IE42492B1 - Preparation of penam derivatives - Google Patents

Abstract

1506518 Tetrazolylpenam derivatives PFIZER Inc 27 Nov 1975 [29 Nov 1974] 48886/75 Heading C2C [Also in Division C3] Novel penam compounds of the formula wherein R is a hydrogen atom, C 1-12 alkyl, C 3-7 cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, furyl, thienyl or pyridyl, or C 2-12 alkenyl, each substituted group containing one or two substituents, each of which is a Cl, Br, I, OH, NO 2 , C 1-4 alkoxy or C 1-4 alkyl ; Y is a group of the formula wherein R 1 is R 2 or a tetrazolylpenam nitrogen protecting group, R 2 is H, C 3-8 alkanoyloxymethyl, C 4-9 alkanyloxyethyl, silyl, phthalidyl or a group of the formula wherein each of R 4 , R 5 and R 6 is H, Cl, Br, F, C 1-4 alkyl, C 1-4 alkoxy, or phenyl, and salts of those compounds wherein R 1 and R 2 are H atoms may be prepared by reacting an optionally R 1 or R 2 substituted 6-amino-2,2-dimethyl- 3-(5-tetrazolyl)penam with an aldehyde of the formula RCHO. A 6-acylamino-2,2-dimethyl-3(5-tetrazolyl)- penam is obtained by acylating an imine of Formula III with a compound of Formula R 3 COX to form an imine of Formula (IV) and hydrolysing the imine to form the product of Formula (V) Detailed preparations of intermediates (I) via the corresponding 6 - triphenylamino - 2,2- dimethyl - 3(5 - tetrazolyl)penams is also described.

Description

This invention relates to a process for the production of 6-acylamino-2,2-dimethyl-3-(5-tetrazolyl)penams. More particularly, it relates to (1) a process which comprises the acylation of an imine (Schiff base) of a 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or a derivative thereof which has a blocking group or pseudo blocking group on the tetrazolyl group by reacting the imine with an organic acid acylating agent Or a reactive derivative thereof, followed by hydrolysis of the acylat10 ion product to produce a 6-acylamino-2,2-dimethyl-3-(5tetrazolyl)penam; (2) imines of 6-amino-2,2-dimethyl-3(5-tetrazolyl)periams; and (3) reaction products of the said imines with acylating agents. 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam of formula (I) herein and certain derivatives thereof wherein a blocking or a pseudo blocking group is attached to the 1- or 2-position of the tetrazolyl group are valuable intermediates for the synthesis, by acylation thereof with an activated derivative of an organic acid acylating agent, i.e., an acid halide, anhydride or ester of novel antibacterial agents, namely, 6-acylamido-2,2dimethyl-3-(5-tettazolyl)penams. Such compounds are described and claimed in Patent Specification No. 40532.

The penicillins, a well known group of antibiotics, have been the subject of many reviews. J G C Nayler in Advances in Drug Research, (N J Harper and A B IS IS Simmonds, eds), Adacemic Press, New York, NY, Vol 7, pages 1-105 (1973), summarizes the recent literature and discusses the various reactions which have been carried out at the amino group of 6-amino-2,2-dimethylpenam-3carboxylic acid (6-APA), the majority of which are directed to formation of a 6-acylamino group. Schiff Bases of 6-APA and their use for the recovery and purification of 6-APA are described in United States Patent Specifications Nos. 3,219,699 and 3,299,800 respectively.

Imine derivatives of 6-APA, salts and esters thereof, and their acylation to an intermediate reaction product which is hydrolyzed to a 6-acylamino-2,2-dimethylpenam-3-carboxylic acid, known trivially as penicillins, are described in United States Patent Specifications No. 3,631,028, 3,647,781, 3,649,625 and 3,657,224 and by Bohme in J Org Chem 38, 230-236 (1973).

The compounds described herein are, for the sake of convenience, identified as penam derivatives. The term “penam has been defined by Sheehan et al in the Journal of the American Chemical Society, 75., 3293 (1953) as referring to the structure Using this terminology, the well-known antibiotic penicillin G is designated as 6-(2-phenylacetamido)-2,2dimethyl-penam-3-carboxylic acid.

Many of the compounds referred to herein are also 42493 -substituted tetrazoles, may exist in two isomeric and 5-substituted tetrazoles forms viz: N-jj -C XN-N When each of R^ or R2 is hydrogen, the two forms 5 co-exist in a dynamic tautomeric equilibrium mixture.

However, in the case wherein R^ or R2 is a substituent other than hydrogen, the two forms represent different chemical entities which do not spontaneously interconvert The present invention provides a process for prepar 10 ing a 6-aeylamino-2,2-dimethyl-3-(5-tetrazolyl)penam or a 6-acylamino-2,2-dimethyl-3-(substituted tetrazol-5-yl) penam which involves acylating an imine (Schiff base) reaction product formed by condensing a 6-amino-2,2dimethyl-3-(5-tetrazolyl)penam (formula I):15 H_N CH· - CHcZS'< 3 i i “3 H-CH (I) with an aldehyde having the formula, R-CHO (II), the said imine having formula (III) :R-CH=N CHo CH_ XS\ / 3 CH C I ! ch3 (III) 43493 with an acylating agent of formula ΚθΟΟΧ to produce an intermediate compound of formula (IV);0=, C — R ι 3 R-CH-N ( X CH X ,S CH C, ' CH3 (IV) and hydrolyzing the said intermediate of formula (TV) to 5 produce a 6-acylamino-2,2-dimethyl-3-(5-tetrazolyl)penam or a 6-acylamino-2,2-dimethyl-3-(substituted tetra2ol-5yl)penam of formula (V):RQ-CO-NH J CH---I I c---\ / CH C, I ’ X I -N ch3 CH_ CH (V) In the above formulae, Y is a tetrazolyl group of 10 the formulas N---u N = N (i) (ii) wherein R^ is Rj or a tetra2olylpenam nitrogen protecting group as hereinafter defined, Rj is a hydrogen atom or a silyl group, preferably a trialkylsilyl group having from one to four carbon atoms per alkyl group, an 219 2 alkanoyloxymethyl group having from three to eight carbon atoms, a 1-alkanoyloxyethyl group having from four to nine carbon atoms, a phthalidyl group or a group of the formula:- wherein each of R., R_, and R, is a hydrogen, chlorine, b o bromine or flourine 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, R is the residue of an aldehyde and is a hydrogen atom, an alkyl group having from one to twelve carbon atoms, a cycloalkyl group having from three to seven carbon atoms, a phenyl, substituted phenyl, naphthyl, substituted naphthyl, furyl, thienyl or pyridyl group or an alkenyl group having from two to twelve carbon atoms, each substituted group being substituted with up to two substituents, each of which is a chlorine, bromine, fluorine or iodine atom or a hydroxy group, a nitro group, an alkoxy group having from one to four atoms or an alkyl group having from one to four carbon atoms. R^CO is the acyl group of an acylating - 7 agent, and X is the residual group of the acylating agent, e.g. a chlorine or bromine atom or a hydroxy group, an azido group an acyloxy group wherein the acyl group is alkanoyl having from one to four carbon atoms or a benzoyl group.

The present invention also provides an imine penam compound of the formula (III) herein.

The imine (Schiff base) compound of formula (III) is readily prepared by condensation of an appropriate aldehyde with the appropriate 6-aroino-2,2-dimethyl-3(tetrazolyl)penam of formula (I). The condensation is preferably conducted by mixing the reactants together in a reaction inert solvent ih equimolar or approximately equimolar proportions at ambient temperature.

The molar ratio of aldehyde to amine is not critical.

A large excess of either compound may be used but, for the sake of economy and ease of recovery of the desired imines, the molar ratio is generally held to 1:1.

The reaction is generally carried out at ambient temperature as noted. However, the temperature is not critical and a higher or lower temperature may be used. Higher temperatures, as expected, require shorter reaction periods than do lower temperatures. Temperatures outside the range of 10°C to 70°C are generally avoided because of unnecessarily long reaction periods or to minimize possible side-reactions, e.g., polymerization of the imine or the aldehyde component. The preferred temperature is from 20° C to 30°C.

The condensation is conducted in a reaction-inert solvent, that is, a solvent which, under the conditions of the condensation, enters into little or no reaction 192 - 8 with the reactants or products. Suitable solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran and ethyleneglycol dimethyl ether, Ν,Ν-dimethylformamide, chlorinated solvents such as methylene chloride or chloro5 form, methyl isobutyi ketone, methylcyelohexanone, alkanols such as those having from one to four carbon atoms and nitriles such as acetonitrile and propionitrile.

Methylene chloride is a favoured solvent since it also serves as a highly useful solvent for the subsequent acylation reaction.

Suitable aldehydes are those of formula (II) wherein R is as defined above.

Preferred aldehydes are benzaldehyde and 4-nitrobenzaldehyde which permit each step of the overall process to proceed smoothly and in good yield. Nonaqueous solvents, e.g., methylene chloride, are favoured when using these aldehydes since the reaction mixture containing the imine product may be used directly in the subsequent reaction without the necessity of isolating the imine.

When either of or R^ is a trialkylsilyl group, an anhydrous non-hydroxylie solvent system is used to avoid hydrolysis of the silyl group. The by-product water generated in the condensation is removed by conduct25 ing the condensation in the presence of a strong water absorbent, e.g., magnesium sulphate, or in the presence of an excess of the silylated 6-amino-2,2-dimethyl-3(5-tetrazolyl)penam, or in the presence of an excess of the silylating agent, e.g., trimethylchlorosilane.

Furthermore, a bis-silylated derivative of formula (I) may be used as reactant in the aldehyde condensation. - 9 Since silylation of 6-amino-2,2-dimethyl--3 - (5-tetrazolyl )penam readily produces a bis-silyl derivative, the bisi silyl derivatives are favoured reactants for this condensation when either of R^ or R2 is a trialkylsilyl group.

Compounds of formula (II) above wherein Y is an unsubstituted 5-tetrazolyl group (R1=R2=H form salts with inorganic and organic bases. Such salts are included within the scope of this invention. Representative of such salts are the sodium and potassium salts, and salts with primary, secondary and tertiary alkylamines wherein the alkyl groups have up to eight carbon atoms. Illustrative of such amines are methylamine, n-butylamine, noctylamine, diethylamine, di-n-hexylamine, ethyl-n-hexylamine, triethylamine, methyl-di-n-butylamine. Also included are salts with other organic bases which have been used to form salts with benzylpenicillin, such as dibenzylamine, ethylenediamine, Ν,Ν'-dibenzylethylenediamine, N-ethylpiperidine and N-benzyl-p-phenethylamine. The salts of formula (III) compounds are frequently useful for altering the solubility characteristics of the parent compounds thus aiding in the recovery from a reaction mixture, in enhancing their solubility in a given solvent or for preparation of easily handled forme of the imines.

The water generated as by-product in the condensation reaction may be removed from non-aqueous solvent systems if desired by appropriate means such as by addition of a solid desiccant such as anhydrous sodium sulphate or magnesium sulphate, or a molecular sieve. Representative of the latter are the natural and synthetic crystalline aluminosilicates. The synthetic materials are preferred because of their greater water-loading 219 2 - 10 capacity relative to the natural crystalline aluminasilicates. Included among such adsorbents are chabazite, gemlinite and analcite, naturally occurring materials, the synthetic Linde 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 is contacted with such material to remove the water, A further useful adsorbent is neutral activated alumina.

Furthermore, a liquid which forms an azeotrope with water may be used as solvent to permit removal of byproduct water from non-aqueous systems. Binary or ternary azeotropes may be used. Representative of such liquids are benzene, carbon tetrachloride, chloroform, diethylether, methylpropylether, 2-methylfuran and ethyl acetate, each of which forms a binary azeotrope with water. Representatives of solvent pairs which form a ternary system with water are sec-butyl alcohol-benzene, sec-butylalcohol-cyclohexene, t-butyl alcohol-benzenet-butylalcohol-cyclohexane and carbon tetrachloride-propyl alcohol. A list of azeotropic systems is presented in Ind Eng Chem 19 508 (1947).

Water also may be used as solvent either alone or in admixture with any of the solvents enumerated above.

The use of an aqueous solvent system is generally avoided in the case of the more reactive imines such as those derived from aliphatic aldehydes, benzaldehyde, aryl substituted aliphatic aldehydes, e.g. phenylacetaldehyde. 42482 alicyclic aldehydes, m-halobenzaldehydes and m-alkylbenzaldehydes. Aqueous solvent systems are often favoured with the less reactive imines such as those derived from hydroxy substituted benzaldehydes and naphthaldehydes.

When an aqueous solvent system, and particularly when water alone is used as solvent, the pH of the reaction mixture is adjusted to from 7.5 to 8.5, preferably 8.0.

The acylation of the imines is accomplished by reacting the imine with an appropriate acylating agent preferably in an aqueous or organic solvent medium. Suitable solvents are those which do not react with the reactants or products to any appreciable extent under the conditions of the reaction. Representative of such solvents are water, acetone, dioxane, tetrahydrofuran, methylene chloride, chloroform, methyl isobutylketone and mixtures of such solvents.

The reaction is preferably conducted at a temperature of from -2O°C to 50°C. The favoured temperature range is from 0°C to 3O°C. The pH of the reaction may vary from 3 to 9. In general, the pH of the acylation reaction is dependent upon the relative stability of the imine. Imines derived from benzaldehyde, m-halobenzaldehydes, aliphatic, alicyclic or aralkyl (e.g. phenylacetaldehyde) aldehydes are acylated at pH 6 to 8 when an aqueous solvent system is used.

The acylation process is applicable to a wide variety of acylating agents such as reactive derivatives of organic acids of the formula RSCOOH wherein R3CO is an acyl group. Typical of reactive derivatives (RgCOX) which may be used are mixed anhydrides, acid halides, - 12 active esters, e.g., thiol, phenolic, cyanomethyl, Nanhydrides and mixtures of organic acid with carbodiimides, carbonyldiimidazole, alkoxy acetylenes.

While any suitable acylating agent may be used, because of the broad antibacterial spectrum of the acylated products, particular interest exists in those wherein the acyl group is of the following formula (VI)·_C (VI) L Q J n 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 eycloalkyl group having from three to seven carbon atoms, a cyclohexenyl or 1,4-cyclohexadienyl group, a 1-amino-eycloalkyl 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-dichlorophenyl)-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, 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, substi- 13 4249 2 tuted tetrazolyl, substituted imidazolyl or substituted pyrazolyl group, each substituted group being substituted by up to two substituents each of which is a fluorine, chlorine or bromine atom or a hydroxy group, an amino group, an N-alkylamino group having from one to four carbon atoms, an Ν,Ν-dialkylamino group having from one to four carbon atoms in each of the alkyl groups, an alkyl group having from one to four carbon atoms, an aminomethyl group, an alkoxy group having from one to four carbon atoms, an alkylthio group having from one to four carbon atoms or a 2-aminoethoxy group, and Q is a hydrogen atom, an alkyl group having from one to six carbon atoms or a hydroxy azido, carboxy, sulpho, carbamoyl, phenoxycarbonyl, indanyloxycarbonyl, sulphoamino, aminoethyl or amino group, or a group of the formula NntcO-CH^NHl^-co-A, wherein A is an alkyl group having from one to six carbon atoms, a phenyl, substituted phenyl, furyl, thienyl, pyridyl, pyrrolyl or amino group, an N-alkylamino group having from one to six carbon atoms, an anilino, substituted anilino, guanidino, acylamino having from two to seven carbon atoms, benzamido, substituted benzamido, thiopheneearboxamido, furancarboxamido, pyridinecarboxamido, aminomethyl, guanidinomethyl, alkane-carboxamidinomethyl having from three to eight carbon atoms, benzamidinomethyl, (substituted benzamidino)methyl, thiophenecarboxamidinomethyl, furancarboxamidinomethyl, pyridinecarboxamidinomethyl, pyrrolecarboxamidinomethyl or 2-benzimidazolecarboxamidinomethyl group, each substituted group being substituted by up to two substituents each of which is fluorine, chlorine, bromine or iodine atom, an alkyl group having from one to four carbon atoms, an alkoxy - 14 group having from one to four carbon atoms or a sulphamyl, carbamoyl or cyano group, and m is O or 1, provided that when R' is 1-aminocycloalkyl, n is 0 and provided that when R' is phenoxy, phenylthio, pyridyl5 thio, substituted phenoxy, substituted phenylthio or substituted pyridylthio and n is 1, Q is hydrogen, alkyl having from one to six carbon atoms, carboxy, sulpho, carbamoyl, phenoxycarbonyl, substituted phenoxycarbonyl, indanyloxycarbonyl or aminomethyl.

In formula (III) R^ is defined, inter alia, as a tetrazolylpenam nitrogen protecting group. It is intended by this term to connote all groups whioh (a) may be used to permit the synthesis of compounds of formula (I) by the processes described hereinafter, and (b, may be removed under conditions whioh leave the β-lactam ring system substantially intact.

The nature of the tetrazolylpenam nitrogen 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 as a tetrazolylpenam nitrogen protecting group in this invention are determined by employing a compound of formula (i) wherein Y^ is the (R^-substituted)-5-tetrazolyl group in question as reactant in the herein-described process for making formula (V) compounds.

As one skilled in the art will recognize, when R^ and R2 are alkanoyloxymethyl, 1-alkanoyloxymethyl or phthalidyl they are, in a sense, tetrazolylpenam nitrogenprotecting groups. However, such groups cannot be 43492 removed without substantial degradation of the β-lactam ring and, thus, fail to meet the criteria set forth above for a tetrazolylpenam nitrogen-protecting group. They are, however, referred to herein as pseudo blocking groups, Exemplary of tetrazolylpenam nitrogen protecting groups are groups of the formula:R, R, '8 wherein R_ is an electron-withdrawing group, and R_ is / o either a hydrogen atom or a further electron-withdrawing group, which may be the same as or different from R?.

The function of the electron-withdrawing groups is to render the hydrogen atom on the adjacent carbon atom sufficiently acidic that the protecting group is removable in a retrograde Michael reaction. Such a reaction is well-known in the art, (e.g. House, Modern Synthetic Reactions, W A Benjamin, Inc. New York/Amsterdam, 1965, page 207). Typical electron-withdrawing groups are cyanoalkoxycarbonyl having from two to seven carbon atoms, phenoxycarbonyl, alkylsulphonyl having from one to six carbon atoms, phenylsulphonyl and SC^NZ^Zj wherein each of and Z2 is a hydrogen atom or an alkyl group having from one to four carbon atoms, a phenyl or a benzyl group. A particularly convenient configuration for this protecting group is that wherein Rg is hydrogen; and preferred values for R? are alkoxycarbonyl having from two to seven carbon atoms and phenylsulfonyl.

A further tetrazolylpenam nitrogen protecting group which may be used is a group of formula C(=O)-ORg. Such - 16 42493 a group may be removed by mild hydrolysis, such as mild alkaline, hydrolysis, or by treatment with a nucleophile, such as an amine, a thiol or thiolate anion. Although a wide variety of such groups known in the art may be used, particularly convenient are those wherein Rg is an alkyl group having from one to six carbon atoms, a benzyl, phenyl or substituted phenyl group, for example, phenyl substituted by up to two substituents, each one of which is a fluorine, chlorine or bromine atom, a nitro group, an alkyl group having from one to four carbon atoms or an alkoxy group having from one to four carbon atoms.

A still further tetrazolylpenam nitrogen protecting group which may be used is a group of the formula -SOg-Rg. Such a group is also removed by hydrolysis, or by treat15 ment with a nucleophilic agent, as indicated for the group C(=O)-O-Rg, and convenient values for Rg are also alkyl having from one to six carbon atoms, benzyl, phenyl, and substituted phenyl, for example, phenyl substituted by up to two substituents each one of which is a fluorine, chlorine or bromine atom, a nitro group, an alkyl group having from one to four carbon atoms or an alkoxy group having from one to four carbon atoms.

Another tetrazolylpenam nitrogen protecting group which may be used is a group of the formula:25 —CH Xwi wherein is phenyl, substituted phenyl, furyl, substituted furyl, thienyl or substituted thienyl, and W2 is hydrogen, alkyl, phenyl, substituted phenyl, furyl, substituted 43192 furyl, thienyl or substituted thienyl. When is phenyl or substituted phenyl, and is hydrogen, alkyl, phenyl or substituted phenyl, this group may be removed by hydrogenolysis. This group also may be removed by solvolysis in trifluoroacetic acid, when the combined effect of and ia sufficient to offer the requisite degree of stability to the incipient carbonium ion of the formula:+CH Particularly preferred configurations for this protecting group which afford satisfactory yields of compounds of formula (V) and are readily removed, are (a) those wherein W2 is hydrogen or alkyl having from one to six carbon atoms, and is phenyl or phenyl substituted with up to two substituents each of which is a fluorine, chlorine, bromine or iodine atom or a hydroxy, nitro, alkyl having from one to six carbon atoms, alkoxy having from one to six carbon atoms, alkanoyloxy having from two to seven carbon atoms, formyloxy, alkoxymethoxy having from two to seven carbon atoms, phenyl, or benzyloxy group, and (b) those wherein W2 is hydrogen or methyl, and is furyl, 5-methylfuryl, thienyl, or 5-methylthienyl.

Yet still another tetrazolylpenam nitrogen protecting group which may be used is phenacyl or a substituted phenacyl. Such a group is removed by reaction with a nucleophilic reagent, such as thiophenoxide. Typical phenacyl groups which may be used are those of the formula:42192 ~CH2—if wherein Ε^θ is a hydrogen, fluorine, chlorine or bromine atom or a nitro or phenyl group.

Highly useful substituent groups for the 5-tetrazolyl group are silyl groups particularly those derived from silylating agents of the formulae NH Si and Si-W, (VII) (VIII) wherein W3 is a halogen atom or W4 and each of and is a hydrogen atom, an alkyl group of from one to four carbon atoms, or a phenyl, benzyl, tolyl or dimethylaminophenyl group, at least one of the said W's being other than halogen and hydrogen; R° is an alkyl group of 1 to 7 carbon atoms, £ is 1 or 2, and ίίθ is a halogen atom or a group of the formula;XW7 42482 - 19 and W7 is a hydrogen atom or an alkyl group of 1 to 7 carbon atoms and Wg is a hydrogen atom or an alkyl group of 1 to 7 carbon atoms or a group of the formula:ΐ3 -si»w4W5 wherein W„, W. and W_ are as defined above. 4 5 The silyl groups are introduced into the tetrazolyl group by methods known to those skilled in the art and may be introduced directly into 6-amino-3-tetrazolylpenams or into protected amino forms thereof. The silylation reaction is preferably conducted in an anhydrous reactioninert, that is, an anhydrous, non-hydroxylic solvent of the type mentioned above, and preferably in methylene chloride, at a temperature of from --10°C to -80°C, and preferably at from -20° C to -60°C. The reaction is often conducted in the presence of an acid-binding agent, that is, a base such as an alkali metal carbonate or a tertiary amine, e.g., diethylaniline, pyridine, quinoline, or lutidine. The base may be a part of the silylating agent as is the case when tho silylating «gent: is of the formula (VIII) wherein W, is ~NW-Wr, or of the formula (VII), and the said agent is used in combination with a compound of formula (viii) wherein Wg is a halogen atom. Representative of suitable silylating agents are those disclosed in United States Patent Specification No. 3,499,909 such as trimethylchlorosilane, hexa-methyldisila2ane, triethylchlorosilane, methyltrichlorosilane, dimethyldichlorosilane, triethylbromosilane, tri-n424S2 - 20 propylchlorosilane, bromomethyldimethylchlorosilane, tri-n-butylchlorosilane, methyldiethylchlorosilane, dimethylethylchlorosilane, phenyldimethylbromosilane, benzylmethylethylchlorosilane, phenylethylmethylchloro5 silane, triphenylchlorosilarie, triphenylfluorosilane, tri-o-tolylchlorosilane, tri-p-dimethylaminophenylchlorosilane, N-ethyltriethylsilylamine, hexaethyldisilazane, triphenylsilylamine, tri-n-propylsilylamine, tetraethyldimethyldisilazane, tetramethyldiethyldisilazane, tetra10 methyldiphenyldisilazane, hexaphenyldisilazane or hexajj-tolyldisilazane or mixtures thereof. The same effect is produced by hexa-alkylcyclotrisilazanes or octaalkylcyclotetrasilazanes. Other suitable silylating agents are silylamides and silylureides, such as a trialkyl15 silylacetamide and a bis-trialkylsilylacetamide as is disclosed in United States Patent Specification No. 3,499,909.

The preferred silylating agents are dimethyldichlorosilane, trimethylchlorosilane and hexamethyldisil20 azane, and especially mixtures of these because of their overall reactivity, availability, ease of handling, satisfactory yields produced and, as regards the mixtures the generation of ammonia by the disilazane which serves as acid-binder. The procedures illustrated herein are those described by Pierce in Silylation of Organic Compounds, Pierce Chemical Company, Rockford, Illinois, United States of America.

The preferred tetrazolylpenam nitrogen protecting groups are those which may be removed by other than acid conditions. Acid conditions are generally avoided in order to prevent or minimize degradation of the β-lactam upon removal of the protecting group from a compound of - 21 formula (V). Illustrative of such protecting groups are those removable by such means as hydrogenolysis (R^ is benzyl or substituted benzyl), treatment with a base (R^ ia p-hydroxybenzyl), or a substituted silyl group (R^ or R2 is trialkylsilyl).

The term tetrazolylpenam 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 soprotected tetrazolylpenam compounds. A group, therefore, may be regarded as a tetrazolylpenam nitrogen protecting group when it (a) can be attached to the tetrazolyl group during or after formation thereof; (b) will permit reaction of the 6-amino group of the tetrazolylpenam; and (c) can be removed from the tetrazolyl group of compounds of formula (V) without substantial degradation of the tetrazolylpenam ring system. Illustrative of such groups in addition to those specifically enumerated herein as tetrazolylpenam nitrogen protecting groups are trialkylsilyl, triphenylmethyl, and substituted triphenylmethyl groups.

The starting materials (formula I) for the process of this invention are prepared by the reaction sequence described 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:42492 (IX) (CgH5)3 C-NH — C-NH-G il wherein G is a group of the formula -C(=O)-O-R„, -SO_-Rn, or CH2CH2R7 wherein Rg and R? are as previously defined, or -CHW^W2, particularly the preferred configurations thereof defined above.

When G is -CEhjCi^Ry or -CHW^W2 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 amine of formula NH2CH2CH2R7 or H2N-CHW^W2. Thus, formation of the mixed anhydride involves reacting an appropriate carboxylate salt of 6-triphenylmethylaminopenxcillanic acid in a reaction15 inert organic solvent, with approximately equimolar proportions of pivaloyl chloride or an 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. Suitable solvents are chlorinated hydrocarbons, such as chloroform, methylene chloride? aromatic hydrocarbons, such as benzene, toluene and xylene; and ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at a temperature of from -50°C to 30°C, and preferably at 0°C and is complete in about one hour. The product is isolated simply by filtering off .-23- · the insoluble materials, and then evaporating the solvent in vacuo to give the crude anhydride. 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. The same solvents identified above for mixed anhydride formation are useful for this reaction.

When this 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.

When G is -C(=0)-0-Rg or -SO2Rg, the amide of formula (V) ie prepared by reacting 6-(triphenylmethylamino)penicillanic acid with an appropriate isocyanate of formula Rg-O-c{=O)-H=C=O or Rg-SC^-N-CsO. The reaction is usually carried out by contacting substantially equimolar quantities of the reactants, in a reaction-inert organic solvent, at a temperature in the range from 0°C to 30°C, for a period of from one hour to twelve hours. The product may be isolated simply by removal of the solvent in vacuo or the solution of the amide may be used in situ for Step 2. The isocyanates of formula Rg-0-(C=0)-N=C=0 are prepared by reaction of a carbamate of formula Rg-O-C(=O)-NH2 with oxalyl chloride.

In Step 2, the product from Step 1, or a simple transformation product thereof in which any phenolic - 24 42482 hydroxy groups are protected by conversion to formyloxy, alkanoyloxy, or alkoxymethyl groups, is converted into an imidoyl chloride 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. 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 pentachloride are operative in the imidoyl chloride forming reaction. Moreover, if desired, the corresponding imidoyl bromide may be used.

In Step 3 of the process, the above imidoyl chloride is converted into a tetrazolylpenam compound of formula (X): 42493 S / — CH. '3 CH.

(X) wherein G is as previously defined. This'transformation comprises treating the said imidoyl chloride in a reactioninert solvent with about one molar equivalent, or sometimes a small excess, of azide ion. The reaction mixture is then stirred at or about ambient temperatures for several hours, for example, overnight, until conversion into the tetrazole is substantially complete. A wide variety of azide ion sources such as trimethylsilyl azide, triethylsilyl azide, potassium or sodium azide, tributylammonium azide, Ν,Ν-dimethylanilinium azide, N-methylmorpholinium azide or pyridinium azide; or tetramethylguanidinium azide are operative in this process. Appropriate solvents when the azide ion source is a trialkylsilyl azide or a trisubstituted ammonium azide are chloroform, methylene chloride, 1,2-dichloroethane and dipolar aprotic solvents such as N-methylpyrrolidone. In reactions where a metal salt of hydrazoic acid constitutes the azide ion source, 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 mixture 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 diluted - 26 43492 with a large excess of dilute alkali, and then after appropriate adjustment of the pH, the product is isolated by solvent extraction.

The N-triphenylmethyl derivatives thus obtained are 5 converted to compounds of formula (i) by treatment with an acid such as methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, hydrogen chloride, hydrogen bromide, acetic, propionic, chloroacetic or trifluoroacetic acid. The reaction is normally carried out by dissolving the starting material in an appropriate solvent and adding about two molar equivalents Of the acid reagent at or about ambient temperature. The reaction is complete within 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. Appropriate solvents are diethyl ether, tetrahydrofuran, dioxane, 1.2- dimethoxyethane, chloroform, methylene chloride, 1.2- dichloroethane, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, hexane,cyclohexane, benzene, methanol, ethanol, and butanol. A favoured procedure comprises the use of p-toluenesulphonic acid in acetone since the p-toluenesulphonate salt of the product often precipitates.

Compounds of formula (V) wherein R^ and R2 of the -tetrazolyl groups are hydrogen, alkanoyloxymethyl, 1alkanoyloxyethyl or phthalidyl are useful antibacterial agents. Compounds Of formula (V) wherein R^ and R2 are triphenylmethyl, and those wherein R^ is a tetrazolylpenam nitrogen protecting group as defined herein are intermedi30 ates for the production of 6-acylamino-2,2-dimethyl-3-(5tetrazolyl)penams wherein R^ and R2 are hydrogen, alkanoyloxymethyl, 1-alkanoyloxymethyl or phthalidyl. Removal 42493 - 27 of the triphenylznefchyl, substituted triphenylmethyl or tetrazolylpenam nitrogen protecting groups by known methods affords the corresponding compounds wherein R^ and R2 are hydrogen. Alkylation of the tetrazolyl groups (R^R =H) by the reaction with alkanoyloxymethyl, 1-alkanoyloxyethyl or phthalidyl chlorides (or bromides) affords bactericidally active compounds.

The 6-acylamido-2,2-dimethyl-3-(5-tefcrazolyl)penams of formula (V) wherein R^ or R2 are hydrogen, alkanoyloxymethyl, 1-alkanoyloxymethyl or phthalidyl are valuable antibacterial agents in vitro and in vivo against a wide variety of gram-positive and gram-negative bacteria.

Their useful activity readily may be demonstrated by in vitro tests against various microorganisms in a brainheart infusion medium by the usual two-fold serial dilution technique. Their in vitro activity 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 ill vivo in animals, including man, not only via the parenteral route of administration but also by the oral route of administration. The oral and parenteral dosage levels for the herein-described compounds are, in general, up to 200 mgAg and 100 mg/kg of the body weight per day, respectively.

For such purposes, the pure compounds or 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. - 28 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, corn or sesame oil) and Other non-aqueous vehicles which will not interfere with the therapeutic efficiency of the preparation and are non-toxic in the volume or proportion used (e.g. glycerol, propylene glycol or sorbitol). Additionally, compositions suitable for extemporaneous preparation of solutions prior to administration advantageously may be made. Such compositions may include liquid diluents, for example propylene glycol, diethyl carbonate, glycerol, or sorbitol; buffering agents, as well as local anaesthetics and inorganic salts to afford desirable pharmacological properties.

Illustrative Examples of the process of this invention. and representative preparations for making the necessary starting compounds are given hereinafter.

Example 1.

N-Benzylidene-6-Amino-2,2-Dimethyl-3-(5-Tetrazolyl)penam Benzaldehyde (2.112 g., 0.02 mol) is added to a solution of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam (4.826 g., 0.02 mol) in methylene chloride (50 ml) con30 taining anhydrous magnesium sulfate (5 g.) at room temperature. The reaction mixture is stirred for 18 hours and is then filtered to remove the magnesium sulfate. - 29 The product ie recovered by evaporation of the solvent under reduced pressure.

It is converted to the triethylamine, t-octylamine, di-n-hexylamine, n-butylamine, dibenzylamine, N,N-dibenzyl5 ethylenediamine, phenethylamine, and N-ethylpiperidine salts by reaction with equimolar quantities of the appropriate amine in methyl chloride solution. Mie salts are recovered by evaporation of the solvent.

EXAMPLE 2.

The procedure of Example 1 is repeated but using the appropriate aldehyde and the appropriate 6-amino-2,2dimethyl-3-(5-tetrazolyl)penam compound (formula I) to produce the following compounds and their amine salts: R-CH»»N—CH - 7S ---CH i 1 — N,- s. , CH S .— CH \ xH------N V ϋ -----N ί R1 R1 R 1 I CrHc 6 5 4-CH30C6H4CH2~CrHK 6 54“C6H5CH2OC6K4CH2 CrHr 6 b 1--0-; CH-CH-CH=C-CH_- 2 -----o C6H5 (CH ) -C=CH-CH=C-CH242492 6 5 2,4-(CH,0) C-H-CH 3 2 6 3C6H5 4-HOC.H.CH.D 4 2C6H54-C2H5°C6H4CH2- 2-H0C6H44-C6H5C6H4CH2- 4-HOC^H. 6 4 3-Cl-4-CH,OC .H,CH. 3 6 3. 4-01¾(C6H5>2CH- 3-BrC6H4 3-BrC6H4CH(C6H5-2'4Cl2C6H3 C6H5CH(CH3)- 4-N°2C6H4 H 2-HOCH 6 4 H 2-CH30C6H4 H ο6η5οη2 HC6H5CH2CH24-CH3OC6H4CH2- C-H-CH=CH 6 5 4-CHC00CHCH,3 6 4 2 4-NO2C6H4 1 °~Ί CH=CH-CH=C-2-CfI3°C6H4 r~s —I (CH )-C=CH-CH=C-C5H9 Hydrogen CH C_H_0-C0 2 5 4-N02C6H4 C H CII,O-CO 6 5 2 CH, H C.H_ 4-C.H_CH_0C.H.CHo- 3 7C7H15f__sn (CH3)-C=CH-CH=C-C11H23 3 -CH. -4 -CH.OC.H. CHO 3 3 6 4 2 1-C H H 10 7 2~C_ H H 10 7 2-furyl H 2-thienyl H |-αί=αι-η N=CH-CH=C- HC6HH4-ft“C3H7°C6H4CH2“ 2-C1-5HOCcH„ 6 3 Γ~“ °-'Ί CH«CH-CH=C~ 2-NO2-3-ClCgII3 4-C2H5OC6H4CH2- 2,6-(OH3)2C6H3 3-CgH5-4-CH3OCgH3CH. 1-(4-CH3cioH6) 1-(2-HO-3-NO2C1oH5) 4-CH3OCgH4CH2 1-(2,6-(CH3O)2C1oH5 c(c6h5)3 2-(4,5-(CH30)2C10Hg) H 2-(3-FCi0H6) H c.hqch=ch 4 9 C_H_0-C0 2 0 3,4(C2H5O)2C6H3 (3,4-Cl2CgH3)OCO4-N02C6H4 CH2CH2CN RRi 2-HOC^H. 6 4 C-H-O-CO 6 5 2-^7 (4-HO.CH )O-CO 2 6 4 2-Thienyl C-H-O-CO 2 OCH3 CcH_CH^O-CO 6 5 2C6H13 C-H-O-CO 6 5 3-ClC^H. CHSO 6 4 3 2 C„H_ CHSO 6 5 3 2 4-N02C6H4C6H5CH2S02C6H11 (3-CH3OC6H4)SO2 3-5-r„CcH_ 2 6 3 hydrogent-C4fi9 [2,4-(NO2)2C6H3]SO2 2-Quinolyl hydrogen 3-indolyl hydrogen 4-quinolyl 4-methoxybenzyl ch2=ch furfurylC6H5CW 4-N°2c6H4 C(C6H5)3/C6H5 0(4-0¾¾)/1-cioh7 0(06^)2(4^-0/7¾)C6H5CH2 C(3-C1C6H4)2(C6H5)C6H5 SKCHs)/ 3,4-F2C6H3 Si(n-c4Hg)3/ c_hr 6 5 Si(n-C4Hg)3/ 3.5-Br2C6H3 hydrogen 2,4~(ΟΗ3)2Ο6Η3 hydrogen 3-HOC,Η. 6 4 CH2CH2S02N(CH3)2 5 3,4-(CH3O)2C6H3 CH_CH COOC.EL d 2 O 0C6H5CW°2C6H5C6H5 ΟΗ2ΟΗ23Ο2Ν(Ο6Η5)2 c6h5ch2 CH-CH_SO_NHCH.CrH_ 2 z z zooC6H5 CH2OCOC(CH3)3/ 10C6H5 CH2OCOCH3 4-ΝΟ2ΟΛ CH2OCOC(CH3)3/ 4-N02C6H4 CH20C0C5Hu 2-H0C6H4 CH(CH3)OCOC(CH3)3 2-H0C,H. 6 4 CH(CH3)OCOCH3 15C6H5 phthalidyl/ ch3 phthalidyl/C6H13 phthalidyl/ Vll CHo0C0C.Hc/ 4 z 5C2H5 20 3~Cl-4-n~C4H9C6H3g(C6H5)3/ 2-H0CgH4 (3-010^)C5H9 C(4-C6HsC6H4)2(C6H5 - 34 M CH=CH-CH=C- c(c6h5)3/ 2-HOCH. 6 4 Si(CH3)/ 4-N°2C6H4 (Si(CH3)3/ CH3 Si(CH3)3/t_C4H9C6H4 2-Gl-6-NO_C^H, Z 6 3 / Corresponding isomeric 2-tetrazolyl derivative also produced.

EXAMPLE 3.

N-Salicylidene-6-Amino -2,2-Dimethyl-3-(5-Tetrazolyl)penam Salicylaldehyde (2.44 g., 0.02 mol) is added to a solution of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam (4.826 g., 0.02 mol) in water (500 ml.) at pH 8.0 and the mixture stirred at room temperature for two hours. Ethylacetate (500 ml.) is added to the reaction mixture, followed by slow addition of sufficient 6N hydrochloric acid to bring the pH to 7. The mixture is stirred for a half hour and the ethylacetate phase separated. The aqueous phase is again extracted with ethyl acetate and the combined ethyl'acetate solutions dried (MgSO^). Evaporation of the solvent in vacuo affords the title compound.

EXAMPLE 4.

Repetition of the procedure of Example 3 but using the appropriate aldehyde affords the following compounds RRl HCH3CH3C5H11 C-H 3 7C12H25C8H17 ch2=chC12H25 (ch3)2c=ch-C6H5 C3H7CH=CHCH7CH2 3-n-C4H90CgH4 2~CH30CgH4 2,6-(CH3)2CgH3 4-XC,H. 6 4 3,5-(NO2)2C6H3 4~t-C,HaCcH. *- 4 9 6 4 2“Br-4~H0C Ji* 6 34'8-((fI0)2C10H5) S-OH^X^H-OC-BL 2 5 6 3C3H5 2-ΟιθΗ7C7H13 i °~~i 2-(I-C1C1oH6) CH=CH-CH=C- 2-(6-CH3Cl0Hgj EXAMPLE 5.

N-4-Nitrobenzylidene-6-Amino-2,2-Dimethyl-3-(4-Methoxybenzyltetrazol-5-yl)penam A mixture of 4-nitrobenzaldehyde, (0.726 g, 6 mmol). - 36 6-amino-2,2-dimethyl-3-(4-methoxybenzyltetrazol-5-yl)penam (1.807 g, 5 mmol) and benzene (250 ml) is stirred and heated to reflux until water is no longer evolved. Evaporation of the reaction mixture under reduced press5 ure affords the title product.

EXAMPLE 6. 6-(Phenylacetamido)-2,2-Dimethyl-3-(5-Tetrazolyl)penam The triethylamine salt of N-benzylidene-6-amino2,2-dimethyl-3-(5-tetrazolyl)penam (1.077 g, 2.5 mmol) is dissolved in methylene chloride (100 ml) and the solution cooled to 0° to 5°C. Phenylacetyl chloride (0.388 g, 2.75 mmol) is added dropwise Over a 30 minute period while maintaining the temperature at 0° to 5°C.

The reaction mixture is stirred for one hour following completion of addition. Cold water (100 ml) is then added and the pH adjusted to 2.0 with concentrated hydrochloric acid. The mixture is stirred for twenty-minutes the aqueous phase discarded and the organic phase washed with water (50 ml).

The organic phase is dried with sodium sulphate and then evaporated to dryness.

Repetition of this procedure but using the appropri ate acyl chloride (R^COCl) in place of phenylacetyl chloride produces 6-acylamino-2,2-dimethyl-3-(5-tetrazol25 yl)penams wherein the acyl group (RgCO) iss HCO 4-H2NS02C6H4CH(NH2)CO ch3co (2-c5h4n)ch(nh2)co n-C3H?C0 HjNCHjCO n-c8Hi7co H2NCOCH=CH-CO - 37 n-Cl2H25C° CH2=*CH~CO CH2=CH(CH2)8CO c3h5c° C3I...C0 JL Ja2-c_H0co 9 6-(A1,4-C6H7)CO i-ra2-c6H10c° 1- (2-CH OC--H,)C0 6 C,H,, SCH„C0 3 Z C6H5CH(NH2)CO CH=CH-CH=C-CO CH=CH-CH=C-CO 2- NHjCHg-C6H4CH2C0 C,HeCH(NHC0CH-NHC(NH)-4bo 2 pyridyl)CO 2,6~(CH3O)2-C6H3CO 3,4-{HO) CgHg-CH(NH2) CO 3- Cl-4-HOC-H-CH(NH-)CO 3 2 I— ° ί CH=CH-CH=C-CH(NH ) CO cnch2co (3-indolyl)CH2CH(NH2) co CgHgCH(NHSO2-2-naphthyl) CO CELCH(NHCOCH-CHNH-) CO 0 5 2 2 2 C HgCH(NHCOCHjMHC(NH)NHj) CO C.HCH(NHCONHC(NH)NH-)CO bo 2 C-H-CH(NHCOCOOC-H-) CO 6 5 2 5 CH=CH-C(CHNH2CO)=CH (ch3)2ch-ch(nh2)co 4-CH_C„H,-SO--NHCO 3 6 4 2 ch3conhco c6h5ch(so3h)co CgHgCH(C00-5-indanyl) CO C,H_C(=NH)NHCONHCH-CO 0 3 2 CHNHCO 6 5 C,H_CH(NHC0CH-C1) CO b 5 2 C.H-CH(NHSO_C_H_)CO 6 5 2 2 5 4-H0C-H.CHOCQ 6 4 2 3- FC'H.C&LC0 o 4 2 CgHgCH(NHCOCH^CO 4- HOC H.CH(NHCONHC-H.-4-OCH,)CO 4 6 4 3 42482 - 38 In like manner, the following compounds are prepared using the appropriate acyl chloride (R/OCl) and the appropriate 6-amino-2,2-dimethyl-3-(substituted tetrazol-5-yl)penam Schiff bases of Example 2: C6H5CH(NH2)- 4-CH_0CcH.CB3 6 4 2 4-H0CgH4CH(NH2) - 4-c6h5ch2°c6h4ch. c6h5och2- 4-H0C6H4CH2 2,6-(CH3O)2C6H3CH2- c6h5ch(ch3) ch3ch2-4-C2H5OC6H4CH2 3-Cl-4-H0C6H3CH2c(c6H5)3 2-H2NCH2C6H4CH2- 4-CH3°C6H4CH22-C4H3SCH2- CH2OCOC(CH3)3 sydnonyl- CH(CH/COCH3 4-H0CHCH(NH )o 4 2 phthalidyl C H_CH(NHC0-2-pyrrolyl) o □CH2CH2SO2C6H5 2-C5H4N-S-CH2- ch/coc/^ 1-H.N-l-C-H,, 2 6 11 C^HeOCO . 6 5 n-C4H9- - 39 - RR1C6H11~ C(4-CH3C6H4)3 ch3ch2sch2- CH=CH-CH=C- CH CHjOCOCHj- ί 0 (CH,)-C«CH-CH=C- JC6H5CH2CH2 CjHgOCO CH3CftJH)NHCH2~ ch2ch2cn CgH5CH(OH)CH2- C_H_OCO 6 5 3-CH3C6H4CH2- (4-ΝΟ„0\ΗΛ )OCO C„H_CH(NHCO-2-furyl) b 5CH3SO2 CgHgCH(NHCO-n-C4H9) - c6h5ch2so2 4-HOC H4CH(NaCHN(CHj)2) - CH2 CH2 SO2N (CHg)2 i-h2n-x-c5h9- CH2CH2SO2NHCH?C6Hs 2-isothiazolyl (3-CH3OCgH4)SO2 EXAMPLE 7. 6-(5-Methyl-3-phenyli soxazole-4-Cafboxamido)-2,2-Dimethyl3-(5-Tetrazolyl)penam The trimethylsilyl derivative of nitrobenzylidene6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam (4.45 g, 0.01 mol) in methylene chloride (100 ml) is treated with triethylamine (1.0 g, 0.01 mole) and the solution cooled to 0° to 5°C in an ice bath. A solution of 5-methyl-3phenylisoxazoleearbonyl chloride (2.2 g, 0.01 mole) in methylene chloride (35 ml) is added over a 10 to 15 minute period and the resulting solution is stirred for 45 minutes at 0° to 5°C. Water (50 ml) is then added and the mixture - 40 stirred at 0 to 5 C as the pH is adjusted to 2.0 with 6N hydrochloric acid. After addition and 20 minutes of stirring the organic layer is separated, cooled with water, dried over anhydrous magnesium sulphate and concen· trated to dryness, the residue is redissolved in ethyl acetate (100 ml) and treated with N-ethylpiperidine (1.13 g, 0.01 mole). The crystalline salt which separates is granulated for 30 minutes, filtered, washed with ethyl acetate and is dried to give 3.1 g (56%) of the N-ethyl10 piperidine salt of the title compound.

EXAMPLE 8.

D-(6-a-amino-4-hydroxyphenylacetamido)-2,2-dimethyl-3(5-tetrazolyl)penam The triethylamine salt of N-4-nitrobenzylidene-615 amino-2,2-dimethyl-3-(5-tetrazolyl)penam (2.14 g, 5 mmole) is dissolved in methylene chloride (75 ml) and the resulting solution cooled to 0° to 5°C in an ice bath. The solution is treated with 1.6 g (5 mmole) of the ethylchloroformate mixed anhydride of the methylacetoacetate enamine of D-a-phenylglyeine (prepared from the enamine in cold acetone (50 ml) and ethylchloroformate (515 mg) containing a drop of N-methylmorpholine) in acetone.

The mixed anhydride is added all at once. After 30 minutes at 0° to 5°C the reaction is treated with water (100 ml) and the pH then adjusted to 2.5 with 6N hydrochloric acid. After 20 minutes at 0° to 5°C the layers are separated and the aqueous solution adjusted to pH 5.1 with IN sodium hydroxide solution. The product crystallizes from solution and is collected by suction filtration and washed first with water and then with acetone. Air drying affords 950 mg (50%) of the title compound. 43498 - 41 EXAMPLE 9. 6-(phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam N“4~nitrobenzylidene-6~amino-2,2-dimethyl-3-(5tetrazolyl)penam (3.73 g, 0.01 mole) is added to water (100 ml) and the pH adjusted to 8.0 with IN sodium hydroxide solution. A solution of phenoxyacetic acid chloride (1.70 g, 0.01 mole) in isopropylether (50 ml) is added dropwise and the pH of the reaction mixture maintained between 7.5 and 8.0 by the concomitant addition of IN sodium hydroxide solution. After the pH has levelled off the isopropyl ether layer is drawn off and discarded.

The aqueous phase is layered with methylisobutylketone (150 ml) and the pH adjusted, with cooling (0° to 5°C), to 2.5 with 6N hydrochloric acid. After stirring for 20 minutes, the pH is readjusted to 8.0 with 4N sodium hydroxide solution. The organic layer is drawn off and discarded. The aqueous solution is layered with fresh methylisobutylketone and the pH readjusted to pH 2.0 with 6N hydrochloric acid. The organic layer is drawn off and treated with sodium 2-ethylhexanoate (2.4 g) in methylisobutylketone (35 ml) dropwise over a 10 minute period.

The precipitated product, the sodium salt, is granulated, collected by filtration, washed with acetone and air dried to give 2.98 g (79%) of the title compound.

PREPARATION A. 6-· (Triphenylmethy lamino)-2,2-dimethyl-3(l-[4-methoxybenzyl)tetrazol-5-yl)penam (A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[4methoxybenzyl]carbamoylpenam To a stirred slurry of 86.4 g, (0.8 mole) of 6-aminopenicillanic acid in 600 ml. of anhydrous chloroform is added 11.2 ml. (0.4 mole) of triethylamine, and the mixture 42493 - 42 is stirred at ambient temperature until a clear solution is obtained (ca. 15 minutes). To this solution 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 IO 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)-2,220 dimethyl-3-(N-[4-methylbenzyl]carbamoyl)penam.

(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-4methoxybenzyl]-tetrazol-5-yl)penam.

To a chloroform solution containing 69.4 g. (0.120 mole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[425 methoxybenzyl]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 phos30 phorus pentachloride is added during 15 minutes, with stirring. Stirring is continued at ca. 10°C. for 10 minutes, and then at ambient temperature for a further - 43 42482 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. (0.060 mole) of pyridine, followed by 2.42 ml. (0.060 mole) of methanol at ca. 25°G., 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)-2,2dimethyl-3-(l~[4-methoxybenzyl]tetrazol-5-yl)penam. The infrared spectrum of the product (KBr disc) shows an absorption band at 1790 cm (β-lactam); and the NMR spectrum (in CDCl^) 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), 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-(tr iphenyImethylamino )-2,2-dimethyl-3-(1-(4-benzyloxybenzyl]tetrazol-5-yl)penam 6-(Triphenylmethylamino)-2,2-dimethyl-3-( N-4-benzyloxybenzyl]-carbamoyl)penam - To a stirred solution of 20.0 g. of 6-triphenylmethylamino-penicillanic acid (Sheehan - 44 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 2.25 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-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzyl30 oxybenzyl]tetrazol-5-yl)penam - The above-described imino chloride is re-dissolved in 8 ml. of dry Ν,Ν-dimethylformamide. To this solution is added 249 mg. of potassium - 45 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 vacuo.

The residue is 980 mg. of 6-(triphenylmethylamino)-2,2dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam.

Its NMR spectrum (in CDCl3) shows absorption bands at 7.30 ppm (multiplet, aromatic hydrogens), 5.45 ppm (quartet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogens), 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-(N-furfuryl20 carbamoyl)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 - 46 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 furfuryl5 amine (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)-2,2-dimethyl-3-(NfurfurylcarbamoyDpenam. The NMR spectrum of this solution showed absorptions at 7.3 ppm (17H, 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-(l-furfuryltetrazol-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 chloro30 form. 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 - 47 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-(1-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-(5-methylfurfuryl]tetrazol-5-yl)penam.

The title compound is prepared according to the procedure of Preparation C, but using 5-methylfurfurylamine in place of furfurylamine. The NMR spectrum (CDCl^) of the product shows absorptions at 7.36 ppm (m, 15H), 6.33 ppm (m, IH), 5.93 ppm (m, IH), 5.50 ppm (s, 2H), 5.20 ppm (s, IH), 4.50 ppm (m, 2H), 3.23 ppm (d, IH), 2.26 ppm (s, 3H), 1.63 ppm (s, 3H) and 0.90 ppm (m, 3H).

PREPARATION E. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-(2,4-dimethoxybenzyl]tetrazol-5-yl)penam.

The title compound is prepared in 46% overall yield from 6-{triphenylmethylamino)penicillanic acid, by replacing the furfurylamine of Preparation C with 2,4-dimethoxybenzylamine. The crude product is purified by recrystall- 48 424 9 2 ization from a mixture of methylene chloride and methanol. The NMR spectrum of the product (CDCl^) shows absorptions at 7.40 ppm (m, 16H), 6.45 ppm (m, 2H), 5.40 ppm (s, 2H), 4.50 ppm (m, 2H), 3.75 ppm (s, 3H), 3.70 ppm (s, 3H), 1.55 ppm (s, 3H) and 0.90 (s, 3H).

PREPARATION F.

The procedure of Preparation E is repeated, except that the furfurylamine is replaced by an equimolar amount of the appropriate amine, to produce the following congeners; 43492 - 49 15 *12 *13 *11 4-CH^CHpO H H 3-Cl 4-CH3O H 3-CH3 4-CH 0 H 3-CrHr 6 5 4-CH30 H 4-CH30 H ch3 H IIC6H5 3-Br H ceH_ 6 5 4-F HC6H5 H H H 4-C-H6 5 H H H H ch3 4-CfL· 3 H CJir 6 5 4-n-C3H?O H II H 4-i-C3H?O- H 2-CH3O 4-CH-O J H - 50 PREPARATION G. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-[4-hydroxybenzyl]tetrazol-5-yl)penam (A) 6-(Triphenylmethylami.no)-2,2-dimethyl-3-(N-[4-hydroxy5 benzyl]carbamoyl)penam To a stirred slurry of 43.2 g. (0.20 mole) of 6-aminopenicillanic 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 43492 12.63 cj. of 6~(triphenylmethylamino)-2,2-dimethyl-3-(N|4-hydroxybenzyl]carbamoyl)penam, m.p. 166~168°C. (dec,).

The infrared spectrum of the product (CHCl, solution) -1 J -1 shows absorptions at 1785 cm (β-lactam) and 1675 cm (amide X). The NMR spectrum of the product (CDCl/ shows absorptions at 7.60-6.40 ppm (multiplet, 20H, aromatic hydrogens and amide hydrogens), 4.70-4.10 ppm (multiplet, 5H, C~5 and C-6 hydrogens, benzyl methylene hydrogen and C-3 hydrogen), 2.98 ppm (doublet, IH, 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-hydroxyben2yl]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 ca. 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 i3 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 IN sodium hydroxide to bring the pH of the - 52 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-(1-[4-hydroxybenzyl]tetrazol-5-yl)penam. The infrared spectrum of the product (in CHCl.) 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).

PREPARATION H. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-[4-acetoxybenzyl]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 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 43492 - 53 1η vacuo. The residue is redissolved in 6 ml. of chloroform and the solution is cooled to ca. 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, 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-dimethyl3-(l-[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)-2,2dimethyl-3-(l~[4~formyloxybenzyl]tetrazol-5-yl)penam and 6-(triphenylmethylamxno)-2,2-dimethyl-3-(1-[4-(methoxymethoxy)benzyl]tetrazol--5-yl)penam, respectively.

PREPARATION I. 6-Amino-2,2-dimethyl-3-(1-[4-methoxybenzylj tetrazol-5-yl)penam p-toluenesulfonate To a stirred slurry of 143 g. of 6~{triphenylmethylamino)-2,2-dimethyl-3-(l-[4-methoxybenzyl]tetrazol-5-yl) penam in 1,000 ml. of dry acetone is added 45.0 g. of ptoluenesulfonic 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 - 54 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-amino-2,25 dimethyl-3-(l-[4-methoxybenzyl]tetrazbl-5-yl)penam ptoluenesulfonate, m.p. 174-175.5°C. The infrared spectrum (KBr disc) of the product shows an absorption band at 1795 cm 1. The NMR spectrum (in DMSO-dg) shows absorption bands at 7.20 ppm (multiplet, aromatic hydrogens), 5.80 IO 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 hydrogen), 1.70 ppm (singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens).

PREPARATION J.

Reaction of the appropriate 6-(triphenylmethylamino)2,2-dimethyl-3-(l-substituted tetrazol-5-yl)penam with p-toluenesulfonic acid monohydrate, substantially according to the procedure of Preparation X provides the following compounds as their p-toluenesulfonate salts.

Compound Yield 6-amino-2,2-dimethyl-3-(1[4-benzyloxybenzyl]tetrazol5- yl)penam 79 6-amino-2,2-dimethyl-3-(1furfuryltetrazol-5-yl)penam 62 6- amino-2,2-dimethyl-3-(l[5-methylfurfuryl]tetrazol-5yl )penam 54 6-amino-2,2-dimethyl-3-(130 [2,4-dimethoxybenzyl]tetrazol5-yl)penam 99 - 55 To a stirred solution of 304 mg. of 6-amino-2,2dimethyl-3-(l-[4-benzyloxybenzyl] tetrazol-5-yl)penam ptoluenesulfonate in 10 ml. of methylene chloride is added 69.7 ill of triethylamine. After 3 minutes, 5 ml. of water are added and the mixture is stirred vigorously.

The organic phase is then removed, diluted with ether, dried using anhydrous magnesium sulfate, and evaporated to dryness in vacuo. The residue is 189 mg. (86% yield) of 6-amino-2,2-dimethyl-3-(l-[4-benzyloxybenzyl]tetrazol5-yl)j>enam free base.

In like manner the products of Preparations Ρ—II and - U are detritylated to the corresponding 6-amino derivatives.

PREPARATION K. 6- Amino-2,2-dimethyl-3 -(5-tetrazolyl)penam A stirred solution of 32.0 g. of 6-amino-2,2dimethyl-3-(l-[4-methoxybenzyl]tetrazol-5-yl)penam ptoluenesulfonate, and 24 ml. of anisole, in 96 ml. of + o trifluoroacetic acid is maintained at 40 - 1 C. for 35 minutes. The trifluoroacetic acid is then removed rapidly by vacuum distillation. A 120-ml portion of ether is added to the residue, which produces a white flocculent suspension. The suspension and solvent is cooled to about 0°C., and to it is then added, portionwise, 80 ml. of 2N sodium hydroxide, giving two clear phases. The pH of the aqueous phase at this point is about 2.7. The layers are separated, and the ether phase is discarded. The pH of the aqueous phase is raised to 4.1 with 2N sodium hydroxide. This aqueous phase is then washed with 100 ml, of ether and filtered. It is combined with the corresponding aqueous phases from four other identical experiments, and the total aqueous solution is - 56 lyophilized to give crude 6-amino-2,2-dimethyl-3-(5-tetrazolyDpenam. This crude product is slurried in a small amount of water and filtered, off. It is then re-suspended in water and brought into solution by raising the pH to 7.4 by the addition of sodium hydroxide solution. The clear solution is extracted with water and the extracts are discarded. The pH of the aqueous phase is adjusted to 4.1 using dilute hydrochloric acid, and the product which precipitates is filtered off. The infrared spectrum of the product shows an absorption at 1795 cm \ Its NMR spectrum (in DMSO-d-) shows absorptions at 5.65 ppm Ό (doublet C-5 hydrogen), 5.20 ppm (singlet, C-3 hydrogen), 4.70 ppm (doublet, C-6 hydrogen), 1.65 ppm (singlet, C-2 methyl hydrogens) and 1.10 ppm (singlet, C-2 methyl hydrogens).

When each of the 6-amino-2,2-dimethyl-3-(l-substituted tetrazol-5-yl)penam p-toluenesulfonate salts of Preparation J is treated with trifluoroacetic acid/ anisole, according to the above procedure, the product in each case is 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam.

PREPARATION L. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam To a stirred solution of 1.69 g. (3 mmole) of 625 (triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl] penam prepared as described in (Preparation G) in 9 ml. of chloroform is added 1ml. (12 mmole) of pyridine. The o , solutxon is cooled to ca. 4 C. m 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 4.3M solution in chloroform 6.45 mmole) is added and the 42493 - 57 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 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-dimethyl3-(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.

PREPARATION M. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl] -tetrazol-5-yl)penam (A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(Ν-ethoxycarbonylcarbamoyl)penam.

To a stirred solution of 4.58 g. (10 mmole) d-(triphenylmethylaminoj-penicillanic acid and 1.45 ml. (10 mmole) of triethylamine, in 75 ml. of acetonitrile, is - 58 added 1.15 g. (10 mmole) of ethoxycarbonyl isocyanate dissolved in 5 ml. of acetonitrile. The resulting solution is stirred at ca. 25°C. for 16 hours, and then the solvent is removed by evaporation in vacuo. The residue is re-dissolved in chloroform, and the chloroform solution is washed successively with water, sodium bicarbonate solution and sodium chloride solution. The chloroform solution is then dried using anhydrous magnesium sulfate and evaporated in vacuo. The residue is again re-dissolved in chloroform, and the chloroform solution is washed With dilute hydrochloric acid, dried using magnesium sulfate, and again evaporated in vacuo. This affords the crude product, which is purified by chromatography using silica gel as the adsorbent an(j eluting the column with chloroform containing 4% by volume of ethanol. The final yield of 6-(triphenylmethylamino)2,2-dimethyl-3-(N-[ethoxycarbonylcarbamoyl)penam is 2.54 g (48% yield). (&) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-[ethoxy20 carbonyl] tetrazol-5-yl)penam To a stirred solution of 529 mg. (1 mmole) of 6(triphenylmethylamino)-2,2-dimethyl-3-(N-[ethoxycarbonyl]carbamoyl)penam and 240 mg. (3 mmole) of pyridine, in 25 ml. of methylene chloride, is added 208 mg. (1 mmole) of phosphorus pentachloride, at 0°C, The reaction mixture o o xs stirred at 0 C. for 0.5 hour and then at ca. 25 C. for 2 hours. The solvents and the excess pyridine are then removed by evaporation in vacuo, and the residue is redissolved in 15 ml. of chloroform. The latter chloroform solution is cooled to 0°C., and 0.47 g. (3 mmole) of tetramethylguanidinium azide is added in several small portions with stirring. Stirring is continued for 2 hours at ambient temperature, and then to the reaction mixture is added a further 15 ml. of chloroform followed by 30 ml. of water. The pH i3 adjusted to 6.5, and then the chloroform layer 13 removed. The chloroform solution is washed with water followed by brine, and then it is dried using anhydrous sodium sulfate. Removal of the solvent by evaporation in vacuo affords crude 6-(triphenylmethylamino )-2,2-dimethyl-3-(1-(ethoxyearbonyl]tetrazol-5yl)penam. The crude product is purified further by chrom10 atography using silica gel.

PREPARATION N.

Starting with 6-(triphenylmethylamino)penieillanic acid and the appropriate isocyanate, and following the procedure of Preparation M, the following compounds are prepared; CH. ΠΤ.Τ 1___N--- R' ,2 C,H_CH„0-C06 5 2 C£HrO-CO6 5 (4--N0 ~C JK. )0-C02 6 4 (3,4-Cl2 CgH3)0-C0· ch3-so2C6H5CH2-S°220 -βοή' ,2 (cont.) C6H5-S°2(3-CH30-C6H4)-S02(2,4-[N02]2 C6H3)-SO2 2J 2 6 3 PREPARATION 0 6-(Triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam To a stirred mixture of 2 ml. of tetrahydrofuran and 4 ml. of water is added 150 mg. of 6-(triphenylmethylamino) 2,2-dimethyl-3-(1-[ethoxycarbonyl]tetra2ol-5-yl)penam.

The pH of the mixture is adjusted to 9.5, and stirring is continued at that pH for a further 30 minutes, at ambient temperature. The bulk of the tetrahydrofuran is removed by evaporation in vacuo, and the residue is partitioned between water and ethyl acetate at pH 9. The ethyl acetate is removed and discarded. Fresh ethyl acetate is added and the pH is adjusted to 2.0. The ethyl acetate layer is removed, washed with water, dried using anhydrous sodium sulfate, and evaporated in vacuo to give the crude title compound.

When each of 6-(triphenylmethylamino)-2,2-dimethyl3-(l-substituted tetrazol-5-yl)penam compounds of Preparation N is hydrolyzed using the above procedure, the product in each case is also 6-(triphenylmethylamino)-2,2dimethyl-3-(5-tetrazolyl)penam.

PREPARATION P. 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam.

To a slurry of dry acetone (5 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazolyl)penam (483 mg., 1.0 mmole) at room temperature is added p-toluenesulfonic acid monohydrate (209 mg., 1.1 mmole). The resulting solution is stirred for 10 minutes after which the solvent - 61 is decanted from the solid which separates. The solid is dissolved in tetrahydrofuran (30 ml.) and placed on a column (300 x 6 mm) packed with 10 g. of Florisil (synthetic magnesium silicate). The column is washed with tetrahydrofuran until a total of 125 ml. is collected. The eluate is concentrated to dryness under reduced pressure at 40°C. to give 210 mg. of solid. The solid is slurried in ether (30 ml.), filtered, washed with ether and air-dried. Yield = 121 mg. (50%). The NMR spectrum (in DMSO~d,) shows absorption bands at 1.08 ppm, (2s, 3H O “ each, C-2 methyls), 4.60 + 5.52 (2d, J = 4.0 Η , 2H, Hg + H. ), 5.10 (s, IB H,) and 5.88 (s, 3H, NH ) ppm. (s, 3H), 3 3 I. 59 ppm (s, 3H), 4.60 ppm (d, IH), 5.52 ppm (d, IH), 5.10 ppm (s. Iff), and 5.88 ppm (s, 3H).

PREPARATION Q. 6-Amino-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl) penam IP a stirred solution of 554 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol5-yl)penam in 2 ml. of acetone is added a solution of 190 mg. of p-toluenesulfonic acid monohydrate in 1 ml. of acetone. Stirring is continued for a further 3 hours, and then the acetone is removed by evaporation in vacuo.

The residue is slurried in ether, filtered and dried, to give the title compound as its p-toluenesulfonate salt.

The above p-toluenesulfonate salt is added to a mixture of 15 ml. of water and 15 ml. of chloroform. The pH of the aqueous phase is adjusted to 7.0 and the chloroform layer is removed. The chloroform is dried using sodium sulfate, and then it is evaporated in vacuo to give the title compound as its free base. - 62 PREPARATION R.

Reaction of the appropriate 6-(triphenylmethylamino)~ 2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam chosen from those in Preparation N with p-toluenesulfonic acid, according to the procedure of Preparation Q provides the following compounds as their p-toluenesulfonate salts. 7/ C,H_CH-0-C0o o i C-H-O-CO6 5 (4-HO -C H )0-002 o 4 (3,4-ci2 c6h3)o-co CH3-SO2~ 06Η50η2-302C6H5-S°2(3-CH3O-C6H4)-SO2)(2.4-[NO2]2 C6H3-SO2PREPARATXON S. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-[2-methoxy1 20 carbonylethyl] tetrazol -5-yl)penam A. 6-(Triphenylmethylamxno)-2,2-dimethyl-3-(N-[2methoxycarbonylethyl]carbamoyl)penam To a stirred solution of 35 g. of 6-(triphenylmethyl42492 - 63 amino)penicillanic acid in 250 ml. of dry, ethanol-free chloroform, is added 11.7 ml. of triethylamine at 0-3°C. The solution thus obtained is then added dropwise, with stirring, at O-6°C., to a second solution, prepared from 7.3 ml. of ethyl chloroformate in 155 ml. of dry, ethanolfree chloroform. Stirring is continued for a further 10 minutes. This affords a chloroform solution of the mixed anhydride of 6-(triphenylmethylamino)penicillanic acid.

In a separate flask, a solution of β-alanine methyl ester is prepared by adding 11.7 ml. of triethylamine to a slurry of 10.73 g. of β-alanine methyl ester hydrochloride and 2 g. of anhydrous sodium sulfate in 115 ml. of dry ethanol-free chloroform, at ca. 1O°C. Stirring is continued for a further 10 minutes.

The latter amino-ester solution is then added dropwise, with stirring at 3-6°C., to the above-described mixed anhydride solution. After the end of the addition, stirring is continued for a further 2 hours.

At this point, the reaction solution is washed successively with three portions of water and one portion of brine. The solution is then dried using anhydrous sodium sulfate, and evaporated in vacuo to give 40.1 g. of crude 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[2methoxycarbonylethyl]carbamoyl)penam as a glassy solid, m.p. 60-70°C. The crude product is purified by extracting it into refluxing ether, treating the filtered solution with activated carbon, and then reprecipitating the product by the addition of petroleum ether.

B. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(l-[230 methoxycarbonylethyl]tetrazol-5-yl)penam To a stirred solution of 2 g. of the amide described - 64 under A above, in 5 ml. of dry, ethanol-free chloroform, is added, at ca. 0°C., 1.36 ml. of pyridine, followed by a solution of 620 mg. of phosgene in 4 ml, of dry, ethanolfree chloroform. The solution is stirred for 2.5 hours, at ambient temperature, and then the solvent is removed by evaporation in vacuo. The residue is re-dissolved in 9 ml. of dry, ethanol-free chloroform, and 580 mg. of tetramethylguanidinium azide is added. The reaction mixture is stirred for 45 minutes, at which point a further 200 mg. of tetramethylguanidinium azide is added. The reaction mixture is then stirred 18 hours to complete the conversion to tetra2ole. To the reaction solution is then added saturated sodium bicarbonate solution, in sufficient quantity that the pH of the aqueous phase is 7.6. The chloroform layer is removed, washed with water at pH 5, washed with water at pH 7, dried using anhydrous sodium sulfate, and finally evaporated in vacuo. This affords 2.19 g. of crude product, which is recrystallized from methanol giving 1.11 g (48% yield) of product with m.p. 100-105°C. The NMR spectrum (CDCl^) shows absorptions at 7.40 ppm (m, 15H), 5.15 ppm (s, IH), 3.80 (m, 4H), 3.70 ppm (s, 3H), 3.10 ppm (t, 2H), 1.70 ppm (ε, 3H) and 1.17 ppm (s, 3H), and further indicates that the product contains methanol of solvation.

PREPARATION T.

The procedure of Preparation S is repeated except that the^S-alanine methyl ester is replaced by the appropriate amine to produce the following compounds - 65 42192 (CcH_). C-NH 6 5 3 CH.

N \ / N — N / R6-CH2CH2 CN C(=O)~O~C3 C(=O)-O-C6H5S°2-CH3 so2-c6h5 SO2-N(CH3)2 80,-8(^ S0_-NH~CH,~C,H_ 2 6 5 PREPARATION U. 6-(Triphenylmethylatnino)-2,2-dimethyl-3-(5-tetrazolyl)penam To a stirred solution of 600 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(l-[2-methoxycarbonylethyl]15 tetrazol-5-yl)penam (containing ca 4.5% of methanol) in ml. of chloroform, is added a solution of 375.2 mg. of diazabicyclo[4.3.0]non-5-ene in 0.5 ml. of chloroform. Stirring is continued for a further 3 hours, and then the solution is diluted with a further 2 ml. of chloroform.

The latter solution is washed quickly with 5 ml. of 2N hydrochloric acid, and then a further 5 ml. of 2N hydrochloric are added. The resulting mixture is cooled to ca 0°C., and the solid which precipitates is filtered off. - 66 giving 323 mg. (71% yield) of the title compound. The NMR spectrum (DMSO-d ) of the product shows absorptions at 7.40 ppm (m, 15H), 5.30 ppm (s, IH), 4.60 ppm (m, 2H), 1.58 ppm (s, 3H) and 0.78 ppm (s, 3H) .

Reaction of each of the 6-(triphenylmethylamino)2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam compounds of Preparation S with diazabicyclo (4.3.0) non-5ene, according to the above procedure, produces in each case, 6-(triphenylmethylamino)-2,2-dimethyl-3-(tetrazol10 5-yl)penam, PREPARATION V. 6-Amino-2,2-dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5yl)penam 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]tetrazol-5-yl)penam is added. Stirring is continued 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 etheracetone 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-2,2dimethyl-3-(2-[pivaloyloxymethyl]tetrazol-5-yl)penam hydrochloride. The infrared spectrum (KBr disc) shows absorptions at 1785 cm 1 (β-lactam) and 1750 cm (ester). The NMR spectrum (DMS0-dg) shows absorptions at 6.70 ppm - 67 (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 W. 6-Amino-2,2-dimethyl-3-(1-[pivaloyloxymethyl 1 tetrazol-5yl)penam The title compound is prepared as its hydrochloride in 90% yield, from 6-(2-phenylacetamido)-2,2-dimethyl-3(l-[pivaloyloxymethyl]tetrazol-5-yl)penam, using the method of Preparation V. The infrared spectrum (KBr disc) shows absorptions at 1760 cm-1 (β-lactam) and 1740 cm (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 X. 6-Amino-2,2-dimethyl-3-(l-pivaloyloxymethyltetrazol-5yl)penam and 6-Amino-2,2-dimethyl-3-(2-pivaloyloxymethyltetrazol-5-yl)penam To a stirred suspension of 2.40 g. of 6-amino-2,2dimethyl-3-(5-tetrazolyl)penam in 15 ml. of Ν,Ν-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 - 68 acetate. The extract is washed with water, dried using anhydrous sodium sulfate, and then it is evaporated ir. vacuo to give a mixture of the title compounds. The individual isomers are obtained by chromatographic separ5 ation 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): acetoxymethyl isobutyryloxymethyl hexanoyloxymethyl 1-acetoxyethyl , 1-pivaloyloxy ethyl 1-hexanoyloxyethyl phthalidyl propionyloxymethyl PREPARATION Y. 6-Amino-2,2-dimethyl-3-(1[2]-triphenylmethyltetrazol-5yl)penam To a stirred slurry of 240 mg. of 6-amino-2,2dimethyl-3-(5-tetrazolyl)penam in 1.5 ml, of dry, ethanolfree chloroform, is added 0.36 ml. of triethylamine. The mixture is stirred until a cloudy solution is obtained, and then ca. 200 mg. of anhydrous sodium sulfate is added.

Stirring is continued for a further 15 minutes and then the mixture is filtered. To the filtrate is added 278.5 43492 - 69 nig. of triphenylmethyl chloride, and the reaction mixture is stored at ambient temperature for 4,5 hours. At this point, the solvent is removed by evaporation in vacuo, leaving the crude title product as a mixture of isomers as indicated. The crude product is re-dissolved in a small volume of chloroform and then absorbed on a small column of silica gel. The column is eluted with chloroform and the first 20 ml. of eluate are collected and evaporated to dryness in vacuo, A small volume of ether is added to the residue, and the mixture is again evaporated to dryness in vacuo. The latter residue is washed with ether, to give 357.4 mg. {77% yield) of a white solid. The NMR spectrum (CDCl/ shows absorptions at 7.15 ppm (broad singlet), 5.70 ppm (doublet), 5.35 (singlet', 4.55 (doublet), 1.60 (singlet) and 1.10 (singlet) .

PREPARATION Z.

Reaction of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with a substituted triphenylmethyl chloride as alkylating agent according to the procedure of Preparation Y affords in each ease a mixture of the corresponding 6-amino-2,2-dimethyl-3-(1-(substituted triphenylmethyl]tetrazol-5-yl)penam and 6-amino-2,2-dimethyl-3-(2[substituted triphenylmethyl]tetrazol-5-yl)penam compounds. In this way, the mixtures of the following compound and its isomer are produced; 42482 2-F H H 3-Cl H H 5 4-Br H H2C2H5 H H4n-C3S7 H H 3-sec-C4Hg H H4-oc2h5 H H 10 H4C6H5 H H 3-CH3 3-CH3 H 3-Cl 3-Cl 4-Cl H 4-OCH. 34~C6H5 H 4-C5H5 15 4-CH34-ch34-ch3 4-i-C3H7 3-OCH3 3-OCH3 The mixtures are separated into the two : chromatography. 42482 - 71 PREPARATION AA Mono-Trimethylsilyl Derivative of 6-Amino-2,2-Dimethyl3-(5-Tetrazolyl)Penams To a stirred suspension of 2.4 g. of 6-amino-2,25 dimethyl-3-(5-tetrazolyl)penam in 50 ml. of chloroform is added 2.8 ml, of triethylamine. Stirring is continued for a further 15 minutes, and then the solution thus obtained, is cooled to 0°C. To this solution is then added 1.08 g. of trimethylsilyl chloride. The cooling bath is removed, and the reaction mixture is stirred for a further one hour at ambient temperature, to give a chloroform solution of the mono-trimethylsilyl derivative of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam.

When the above procedure is repeated, except that IS the trimethylsilyl chloride used therein ia replaced by an equimolar amount of triethylsilyl chloride and tri-nbutylsilyl chloride, respectively, the products are the mono-triethylsilyl and the mono-tri-n-butylsilyl derivative of 6-amino-2,2-dimethyl-3-(5-tetr azolyl)penam, respectively.

PREPARATION 8B Bis-Trialkylsilyl Derivatives of 6-Amino-2,2-dimethyl-3(5-Tetrazolyl)penam To a stirred suspension of 2.4 g. of 6-amino-2,225 dimethyl-3-(5-tetrazolyl)penam in 50 ml. of chloroform is added 4.2 ml. of triethylamine. Stirring is continued for a further 15 minutes, and the solution thus obtained is cooled to 0°C. To this solution is then added 2.16 g. of trimethylsilyl chloride. The cooling bath is removed, and the reaction mixture stirred at ambient temperature for one hour and then is refluxed for one hour. It is then cooled to ambient temperature giving a chloroform - 72 solution of the bis-trimethylsilyl derivative of 6-amino2,2-dimethyl-3-(5-tetrazolyl)penam.

When the above procedure is repeated, except that the trimethylsilyl chloride used therein is replaced by an equimolar amount of triethylsilyl chloride and triisopropylsilyl chloride, respectively, the products are the bis-triethylsilyl and the bis-triisopropyl derivative of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, respectively

Claims (15)

1. CLAIMS:A penam compound of the general formula:R-CH=N. • CH- CH I N CH„ CH (III) \ v wherein R ia a hydrogen atom, an alkyl group having from one to twelve carbon atoms, a cycloalkyl group having from three to seven carbon atoms, a phenyl, substituted phenyl, naphthyl, substituted naphthyl, furyl, thienyl or pyridyl group, or an alkenyl group having from two to twelve carbon atoms each substituted group being substituted with up to two subBtituents, each of which is a chlorine, bromine, fluorine or iodine atom or a hydroxy group, a nitro group, an alkoxy group having from one to four carbon atoms or an alkyl group having from one to four carbon atoms? and Y is a group of the formula:- wherein is R 2 or a tetrazolylpenam nitrogen protecting group as hereinbefore defined, R 2 is a hydrogen atom, a 20 silyl group, an alkanoyloxymethyl group having from three to eight carbon atoms, a 1-alkanoyloxyethyl group having from four to nine carbon atoms, a phthalidyl group, or a group of the formula:42492 wherein each of R., R_ and R is a hydrogen, chlorine, bromine or fluorine atom, an alkyl group having from one

2. A compound according to claim 1, wherein R% is a trialkylsilyl group having from one to four carbon atoms

3. N-Behzylidene-6-amino-2,2-dimethyl-3-(5-tetrazolyl) penam. 4. 249 2 - 77 hydroxy, azido, carboxy, sulpho, carbamoyl, phenoxycarbonyl, indanyloxycarbonyl, sulphoamino, aminomethyl or amino group, or a group of the formula NHiCO-CHj-NHjm-COA, wherein A is an alkyl group having from one to six carbon atoms, a phenyl, substituted phenyl, furyl, thienyl, pyridyl, pyrrolyl or amino group, a N-alkylamino group having from one to six carbon atoms, an anilino, substituted anilino, guanidino, acylamino having from two to seven carbon atoms, benzamido, substituted benzamido, thiopheneearboxamido, furancarboxamido, pyridinecarboxamido, aminomethyl, guanidinomethyl, alkanecarboxamidinomethyl having from three to eight carbon atoms, benzamidinomethyl, (substituted benzamidino)methyl, thiopheneearboxamidinomethyl, furancarboxamidinomethyl, pyridinecarboxamidinomethyl, pyrrolecarboxamidinomethyl or 2benzimidazolecarboxamidinomethyl group, each substituted group being substituted by up to two substituents, each of Which is a fluorine, chlorine, bromine or iodine atom, an alkyl group having from one to four carbon atoms, an alkoxy group having from one to four carbon atoms, or a sulphamyl, carbamoyl or cyano group, and m is 0 or 1 provided that when R* is 1-amino-cycloalkyl, n is 0, and provided that when R' is phenoxy, phenylthio, pyridylthio, substituted phenoxy, substituted phenylthio or substituted pyridylthio and n is 1, Q is hydrogen, alkyl having from one to six carbon atoms, carboxy sulpho, carbamoyl, phenoxycarbonyl, substituted phenoxycarbonyl, indanyloxycarbonyl or aminomethyl.

4. N-Salicylidene-6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam. 15 5. N-4-Nitrobenzylidene-6-amino-2,2-dimethyl-3-(4methoxybenzyltetrazol-5-yl)penam.

5. Group having from three to seven carbon atoms, a cyclohexenyl or 1,4-cyclohexadienyl 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-dichloro10 phenyl)-4-isoxazolyl or 5-methyl-3-(2-chloro-6-fluorophenyl)-4-isoxazolyl group, a 2-alkoxy-l-naphthyl group having from one to four carbon atoms in the alkoxy group, a phenyl, phenoxy, phenylthio, pyridylthio, benzyl, sydnonyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, 15 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, 20 substituted pyrimidinyl, substituted triazolyl, substituted tetrazolyl, substituted imidazolyl or substituted pyrazolyl group each substituted group being substituted by up to two substituents each of which is a fluorine, chlorine or bromine atom or a hydroxy group, an amino 25 group, a N-alkylamino group having from one to four carbon atoms, a N,N-dialkylamino group having from one to four carbon atoms in each of the alkyl groups, an alkyl group having from 1 to 4 carbon atoms, an aminomethyl group, an alkoxy group having from one to four carbon 30 atoms, an alkylthio group having from one to four carbon atoms or a 2-aminoethoxy group, and Q is a hydrogen atom, an alkyl group having from one to six carbon atoms or a 5. 5 to four carbon atoms, an alkoxy group having from one to four carbon atoms or a phenyl group and salts of those compounds wherein both R^ and R 2 are hydrogen atoms.

6. A compound according to claim 1 substantially as hereinbefore described with reference to Examples 1 to 5.

7. A process for the preparation of an imine of 20 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or a 6-amino2,2-dimethyl-3-(substituted tetrazol-5-yl)penam, of 42483 - 75 formula (III) as defined in claim 1, which comprises condensing 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or a 6-amino-2,2-dimethyl-3-(substituted tetrazol-5-yl)penam with an aldehyde of the formula: R-CHO(II), wherein R is as defined in claim 1.

8. A process according to claim 7, substantially as hereinbefore described with reference to Examples 1 to

9. A process for the preparation of a 6-acylamino2,2-dimethyl-3-(5-tetrazolyl)penam or a 6-acylamino-2,2dimethyl-3-(substituted tetrazol-5-yl)penam, which comprises acylating with a compound of the formula RgCOX an imine of formula (III) as defined in claim 1, to produce an imine reaction product of the formula 0=C-R, I S R-CH-N X \ x CH -, I 'CH---CH cf 3 X 'CH. (IV) wherein R and Y are as defined in claim 1, X is the residual group of the acylating agent and R^CO is the acyl group of the acylating agent, and hydrolyzing the said imine reaction product,

10. - A process according to claim 9, wherein Rg-COis a group of the formula:- n (VI) - 76 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 10 per alkyl group.

11. A process according to claim 10 wherein R' is phenyl, Q is amino and n is 1.

12. A process according to claim 10, wherein R' is substituted phenyl, Q is amino and n is 1. - 78

13. A process according to claim 12, wherein R' is hydroxy substituted phenyl, Q is amino and n is 1.

14. A process for the preparation of 6-acylamino2,2-dimethyl-3-(5-tetrazolyl)penam or a 6-acylamino-2,25 dimethyl-3-(substituted tetrazol-5-yl)penam according to claim 9 and substantially as hereinbefore described with reference to Examples 6 to 9.

15. 6-Acylamino-2,2-dimethyl-3-(tetrazolyl)penams and 6-acylamino-2,2-dimethyl-3-(substituted tetrazol-510 yl)penams whenever prepared by a process according to any one of claims 9 to 14.