BE826569A - PROCESS FOR THE PRODUCTION OF 6-AMINO-2, 2-DIMETHYL-3- (5-TETRAZOLYL) PENAMES COMPOUNDS, AND CERTAIN DERIVATIVES THEREOF - Google Patents

Description

       

  Process for the production of 6-anino-2,2-dimethyl-3- compounds
(5-tetrazolyl) penams, and certain derivatives "thereof.

  
 <EMI ID = 1.1>

  
derivatives which contain a blocking or pseudo-blocking group on the tetrazolyl part, in 6-amino-2,2-dimethyl-3- (5-

  
 <EMI ID = 2.1>

  
below) and some of its derivatives in which is attached a blocking or pseudo-blocking group in position 1 or 2 of the tetrazolyl part are intermediates which can be used for the synthesis of a new category of antibacterial agents; at

  
 <EMI ID = 3.1>

  
such compounds are described in the pending patent application

  
N [deg.] 1/6234 filed October 17, 1974.

  
A chemical cleavage of the acyl side chains of penicillins and cephalosporins is described in the U.S. patent. N [deg.] 3,499,909. The method comprises protecting the caboxylic groups of penicillins or cephalosporins by converting them to silyl esters. The silyl esters are then reacted with a halogenating agent at a lower temperature.

  
 <EMI ID = 4.1>

  
with an alcohol at a temperature below about -20 [deg.] C. The imino ether thus prepared is then hydrolyzed under acidic conditions to obtain 6-aminopenicillanic acid or 7-aminocephalosporanic acid.

  
For convenience, the compounds described in the present specification are identified as derivatives of penam. The ter .- .. e

  
 <EMI ID = 5.1>

  
Air.crican Chemical Society, 75 3293 (1953), as relating to structure:

  

 <EMI ID = 6.1>


  
Using this terminology, the antibiotic penicillin G well

  
 <EMI ID = 7.1> <EMI ID = 8.1>

  
Most of the reagents of the present invention are also tetrazoles substituted in the 5 position, and tetrazoles substituted in the 5 position can exist in two isomeric forms, namely:

  

 <EMI ID = 9.1>


  
The technician introduced to the art will appreciate that when

  
 <EMI ID = 10.1>

  
two forms coexist in a mixture of dynamic equilibrium

  
 <EMI ID = 11.1>

  
substituting other than hydrogen, the two forms represent different chemical entities which do not spontaneously convert into each other.

  
The process of the present invention for the preparation of a 6-amino-2,2-dimethyl-3- (5-tetrazolyl) penam compound of the formula:

  

 <EMI ID = 12.1>


  
 <EMI ID = 13.1>

  

 <EMI ID = 14.1>


  
formulas in which R. is chcisi in the group comprising

  
 <EMI ID = 15.1>

  
nature is defined below;

  
 <EMI ID = 16.1>

  
trialkylsilyl group comprising from 1 to 4 carbon atoms

  
 <EMI ID = 17.1>

  
holding from 4 to 9 carbon atoms, the phthalidyl group and
 <EMI ID = 18.1>
 <EMI ID = 19.1>

  
group comprising hydrogen, a chloro, bromo, flucro, alkyl group containing from 1 to 4 carbon atoms, alkoxy group containing

  
1 to 4 carbon atoms and phenyl.

  
includes:
(a) reacting a compound selected from the group consisting of:

  

 <EMI ID = 20.1>


  
formula in which R is chosen from the group comprising

  
 <EMI ID = 21.1>

  
chosen from the group comprising:

  

 <EMI ID = 22.1>


  
 <EMI ID = 23.1>

  
 <EMI ID = 24.1>

  
 <EMI ID = 25.1>

  
trialkylsilyl containing 1 to 4 carbon atoms with an alkyl group, an alkanoyloxymethyl group containing 3 to 8 carbon atoms, a 1-alkanoyloxyethyl group containing <EMI ID = 26.1>
 <EMI ID = 27.1>
 <EMI ID = 28.1> group comprising hydrogen, a chloro, bromo, fluoro, alkyl group containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms and phenyl, under anhydrous conditions with an agent of halogenation at a temperature below about 0 [deg.] C to give the corresponding imino halide;

  
(b) reacting said imino halide at a temperature below about -20 [deg.] C with an alcohol of the formula R'-OH wherein R 'is selected from the group consisting of an alkyl group containing from 1 to 12 carbon atoms. carbon, phenylalkyl containing 1 to 7 carbon atoms in the alkyl part, hydroxyalkyl containing 2 to 12 carbon atoms, alkoxyalkyl containing 3 to 12 carbon atoms, monocyclic aryloxyalkyl 'containing 2 to 7 carbon atoms in the the alkyl part, monocyclic aralkoxyalkyl containing from 4 to 7 carbon atoms in the alkyl part, and hydroxy-alkoxyalkyl containing from 4 to 7 carbon atoms to give the corresponding imino ether, and
(c) reacting said imino ether under aqueous conditions to break the imino double bond.

  
The process is widely applicable to a wide variety of compounds of formula II in which R represents an organic acyl group which does not react with the halogenating agent. The choice of such a compound is strongly determined by availability factors and economics. For such reasons, favorable representatives of the acyl group RCO- are those derived from alkanoic acids containing up to 7 carbon atoms, and substituted alkanoic acids such as phenylpropionic acid, chloroacetic acid. Representatives

  
 <EMI ID = 29.1>

  
 <EMI ID = 30.1>

  
Compounds of formula I wherein R 1 and R 2 are each hydregene, with good quality and high yield. The method further provides a suitable procedure for improving the

  
 <EMI ID = 31.1>

  
from 6-aminopenicillanic acid by the process described below and which contain various impurities such as penicilloic acids and polymeric substances which originate from

  
polymerization of certain blocking groups, such as p-methoxybenzyl and p-hydroxybenzyl groups after their removal from the tetrazolyl part, and with unreacted starting material.

  
The process of the present invention is carried out when applied to compounds of formula II in which R 1 and R 2 are different from hydrogen by reacting the appropriate compound of formula II in a solvent inert to reacting under anhydrous conditions at a temperature below about -20 [deg.] C with a suitable halogenating agent in the presence of an acid binding agent to give an imino halide. Representative solvents are chloroform, methylene chloride, 1,2-

  
 <EMI ID = 32.1>

  
lic of ethylene glycol, nitromethane, diethyl ether, isopropyl ether, etc. Suitable halogenating agents are phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosgene, p-toluenesulfonyl chloride, oxalyl chloride, etc.

  
Representative acid binding amines are tertiary amines such as dimethylaniline, quinoline, lutidine, pyridine.

  
 <EMI ID = 33.1>

  
halide, to a corresponding imino ether by treatment with a primary alcohol at a temperature between about -20 [deg.] C and about -60 [deg.] C, and preferably at about -40 [deg.] C, in anhydrous conditions. Suitable alcohols are alkanols containing 1 to 12 carbon atoms, and preferably 1 to 4 carbon atoms, phenylalkanols containing 1 to 7 carbon atoms in the alkanol moiety; alkanediols containing from 2 to 6 carbon atoms; alkoxyalkanols containing from 2 to 6 atoms of <EMI ID = 34.1>

  
ethanol, 2-butoxyethanol. The preferred alcohols are methane, ethanol, propanol and butanol. In this step, silyl groups are also removed, if they are present on the tetrazolyl part as protective groups.

  
The imino ether is then broken down by moderate hydrolysis with water in the presence of an acid catalyst such as phosphoric acid or hydrochloric acid.

  
When R or R 2 of the tetrazolyl part is hydrogen, it is protected by replacing it with a protecting group for the nitrogen of tetrazolylpenam as defined in the present description. A preferred protecting group is the trialkylsilyl group in view of the fact that such a group is easily substituted on the tetrazolyl part and is easily removed under mild conditions as described in the present description.

  
 <EMI ID = 35.1>

  
being a trialkylsilyl group containing from 1 to 4 carbon atoms per alkyl group, an alkanoyloxymethyl group containing from 3 to 8 carbon atoms, a-1-alkanoyloxyethyl group containing from 4 to 9 atoms. carbon, triphenylmethyl, substituted triphenylmethyl and phthalidyl. R, is further defined as being a protecting group for the nitrogen of tetrazolylpenam. By this term is meant all the groups known, or obvious, to the technicians, which can be used (a) to allow the synthesis of the compounds of formula I and II by the methods described below, and (b) which can be removed under conditions such that the 3-lactam core system is left substantially intact.

  
The nature of the nitrogen protecting group of tetrazolylpenam is not critical in the present invention. It is more its ability to perform a specific function than its structure that is important. One skilled in the art can readily and easily select and identify the appropriate protecting groups. The suitability and efficacy of a group as a protecting group for <EMI ID = 36.1>

  
as reagent in the method described herein for making compounds of formula I.

  
As the technician introduced in this technique can

  
 <EMI ID = 37.1>

  
such as alkanoyloxymethyl, 1-alkanoyloxyethyl and phthalidyl groups are in some sense protective groups for the nitrogen of tetrazolylpenam. However, such groups cannot be removed without substantial degradation of the O-lactam ring and, therefore, they do not meet the criteria set out above for a "tetrazolylpenam nitrogen protecting group". They are however referred to in the present description as being “pseudo-blocking groups”.

  
Examples of protective groups for the nitrogen of tetrazolylpenam are:

  

 <EMI ID = 38.1>


  
formula in which R6 is an electron withdrawing group, and

  
 <EMI ID = 39.1>

  
the hydrogen atom on the adjacent carbon atom sufficiently acidic so that the protecting group can be removed in the Michael reaction. Such a reaction is well known in the art, (eg, House, "Modern Synthetic Reactions", W.A. Benjamin, Inc., New York / Amsterdam,
1965, page 207). Typical electron withdrawing groups are cyano, alkoxycarbonyl groups containing from 2 to 7 carbon atoms, phenoxycarbonyl, alkylsulfonyl groups containing from 1 to 6 atoms.

  
 <EMI ID = 40.1>

  
Z2 are each selected from the group consisting of hydrogen, an alkyl group containing 1 to 4 carbon atoms, phenyl and benzyl. A particularly suitable configuration for this protecting group is that in which R &#65533; is hydrogen and preferred representatives for R6 are alkoxycarbonyl groups containing from 2 to 7 carbon atoms and the group <EMI ID = 41.1>

  
removing such a group by moderate hydrolysis, such as moderate alkaline hydrolysis, or by treatment with a product

  
 <EMI ID = 42.1>

  
that a wide variety of such groups known in the art can be used, more particularly suitable groups are those in which Ra is an alkyl group containing from 1 to 6 carbon atoms, benzyl, phenyl or substituted phenyl, for example, the maximum substituted phenyl group. by two parts each chosen from an alkyl group and

  
an alkoxy group, containing from 1 to 4 carbon atoms.

  
Another protecting group for the nitrogen of tetrazolylpenam

  
 <EMI ID = 43.1>

  
also removes such a group by hydrolysis, or by treatment with a nucleophilic agent, as indicated for the

  
 <EMI ID = 44.1>

  
also alkyl groups containing from 1 to 6 carbon atoms, benzyl, phenyl, and substituted phenyl, for example, the phenyl group substituted at most by two parts each selected from the group consisting of nitro, flu &#65533; ro, chloro groups , bromo, alkyl containing 1 to 4 carbon atoms and alkoxy containing 1 to 4 carbon atoms.

  
Another tetrazolylpenam nitrogen protecting group that can be used is:

  

 <EMI ID = 45.1>


  
formula wherein W is phenyl, substituted phenyl, furyl, substituted furyl, thienyl or substituted thienyl, and

  
 <EMI ID = 46.1>

  
killed, furyl, substituted furyl, thienyl or substituted thienyl.

  
 <EMI ID = 47.1>

  
is hydrogen, an alkyl, phenyl or substituted phenyl group, this group can be removed by hydrogenolysis. We can also

  
 <EMI ID = 48.1>

  
 <EMI ID = 49.1>

  
to give the necessary degree of stability to the nascent carbonium ion.

  

 <EMI ID = 50.1>


  
More particularly preferred configurations for this protecting group which give satisfactory yields of the compounds of formula I and are easily removed are (a) those

  
 <EMI ID = 51.1>

  
having 1 to 6 carbon atoms, and W- is a phenyl or phenyl group substituted with up to two groups selected from

  
 <EMI ID = 52.1>

  
fluera, chloro, bromo, iodo, alkyl containing 1 to 6 carbon atoms, alkoxy group containing 1 to 6 carbon atoms, alkanoyloxy containing 2 to 7 carbon atoms, formyloxy, alkoxymethoxy containing 2 to 7 carbon atoms , phenyl, and

  
 <EMI ID = 53.1>

  
 <EMI ID = 54.1>

  
 <EMI ID = 55.1>

  
which can be used is the phenacyl or substituted phenacyl group. Such a group is removed by reaction with a nucleophilic reagent, such as thiophenoxide. Typical phenacyl groups which can be used are those of the formula:

  

 <EMI ID = 56.1>


  
formula wherein R9 is selected from the group consisting of hydrogen, nitro, fluoro, chlorine, bromo, and phenyl groups.

  
Substituent groups which can be widely used

  
 <EMI ID = 57.1>

  
are silyl groups, more particularly those derived from silvlation agents chosen from the group comprising:

  

 <EMI ID = 58.1>
 

  
 <EMI ID = 59.1>

  
 <EMI ID = 60.1>

  
carbon atoms, phenyl, benzyl, tolyl and dimethylaminophenyl,

  
 <EMI ID = 61.1>

  
uncomfortable ; R [deg.] Is an alkyl group containing from 1 to 7 atoms of

  
 <EMI ID = 62.1>

  
from the group comprising a halogen and

  

 <EMI ID = 63.1>


  
and W7 is selected from the group consisting of hydrogen and a

  
 <EMI ID = 64.1>

  
chosen from the group comprising hydrogen, alkyl groups

  
 <EMI ID = 65.1>

  

 <EMI ID = 66.1>


  
The silyl groups are introduced into the tetrazolyl part by methods known in the art. The silylation reaction is carried out in a solvent inert to the anhydrous reaction, that is to say, an anhydrous, non-hydroxylic solvent of the type mentioned above, and preferably in methylene chloride. , at a temperature between approximately -10 [deg.] C and approximately -80 [deg.] C, and more particularly at a temperature between -20 [deg.] C and -60 [deg.] C. The reaction is often carried out in the presence of an acid binding agent, i.e., a base such as an alkali metal carbonate or a tertiary amine, such as, for example, diethylaniline, pyridine, quinoline, and lutidine. The base can be part of the silylating agent as is the case when the silylating agent

  
 <EMI ID = 67.1>

  
 <EMI ID = 68.1>

  
 <EMI ID = 69.1>

  
halogen. Appropriate and representative silylating agents

  
 <EMI ID = 70.1>

  
trimethylchlorosilane, hexamethyldisilazane, triethyl- <EMI ID = 71.1>

  
methylbromosilane, benzylmethylethylchlorosilane, phenylethylmethylchlorosilane, triphenylchlorosilane, triphenylfluorosilane, tri-o-tolychlorosilane, tri-p-dimethylaminophenylchlorosilar.e, N-ethyltriethylethyl-ethyline-ethyl-ester, tri-ethyl-esterosilane

  
 <EMI ID = 72.1>

  
tetraethyldimethyldisilazane, tetramethyldiethyldisilazane, tetramethyldiphenyldisilazane, hexaphenyldisilazane, hexa-ptolyldisilazane, etc ... and mixtures of these products. The same effect is obtained by hexa-alkylcyclotrisilazanes or octaalkylcyclotetrasilazanes. Other suitable silylating agents are silylamides and silylureides, such as a trialkylsilylacetamide or a bis-trialkylsilylacetamide as described in the United States patent. N [deg.] 3,499,909.

  
The preferred silylating agents are dimethyldichlorosilane, chlorosilane and hexamethyldisilazane, and more particularly mixtures of these products in view of their overall reactivity, their availability, their ease of handling, the satisfactory yields obtained and, in what concerns the mixtures, the production of ammonia by the disilazane which

  
serves as an acid binding agent. The methods illustrated in the present invention are those described by Pierce in "Silylation

  
of Organic Compounds ”, Pierce Chemical Company, Rockford, Illinois.

  
Preferred tetrazolylpenam nitrogen protecting groups are those which can be removed under conditions other than acidic conditions. Acidic conditions are generally avoided in order to avoid or reduce the degradation of O-lactam.

  
when removing the protecting group from a compound of formula I. Illustrative examples of such protecting groups are those which can be removed by means such as hydrogenolysis (R is a benzyl or substituted benzyl group), treatment with a base (R. is the p-hydroxybenzyl group),

  
or a substituted silyl group (R 1, where R 2 is a trialkylsilyl group).

  
The term "tetrazolylpenam nitrogen protecting group" means, in its most general sense, that it embraces groups which protect the tetrazole ring during or after its <EMI ID = 73.1>

  
when (a) it can be attached to the tetrazolyl group during or after its formation; (b) when it allows the reaction of the C-6 acylamido group of tetrazolylpenam; and (c) when it can be removed from the tetrazolyl moiety of compounds of formula I or

  
II without significant degradation of the tetrazolylpenam nucleus. Illustrative examples of such groups, in addition to those specifically listed in the present specification as tetrazolylpenam nitrogen protecting groups, are

  
 <EMI ID = 74.1>

  
substituted.

  
The products of formula I are recovered according to standard methods.

  
 <EMI ID = 75.1>

  
hydrogens, the 6-amino-2,2-dimethyl-3- (5-tetrazolyl) penam is recovered by adjusting the pH of the reaction mixture to approximately 4.2,

  
the isoelectric point, to precipitate the product. When R is the p-methoxybenzyl group, the product is recovered by adding n-hexane to the reaction mixture containing the imino ether to remove the product from solution.

  
The crude product is separated, washed with hexane and then dissolved in a suitable solvent, such as, for example, methylene chloride. The solution is washed with brine, dried and evaporated under reduced pressure to obtain the product.

  
Preparation of starting materials

  
The starting materials (formula II) for this process are prepared by acylating a 6-amino-2,2-dimethyl-3- (5-tetrazolyl) pename.
(Formula I) by the reaction sequence described below.

  
In the first step, the 6- (triphenyl-

  
 <EMI ID = 76.1>

  
5838, 1959) to an amide of the formula:

  

 <EMI ID = 77.1>
 

  
 <EMI ID = 78.1> defined previously and -CHW1W2, more particularly its preferred configurations defined above.

  
 <EMI ID = 79.1>

  
the mixed anhydride, followed by the reaction with an equimo-

  
 <EMI ID = 80.1>

  
Therefore, the formation of the mixed anhydride comprises reacting an appropriate carboxylic salt of 6-triphenylmethylaminopenicillanic acid in an organic solvent inert to the reaction, with approximately equimolar proportions of pivaloyl chloride or lower alkyl chloroformates. Suitable salts are, for example, alkali metal salts, such as sodium or potassium salts, and amine salts, such as triethylammonium, pyridinium, sodium salts.

  
 <EMI ID = 81.1>

  
suitable 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 about -50 [deg.] C to about + 30 [deg.] C, and preferably at about 0 [deg.] C, and is completed after about one hour. . The product is simply isolated by filtering off the insoluble products, followed by evaporation of the solvent in vacuo to give the crude anhydride. It is not necessary to isolate the mixed anhydride.

   It can be used in situ for the reaction with the amine simply by contacting the reactants in an inert solvent, for about 0.5 to about 2.0 hours, at a temperature in the range of about -30 [deg.] C and about + 30 [deg.] C and preferably at about 0 [deg.] C. The same solvents as identified above can be used for the present reaction for the formation of the mixed anhydride.

  
When this reaction is carried out in a water-immiscible solvent, the product is usually isolated by washing the

  
 <EMI ID = 82.1>

  
organic by vacuum dryness to give the crude product. This last product can be used immediately for step 2, or <EMI ID = 83.1>

  
reaction with water, and then use the thus prepared solution of the amide directly in step 2.

  
 <EMI ID = 84.1>

  
of formula V by reacting 6- (triphenylmethylamino) penicillanic acid with the appropriate isocyanate of formula

  
 <EMI ID = 85.1>

  
reaction by contacting substantially equimolar amounts of the reactants, in an organic solvent inert to the reaction, at a temperature in the range of about 0 [deg.] C to about 30 [deg.] C , for a time of about an hour to about 20 hours. The product can simply be isolated by removing the solvent in vacuo or the solution of the amide can be used in situ for step 2. The isocyanates of formula are prepared.

  
 <EMI ID = 86.1>

  
In step 2, the product of step 1, or its simple transformation product in which all the phenolic hydroxyl groups are protected by transformation into formyloxy, alkanoyloxy or alkoxymethyl groups, is converted into an imidoyl chloride by reaction of said amide in an organic solvent inert to reaction with phosgene or a tertiary mine. Usually about one molar equivalent of phosgene is used, but sometimes up to about 2 or 3 molar equivalents is used. 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 of from about -20 [deg.] C to about + 30 [deg.] C, and preferably at about 25 [deg.] C. It usually takes a few hours to complete.

   A wide variety of amines can be used in this process.

  
 <EMI ID = 87.1>

  
Typical solvents which can be used are chlorinated hydrocarbons, such as chloroform, methylene chloride and 1,2-dichloroethane, and ethers such as tetrahydrofuran and 1,2-dimethoxyethane. If desired, the chloru-

  
 <EMI ID = 88.1>

  
but in many cases it is convenient to use the iminochloride in situ.

  
 <EMI ID = 89.1>

  
re can be used in the reaction for the formation of imidoyl chloride. In addition, if desired, the corresponding imidoyl bromide can be used.

  
In step 3 of the process, the above imidoyl chloride is converted into a tetrazolylpenam compound of formula VI:

  

 <EMI ID = 90.1>


  
formula in which G has been defined previously. This transformation comprises treating said imidoyl chloride in a reaction inert solvent with about one molar equivalent, or sometimes a small excess, of an azide ion. We let

  
 <EMI ID = 91.1>

  
or in the vicinity for a few hours, eg overnight, until conversion to tetrazole is substantially complete. A wide variety of sources of azide ions such as trimethylsilyl azide, triethylsilyl azide, azo-

  
 <EMI ID = 92.1>

  
inium and pyridinium azide; tetramethylguanidium azide can be used in this process. Suitable solvents in the event that the source of the azide ion is trialkylsilyl azide or substituted ammonium azide are chloroform, methylene chloride, 1,2-dichloroethane, and dipolar aprotic solvents such as N-. methylpyrrolidone. In reactions where

  
 <EMI ID = 93.1>

  
azide, dipolar aprotic solvents are becoming the type of solvent of choice. Isolation of the product is accomplished using normal procedures. When the solvent is a low-boiling chlorinated hydrocarbon, the reaction mixture is washed with dilute alkali and then the organic solvent is removed by evaporation. When the solvent is a dipolar aprotic solvent, dilute

  
the reaction mixture with a large excess of dilute alkali, then after adjusting the pH appropriately, isolate <EMI ID = 94.1>

  
into compounds of formula I by treatment with an acid such as methanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, hydrochloric acid, hydrobromic acid,

  
 <EMI ID = 95.1>

  
The reaction is normally carried out by dissolving the starting material in a suitable solvent and adding about 2 molar equivalents of the acidic reagent at or near room temperature. The reaction is complete after about 1 hour, and

  
the product is present in the reaction medium in the form of the acid addition salt corresponding to the acid reagent used. Suitable solvents are diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, chloroform, methylene chloride, 1,2-dichloroethane, acetone, methyl ethyl ketone, acetate d. 'ethyl, butyl acetate, hexane, cyclohexane,

  
 <EMI ID = 96.1>

  
Preferred includes the use of p-toluenesulfonic acid in acetone since the p-toluenesulfonate from the product often precipitates.

  
The compounds of formula I are then converted into acylated derivatives of formula II by acylation with an activated derivative of a carboxylic acid, such as an acid chloride, a mixed anhydride, an activated ester or the reactive intermediate formed by the. acid and dicyclohexylcarbodiimide or other peptide bond forming reagent. A typical acylation process comprises reacting a compound of formula I in a reaction inert solvent, such as, for example, methylene chloride, chloroform,

  
 <EMI ID = 97.1>

  
acetone, methyl ethyl ketone, or N, N-dimethylformamide, with an equimolar amount of a suitable acid chloride, preferably phenacetyl chloride or phenoxyacetyl chloride, at a temperature between about -40 [deg.] C and around
30 [deg.] C and preferably from about -10 [deg.] C to about 10 [deg.] C. The product is isolated by normal methods such as evaporating the reaction mixture to dryness and treating the residue with a water immiscible solvent and with water. It is removed by filtration

  
 <EMI ID = 98.1>

  
aqueous phase to an appropriate value and the phase containing the product is separated and then evaporated.

  
 <EMI ID = 99.1>

  
I in a mixture of water and a water-miscible solvent at a

  
 <EMI ID = 100.1>

  
maintains the pH from about 6 to about 8 by adding sodium or potassium hydroxide. The product is isolated by known methods.

  
In the mixed anhydride acylation process, the anhydride of a suitable carboxylic acid and a

  
 <EMI ID = 101.1>

  
ethyl formate, with the appropriate compound of formula I in a 1: 1 molar ratio in a reaction inert solvent such as those listed above at a temperature of about
-10 [deg.] C to 30 [deg.] C, preferably between -10 [deg.] C and 0 [deg.] C. The products are isolated as described above and by other methods <EMI ID = 102.1>

  
Normally the reaction is carried out in the presence of an equimolar amount of a tertiary amine, such as triethylamine.

  
Another variant of acylation involves converting the appropriate carboxylic acid into an active ester such as p-nitrophenyl, 2,4,6-trichlorophenyl, thiophenyl esters,

  
 <EMI ID = 103.1>

  
followed by treatment with a compound of formula I or a salt thereof. The acylation is carried out by dissolving the active ester and the compound of formula I, or a salt thereof, in a dipolar aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone. The solution is allowed to stand at around room temperature for a few hours, eg, overnight, and then the product is isolated by normal methods.

  
Another method of acylation comprises contacting a suitable compound of formula I with a carboxylic acid in the presence of certain agents known in the art to form peptide bonds. Such agents include carbodiimides, for example, dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, methoxyacetylene and N-ethoxy-

  
 <EMI ID = 104.1>

  
in a solvent such as acetonitrile, N, N-dimethylformamide or N-methylpyrrolidone.

  
It should be implicitly observed that in the processes described <EMI ID = 105.1>

  
 <EMI ID = 106.1>

  
6-amino group with tri (lower alkyl) silyl substituents. Said tri (lower alkyl) silyl substituents are then removed and replaced by hydrogen at the end of the acylation by rapid exposure of the product to a proton solvent system, such as water or a lower alkanol, for example. , methanol or ethanol. Due to its commercial availability, the trimethylsilyl group is preferred. It can be introduced into the compound

  
starting from formula I by methods well known in the art, such as, for example, using trimethylchlorosilane or

  
N-trimethylsilylacetamide, as discussed by Birkofer and Ritter in Angewandte Chemie (International Edition in English), 4, 417-418 and 426 (1965).

  
 <EMI ID = 107.1>

  
5-tetrazolyl are hydrogen, alkanoyloxymethyl, 1-alkanoyloxyethyl or phthalidyl are used as anti-

  
 <EMI ID = 108.1>

  
the triphenylmethyl group and those in which R, is a

  
 <EMI ID = 109.1>

  
nitrogen protector of tetrazolylpenam by known methods provides the corresponding compounds in which R. and R2 are &#65533; hydrogen. Acylation of the 6-amino group of the resulting compounds and, if desired, alkylation of the tetrazolyl moieties

  
 <EMI ID = 110.1>

  
They are anti-bacterial agents valid in vitro and in vivo

  
 <EMI ID = 111.1>

  
negative. Their useful activity can easily be demonstrated by in vitro assays against different organisms in a heart and brain infusion medium using the two-fold serial dilution technique. their in vitro activity <EMI ID = 112.1>

  
sterilization applications, such as, for example, for surgical instruments. They are also effective anti-bacterial agents in vivo for animals, including humans, not only by parenteral administration but also by oral administration. Dosage levels for oral and parenteral administration for the compounds described in the present invention are, in general, on the order of an amount of up to 200 mg / kg and 100 mg / kg of body weight per day, respectively.

  
For such uses, the pure products or their mixtures with other antibiotic products can be used. They can be administered alone or in combination with a pharmaceutical carrier based on the chosen administration and normal pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch, lactose, certain types of clay, etc ... or in the form of capsules, alone or in admixture with the same excipients or equivalent excipients. They can also be administered orally in the form of elixirs or oral suspensions which may contain flavoring agents and

  
coloring agents, or they can be injected parenterally, ie, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile solution which may be a solution.

  
aqueous solution such as water, isotonic saline, isotonic dextrose, Ringer's solution, or a non-aqueous solution such as oils of animal origin (cottonseed oil, peanut oil, corn oil , sesame oil) and other non-aqueous vehicles which do not interfere with the therapeutic efficacy of the preparation and which are not toxic by the volume or proportion used

  
(glycerol, propylene glycol, sorbitol). In addition, suitable compositions for extemporaneous preparation of solutions prior to administration can be advantageously made. Such compositions can contain liquid diluents, for example, propylene glycol, diethyl carbonate, glycerol,

  
 <EMI ID = 113.1>

  
local anesthetics and mineral salts to provide ....

  
 <EMI ID = 114.1>

  
present invention and representative preparations for preparing the necessary starting materials.

  
EXAMPLE 1

  
 <EMI ID = 115.1>

  
To a flame-dried flask fitted with a magnetic stirrer, a thermometer and a drying tube are added 10 ml of methylene chloride, 0.716 g of 6- (2-phenylacetamido) -2,2-dimethyl -3- (5-tetrazolyl) penam and 0.630 g of N, N-dimethylaniline at room temperature. Then 0.382 ml of chlorotrimethylsilane is added and the reaction mixture is cooled in an acetone-carbon dioxide snow bath at -50 [deg.] C. 0.456 g of phosphorus pentachloride was added to the clear off-white solution all at once and the reaction mixture was stirred at -35 to -45 [deg.] C for two hours. It is then cooled to -60 [deg.] C and stirring is continued while adding 3.5 g of n-butyl alcohol using a syringe through a serum stopper.

   The temperature is allowed to rise to
-40 [deg.] C, temperature which rose to -50 [deg.] C during addition of alcohol and stirring continued for two more hours.

  
The reaction mixture is then transferred to a vessel, 3 ml of water are added and the pH is adjusted to 4.5 with sodium bicarbonate and then to 4.2 with 5% hydrochloric acid. The mixture is cooled and the yellow-brown precipitate is removed by filtration,

  
it is washed with ether and dried under vacuum to obtain 0.235 g
(yield 48.9%) of product. PF 186 [deg.] C. (decomposition).

  
By repeating this process but replacing the phosphorus pentachloride with an equivalent amount of phosphorus pentabromide, phosphorus oxychloride, phosgene or phosphorus tribromide, the same product is obtained.

  
When replacing chlorotrimethylsilane with dichlorodimethylsilane in the above process, the same product is obtained.

EXAMPLE II

  
 <EMI ID = 116.1>

  
tetrazol-5-yl) Pename

  
A flame-dried flask is charged with 5.0 ml of chloride.

  
 <EMI ID = 117.1>

  
freshly distilled. The resulting solution is stirred and made <EMI ID = 118.1>

  
phosphorus chloride and the mixture is then stirred between -25 and
-20 [deg.] C for 4 hours. The mixture is then cooled to -30 [deg.] C, 600 mg of n-propanol are quickly added dropwise and the reaction mixture is stirred for one hour at -25 to -20 [deg.] C. It is then treated with 4 ml of brine and stirred rapidly while allowing it to warm to room temperature. 60 ml of hexane are slowly added dropwise to the reaction mixture during the heating phase. The orange oil which separates out is recovered by decantation from the organic solution and washed twice with hexane. It was then dissolved in methylene chloride, the resulting solution washed once with brine and evaporated under reduced pressure to obtain 360 mg (94% yield) of the product as a foam.

  
whitish.

  
By repeating the above process, but replacing the phosphorus pentachloride with an equivalent amount of phosphorus oxychloride, phosphorus pentabromide, or p-toluenesulfonyl chloride, the same product is obtained.

EXAMPLE III

  
 <EMI ID = 119.1>

  
pename

  
To a stirred solution of 0.932 g (7.21 mole) of quinoline in 8.0 ml of chloroform is added 0.840 g (4.05 mole) of phosphorus pentachloride. The suspension is cooled to -15 [deg.] C, then 1.81 g (3.84 m mol) of 6- (2-phenylacetamido) - are added.

  
 <EMI ID = 120.1>

  
Stirring is continued for a further 30 minutes, at about -5 [deg.] C, then 2.15 g (35.7 mole) of n-propanol are added. Stirring is continued for another 30 minutes, again in the vicinity of
-5 [deg.] C, then 25 ml of an isopropyl ether-acetone mixture are added
90:10, then immediately a solution of 1.25 g of sodium chloride in 6.02 ml of water. The temperature is rising

  
at 15 [deg.] then drop again to -15 [deg.] C. The precipitate which has formed is filtered off and dried to give 1.33 g.

  
 <EMI ID = 121.1>

  
(KBr pellet) shows absorptions at 1785 cm (0-lactam)

  
 <EMI ID = 122.1> <EMI ID = 123.1>

  
1H, C-3 hydrogen), 5.70 ppm (doublet, 1H, C-6 hydrogen). 1.75 ppm
(singlet, 3H, methyl C-2 hydrogens), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1.10 ppm (singlet, 3H, methyl C-2 hydrogens).

EXAMPLE IV

  
 <EMI ID = 124.1>

  
pename

  
The compound represented in the previous title is prepared in the form of its hydrochloride in a yield of 90%, from

  
 <EMI ID = 125.1>

  
tetrazol-5-yl) penania, using the method of Example III. The infra-red spectrum (KBr pellet) shows absorptions

  
 <EMI ID = 126.1>

  
(DMSO-d6) shows absorptions at 6.71 ppm (singlet, 2H, pivaloxy methylene hydrogens), 5.88 ppm (singlet, 1H, C-3 hydrogen), 5.83 ppm (doublet, 1H, C- hydrogen) 5), 5.20 ppm (doublet, 1H, C-6 hydrogen), 1.80 ppm (singlet, 3H, methyl C-2 hydrogens), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1 , 16 ppm (singlet,

  
 <EMI ID = 127.1>

EXAMPLE V

  
 <EMI ID = 128.1>

  
The procedure of Example I was repeated but using 6- (2-phenoxyacetamido) -2,2-dimethyl-3- (5-tetrazolyl) penam as a reagent in place of the 6-phenylacetamido analog compound to obtain the compound represented in the previous title.

EXAMPLE VI

  
 <EMI ID = 129.1>

  
tetrazol-5-yl) peach

  
By following the procedure of Example II but using

  
 <EMI ID = 130.1>

  
corresponding reagent, the product represented in the previous title is obtained.

  
In the same way the 6- (2-arylacetamido) -2,2-dimethyl-3-

  
 <EMI ID = 131.1>

  
corresponding penames.

  
 <EMI ID = 132.1>

  
oxymethyl of Preparation X to produce, in each example, the corresponding 6-amino-2,2-dimethyl-3- (substituted tetrazcl-5-yl) penams in which the substituent is an alkanoyloxyalkyl or phthalidyl group.

EXAMPLE VIII

  
The procedure of Example I is repeated using

  
 <EMI ID = 133.1>

  
n-butyl in Example I for the formation of the imino ether by the following alcohols:

  

 <EMI ID = 134.1>

PREPARATION A

  
 <EMI ID = 135.1>

  
 <EMI ID = 136.1>

  
To a stirred suspension of 86.4 g (0.8 mol) of 6-aminopenicillanic acid in 600 ml of anhydrous chloroform is added 11.2 ml.
(0.04 mol) of triethylamine, and the mixture is stirred at room temperature until a clear solution is obtained (about 15 min). Then added to this solution, discontinuously for about
25 minutes, 134.9 g (0.44 mol) of triphenylmethyl chloride, 90% purity, at room temperature. Stirring is continued for an additional 64 hours, then 5.6 ml of triethylamine is added. The solution is cooled to between 0 and 5 [deg.] C, then an ice-cooled solution is added dropwise over 30 minutes while maintaining the reaction temperature between 4 and 9 [deg.] C.
38 ml (0.4 mol) of ethyl chloroformate in 80 ml of chloro- <EMI ID = 137.1>

  
amine, below the surface of the solvent, between 4 and 9 [deg.] C, for a period of 30 minutes. Stirring is continued for

  
30 minutes more between 3 and 6 [deg.] C, then for 20 minutes while

  
 <EMI ID = 138.1>

  
reaction mixture with water, followed by washing with brine. Finally, it is dried over magnesium sulfate to obtain a chloroform solution of 6- (triphenylmethylamino) -2,2-dimethyl-3-

  
 <EMI ID = 139.1>

  
tetrazol-5-yl) pename

  
To a chloroform solution containing 69.4 g (0.120 mol) of 6- (triphenylmethylamino) -2,2-dimethyl-3- (N-4-methoxybenzyl carbamoyl) penam, and having a volume of 133.3 ml, prepared by the process described in (A) above, one adds 132.7 ml of additional chloroform, then 29.1 ml (0.360 mol) of

  
 <EMI ID = 140.1>

  
15 minutes with stirring 26.22 g (0.126 mol) of phosphorus pentachloride. Stirring is continued at a temperature close to
10 [deg.] C for 10 minutes, then at room temperature for an additional 1.5 hours to give an imino chloride solution. To 1 / 6th of this imino chloride solution is added 4.85 ml (0.060 mol) of pyridine, then

  
 <EMI ID = 141.1>

  
After 15 minutes of additional stirring, 2.03 g are added.
(0.038 mol) of ammonium chloride, then 2.59 g

  
(0.039 mole) of 95% pure sodium azide. The reaction mixture is then stirred at room temperature for an additional 4 hours. At this time, 400 ml of water and 200 ml of chloroform are added, then the two layers are separated. The organic layer is washed with water, dried using magnesium sulfate, and then concentrated to low volume in vacuo. This final chloroform solution is added dropwise with stirring in a large volume of diisopropyl ether, and after 30 minutes, the precipitate which has formed is removed by filtration. This provides 6.1 g of

  
 <EMI ID = 142.1>

  
zol-5-yl) pename. The infra-red spectrum of the product (tablet of

  
 <EMI ID = 143.1>

  
NMR spectrum (in CDC13) shows absorptions at 7.25 ppm <EMI ID = 144.1>

  
1.50 ppm (singlet, C-2 hydrogens methyl) and 0.75 ppm (singlet, C-2 hydrogens methyl).

PREPARATION B

  
 <EMI ID = 145.1>

  
 <EMI ID = 146.1>

  
triphenylmethylamino-penicillanic acid (Sheehan and Henery-Logan,

  
 <EMI ID = 147.1>

  
140 ml of acetone at 0-5 [deg.] C, 6.08 ml of triethylamine are added

  
then 5.78 ml of isobutyl chloroformate.

  
After an additional ten minutes, the mixture is filtered directly through a stirred solution of 9.28 g of 4-benzyloxybenzylamine in
1,000 ml of water and 300 ml of acetone at room temperature. The mixture thus obtained is stirred for 4 minutes, then an additional 500 ml of water is added. Stirring is continued for a further 7 minutes, then the reaction mixture is extracted with ether. The ether is dried using anhydrous magnesium sulfate, then evaporated to dryness in vacuo. The crude product thus obtained is redissolved in 200 ml of ether, and the solution is then added dropwise over 10 minutes in 2,500 ml of hexane. The solid which precipitates is filtered off, this

  
 <EMI ID = 148.1>

  
of the amide described above in 10 ml of dry chloroform, at 0-5 [deg.] C, 0.99 ml of pyridine is added, followed by the addition of

  
5.42 ml of a 2.26 M solution of phosgene in chloroform. The reaction mixture is then stirred at room temperature overnight. At this time, it is evaporated to dryness in vacuo, which gives a viscous gum, which is extracted with 100 ml of ether.

  
 <EMI ID = 149.1>

  
chloride in the form of a yellow foam.

  
 <EMI ID = 150.1> <EMI ID = 151.1> cloudy at room temperature, for 2.25 hours. The solvent is evaporated off at room temperature under high vacuum, which leaves a brown gum. This residue is distributed between 60 ml of water and 150 ml of ether. The ethereal phase is separated, washed with saturated brine, dried using anhydrous sodium sulfate, and finally evaporated to dryness in vacuo. The residue is

  
 <EMI ID = 152.1>

  
CDC13) shows absorption bands at 7.30 ppm (multiplet, aromatic hydrogens), 5.45 ppm (quartet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 5.00 ppm (singlet , benzyl hydrogens), 4.40 ppm (multiplet, C-5 and C-6 hydrogens), 1.40 ppm
(singlet, hydrogen C-2) and 0.70 ppm (singlet, hydrogen C-2).

PREPARATION C

  
 <EMI ID = 153.1>

  
amoyl) pename

  
To a stirred suspension of 2.16 g (1 mole) of 6-aminopenicillanic acid in 1500 ml of chloroform is added 278 ml (2%) of triethylamine at 25-30 [deg.] C. 306 g (1.1 mol) of chloride are added to the solution thus obtained batchwise over 25 minutes.

  
of triphenylmethyl at 25-30 [deg.] C. Stirring is continued for

  
44 hours at room temperature.

  
A 522 ml (0.25 mole) fraction of the mixture is cooled to 4 [deg.] C.

  
 <EMI ID = 154.1>

  
dente, then 3.5 ml of triethylamine are added. 23.75 ml of ethyl chloroformate at 5-10 [deg.] C. are then added with vigorous stirring. Stirring is continued for another 30 minutes at approximately 6 [deg.] C after the end of the addition, then 8.43 ml is injected into the reaction medium below the surface of the solvent.

  
furfurylamine. Then injected into the reaction medium in the same manner at intervals of 10 minutes, 3 additional portions of furfurylamine (5.90 ml, 4.22 ml and 3.54 ml). The

  
 <EMI ID = 155.1>

  
and the temperature is maintained at around 6 [deg.] C throughout the addition of the amine. When the addition of the amine is complete, the cooling bath is removed and the <EMI ID = 156.1> stirred.

  
then wash successively with 3 parts of water and one part of salt water. Finally, it is dried using anhydrous magnesium sulfate. This provides 610 ml of a chloroform solution.

  
 <EMI ID = 157.1>

  
pename. The NMR spectrum of this solution shows absorptions at 7.3 ppm (17H, m), 6.2 ppm (1H, m), 4.35 ppm (3H, m), 4.05 ppm
(2H, s), 1.6 ppm (3H, s) and 1.35 (3H, s).

  
 <EMI ID = 158.1>

  
azol-5-yl) pename

  
To a stirred solution of 3.05 g (5.7 nmol) of 6- (triphenyl-

  
 <EMI ID = 159.1>

  
8 ml of chloroform at 0 ° C., 1.35 ml (17 mmol) of pyridine are added, then 2.64 ml of a 4.33 M solution of phosgene in chloroform. Stirring is continued for 1 hour at 25 [deg.] C. The chloroform and excess phosgene and pyridine are then removed by evaporation in vacuo, and the residue is redissolved in 5 ml of chloroform. The solution is cooled to 0 ° C., then 2.25 g (14.4 mmol) of tetramethylguanidium azide are added in small parts. Stirring is continued for 15 minutes at room temperature then 20 ml of chloroform are added, then 30 ml of water and the pH is adjusted to 10.5. We

  
separates the chloroform layer, it is washed with water,

  
 <EMI ID = 160.1>

  
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 on a column of silica gel for chromatography. Elution of the column with chloroform followed by evaporation in vacuo of the appropriate fractions provides the

  
 <EMI ID = 161.1>

  
 <EMI ID = 162.1>

  
at 7.40 ppm (m, 16H), 6.40 ppm (m, 2H), 5.50 ppm (s, 2H), 5.20 ppm
(s, 1H), 4.90 ppm (m, 2H), 1.60 ppm (s, 3H), and 0.80 ppm (s, 3H).

PREPARATION D

  
 <EMI ID = 163.1>

  
tetrazol-5-yl) pename

  
The compound represented in the previous title is prepared according to the procedure for Preparation C, but using 5-methylfurfurylamine instead of furfurylamine. Spectrum

  
 <EMI ID = 164.1> <EMI ID = 165.1>

  
1.63 ppm (s, 3H) and 0.90 ppm (m, 3H).

PREPARATION E

  
 <EMI ID = 166.1>

  
benzyl tetrazol-5-yl) pename

  
The compound represented by the previous title is prepared in a total yield of 46% from 6- (triphenylmethylamino) penicillanic acid, replacing the furfurylamine of Preparation C with 2,4-dimethoxybenzylamine. The crude product is purified by recrystallization from a mixture of methylene chloride and methanol. The NMR spectrum of the product (CDCl3) 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 give the following related products:

  

 <EMI ID = 167.1>
 

  

 <EMI ID = 168.1>

PREPARATION G

  
 <EMI ID = 169.1>

  
 <EMI ID = 170.1>

  
To a stirred suspension of 43.2 g (0.20 mol) of acid

  
 <EMI ID = 171.1>

  
(0.40 mol) of triethylamine, then 61.2 g (0.22

  
 <EMI ID = 172.1>

  
continue stirring for another 48 hours at room temperature.

  
A portion of 120 ml (containing 0.060 mol of

  
 <EMI ID = 173.1>

  
previous chloroform solution. We dilute it with 40 mi of

  
 <EMI ID = 174.1>

  
 <EMI ID = 175.1>

  
 <EMI ID = 176.1>

  
of ethyl chloroformate, with stirring. Stirring is continued for 30 minutes while cooling in an ice bath, then 7.5 g (0.060 mol) of 4-hydroxybenzylamine are added. Stirring is continued for 10 minutes under cooling in an ice bath, then for an additional hour without cooling. At this time, the chloroform solution is washed with water, followed by washing with brine, then dried using sulfate of <EMI ID = 177.1>

  
chloroform and absorbed in a column containing chromatographic grade silica gel. The column was eluted with chloroform, withdrawing 400 ml fractions. Fractions 9 to 15 are combined and concentrated as an oil, which solidifies when triturated with methylene chloride. After further trituration with ether, 12.63 g are obtained.

  
 <EMI ID = 178.1>

  
carbamoyl) penam, mp 166-168 [deg.] C (decomposition). The infra-

  
 <EMI ID = 179.1>

  
 <EMI ID = 180.1>

  
 <EMI ID = 181.1>

  
plet, 20H, aromatic hydrogens and amide hydrogen), 4.70-4.10 ppm (multiplet, 5H, C-5 and C-6 hydrogens, methylene hydrogens

  
of benzyl and hydrogen C-3), 2.98 ppm (doublet, 1H, nitrogen amine), 1.64 ppm (singlet, 3H, C-2 hydrogens methyl) and 1.31 ppm (singlet, 3H, C- hydrogens) 2 methyl).

  
 <EMI ID = 182.1>

  
(prepared as described in A) in 9 ml of chloroform is added 1 ml (12 mmol) of pyridine. The solution is cooled to around 4 [deg.] C in an ice bath and 0.80 ml of chlorotrimethylsilane is added. The solution is stirred for 40 minutes

  
at room temperature, then cooled again to around 4 [deg.] C. Phosgene (1.5 ml in 4.3 M chloroform solution) (6.45 mmol) was added and the cooling bath removed. Stirring is continued for an additional 1.5 hours, then all volatile compounds are removed by evaporation in vacuo.

  
The oily residue is redissolved in 6 ml of chloroform and the solution is cooled to about 4 [deg.] C in an ice bath. 0.95 g (6 mmol) of azide are added to the stirred solution.

  
 <EMI ID = 183.1>

  
one more hour at room temperature. At this time, we add
25 ml of water, then enough sodium hydroxide

  
sodium 1 N to bring the pH of the aqueous phase to 10. The chloroform layer is separated, washed with water, dried in <EMI ID = 184.1>

  
chloroform and absorbed in a column containing 30 g of chromatographic grade silica gel. The column is eluted with chloroform, taking 50 ml fractions. Fractions 13 to 19 are combined and concentrated in vacuo to obtain 0.71 g of

  
 <EMI ID = 185.1>

  
 <EMI ID = 186.1>

  
 <EMI ID = 187.1>

  
(CDC1,) shows absorptions at 7.80-6.67 ppm (multiplet, 20H, aromatic hydrogens and phenolic hydrogens), 5.66-5.10 ppm
(quartet, 2H, methylene hydrogen of benzyl), 5.02 ppm (singlet, 1H, hydrogen C-3), 4.60-4.20 ppm (multiplet, 2H, hydrogen C-5 and C-6, 3, 10 ppm (doublet, 1H, hydrogen amine), 1.94 ppm (singlet,

  
 <EMI ID = 188.1>

  
C-2 methyl).

PREPARATION H

  
 <EMI ID = 189.1>

  
tetrazol-5-yl) pename

  
To a stirred solution of 1 69 g (3 mmol) of 6- (triphenyl-

  
 <EMI ID = 190.1>

  
1 ml (12 mmol) of pyridine is added to 9 ml of chloroform.

  
The solution is cooled to about 4 [deg.] C in an ice bath and 235 mg of acetyl chloride are slowly added. The solution is stirred for 2 hours at room temperature, then cooled.

  
 <EMI ID = 191.1>

  
 <EMI ID = 192.1>

  
remove the cooling bath. Stirring is continued for an additional 1.5 hours, then all volatile compounds are removed by evaporation in vacuo. The residue is redissolved in

  
6 ml of chloroform and the solution is cooled to about 4 [deg.] C in an ice bath. 0.95 g is added to the stirred solution.

  
 <EMI ID = 193.1>

  
stirring for an additional hour at room temperature. At this time, 25 ml of water are added, then enough

  
 <EMI ID = 194.1>

  
10 to 10 aqueous solution. The chloroform layer is separated, washed with water, dried using sodium sulfate, and evaporated to dryness in vacuo. This provides the 6- (triphenylmethyl-

  
 <EMI ID = 195.1> <EMI ID = 196.1>

  
the acetyl chloride is replaced respectively by an equimolar amount of formic-acetic anhydride and of chloromethyl methyl ether, the product obtained is respectively 6- (triphenyl-

  
 <EMI ID = 197.1>

PREPARATION I

  
6-Amino-2,2-dimethyl-3- (1- 4-methoxybenzyl tetrazol-5-yl) -pename p-toluene sulfonate

  
To a stirred suspension of 143 g of 6- (triphenylmethylamino) -

  
 <EMI ID = 198.1>
1000 ml of dry acetone are added 45.0 g of p-toluenesulfonic acid monohydrate at room temperature. The solids dissolve slowly, giving a clear solution. After 15 minutes, the product begins to precipitate. Stirring is continued for an additional 45 minutes after product begins to appear, then a first crop of product is filtered off and washed with chloroform. The acetone is evaporated to dryness, and the solid residue is suspended for 45 minutes in 300 ml of chlorrorm. This provides a second crop of product. The two crops were mixed, suspended for 1 hour in 1,000 ml of chloroform, collected by filtration, and dried in vacuo to give 123 g of <EMI ID = 199.1>

  
absorption at 7.20 ppm (multiplet, aromatic hydrogens), 5.80 ppm (multiplet, benzyl hydrogens, C-5 hydrogen and C-3 hydrogens), 5.20 ppm (doublet, C-6 hydrogen), 3 , 75 ppm (singlet, methoxy hydrogens), 2.35 ppm (singlet, methyl sulfonate hydrogens), 1.70 ppm (singlet, C-2 hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens).

PREPARATION J

  
 <EMI ID = 200.1>

  
Preparation I, provides the following compounds in the form of their <EMI ID = 201.1>

  

 <EMI ID = 202.1>


  
To a stirred solution of 304 mg of p-toluenesulfonate

  
 <EMI ID = 203.1>

  
in 10 ml of methylene chloride is added 69.7 &#65533; 1 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 over anhydrous magnesium sulfate, and evaporated in vacuo to dryness. The residue consists of

  
 <EMI ID = 204.1>

  
 <EMI ID = 205.1>

  
Likewise, the products of preparations F-H and S-U are detritylated into the corresponding 6-amino derivatives.

PREPARATION K

  
 <EMI ID = 206.1>

  
only at 40 + 1 [deg.] C for 35 minutes. The trifluoroacetic acid is then rapidly removed by vacuum distillation. A 120 ml portion of ether is then added to the residue, which produces a white flocculant suspension. The solvent is cooled and

  
the suspension &#65533; approximately 0 [deg.] C, and then added to it, batchwise, 80 ml of 2N sodium hydroxide, which gives two clear phases. The pH of the aqueous phase at this time is approximately

  
2.7. We separate the layers, and we discard the ethereal phase. The pH of the aqueous phase is brought to 4.1 with sodium hydroxide

  
 <EMI ID = 207.1>

  
filtered. It is combined with the corresponding aqueous phases from four other identical operations, and the solution

  
 <EMI ID = 208.1> <EMI ID = 209.1>

  
addition of sodium hydroxide solution. The clear solution is extracted with ether and the extracts discarded. The pH of the aqueous phase is adjusted to 4.1 using dilute hydrochloric acid, and the product which precipitates is removed by filtration. The infra-red spectrum of the product shows absorption at

  
 <EMI ID = 210.1>

  
at 5.65 ppm (C-5 hydrogen doublet), 5.20 ppm (singlet, C-3 hydrogen), 4.70 ppm (doublet, C-6 hydrogen), 1.65 ppm (singlet, C-2 hydrogen methyl) and 1.10 ppm (singlet, C-2 hydrogens methyl).

  
When treating each of the 6-amino-p-toluene sulfonates

  
 <EMI ID = 211.1>

  
J with a trifluoroacetic acid / anisole mixture, according to the preceding procedure, in each case the product is 6-amino2,2-dimethyl-3- (5-tetrazolyl) penam.

PREPARATION L

  
 <EMI ID = 212.1>

  
 <EMI ID = 213.1>

  
 <EMI ID = 214.1>

  
 <EMI ID = 215.1>

  
chlorotrimethylsilane. The solution is stirred for 40 minutes at room temperature, then cooled again to about

  
 <EMI ID = 216.1>

  
 <EMI ID = 217.1>

  
Stirring is continued for a further 1.5 hours, then all volatile compounds are removed by evaporation under vacuum. The oily residue is redissolved in 6 ml of chloroform and the solution is cooled to about 4 [deg.] C in an ice bath. 0.95 g (6 mmol) of tetra- azide is added to the stirred solution.

  
 <EMI ID = 218.1>

  
more at room temperature. At this point, 25 ml of water is added, followed by the addition of a sufficient amount of sodium hydroxide.

  
 <EMI ID = 219.1>

  
 <EMI ID = 220.1> <EMI ID = 221.1>

  
To a stirred solution of 200 mg of the purified trimethylsilyloxybenzyl derivative in 4 ml of tetrahydrofuran, 0.3 ml of 1, ON sodium hydroxide is added. The solution was stirred at room temperature for 50 minutes, then the pH was adjusted to 5.7 using hydrochloric acid. The solvent is removed by evaporation in vacuo to obtain 6- (triphenylmethylamino) -

  
 <EMI ID = 222.1>

  
tetrazol-5-yl) pename

  
A. 6- (Triphenylmethylamino) -2,2-dimethyl-3- (N-ethoxycarbonylcarbamoyl) pename

  
To a stirred solution of 4.58 g (10 mmol) of 6- (triphenylmethylamino) penicillanic acid and 1.45 ml (10 mmol) of triethyl-

  
 <EMI ID = 223.1>

  
of ethoxycarbonyl isocyanate dissolved in 5 ml of acetonitrile.

  
 <EMI ID = 224.1>

  
hours, then the solvent is removed by evaporation in vacuo. The residue is dissolved in chloroform, and the chloroform solution is washed successively with water, a bicarbo- solution.

  
 <EMI ID = 225.1>

  
then the chloroform solution using anhydrous magnesium sulfate and evaporated in vacuo. The residue is again dissolved in chloroform, and the chloroform solution is washed with dilute hydrochloric acid, dried using magnesium sulfate and evaporated again in vacuo. This provides the crude product, which is purified by chromatography using silica gel as an absorbent and deluting the column with chloroform containing 4% by volume ethanol. The

  
 <EMI ID = 226.1>

  
tetrazol-5-yl) pename

  
To a stirred solution of 529 mg (1 mmol) of 6- (triphenyl-

  
 <EMI ID = 227.1>

  
and 240 mg (3 mmol) of pyridine, in 25 ml of methylene chloride, 208 mg (1 mmol) of phosphorus pentachloride at 0 [deg.] C are added. The reaction mixture is stirred at 0 [deg.] C for 0.5 hour <EMI ID = 228.1>

  
 <EMI ID = 229.1>

  
redissolve the residue in 15 ml of chloroform. This last chloroform solution is cooled to 0 [deg.] C, and 0.47 g is added.
(3 mmol) of tetramethylguanidinium azide in several small parts with stirring. Stirring is continued for

  
2 hours at room temperature, and 15 ml of additional chloroform are added to the reaction mixture, then

  
30 ml of water. The pH is adjusted to 6.5, and the chloroform layer is removed. The chloroform solution is washed with water,

  
then with brine, then dried using anhydrous sodium sulfate. Vacuum evaporative removal of the solvent affords 6- (triphenylmethylamino) -2,2-dimethyl-3-

  
 <EMI ID = 230.1>

  
crude product by chromatography using

  
silica gel.

PREPARATION N

  
Starting with 6- (triphenylmethylamino) penicillanic acid and the appropriate isocyanate, and following the procedure of Preparation M, the following compounds are prepared:

  

 <EMI ID = 231.1>


  
PREPARATION 0

  
 <EMI ID = 232.1> <EMI ID = 233.1>

  
mixture to 9.5, and stirring is continued at this pH for an additional 30 minutes at room temperature. Most of the tetrahydrofuran is removed by vacuum distillation, 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 was collected, washed with water, dried using anhydrous sodium sulfate, and evaporated in vacuo to obtain the crude compound shown in the previous title.

  
When each of the 6- (triphenyl-

  
 <EMI ID = 234.1>

  
preparation N using the previous procedure, we also obtain in each case 6- (triphenylmethylamino) -

  
 <EMI ID = 235.1>

  
 <EMI ID = 236.1>

  
mmol) of 6-triphenylmethylamino-2,2-dimethyl-3- (5-tetrazolyl)

  
 <EMI ID = 237.1>

  
p-toluenesulfonic acid monohydrate. The resulting solution was stirred for 10 minutes and then 30 ml of ether was added over a period of 5 minutes. The mixture is stirred for 10 minutes, after which time the solvent is decanted from the solid

  
that separates. The solid is dissolved in tetrahydrofuran
(30 ml) and the solution is placed in a column (300 x 6 mm) loaded with 10 g of Florisil (synthetic magnesium silicate). The column is washed with tetrahydrofuran until a total of 125 ml has been collected. The eluate is concentrated to dryness under reduced pressure at 40 [deg.] C to obtain 210 mg of solid. The solid was suspended in ether (30 ml), the solution filtered, washed with ether and air dried. Yield =

  
 <EMI ID = 238.1>

  
 <EMI ID = 239.1>

  
 <EMI ID = 240.1>

  
(d, 1H), 5.10 ppm (s, 1H), and 5.88 ppm (s, 3H).

  
 <EMI ID = 241.1> <EMI ID = 242.1>

  
stirring for a further 3 hours, then the acetone is removed by evaporation in vacuo. The residue is suspended in ether, filtered and dried to obtain the compound shown in the previous title as its p-toluenesulfonate.

  
The above p-toluenesulfonate 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 was dried using sodium sulfate, then evaporated in vacuo to obtain the compound shown in the previous title as the free base.

PREPARATION R

  
The reaction of the appropriate 6- (triphenylmethylamino) -2,2-dimethyl-3- (1tetrazol-5-yl) -substituted penam selected from those of

  
 <EMI ID = 243.1>

  
of Preparation Q, leads to the following compounds in the form of their p-tolu & nesulfonates.

  

 <EMI ID = 244.1>
 

  
 <EMI ID = 245.1>

  
penicillanic acid in 250 ml of dry chloroform, not containing ethanol, 11.7 ml of triethylamine at 0-3 [deg.] C are added. The solution thus obtained is then added dropwise with stirring.

  
 <EMI ID = 246.1>

  
Ethyl chloroformate in 150 ml of dry chloroform, not containing ethanol. Stirring is continued for an additional 10 minutes. This provides a chloroform solution of a mixed anhydride of 6- (triphenylmethylamino) penicillanic acid.

  
In a separate flask, a solution of the methyl ester of O-alanine is prepared by adding 11.7 ml of triethylamine to a suspension of 10.73 g of the hydrochloride of the ester.

  
 <EMI ID = 247.1>

  
in 115 ml of dry chloroform, not containing ethanol at about 10 [deg.] C. Stirring is continued for an additional 10 minutes.

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

  
At this time, the reaction solution is washed successively with three parts of water and one part of salt water. The solution was then dried using anhydrous sodium sulfate, and evaporated in vacuo to obtain 40.1 g of 6- (triphenylmethyl-

  
 <EMI ID = 248.1>

  
crude in the form of a glassy product, mp 60-70 [deg.] C. The crude product is purified by extracting it in ether under reflux, treating the filtered solution with activated charcoal, then

  
 <EMI ID = 249.1>

  
To a stirred solution of 2 g of the amide described under A below.

  
 <EMI ID = 250.1>

  
 <EMI ID = 251.1>

  
 <EMI ID = 252.1>

  
 <EMI ID = 253.1>

  
* * '** *

  
 <EMI ID = 254.1>

  
dry, not containing ethanol, and 580 mg of tetramethylguanidinium azide are added. The reaction mixture is stirred for

  
45 minutes, after which time 220 mg of additional tetramethylguanidinium azide are added. The reaction mixture is then stirred for 18 hours to allow the conversion to the tetrazole to be completed. A saturated solution of sodium bicarbonate in an amount sufficient so that the pH of the aqueous phase is 7.6 is then added to the reaction mixture. The chloroform layer was removed, washed with water at pH 5, washed with water at pH 7, dried using anhydrous sodium sulfate, and finally evaporated in vacuo. This provides 2.19 g of crude product, which is recrystallized from methanol to give 1.11 g (48% yield) of a product of mp 100-105 [deg.] C. The

  
 <EMI ID = 255.1>

  
5.15 ppm (s, 1H), 3.80 (m, 4H), 3.70 ppm (s, 3H), 3.10 ppm (t, 2H), 1.70 ppm (s, 3H) and 1 , 17 ppm (s, 3H) and it further shows that the product contains methanol as a solvated product.

PREPARATION T

  
The procedure of Preparation S is repeated except that the methyl ester of (3-alanine is replaced by the appropriate amine to give the following compounds:

  

 <EMI ID = 256.1>
 

  
PREPARATION U 'beautiful 0.0

  
 <EMI ID = 257.1>

  
in 0.5 ml of chloroform. Stirring is continued for three

  
 <EMI ID = 258.1>

  
additional. This last solution is washed quickly with

  
5 ml of 2N hydrochloric acid, then an additional 5 ml of 2N hydrochloric acid was added. The resulting mixture was cooled to about 0 [deg.] C, and the solid which precipitated was filtered off to give 323 mg (71% yield) of the compound represented in the previous title. The NMR spectrum (DMSO-d6) of the product shows absorptions at 7.40 ppm (m, 15H), 5.30 ppm (s, 1H), 4.60 ppm (m, 2H), 1.58 ppm (s , 3H) and 0.78 ppm (s, 3H).

  
 <EMI ID = 259.1>

  
2,2-dimethyl-3- (1-substituted tetrazol-5-yl) penam of the preparation

  
 <EMI ID = 260.1>

  
preceding operation, provides in each case 6- (triphenylmethylamino) -2,2-dimethyl-3- (tetrazol-5-yl) penam.

PREPARATION V

  
 <EMI ID = 261.1>

  
pename

  
To a stirred solution of 0.932 g (7.21 mmol) of quinoline in 8.0 ml of chloroform is added 0.840 g (4.05 mmol) of phosphorus pentachloride. The suspension is cooled to -15 [deg.] C and then 1.81 g (3.84 mmol) of 6- (2-phenylacetamido) -2.2- are added.

  
 <EMI ID = 262.1>

  
stirring for a further 30 minutes at about -5 [deg.] C, then 2.15 g (35.7 mmol) of n-propanol are added. Stirring is continued for a further 30 minutes, again at about -5 [deg.] C, then 25 ml of a 90:10 isopropyl ether-acetone mixture is added, and immediately afterwards a solution of 1.35 g. chloride

  
 <EMI ID = 263.1>

  
it drops again to -15 [deg.] C. The precipitate which forms is filtered off and dried to give 1.33 g.

  
 <EMI ID = 264.1> <EMI ID = 265.1>

  
 <EMI ID = 266.1>

  
hydrogen C-3), 5.70 ppm (doublet, 1H, hydrogen C-6), 1.75 ppm
(singlet, 3H hydrogens C-2 methyl), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1.10 ppm (singlet, 3H, C-2 hydrogens methyl).

PREPARATION W

  
 <EMI ID = 267.1>

  
penny

  
The compound represented in the previous title is prepared in the form of its hydrochloride in a yield of 90%, from

  
 <EMI ID = 268.1>

  
tion V. The infra-red spectrum (KBr pellet) shows absorption

  
 <EMI ID = 269.1>

  
 <EMI ID = 270.1>

  
pivaloyloxy methylene hydrogens), 5.88 ppm (singlet, 1H, C-3 hydrogen), 5.83 ppm (doublet, 1H, C-5 hydrogen), 5.20 ppm (doublet,

  
1H, C-6 hydrogen), 180 ppm (singlet, 3H, C-2 hydrogens methyl), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1.16 ppm (singlet, 3H, C-2 hydrogens methyl).

PREPARATION X

  
 <EMI ID = 271.1>

  
pename

  
and

  
 <EMI ID = 272.1>

  
name

  
To a stirred suspension of 2.40 g of 6-amino-2,2-dimethyl-

  
 <EMI ID = 273.1>

  
add 2.8 ml of triethylamine. Stirring is continued for

  
15 minutes more, then 2.68 g of chloromethyl pivalate are added. This mixture is stirred at room temperature for

  
5 hours, then diluted with 100 ml of water. Then extract it

  
 <EMI ID = 274.1>

  
using anhydrous sodium sulfate, then evaporated in vacuo to obtain a mixture of the compounds shown in the previous title. The individual isomers are obtained by chromatographic separation of the crude product.

  
By repeating the procedure but replacing the chloride

  
 <EMI ID = 275.1> <EMI ID = 276.1>

  
isomer of the corresponding monoalkylated products in which the alkanoyloxyalkyl or phthalidyl substituent is located in position 1 or in position 2 on the tetrazole ring. The following compounds are prepared in this way. (For convenience, only the alkyl substituent is shown in the table):

  
acetoxymethyl

  
isobutyryloxymethyl

  
hexanoyloxymethyl

  
1-acetoxyethyl

  
 <EMI ID = 277.1>

  
1-hexanoyloxyethyl

  
phthalidyl

  
propionylcxymethyl

PREPARATION Y

  
 <EMI ID = 278.1>

  
pename

  
To a stirred suspension of 240 mg of 6-amino-2,2-dimethyl3- (5-tetrazolyl) penam in 150 ml of dry, chloroform-free

  
 <EMI ID = 279.1>

  
until a cloudy solution is obtained, then about 200 mg of anhydrous sodium sulfate is added. We continue to agitate

  
 <EMI ID = 280.1>

  
278 mg of triphenylmethyl chloride is added to the filtrate, and the reaction mixture is left at room temperature for 4.5 hours. At this point, the solvent is removed by evaporation in vacuo, leaving the product shown in the previous title in the crude state, in the form of a mixture of isomers as indicated. The crude product is redissolved in a small volume of chloroform and adsorbed in a small column of silica gel. The column is eluted with chloroform and the first 20 ml of the 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 obtain 357.4 mg (yield 77%) of a

  
 <EMI ID = 281.1>

  
7.15 ppm (large singlet), 5.70 ppm (doublet), 5.35 (singlet), 4.55
(doublet), 1.60 (singlet) and 1.10 (singlet).

PREPARATION Z

  
 <EMI ID = 282.1> <EMI ID = 283.1> corresponding. In this way, mixtures of the following compound and its isomer are prepared:

  

 <EMI ID = 284.1>


  
chromatography.

AA PREPARATION

  
 <EMI ID = 285.1> <EMI ID = 286.1>

  
then the solution thus obtained is cooled to 0 [deg.] C. 1.8 g of trimethylsilyl chloride is then added to this solution. The cooling bath is removed, and the reaction mixture is stirred for an additional hour at room temperature, to obtain a chloroform solution of the mono-trimethylsilyl derivative of

  
 <EMI ID = 287.1>

  
When the previous procedure is repeated, except that the trimethylsilyl chloride used in this procedure is replaced respectively by an equimolar amount of triethylsilyl chloride and of tri-n-butylsilyl chloride, the mono- derivative is respectively obtained. triethylsilyl and the mono-

  
 <EMI ID = 288.1>

  
tetrazolyl) pename

  
To a stirred suspension of 2.4 g of 6-amino-2,2-dimethyl-3-
(5-tetrazolyl) pename in 50 ml of chloroform, 4.2 ml of triethylamine are added. Stirring is continued for a further 15 minutes, and the resulting solution is cooled to 0 [deg.] C. We add

  
 <EMI ID = 289.1>

  
The cooling bath is removed, and the reaction mixture is stirred at temperature for 1 hour and then placed under reflux for one hour. It is then cooled to room temperature which gives a chloroform solution of the bistrimethylsilyl derivative of 6-amino-2,2-dimethyl-3- (5-tetrazolyl) penam.

  
When the previous procedure is repeated, except that the trimethylsilyl chloride used in this procedure is replaced respectively by an equimolar amount of triethylsilyl chloride and of triisopropylsilyl chloride, the bis-tri-ethylsilyl derivative is obtained respectively. and the

  
 <EMI ID = 290.1>

  
pename.

CC PREPARATION

  
 <EMI ID = 291.1>

  
and 5 ml of trifluoroacetic acid. We follow the progress of <EMI ID = 292.1>

  
and by recording their nuclear magnetic resonance spectrum. After 25 minutes, it is found that the elimination of the group

  
 <EMI ID = 293.1>

  
At this point, the reaction solution is added to a vigorously stirred and ice-cooled solution of 10 ml of pyridine in 50 ml of chloroform. Stirring is continued for 5 minutes, then 0.24 ml of phenylacetyl chloride is added. We

  
remove the cooling bath and stir the reaction mixture for an additional 20 minutes. A part of 100 ml of water is added, then the pH of the aqueous phase is adjusted to 2.5 by a dropwise addition of 0.5 N hydrochloric acid. The chloroform layer is separated, washed with a saturated saline solution,

  
it is dried using anhydrous sodium sulfate and then evaporated to dryness in vacuo. The crude product thus obtained is redissolved in chloroform, and the solution is divided into two equal parts. An equal volume of water is added to one of these parts. The layers are stirred vigorously and the pH of the aqueous phase is brought to 6.9 by the dropwise addition of a 0.1 N sodium hydroxide solution. The chloroform is separated and discarded, then a solution is added. amount of fresh chloroform equal to

  
the aqueous phase. The phases are stirred vigorously and the pH is adjusted to 2.5 using dilute hydrochloric acid. The chloroform is separated, washed with saturated salt water,

  
dried over anhydrous magnesium sulfate and then evaporated to dryness in vacuo. This provides 197 mg of an oily residue. We dissolve

  
the residue in 3 ml of chloroform, a solution which is then added dropwise to 30 ml of hexane. It is removed by filtration

  
 <EMI ID = 294.1>

  
6 - (2-phenylacetamido) -2,2-dimethyl-3- (5-tetrazolyl) penam. Spectrum

  
 <EMI ID = 295.1>

  
7.20 ppm (s, 5H), 5.55 ppm (m, 2H), 5.15 ppm (s, 1H), 3.60 ppm
(s, 2H), 1.40 ppm (s, 3H) and 1.05 ppm (s, 3H).

  
The minimum inhibitory concentration (MIC) of the compound represented in the previous title with respect to a strain of

  
 <EMI ID = 296.1> <EMI ID = 297.1>

  
acetyl, batchwise, the pH of the solution being maintained between

  
7 and 8 during the addition, using 0.1 N sodium hydroxide. This solution is stirred for an additional 30 minutes at 0 [deg.] C and at pH 8. It is then extracted with chloroform, and we throw out the extracts. The aqueous phase is acidified to pH 2 with dilute hydrochloric acid, then it is then extracted with chloroform. The last extracts were dried using calcium sulfate and then evaporated in vacuo to give the crude product as a gummy solid. It is purified by dissolving it in

  
20 ml of chloroform, adding the resulting solution dropwise to 250 ml of hexane. The precipitate is removed by filtration.

  
 <EMI ID = 298.1>

  
amorphous white. IR spectrum (KBr pellet): 1785, 1670 and 1540

  
 <EMI ID = 299.1>

  
 <EMI ID = 300.1>

  
 <EMI ID = 301.1>

  
The minimum inhibitory concentration (MIC) of the compound represented in the previous title with respect to a strain of

  
 <EMI ID = 302.1>

  
In the same way, the acylation of 6-amino-2,2dimethyl-3- (substituted tetrazol-5-yl) penames of preparations I, J,

  
 <EMI ID = 303.1>

  
phenylacetyl chloride to give the corresponding acyl derivatives.

EE PREPARATION

  
 <EMI ID = 304.1>

  
pename

  
 <EMI ID = 305.1>

  
 <EMI ID = 306.1>

  
 <EMI ID = 307.1>

  
temperature to -20 [deg.] C and stirring continued for 2d minutes.

  
 <EMI ID = 308.1>

  
of water and adjusting the pH to 7.0. The resulting solution is stirred <EMI ID = 309.1>

  
 <EMI ID = 310.1>

  
the pH to 1.5 with dilute hydrochloric acid. The mixture is maintained at this temperature and at this pH for 30 minutes, then the tetrahydrofuran is removed by evaporation in vacuo. The aqueous residue was extracted with ethyl acetate followed by extraction with ether, and the extracts were discarded. The pH of the remaining aqueous phase is brought to 5.4 and the product begins to deposit by crystallization. After 1 hour, it is collected by filtration and dried. The gross yield is 68.8 g.

  
The product is suspended in water at 25 [deg.] C, and the pH is reduced to 1.5. After stirring for a short time, insoluble products are filtered off, and the filtrate is extracted with ether. The aqueous solution is then cooled.

  
 <EMI ID = 311.1>

  
solid which precipitates, giving 62.7 g (yield 58.7%) of

  
 <EMI ID = 312.1>

  
7.60 ppm (s, 5H), 5.70 ppm (d, 1H), 5.55 ppm (d, 1H), 5.20 ppm

  
 <EMI ID = 313.1>

  
Analysis:

  

 <EMI ID = 314.1>


  
 <EMI ID = 315.1>

  
Sodium 2-phenylacetate from methyl acetoacetate and D-2-amino-2-phenylacetic acid by the method used by Long et al. (J. Chem. Soc., London, Part C, 1920 1971) for the corresponding p-hydroxy compound.

  
The minimum inhibitory concentration (MIC) of the compound represented in the previous title with respect to a strain of

  
 <EMI ID = 316.1>

FF PREPARATION

  
 <EMI ID = 317.1> <EMI ID = 318.1>

  
penam in 105 ml of acetone, 2.6 ml of 25% aqueous sodium iodide are added, followed by 4.35 g (0.0290 mole) of

  
chloromethyl pivalate. The mixture is refluxed for 4.5 hours and then cooled to room temperature. Then 100 ml of water was added to the mixture, and the resulting suspension was extracted with ethyl acetate. The extracts are dried and evaporated to obtain 6.3 g of white foam. The minimum inhibitory concentration (MIC) of this mixture of the compounds represented in the previous title with respect to Strep. pyogenes is

  
 <EMI ID = 319.1>

  
The white foam is redissolved in a small volume of an 80:20 chloroform-ethyl acetate mixture and absorbed in a column containing 180 g of chromatographic grade silica gel. The column is then eluted using an 80:20 chloroform-ethyl acetate mixture, taking fractions. Each fraction consists of 700 drops of solvent. Fractions 55-95 were combined and evaporated in vacuo to obtain 2.3 g of

  
 <EMI ID = 320.1>

  
3.85 (s, 2H), 1.65 (s, 3H), 1.36 (s, 9H) and 1.20 (s, 3H) ppm. Fractions 100 to 164 were combined and evaporated in vacuo to obtain 0.80 g of 6- (2-phenylacetamido) -2,2-dimethyl-3- (1-

  
 <EMI ID = 321.1>

  
6.80 (s, 2H), 6.50 (s, 2H), 5.60 (s, 1H), 3.85 (s, 2H), 1.75 (s,

  
 <EMI ID = 322.1>

GG PREPARATION

  
 <EMI ID = 323.1>

  
 <EMI ID = 324.1>

  
nutes more at -15 [deg.] C. This mixture is then added to an <EMI ID = 325.1>

  
(1.0 mmol) of triethylamine. The reaction mixture is stirred at
-15 [deg.] C for 1 hour, then at 5 [deg.] C for one hour.

  
 <EMI ID = 326.1>

  
suspends the white solid thus obtained in 10 ml of a 1: 1 water-tetrahydrofuran mixture. The suspension is cooled to

  
 <EMI ID = 327.1>

  
for 45 minutes, adding additional acid to maintain the pH at 2.1 if necessary. At this time, the tetrahydrofuran is removed by evaporation in vacuo, the residual aqueous phase is saturated with sodium chloride, and the product is extracted into ethyl acetate. The ethyl acetate is dried and evaporated in vacuo to give, - after trituration of the residue with ether, 425 mg (yield 81%) of 6- hydrochloride.

  
 <EMI ID = 328.1>

  
 <EMI ID = 329.1>

  
 <EMI ID = 330.1>

  
 <EMI ID = 331.1>

  
methinc side chain hydrogen), 5.00 ppm (singlet, 1H,

  
 <EMI ID = 332.1>

  
1.07 ppm (singlet, 9H, t-butyl hydrogens) and 0.96 ppm (singlet,

  
 <EMI ID = 333.1>

  
the minimum inhibitory concentration (MIC) of the compound

  
 <EMI ID = 334.1>

  
is 0.39 &#65533; g / ml.

  
 <EMI ID = 335.1>

  
 <EMI ID = 336.1>

  
 <EMI ID = 337.1>

  
 <EMI ID = 338.1>

  
 <EMI ID = 339.1>

  
 <EMI ID = 340.1>

  
 <EMI ID = 341.1>

  
 <EMI ID = 342.1> <EMI ID = 343.1>

  
1.03 ppm (singlet, 3H).

PREPARATION II

  
 <EMI ID = 344.1>

  
according to the preparation procedure FF gives the compound of the preceding title in the form of a mixture of isomers, PF 55-70 [deg.] C,

  
 <EMI ID = 345.1>

  
NMR (CDCl3). 7.20 (s, 6H), 6.25 (m, 1H), 5.75-5.40 (m, 2H), 5.20
(s, 1H), 3.60 (s, 2H), 2.00 (m, 6H), 1.45 (s, 3H) and 0.95 (s, 3H) ppm.

PREPARATION DD

  
 <EMI ID = 346.1>

  
tetrazol-5-yl) pename

  
Reaction of the sodium salt of 6- (2-phenylacetamido) -2,2dimethyl-3- (5-tetrazolyl) penam with 3-bromophthalidyl halide, according to the preparation procedure GG & gives the compound of previous title in the form of a mixture of isomers, mp 70-85 [deg.] C, yield 91%. IR (KBr pastille): 1785, 1675 and

  
 <EMI ID = 347.1>

  
5.80 (m, 2H), 5.20 (m, 1H), 3.60 (s, 2H), 1.60 (s, 3H) and 1.00
(s, 3H) ppm.


    

Claims (1)

<EMI ID = 348.1> <EMI ID = 349.1> <EMI ID = 350.1> <EMI ID = 351.1> <EMI ID = 352.1> <EMI ID = 353.1> and a protecting group for the nitrogen of tetrazolylpenam; <EMI ID = 354.1> <EMI ID = 355.1> carbon by alkyl group, alkanoyloxymethyl groups containing from three to eight carbon atoms, 1alkanoyloxyethyl groups containing from four to nine carbon atoms, phthalidvle crossings and <EMI ID = 356.1> <EMI ID = 357.1> <EMI ID = 358.1> fluoro, alkyl containing one to four carbon atoms, alkoxy containing one to four carbon atoms, and phenyl; characterized by (a) reacting a compound selected from the group consisting of <EMI ID = 359.1> formula in which R is selected from the group comprising the <EMI ID = 360.1> <EMI ID = 361.1> <EMI ID = 362.1> <EMI ID = 363.1> and a protecting group for the nitrogen of tetrazolylpenam; <EMI ID = 364.1> trialkylsilyl containing from one to four carbon atoms per alkyl group, alkanoyloxymethyl groups containing from three to eight carbon atoms, 1-alkanoyloxyethyl groups containing from four to nine carbon atoms, the phthalidyl group and <EMI ID = 365.1> <EMI ID = 366.1> group comprising hydrogen, chloro, bromo, fluoro, alkyl containing one to four carbon atoms, alkoxy containing one to four carbon atoms, and phenyl, under anhydrous conditions with a halogenating agent at a temperature less than about 0 [deg.] C to give the corresponding imino halide; (b) Reaction of said imino halide at a temperature below about -20 [deg.] C with an alcohol of the formula R'-OH in which R 'is selected from the group consisting of alkyl groups containing from one to four atoms of carbon, phenylalkyl <EMI ID = 367.1> alkyl, hydroxyalkyl containing two to four carbon atoms, alkoxyalkyl containing three to six carbon atoms, monocyclic aralkoxyalkyl containing three to five carbon atoms in the alkyl group, and hydroxy-alkoxyalkyl containing four to seven carbon atoms for give the corresponding imino ether; (c) reacting said imino ether under acidic conditions with water, (d) if necessary the elimination of a protective group <EMI ID = 368.1> in H. 2) Method according to claim 1, characterized in that the halogenation agent is chosen from the group comprising phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride and phosgene. 3. Method according to one of claims 1 and 2, characterized in that the halogenation reaction is carried out at a temperature between -10 [deg.] C and -40 [deg.] C. 4. Method according to one of revend'-cations 1 to 3, characterized in that one carries out the reaction of the imino halide with <EMI ID = 369.1> 5. Method according to one of claims 1 to 4, characterized in that said protecting group for the nitrogen of tetrazolyl- <EMI ID = 370.1> comprising phenyl or phenyl groups substituted with at most two groups chosen from the group comprising hydroxyl, nitro, fluoro, chloro, bromo, iodo, alkyl groups <EMI ID = 371.1> 5 six carbon atoms, acetoxy, formyloxy, methoxymethoxy, <EMI ID = 372.1> 5-methylthienyl. 6. Method according to one of claims 1 to 5, characterized in that R2 is an alkanoyloxymethyl group. 7. Compound of formula: <EMI ID = 373.1> <EMI ID = 374.1> <EMI ID = 375.1> <EMI ID = 376.1> <EMI ID = 377.1> <EMI ID = 378.1> is chosen from the group comprising hydrogen, trialkylsilyl groups containing from one to four carbon atoms per alkyl group, alkanoyloxymethyl group containing from three to eight carbon atoms, 1-alkanoyloxyethyl containing from four to nine carbon atoms, phthalidyl and <EMI ID = 379.1> <EMI ID = 380.1> group comprising hydrogen, chloro, bromo, flucro, alkyl containing from one to four carbon atoms, alkoxy containing from one to four carbon atoms and phenyl, and Z is selected from the group comprising chloro and OR 'groups in which R 'is selected from the group comprising the alkyl groups containing from one to four carbon atoms, phenyl-alkyl containing from one to three carbon atoms in the group alkyl, hydroxyalkyl containing two to four carbon atoms, alkoxyalkyl containing three to six carbon atoms, monocyclic araLkoxyalkyl containing three to five carbon atoms in the alkyl group, and hydroxyalkoxyalkyl containing four to seven carbon atoms, with the restriction that <EMI ID = 381.1> Z is OR '. 9. A compound according to claim 7, characterized in that Z is the chloro group. 10. A compound according to claim 9, characterized in that R is the benzyl group. 11. Compound according to claim 9, characterized in that R is the phenoxymethyl group. PFIZER INC. The reader's attention is drawn to the following material error in the text of the patent mentioned under: <EMI ID = 382.1> <EMI ID = 383.1> <EMI ID = 384.1> This correction is justified by the text of the description from line 31 page 5 to line 9 page 6, which indicates that the transformation into an imino ether of the imino chloride bearing a silyl group on the tetrazolyl part also results in the elimination of the silyl group with the chlorine atom. We have <EMI ID = 385.1> The undersigned is aware that no attached document in the file of a patent for invention cannot be of such a nature as make either the description or the drawings, modifications substantive and declares that the content of this note does not no such changes and has no other purpose than to report a or more hardware errors. It recognizes that the content of this note cannot have the effect of making the or partially the patent application N [deg.] 1/6513 if it was not fully or partially under the legislation currently in force. He authorizes the administration to attach this note in the patent file and to issue a photocopy.