(triphenylmethylamino )-2,2-dimethyl-3-(1-(4-methoxybenzyl]tetrazoi-5-yl) penam in 1,000 ml. of dry acetone is added 45.0 g. of p,toluenesulfonic acid monohydrate, at ambient temperature. The solids slowly dissolve, giving a clear solution.
After about 15 minutes, the product starts to precipitate. Stirring is continued for a further 45 minutes after the product starts to appear, and then a first crop of product is filtered off and washed with chloroform. The acetone is evaporated to dryness, and the solid residue is slurried for 45 minutes in 300 ml. of chloroform. This affords a second crop of product. The two crops are combined, slurried for 1 hour in 1,000 ml. of chloroform, filtered off, and dried in vacuo giving 123 g. of 6-amino2,2-dimethyl-3-(1-(4-methoxybenzyl]tetrazoi-5-yl)penam p-toluenesulfonate, m.p. 174-175.5°C. The infrared spectrum (KBr disc) of the product shows an absorption band at 1795 cm-''·. The NMR spectrum (in DMSO-dg) shows absorption bands at 7.20 ppm (multiplet, aromatic hydrogens), 5.80 ppm (multiplet, benzyl hydrogens, C-5 hydrogen and C-3 hydrogens), 5.20 ppm (doublet, C-6 hydrogen), 3.75 ppm (singlet, methoxy hydrogens), 2.35 ppm (singlet, sulfonate methyl hydrogens), 1.70 ppm (singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, c-2 methyl hydrogens).
PREPARATION G.
6-(Triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl) penam
To a stirred solution of 1.69 g. (3 mmole) of 6(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]penam prepared as described in (Preparation c) in 9 ml. of chloroform is added 1 ml. (12 mmole) of pyridine. The solution is cooled to ca. 4°C. in an ice-bath and 0.80 ml. of chlorotrimethylsilane is added. The solution is stirred for 40 minutes at ambient temperature, and then it is again cooled to ca. 4°C. Phosgene (1.5 ml. of a 4.3 M solution in chloroform 6.45 mmole) is added and the cooling bath is removed. Stirring is continued for a further 1.5 hours, and then all the volatile components are removed by evaporation in vacuo. The oily residue is redissolved ih 6 ml, of chloroform and the solution is cooled to cti. 4°C. in an ice-bath. To the stirred solution is added 0.95 g. (6 mmole) of tetramethylguanidinium azide, and then stirring is continued for a further 1 hour at ambient temperature. At this point, 25 ml. of water is added, followed by sufficient IN sodium hydroxide to bring the pH of the aqueous phase to 10. The chloroform layer is removed, washed with water, dried using sodium . sulfate, and evaporated to dryness in vacuo, This affords crude 6-(triphenylmethylamino)-2,2-dimethyl-3-(1[4-trimethylsilyloxybenzyl]tetrazol-5-yl)penam, which is purified by chromatography on silica gel using chloroform as eluant.
To a stirred solution of 200 mg. of the purified trimethylsilyloxybenzyl derivative, in 4 ml. of tetrahydrofuran, is added 0.3 ml. of 1.0N sodium hydroxide.
The solution is stirred at ambient temperature for 50 minutes, and then the pH is adjusted to 5.7 using 5% hydrochloric acid. The solvent is removed by evaporation in vacuo to yield crude 6-(triphenylmethylamino)-2,2dimethyl-3-(5-tetrazolyl)penam.
- 50 PREPARATION Η.
6-Amino-2,2-dimethyl-3-(2-[pivaloyloxymethyl] tetrazol-5yUpenam
To a stirred solution of 0.932 g. (7.21 mmole) of quinoline in 8.0 ml. of chloroform is added 0.840 g.
(4.05 mmole) of phosphorus pentachloride. The suspension is cooled to -15°C., and then 1.81 g. (3.84 mmole) of 6-(2-phenylacetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl] tetrasol-5-yl)penam is added. Stirring is contin10 ued for a further 30 minutes, at ca. -5°C., and then
2.15 g. (35.7 mmole) of n-propanol is added. Stirring is continued for a further 30 minutes, again at ca. -5°C., and then 25 ml. of 90:10 isopropyl ether-acetone is added, followed immediately by a solution of 1.35 g. of sodium chloride in 6.02 ml. of water. The temperature rises to 15°C. and then it is lowered again to -15°C. The precipitate which has formed is filtered off and dried, giving 1.33 g. (88% yield) of 6-amino-2,2-dimethy1-3-(2[pivaloyloxymethyl] tetrazol-5-yl)penam hydrochloride.
The infrared spectrum (KBr disc) shows absorptions at 1785 cm (β-lactam) and 1750 cm (ester). The NMR spectrum (DMSO-d^) shows absorptions at 6.70 ppm (singlet, 2H, pivaloyloxy methylene hydrogens), 5.75 ppm (doublet, IH, C-5 hydrogen), 5.50 ppm (singlet, IH, C-3 hydrogen), 5.70 ppm (doublet, IH, C-6 hydrogen), 1.75 ppm (singlet, 3H, C-2 methyl hydrogens), 1.20 ppm (singlet,
9H, t-butyl hydrogens) and 1.10 ppm (singlet, 3H, C-2 methyl hydrogens).
preparation i.
6-Amino-2,2-dimethyl-3-(1-[pivaloyloxymethyl]tetrazol5-yl)penam
The title compound is prepared as its hydrochloride.
in 90% yield, from 6-(2-phenylacetamido)-2,2-dimethyl-3(1-|pivaloyloxymethyl|tetrazol-5-yl)penam, using the method of Preparation M. The infrared spectrum (KBr disc) shows absorptions at 1780 cm-1 (β-lactam) and 1740 cm 1 (ester). The NMR spectrum (DMSO-dg) shows absorptions at 6.71 ppm (singlet, 2H, pivaloyloxy methylene hydrogens), 5.88 ppm (singlet, IH, C-3 hydrogen), 5.83 ppm (doublet, IH, C-5 hydrogen), 5.20 ppm (doublet, IH, C-6 hydrogen), 1.80 ppm (singlet, 3H, C-2 methyl hydrogens), 1,20 ppm (singlet, 9H, t-butyl hydrogens) and 1.16 ppm (singlet, 3H, C-2 methyl hydrogens).
PREPARATION J.
6-Amino-2,2-dimethyl-3-(1-pivaloyloxymethyltetrazol-5yl)penam and
6-Amino-2,2-dimethyl-3-(2-pivaloyloxymethyltetrazol-5yl)penam
To a stirred suspension of 2.40 g. of 6-amino-2,2dimethyl-3-(5-tetrazolyl)penam in 15 ml. of N,N-dimethylformamide, is added 2.8 ml. of triethylamine. Stirring is continued for a further 15 minutes, and then 2.68 g. of chloromethyl pivalate is added. The mixture is stirred at ambient temperature for 5 hours, and then it is diluted with 100 ml. of water. It is then extracted with ethyl acetate. The extract is washed with water, dried using anhydrous sodium sulfate, and then it is evaporated in vacuo to give a mixture of the title compounds. The individual isomers are obtained by chromatographic separation of the crude product.
Repetition of this procedure but substituting 3bromophthalide or the appropriate alkanoyloxyalkyl chloride for pivaloyloxymethyl chloride affords an isomeric mixture of the corresponding monoalkylated products in which the alkanoyloxyalkyl or phthalidyl substituent is located at the 1- or the 2-position of the tetrazole ring. The following compounds are thus prepared. (For convenience only the alkyl substituent is tabulated):
ac etoxymethyl isobutyryloxymethyl hexanoyloxymethyl 1-acetoxyethyl
1-pivaloyloxyethyl
1-hexanoyloxyethyl phthalidyl
PREPARATION K.
6-(2-Phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam
A flask containing 965 mg. of 6-amino-2,2-dimethyl3-(l-[4-methoxybenzyl]tetrazol-5-yl)penam p-toluenesulfonate, 40 drops of anisole, and 5 ml. of trifluoroacetic acid is immersed in a water-bath maintained at 35-4O°C.
The progress of the reaction is followed by removing samples at intervals, and recording their nuclear magnetic resonance spectra. After about 25 minutes, the removal of the 4-methoxybenzyl group is found to be approximately 90% complete. At this point the reaction solution is added to a rapidly-stirred, ice-cold solution of 10 ml.
of pyridine in 50 ml. of ohloroform. Stirring is continued for 5 minutes, and then 0.24 ml. of phenylacetyl chloride is added. The oooling bath is removed and the reaction mixture is stirred for a further 20 minutes. A 100-ml. portion of water is added, and the pH of the aqueous phase is then adjusted to 2.5 by the dropwise addition of 0.5 N hydrochloric acid. The chloroform layer is separated off, washed with saturated
- 53 brine, dried using anhydrous sodium sulfate and then it is evaporated to dryness in vacuo. The crude product thus obtained is re-dissolved in chloroform, and the solution is divided into two equal portions. To one of these portions is added an equal volume of water. The layers are stirred vigorously and the pH of the aqueous phase is raised to 6.9 by the dropwise addition of 0.1N sodium hydroxide solution. The chloroform is separated off and discarded, and then an equal quantity of fresh chloroform is added to the aqueous phase. The layers are stirred vigorously and the pH is adjusted to 2.5 using dilute hydrochloric acid. The chloroform is separated off, washed with saturated brine, dried using anhydrous magnesium sulfate and then evaporated to dryness in vacuo, This affords 197 mg. of an oily residue. The residue is re-dissolved in 3 ml. of chloroform which is then added dropwise to 30 ml. of hexane. The fluffy white solid which precipitates is filtered off, giving 80 mg. of 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. IR (KBr disc): 1795, 1660 and 1510 cm-1. NMR (CDClg): 7.20 ppm (s, 5H), 5.55 ppm (m, 2H), 5,15 ppm (s, IH),
3.60 ppm (s, 2H), 1.40 ppm (s, 3H) and 1.05 ppm (s, 3H).
The MIC of the title compound against a strain of Streptococcus pyogenes is <0.1 |ig/ml.
PREPARATION L.
6-(2-Phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam A stirred slurry of 480 mg. of 6-amino-2,2-dimethyl3-(5-tetrazolyl)penam in 10 ml. of water is cooled to 0°C., and then the pH is adjusted to 8.0 using IN sodium hydroxide. To this solution is then added 0.25 ml. of phenoxyacetyl chloride, in portions, with the pH of the solution being maintained between 7 and 8 during the addition, using 0.1N sodium hydroxide. The solution is . o stirred for a further 30 minutes at 0 C. at pH 8. It is then extracted with chloroform, and the extracts are discarded. The aqueous phase is acidified to pH 2 with dilute hydrochloric acid, and then it is further extracted with chloroform. The latter extracts are dried using calcium sulfate and then evaporated in vacuo to give the crude product as a gummy solid. This is purified by dissolving it in 20 ml. of chloroform, and adding the resultant solution dropwise to 250 ml. of hexane. The precipitate Which forms is filtered off, giving 385 mg. of 6-{2-phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as a white amorphous solid. IR spectrum (KBr disc): 1785, 1670 and 1540 cm“·'·. NMR spectrum (DMSO-dg)
7.50-6.70 ppm (m, 5H), 5.70 ppm (m, 2H), 5.35 ppm (s, 3H),
4.60 ppm (s, 2H), 1.60 ppm (s, 3H) and 1.05 ppm (a, 3H).
The MIC of the title compound against a strain of Streptococcus pyogenes is <0.1 |J,g/ml.
PREPARATION M*
6-(2-Phenylacetamido)-2,2-dimethyl-3-(l-jpivaIoyloxymethyl] tetrazoi-5-yl)penam and
6-(2-Phenylaeetamido)-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam
To a stirred suspension of 10.0 g. (0.0264 mole) of 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl) penam sodium salt, in 105 ml. of acetone, is added 2.6 ml. of 25% aqueous sodium iodide, followed by 4.35 g. (0.0290 mole) of chloromethyl pivalate. The mixture is refluxed for 4.5 hours, and then it is cooled to ambient temperature. To the mixture is then added 100 ml. of water, and the resulting suspension is extracted with ethyl acetate. The extracts are dried and evaporated to give 6.3 g. of white foam. The MIC of this mixture of the title compounds against Strep. pyogenes is 0.2 u,g/ml.
The white foam is re-dissolved in a small volume of 80:20 chloroform-ethyl acetate and absorbed on a column of 180 g. of chromatographic grade silica gel. The column is then eluted with 80:20 chloroform-ethyl acetate taking fractions. Each fraction consists of 700 drops of solvent. Fractions 55-95 are combined and evaporated in vacuo to give 2.03 g. of 6-(2-phenylacetamido)-2,2dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam.
IR (KBr disc): 1785, 1760, 1670 and 1515 cm-1. NMR (DMS0-dg/D20): 7.50 (s, 5H), 6.70 (s, 2H), 6.00-5.60 (m, 2H), 3.85 (s, 2H), 1.65 (s, 3H), 1.36 (s, 9H) and 1.20 (s, 3H) ppm. Fractions 100-164 are combined and evaporated in vacuo to give 0.80 g, of 6-(2-phenylacetamido) -2,2-dimethyl-3-(1-[pivaloyloxymethyl] tetrazol-5yl)penam. IR (KBr disc): 1780, 1760, 1670 and 1515 cm-1. NMR (DMSO-dg- (D20): 7.50 (s, 5H), 6.80 (s, 2H),
6.50 (s, 2H), 5.60 (s, IH), 3.85 (s, 2H), 1.75 (s, 3H), 1.36 (s, 9H) and 1.34 (s, 3Π) ppm.
PREPARATION N.
6-(2-Phenylacetamido)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam
To a stirred solution of 189 mg. of 6-amino-2,2dimethyl-3-(l-[4-benzyloxybenzyl]tetrazol-5-yl)penam in 4 ml. Of chloroform, is added, at ambient temperature, 0.038 ml. of pyridine followed by 0.057 ml. of phenylacetyl chloride. Stirring is continued for a further 45 minutes, and then the reaction mixture is diluted with 25 ml. of chloroform and then washed with water. The organic phase is dried using anhydrous magnesium sulfate and then evaporated in vacuo. The residue is 209 mg.
- 56 (86% yield) of 6-(2-phenylacetamido)-2,2-dimethyl-3-(l-[4benzyloxybenzyl]tetrazol-5-yl)penam. The NMR spectrum (in CDClg) shows absorptions at 7.50-6.70 ppm (multiplet, aromatic hydrogens), 6.4 ppm (doublet, amide hydrogen),
.80-5.20 ppm (multiplet, benzyl hydrogens and C-5 and
C-6 hydrogens), 5.10 ppm (singlet, C-3 hydrogen), 5.05 ppm (singlet, benzyl hydrogens), 3.60 ppm (singlet, phenylacetyl methylene hydrogens), 1.30 ppm (singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens).
PREPARATION 0.
6-(2-Phenylacetamido)-2,2-dimethyl-3-(1-[2] -[methoxymethyl] tetraz0l-5-yl)penam
Reaction of 6-(2-phenylacetamido)-2,2-dimethyl-3(5-tetrazolyl)penam sodium salt with chlorophenyl ether according to the procedure of Preparation U produces the title compound as a mixture of isomers.
Claims (6)
1. CLAIMS i1. A process for preparing a 3-methyl-4-(5-tetrazolyl ) - /5? -cephem which comprises heating a 2,2-dimethyl3-(5-tetrazolyl)penam sulphoxide in the presence of an 5 acid reacting substance at a temperature of from 80°C to 175°C for a time sufficient to effect the conversion thereof.
2. A process according to claim 1, in which the reaction is conducted in a liquid medium. 10
3. A process according to claim 2, wherein the liquid medium is a tertiary carboxamide, a tertiary urea derivative, a tertiary sulphonamide or a mixture thereof.
4. A process according to claim 2 or 3, wherein the liquid medium serves both as acid reacting substance 15 and liquid medium.
5. A process for preparing a 3-methyl-4-(5-tetra3 zolyl)-4 -cephem according to claim 1 and substantially as hereinbefore described with reference to the Examples.
6. 3-Methyl-4-(5-tetrazolyl}-A -cephem compounds 20 of formula (ll) herein whenever prepared by a process according to any one of claims 1 to 4 or 5.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52144474A | 1974-11-06 | 1974-11-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE41799L IE41799L (en) | 1976-05-06 |
IE41799B1 true IE41799B1 (en) | 1980-03-26 |
Family
ID=24076758
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE2059/75A IE41799B1 (en) | 1974-11-06 | 1975-09-19 | Process for preparing 3-methyl-4-(5-tetrazolyl)- 3-cephem compounds |
Country Status (11)
Country | Link |
---|---|
JP (1) | JPS5170790A (en) |
BE (1) | BE835299A (en) |
CA (1) | CA1050010A (en) |
DE (1) | DE2546503A1 (en) |
DK (1) | DK496975A (en) |
ES (2) | ES442360A1 (en) |
FR (1) | FR2290445A1 (en) |
GB (2) | GB1520479A (en) |
IE (1) | IE41799B1 (en) |
LU (1) | LU73730A1 (en) |
NL (1) | NL7512960A (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4845088A (en) * | 1985-07-01 | 1989-07-04 | Merck & Co., Inc. | Tetrazolyl derivatives of beta-lactams useful as elastase inhibitors |
US4699904A (en) * | 1985-07-01 | 1987-10-13 | Merck & Co., Inc. | Tetrazolyl derivatives of β-lactams useful as elastase inhibitors |
JP6006201B2 (en) * | 2011-04-28 | 2016-10-12 | 塩野義製薬株式会社 | Novel cephem compounds having catechol or pseudo-catechol structure |
-
1975
- 1975-09-19 IE IE2059/75A patent/IE41799B1/en unknown
- 1975-10-17 DE DE19752546503 patent/DE2546503A1/en active Pending
- 1975-10-28 CA CA238,486A patent/CA1050010A/en not_active Expired
- 1975-10-31 GB GB45549/75A patent/GB1520479A/en not_active Expired
- 1975-10-31 GB GB52782/77A patent/GB1520480A/en not_active Expired
- 1975-11-04 JP JP50132413A patent/JPS5170790A/en active Pending
- 1975-11-05 NL NL7512960A patent/NL7512960A/en not_active Application Discontinuation
- 1975-11-05 LU LU73730A patent/LU73730A1/xx unknown
- 1975-11-05 BE BE1006996A patent/BE835299A/en unknown
- 1975-11-05 ES ES442360A patent/ES442360A1/en not_active Expired
- 1975-11-05 DK DK496975A patent/DK496975A/en unknown
- 1975-11-06 FR FR7533931A patent/FR2290445A1/en active Granted
-
1976
- 1976-09-29 ES ES451958A patent/ES451958A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
ES442360A1 (en) | 1977-04-01 |
DE2546503A1 (en) | 1976-05-13 |
DK496975A (en) | 1976-05-07 |
NL7512960A (en) | 1976-05-10 |
FR2290445B1 (en) | 1978-05-12 |
ES451958A1 (en) | 1977-10-01 |
CA1050010A (en) | 1979-03-06 |
BE835299A (en) | 1976-05-05 |
GB1520480A (en) | 1978-08-09 |
GB1520479A (en) | 1978-08-09 |
IE41799L (en) | 1976-05-06 |
JPS5170790A (en) | 1976-06-18 |
LU73730A1 (en) | 1976-09-06 |
FR2290445A1 (en) | 1976-06-04 |
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