BE876466A - PENICILLANIC ACID DERIVATIVE AND ITS PREPARATION PROCESS - Google Patents

Description

       

  "Derivative of penicillanic acid and its preparation process"

  
as

PATENT

  
Priority of the five patent applications filed in Japan, respectively, on May 26, 1978 under n [deg.] 62164/1978, June 13, 1978

  
under the n [deg.] 70365/1978, on August 11, 1978 under the n '97309/1978,

  
August 29, 1978 under the n [deg.] 104362/1978 and September 7, 1978

  
under the n [deg.] 109157/1978, all five in the name of the aforesaid company The present invention relates to a derivative of pënicillanic acid corresponding to the formula:

  

 <EMI ID = 1.1>


  
in which R, is a hydrogen atom or an alkyl group

  
 <EMI ID = 2.1>

  
R3 is a hydroxy group or a lower alkanoyl-oxy group;

  
 <EMI ID = 3.1>

  
to adjacent carbon atoms, the position of the substituent R3 being selected from positions 3 to 5 when R is a lower alkyl group and R- is a hydroxy group, from

  
 <EMI ID = 4.1>

  
substituents; the invention also relates to a salt of this derivative.

  
In British Patent No. [deg.] 1,250,611, United States Patent No. [deg.] 3,931,405, Patent Application published in the Federal Republic of Germany no [deg.] 2,311,328 and Japanese Patent Publication No. [deg.] 3532/78 discloses a variety

  
 <EMI ID = 5.1>

  
Prior art references only mention compounds in which the benzoyl group is substituted by a hydroxy group or by a lower alkanoyl-oxy group.

  
In British Patents n [deg.] 1,301,961 and 1,426.199, as well as in United States Patents n [deg.]
3.933.795, 3.956.442, 3.939.149, 3.959.258, 3.974.140, <EMI ID = 6.1>

  
 <EMI ID = 7.1>

  
does not mention compounds in which the benzoyl group is replaced by a hydroxy group. The definition of the substituents of the benzoyl group referred to in these prior art references includes a "lower alkanoyl-oxy group", but no explanation is given suggesting the number of such lower alkanoyl-oxy groups, either. as bonding to adjacent carbon atoms.

  
In British Patent No. [deg.] 1.260.882, it is described

  
 <EMI ID = 8.1>

  
as a benzoyl group, for example, 4-chloro-3-hydroxybenzoyl group, 3-chloro-4-hydroxybenzoyl group and m-hydroxybenzoyl group. This prior art reference also mentions p-acetoxybenzoyl group, 2-acetoxy-3-chlorobenzoyl group, o-acetoxybenzoyl group, 2-acetoxy-3-methyl-5-chlorobenzoyl group, 2-acetoxy5- group. methylbenzoyl, the 2-acetoxy-4,6-dimëthylbenzoyl group,

  
2-acetoxy-5-t-butylbenzoyl group, 3-methyl-2pivaloyloxybenzoyl group and 2,4-diacetoxybenzoyl group. However, no mention is made of a benzoyl group having two or more hydroxy groups or a benzoyl group having several adjacent lower alkanoyl-oxy groups.

  
In the patent application published in the Federal Republic

  
 <EMI ID = 9.1>

  
 <EMI ID = 10.1>

  
ureido) -benzylpenicillin, there is no mention

  
a compound in which the benzoyl group is substituted by two or more hydroxy groups or by lower alkanoyl-oxy groups.

  
Among the prior art references described

  
 <EMI ID = 11.1>

  
the benzoyl group has several adjacent substituents, in particular, groups containing oxygen, there are

  
 <EMI ID = 12.1>

  
 <EMI ID = 13.1>

  
place, British Patent No. [deg.] 1,260,882 mentioning, as benzoyl group, for example, the 3,4-dimethoxybenzoyl group,

  
 <EMI ID = 14.1>

  
benzoyl. However, neither of these two references discloses a compound in which the benzoyl group has several adjacent hydroxy or lower alkanoyl-oxy groups.

  
As explained above, the penicillanic acid derivative of formula (I) according to the present invention is a new compound which has not yet been described in any prior art reference.

  
The penicillanic acid derivative of the present invention has, in the benzoyl group, two to three groups

  
 <EMI ID = 15.1>

  
adjacent to each other and, therefore, this compound is believed to exert a greater effect than any compound described in the above references of the prior art.

  
The penicillanic acid derivative of the present invention exerts, against bacteria belonging to the genus Pseudomonas in in vitro and animal tests, an antibacterial activity superior to that of the compounds illustrated in the aforementioned references of the prior art or to carbenicillin which is considered a

  
specific agent effective against bacteria belonging

  
to the genus Pseudomonas; this derivative also has a high ability to prevent infections caused by these bacteria. Further, the penicillanic acid derivative of the present invention is not only stable under neutral, <EMI ID = 16.1> acidic conditions. Accordingly, the penicillanic acid derivative of formula (I) is an effective antibacterial agent.

  
 <EMI ID = 17.1>

  
(I) has 1 to 4 carbon atoms and may or may not be branched; there will be mentioned, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, and the like. A methyl group and an ethyl group are preferred examples. The lower alkanoyl group of the lower alkanoyl-oxy group represented by R- contains 2 to 4 carbon atoms and may or may not be branched. For example, there will be mentioned an acetyl group, a propionyl group, an n-butyryl group and an isobutyryl group. An acetyl group is preferred.

  
 <EMI ID = 18.1>

  
is a hydroxy group, if the latter is present on the benzoyl ring in position 2 or 6, the ureido group becomes unstable,

  
 <EMI ID = 19.1>

  
 <EMI ID = 20.1>

  
hydroxy group, the positions of this R3 substituent are either the 3 and 4 positions, or the 3,4 and 5 positions. For other combinations of R, and R3 'the positions of the R3 substituent are either the 2 and 3 positions , 3 and 4, 2, 3 and 4,

  
3, 4 and 5, 2, 4 and 5, 2, 3 and S, or positions 2, 3 and 6, 2 and 3, 3 and 4, positions 3, 4 and 5 being preferred.

  
The penicillanic acid derivative of formula (I) of the present invention has one group. carboxy and hence it can form salts with different basic substances in this group. All these salts also come within the scope of the present invention. Among the salts of the compound according to the present invention, mention will be made, for example, of inorganic basic salts, in particular the salts <EMI ID = 21.1>

  
as organic basic salts, for example, the salts of p-rocaine and dibenzylethylenediamine. These salts can be prepared by treating a free carboxy group of the penicillanic acid derivative with the organic or inorganic bases described above.

  
Due to the asymmetric carbon atom of the 6-acetoamido group, some final compounds of the present invention have their optical isomers, i.e. isomers

  
DL, D and L. All these isomers are also included in the

  
within the scope of the present invention.

  
The present invention also relates to a method

  
for the preparation of a penicillanic acid derivative of formula

  
(I) or one of its salts.

  
According to one aspect of the present invention, this method

  
 <EMI ID = 22.1>

  
killed of formula:

  

 <EMI ID = 23.1>


  
 <EMI ID = 24.1>

  
R3 radical meet the definitions given above, or a reactive derivative of this acid, with 6-aminopenicillanic acid or one of its reactive derivatives to obtain a penicillanic acid derivative of formula (I) or a salt of this derivative .

  
The expression “reactive derivative of substituted ureidophenylacetic acid of formula (II)” denotes a derivative of this acid, the carboxylic group of which is activated for the reaction.

  
 <EMI ID = 25.1>

  
mixed with an alkyl carbonate; a mixed anhydride with phenylphosphoric acid; a mixed anhydride with an aromatic carboxylic acid; esters such as 1-hydroxybenztriazolyl ester, 2,4-dinitrophenyl ester, Nhydroxysuccinimidyl ester, N-hydroxyphthalimidyl ester, pentachlorophenyl ester, phenylazophenyl ester, cyanomethyl ester and ester methoxymethyl; amides such as those formed with imidazole, triazole,

  
 <EMI ID = 26.1>

  
substituted ureidophenylacetic of formula (II) can be a

  
 <EMI ID = 27.1>

  
lower alkanoyl-oxy and if R2 is hydrogen.

  
The term "reactive penicillanic acid derivative" denotes a derivative of penicillanic acid in which the 6-amino group is activated into a reactive form. For example, the introduction of the trimethylsilyl group into the 6-amino group sufficiently causes the necessary reaction of amide formation.

  
This amide formation reaction is generally carried out in a solvent. The solvent used in this reaction is an inert organic solvent such as acetone,

  
* tetrahydrofuran, dimethylformamide, pyridine, acetonitrile, dioxane, chloroform, dichloromethane or ethyl acetate. The water-miscible solvents can be used as an aqueous mixture.

  
The reaction is generally carried out with cooling, at room temperature or with heating depending on the particular reagents employed. However, the temperature

  
 <EMI ID = 28.1>
-30 and 35 [deg.] C. The reaction time varies between a few tens of minutes and a few tens of hours depending on the reaction temperature, the particular reagents and the solvent used. However, the reaction is generally carried out at a temperature between -30 and 35 [deg.] C for a period of 0.5 to 48 hours, preferably at a temperature of between -20 and 20 [deg.] C for a period of 0.5 to 48 hours. a period of 1 to 24 hours.

  
The desired compound can be isolated from the reaction mixture by any technique usually adopted to isolate a penicillin, for example, extraction with an organic solvent such as dichloromethane, chloroform or ethyl acetate, as well as chromatography on silica gel, ion exchange resin, crosslinked dextran, highly porous polymer of styrene or acrylic ester, or the like.

  
Substituted ureidophenylacetic acid of formula (II) is new and can be readily prepared, for example, by

  
 <EMI ID = 29.1>

  
with a benzoyl isocyanate or an N-benzoylN-lower alkyl-carbamoyl halide, the hydroxy groups of which are protected, the protecting groups then being removed.

  
A useful protecting group or a technique for removing this group will be described in detail in the discussion given in connection with a compound of formula (III), in particular, to

  
 <EMI ID = 30.1> Another aspect of the present invention relates to a process for preparing a penicillanic acid derivative of formula (I) above in which R3 is a hydroxy group, as well as a salt of this drift. In other words, this process consists in removing protective groups from a protected penicillanic acid derivative of the formula:

  

 <EMI ID = 31.1>


  
 <EMI ID = 32.1>

  
 <EMI ID = 33.1>

  
 <EMI ID = 34.1>

  
a protected hydroxy group; n is 2 or 3; at least

  
 <EMI ID = 35.1>

  
 <EMI ID = 36.1>

  
 <EMI ID = 37.1>

  
 <EMI ID = 38.1>

  
uncomfortable ; Y is a hydrogen atom or a protecting group for the carboxy group, while at least one of the radicals

  
 <EMI ID = 39.1>

  
to form a derivative of penicillanic acid corresponding to the formula
 <EMI ID = 40.1>
  <EMI ID = 41.1>

  
 <EMI ID = 42.1>

  
R32 radicals are attached to adjacent carbon atoms

  
 <EMI ID = 43.1>

  
R3 in formula (I).

  
In formula (III), a group protecting the group

  
 <EMI ID = 44.1>

  
easily removable under moderate conditions. Among these protecting groups, there may be mentioned, for example,

  
 <EMI ID = 45.1>

  
propionyl group, a butyryl group or an isobutyryl group.

  
Although the removal of this lower alkanoyl group can be accomplished by any conventional method adopted for penicillin derivatives, it is desirable

  
 <EMI ID = 46.1>

  
view of the removal of this lower alkanoyl group is excellent, the subsequent purification of the product being able to

  
be done easily. Based on these points of

  
 <EMI ID = 47.1>

  
holiday. The base useful in this process is an inorganic base such as an ammonium or alkali metal salt of a weak acid, for example, carbonic acid, acetic acid or phosphoric acid, ammonia or an ammonium form of a weakly acidic ion exchange resin, or an organic base such as a primary, secondary or tertiary lower alkyl-amine or a primary, secondary or tertiary amine comprising 1 to 3 hydroxy-lower alkyl groups or an alicyclic amine, for example, piperidine or morpholine.

  
The elimination of the protecting groups according to this technique is carried out by depositing this base in a solvent in the presence of a substance comprising one or more alcoholic hydroxy groups. In this embodiment, it is preferable to use a base soluble in the substance having the alcoholic hydroxy group (s), as well as in

  
the solvent used, preferably a base containing at least one basic nitrogen atom, for example, ammonia, propylamine, diethylamine, triethylamine, diethylaminoethanol, ethanolamine, triethanolamine, piperidine or

  
morpholine. In addition to these bases, one can also use

  
an ammonium form of a weakly acidic ion exchange resin in the form of a suspension in the aforementioned solvent.

  
Among the substances which can be used and which have one or more alcoholic hydroxy groups, there is an alcohol such as methanol, ethanol, ethylene glycol or glycerin; or a hydroxy-lower alkyl-amine

  
such as diethylaminoethanol, ethanolamine or triethanolamine.

  
A solvent can be used which can dissolve the salt

  
the base with the protected penicillanic acid derivative and

  
a penicillanic acid derivative constituting the desired product. Among these solvents, there will be mentioned, for example,

  
polar non-proton solvents such as dimethylformamide, as well as non-polar solvents such as dichloromethane and chloroform. In addition, substances having one or more alcoholic hydroxy groups can be used as desirable solvents, as long as they meet the requirements for solvents as discussed above, for example, methanol and glycerin. .

  
Among the preferred combinations of these substances

  
with a solvent in order to remove the protective group, mention will be made of the methanol / ammonia, triethylamine /

  
 <EMI ID = 48.1>

  
of the base varies depending on the number of protecting groups <EMI ID = 49.1>

  
However, this base is usually present in an amount of 1 to 15 moles, preferably 3 to 10 moles per mole of the protected penicillanic acid derivative.

  
The amount of the substance having one or more alcoholic hydroxy groups is generally greater than that of the protected pnicillanic acid derivative. Although this substance can be used in a large excess as a solvent, it is usually used in an amount of

  
 <EMI ID = 50.1>

  
if it is not used as a solvent. In the case of a triethylamine / triethanolamine / dimethylformamide system (one of the preferred combinations), the triethylamine is usually employed in an amount of 0.1 to 10 moles, preferably 2 to 4 moles, while the triethylamine is used. usually triethanolamine in an amount of 0.7 to 10 moles, preferably 3 to 5 moles per mole of the protected penicillanic acid derivative. If a methanol / ammonia system is used, the amount of ammonia is in the range of 1.1 to 10

  
 <EMI ID = 51.1>

  
penicillanic acid, while methanol is used

  
in an amount sufficient to act as a solvent.

  
Although the reaction temperature will vary depending on the particular substance having one or more alcoholic hydroxy groups, as well as the base and solvent used, this temperature is usually chosen within the range of -30 to 40 [deg.] vs. In particular, if the substance having one or more alcoholic hydroxy groups also acts as a base, the temperature is usually between 10 and 40 [deg.] C, preferably between <EMI ID = 52.1>

  
 <EMI ID = 53.1>

  
 <EMI ID = 54.1>

  
The reaction time is usually 30 minutes, to 20 hours, preferably 1 to 10 hours.

  
In addition to the embodiment described above for the removal of protecting groups, other techniques can be adopted in order to remove these protecting groups from the protected penicillanic acid derivative of formula (III). One of these techniques is carried out using a combination of a base containing nitrogen atoms such as ammonia or a primary or secondary lower alkyl-amine with a non-proton solvent such as dimethylformamide capable of dissolving the salt of the derivative. of penicillanic acid with this base.

  
Another technique is to use (a) a base such as an inorganic base, for example, ammonia, ammonium bicarbonate, ammonium carbonate, ammonium phosphate, ammonium acetate, an alkali metal bicarbonate, an alkali metal carbonate or an alkali metal acetate; an organic base such as ethylamine,

  
 <EMI ID = 55.1>

  
or an ammonium form of a weakly acidic ion exchange resin and (b) a solvent such as water or an aqueous mixture of a hydrophilic non-proton solvent such as dioxane and acetone.

  
 <EMI ID = 56.1>

  
be a benzyl group. In this case, this benzyl group is removed by catalytic reduction with a palladium-carbon catalyst.

  
 <EMI ID = 57.1>

  
ester with carboxy group = The trimethylsilyl group attached to the carboxy group is easily removed by treatment with water or alcohol. Among the desirable protecting groups for Y is an organic or inorganic base capable of forming a salt of the carboxy group, for example, alkali metals, alkaline earth metals, and tertiary amines such as triethylamine, N-methyl. -piperidine and

  
 <EMI ID = 58.1>

  
tement with an acid.

  
The protected penicillanic acid derivative of formula
(III) can be prepared in various ways. For example, it is prepared by reacting a substituted ureidophenylacetic acid derivative corresponding to formula (II) or to formula:

  

 <EMI ID = 59.1>


  
 <EMI ID = 60.1>

  

 <EMI ID = 61.1>


  
in which Y has the meaning defined in formula (III).

  
 <EMI ID = 62.1>

  
corresponding to formulas (V) and (VI) has the meaning defined above. The reaction conditions for this amide formation reaction have been set out previously for <EMI ID = 63.1>

  
reactive derivative.

  
In this amide-forming reaction, it is evident that a substituted ureidophenylacetic acid is reacted with a carbodiimide to activate the carboxy group prior to the amide-forming reaction.

  
 <EMI ID = 64.1>

  

 <EMI ID = 65.1>


  
 <EMI ID = 66.1>

  
formula (III), with a benzoyl isocyanate of formula:

  

 <EMI ID = 67.1>


  
 <EMI ID = 68.1>

  
 <EMI ID = 69.1>

  
adjacent carbon atoms, the position of the substituent being

  
 <EMI ID = 70.1> <EMI ID = 71.1>

  

 <EMI ID = 72.1>


  
in which n and R33 have the meanings defined above

  
 <EMI ID = 73.1>

  
is chosen from positions 3-5, while X is a

  
 <EMI ID = 74.1>

  
 <EMI ID = 75.1>

  
or one of its reactive derivatives of formula:

  

 <EMI ID = 76.1>


  
 <EMI ID = 77.1>

  
with a benzoyl halide of the formula:

  

 <EMI ID = 78.1>


  
in which n, R33 and X have the meanings defined above.

  
Another aspect of the present invention relates to a process for the preparation of a penicillanic acid derivative of formula (I) wherein R3 is a lower alkanoyloxy group, or a salt thereof. In other words, the characteristic of the process of this aspect of the invention is the preparation of a penicillanic acid derivative of the formula:

  

 <EMI ID = 79.1>


  
 <EMI ID = 80.1>

  
above in formula (I), while R34 has the meaning defined in formula (XIII), or a salt of this derivative, by

  
 <EMI ID = 81.1>

  
reactive derivatives of formula:

  

 <EMI ID = 82.1>


  
 <EMI ID = 83.1>

  
Y is a hydrogen atom or a protecting group for the carboxy group, with a benzoyl isocyanate of the formula:

  

 <EMI ID = 84.1>


  
 <EMI ID = 85.1>

  
lower alkanoyl-oxy, at least two of these radicals being linked to adjacent carbon atoms, or else with a benzoylcarbamoyl halide of formula:

  

 <EMI ID = 86.1>


  
 <EMI ID = 87.1>

  
 <EMI ID = 88.1> of halogen, to then optionally transform Y into a hydrogen atom.

  
In the description of this process, the expression "derivative

  
 <EMI ID = 89.1>

  
introduction of a trimethylsilyl group on the amino group.

  
The special protecting group for Y in formula
(XII) and a suitable technique for the removal of this protecting group are the same as those mentioned in the disclosure relating to the formula (III). In the case of the reaction with a benzoyl isocyanate of formula (XIII), a penicillanic acid derivative of formula (XV) is obtained in

  
 <EMI ID = 90.1>

  
benzoylcarbamoyl halide of formula (XIV), one obtains

  
the derivative of formula (XV) in which R .. is a group

  
lower alkyl.

  
The reaction is generally carried out in a solvent.

  
The solvent useful for this reaction is an inert organic solvent such as dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, dioxane or the like. Any water miscible solvent can be used as a mixture. aqueous.

  
The reaction is generally carried out with cooling, at room temperature or with heating depending on the particular reagents and solvent used. However, the reaction temperature is usually between -30 and
35 [deg.] C, preferably between -20 and 20 [deg.] C. The reaction time varies between a few tens of minutes and a few tens of hours depending on the temperature and the solvent used. However, the reaction is usually carried out at a temperature between -30 and 35 [deg.] C for several tens of minutes to 24 hours, preferably at a temperature between -10 and 20 [deg.] C for 0.5 to 5 hours.

  
The desired compound can be isolated from the reaction mixture by any technique customarily adopted to isolate a penicillin, for example, by extraction with an organic solvent such as dichloromethane, chloroform or ethyl acetate, as well as by chromatography. on silica gel, on ion exchange resin, on crosslinked dextran, on a very porous polymer of styrene or acrylic ester or the like.

  
According to yet another aspect of the present invention, there is provided a process for preparing an acid derivative.

  
 <EMI ID = 91.1>

  
hydrogen and R3 is lower alkanoyl-oxy, or a salt thereof. This process consists of making a

  
 <EMI ID = 92.1>

  

 <EMI ID = 93.1>


  
in which R. has the meaning defined above for formula (I), R22 is a hydrogen atom and Y is a hydrogen atom or a protecting group for the carboxy group, or a reactive derivative of this penicillin, with a benzoyl halide of the formula:

  

 <EMI ID = 94.1>


  
in which n and R34 have the meanings defined above for the formula (XIII) and X is a halogen atom, then optionally transforming Y into a hydrogen atom for <EMI ID = 95.1>

  
formula (XVI) is a penicillin derivative in which the terminal amino group is activated in a reactive form. For example, activation is carried out by introducing a trimethylsilyl group.

  
The particular protecting group for Y in the formula
(XVI), as well as a technique for removing this protecting group in this process are the same as those described above with respect to the formula (III).

  
The reaction is generally carried out in a solvent. The solvent used in this reaction is an inert organic solvent such as dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, dioxane or the like. Any water miscible solvent can be used as an aqueous mixture.

  
The reaction is generally carried out with cooling or at room temperature depending on the particular reagents and the solvent used. However, the reaction temperature is usually between -10 [deg.] C and room temperature, preferably between 0 and 10 [deg.] C. The reaction time varies between a few tens of minutes and a few tens of hours depending on the temperature and the solvent used. However, the reaction is usually carried out at a temperature between -10 [deg.] C and room temperature for a period of 1 to 48 hours, preferably at a temperature of 0 to 10 [deg.] C for a period of time. from 1 to 10 hours.

  
The desired compound can be isolated from the reaction mixture by any technique usually adopted for isolating a penicillin, for example, by extraction with an organic solvent such as, for example, dichloromethane, <EMI ID = 96.1>

  
written on silica gel, on ion exchange resin, on crosslinked dextran, on a highly porous polymer of styrene or an acrylic ester or the like.

  
An optical isomer such as the isomer can be prepared

  
D or L of the desired compound of formula (I) using an optically active starting compound in the form of an acid

  
 <EMI ID = 97.1>

  
which is prepared by a usual optical doubling technique, for example, a technique mentioned by JP Greenstein, M. Winitz, "Chemistry of the Amino Acids", volume 1, pages 715-760, "John Wiley and Sons", NY (1961).

  
The compound object of the present invention may be formulated into various pharmaceutical preparations suitable for different modes of administration in a manner analogous to that adopted for other penicillin compounds. Accordingly, one aspect of the present invention encompasses a pharmaceutical composition for humans or animals. The preparation is obtained using a usual pharmaceutical carrier, diluent and / or excipient.

  
In particular, an emulsion, solution or suspension can be formulated in an aqueous or oily vehicle for injection. A suppository is also obtained by using a conventional suppository base, for example, coconut oil or other glycerides.

  
The content of the active compound varies according to the mode of ad-

  
 <EMI ID = 98.1>

  
and is, for example, between 5 and 99%, preferably between
10 and 60%.

  
The dose administered to a human is usually in the range of 100 to 3,000 mg per day for an adult. Administration in an amount between 500 and 2,000 mg per day is preferred for an adult, although the amount varies depending on body weight: age, symptom, mode of administration or frequency of administration. administration.

  
The minimum inhibitory amount for different types of bacteria has been determined against different compounds

  
 <EMI ID = 99.1>

  
line (carboxybenzylpenicillin); the results obtained are shown in the table below. The compounds subjected to this test are the following:

  
 <EMI ID = 100.1> <EMI ID = 101.1>

  

 <EMI ID = 102.1>
 

  

 <EMI ID = 103.1>
 

  
Processes for the preparation of certain compounds of

  
the present invention are illustrated by the following examples.

Example 1

  
(1) While stirring and cooling, add

  
10.1 g of oxalyl chloride to a solution of 7.5 g of 3,4diacetoxybenzamide in 80 ml of 1,2-dichloroethane. The mixture is gradually heated to reflux temperature and reacted at reflux for 13 hours. At the end of the reaction, by distillation under reduced pressure, the solvent and the excess oxalyl chloride are separated off to obtain the 3,4-diacetoxybenzoyl isocyanate which is dissolved in 40 ml.

  
of anhydrous dichloromethane for the subsequent reaction.

  
(2) 40 ml of N, O-bis- (trimethylsilyl) -acetamide are added dropwise to a suspension of 12.8 g of three-molecule ampicillin in 100 ml of anhydrous dichloromethane, at room temperature. , then stir until the mixture becomes clear. The solution previously formed under (1) above in dichloromethane is added dropwise to the clear solution thus obtained, while maintaining the temperature between 5 and 10 [deg.] C, then the mixture is stirred at the same temperature during 2 hours. Then, the mixture is evaporated to dryness under reduced pressure and at room temperature, and to the residue is added anhydrous methanol, then the mixture is again evaporated to dryness under reduced pressure.

   To the residue are added 300 ml of ethyl acetate and 100 ml of cold 2N hydrochloric acid, then the organic layer is separated. The separated organic layer was washed with water and extracted three times with cold saturated aqueous sodium bicarbonate solution in a total amount of 200 ml. The combined aqueous layer is washed with 200 ml of ethyl acetate and, after adjusting the pH

  
to about 2.5 with cold 2N hydrochloric acid, extracted again with 150 ml of ethyl acetate. The separated organic layer is washed with cold aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, treated with activated carbon and concentrated by evaporation at room temperature and under reduced pressure. The residue is treated with 80 ml of n-hexane

  
 <EMI ID = 104.1>

  
Pale yellow amorphous solid.

  
Thin layer chromatography: Rf: 043, support: gel of

  
 <EMI ID = 105.1>

  
"E. Merck", Darmstadt).

  
Developer: ethyl acetate / ethanol / acetic acid (25: 5: 1 by volume).

  
 <EMI ID = 106.1>

  
max
3.700-2.300, 1.770, 1.700-1.620, 1.525, 1.490.

  
Nuclear magnetic resonance spectrum: (dimethylsulfoxide-

  
 <EMI ID = 107.1>

  
2.28 (6H, s), 4.23 (1H, s), 5.3-6.1 (3H, m), 7.0-8.0 (8H, m).

Example 2

  
In 30 ml of methanol, 2 g of the acid are dissolved

  
 <EMI ID = 108.1>

  
mido) -pénicillanique obtained in Example 1 and, to the solution thus obtained, 3.7 ml of methanolic ammonia (0.0075 g / ml) are added dropwise, while stirring and maintaining the temperature between - 15 and -10 [deg.] C. Stirring is continued for 75 minutes while allowing the temperature of the mixture to rise gradually to about 0 [deg.] C to complete the reaction. Then, the reaction mixture is added to a mixture of 150 ml of 5% aqueous hydrochloric acid and 150 ml of ethyl acetate while stirring and cooling with ice water. The organic layer is separated from the mixture and extracted with 100 ml of a cold saturated aqueous solution of sodium bicarbonate. The separated aqueous layer is washed with ethyl acetate and, after adjusting the pH to about 2.5 with cold 2N hydrochloric acid,

  
it is again extracted with 100 ml of ethyl acetate. The separated organic layer is washed with cold aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation.

  
at room temperature and under reduced pressure. The residue is treated with 80 ml of n-hexane to obtain 1.2 g of acid.

  
 <EMI ID = 109.1>

  
mido) -penicillanic acid as a pale yellow amorphous solid. Thin layer chromatography: Rf 0.39, support: gel of

  
 <EMI ID = 110.1>

  
"E. Merck", Darmstadt).

  
Developer: ethyl acetate / ethanol / acetic acid (25: 5: 1

  
in weight).

  
Infrared ray absorption spectrum: KBr (cm- <1>)

  
max
3.700-2.300, 1.770, 1.740, 1.690-1.620, 1.550-1.480.

  
Nuclear Magnetic Resonance Spectrum: (dimethylsulfoxyded6, 60MHz) &#65533; (parts per million) 1.41 (3H, s), 1.53 (3H, s), 4.22 (1H, s), 5.3-6.0 (3H, m), 6.6-7 , 7 (8H, m).

  
Ultraviolet ray absorption spectrum: (C2HSOH)

  
 <EMI ID = 111.1>

  
Chromogenic reaction with ferric chloride: positive
(dark green).

Example 3

  
The process adopted in Example 1 (2) is repeated, with the exception that instead of 12.8 g of three-molecule ampicillin, 13.1 g of three-molecule amoxicillin are used.

  
 <EMI ID = 112.1>

  
penicillanic acid as a pale yellow amorphous solid.

  
 <EMI ID = 113.1>

  
 <EMI ID = 114.1>

  
"E. Merck", Darmstadt).

  
Developer: ethyl acetate / ethanol / acetic acid (25: 5: 1

  
in volume).

  
 <EMI ID = 115.1>
3.700-2.300, 1.770, 1.710-1.630, 1.550-1.450.

  
Nuclear magnetic resonance spectrum: (dimethylsulfoxyded6, 60MHz) o (parts per million) 1.47 (3H, s), 1.56 (3H, s), 2.28 (6H, s), 4.24 (1H, s), 5.3-6.0 (3H, m), 6.6-8.2 (7H, m).

Example 4

  
The process adopted in Example 2 is repeated, with this

  
 <EMI ID = 116.1>

  
acetamido) -penicillanic acid as a pale yellow amorphous solid.

  
Thin layer chromatography: Rf 0.35, support: gel of

  
 <EMI ID = 117.1>

  
"E. Merck", Darmstadt).

  
Developer: ethyl acetate / ethanol / acetic acid (25: 5: 1 by volume).

  
 <EMI ID = 118.1>
3.700-2.300, 1.770, 1.740-1.630, 1.560-1.480.

  
Nuclear magnetic resonance spectrum: (dimethylsulfoxide-

  
 <EMI ID = 119.1>

  
4.22 (1H, s), 5.3-5.9 (3H, m), 6.5-7.6 (7H, m).

  
 <EMI ID = 120.1>

  
 <EMI ID = 121.1>

  
Chromogenic reaction with ferric chloride: positive (dark green).

  
1

  
 <EMI ID = 122.1>

  
(1) The process adopted in Example 1 (1) is repeated, with the exception that 8 g of 3,4,5-triacetoxybenzamide and 8.6 g of oxalyl chloride are used instead of 7.5 g of 3,4-diacetoxybenzamide and 10.1 g of oxalyl chloride to obtain a solution of 3,4,5-triacetoxybenzoyl isocyanate in 40 ml of anhydrous dichloromethane.

  
(2) 10.9 g of three-molecule ampicillin are reacted with the isocyanate obtained in (1) above in the same manner as in Example 1 (2) to obtain 5 g of 'acid

  
 <EMI ID = 123.1>

  
acetamido) -penicillanic acid as a pale brown amorphous solid.

  
Thin layer chromatography: Rf 0.41, support: gel of

  
 <EMI ID = 124.1>

  
E. Merck ", Darmstadt).

  
Developer: ethyl acetate / ethanol / acetic acid (25: 5: 1 by volume).

  
 <EMI ID = 125.1>
3.700-2.300, 1.775, 1.700-1.600, 1.520, 1.485.

  
Nuclear Magnetic Resonance Spectrum: (dimethylsulfoxide- d6, 60MHz) &#65533; (parts per million) 1.46 (3H, s), 1.55 (3H, s), 2.30 (9H, s), 4.26 (1H, s), 5.3-6.1 (3H , m), 7.2-7.7 (5H, m), 7.33 (2H, s).

Example 6

  
 <EMI ID = 126.1>

  
obtained in Example 5 in 30 ml of methanol and, to the solution thus obtained, 3.7 ml of methanolic ammonia (0.075 g / ml) are added dropwise, while stirring and maintaining the temperature between -15 and -12 [deg.] C. Stirring is continued for 40 minutes while allowing to rise gradually

  
 <EMI ID = 127.1> reaction. Then, the reaction mixture is added to a

  
 <EMI ID = 128.1>

  
ethyl acetate while stirring and cooling with ice water. The separated organic layer is extracted with
100 ml of a cold aqueous solution of saturated sodium bicarbonate. The separated aqueous layer is washed with ethyl acetate and, after adjusting the pH to about 2.5 with

  
of cold 2N hydrochloric acid, it is extracted again with
100 ml of ethyl acetate. The ethyl acetate layer was washed with cold aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the solvent by distillation at room temperature and under reduced pressure, 20 ml of ethyl acetate is added to the residue, then the insoluble solids are separated by filtration. The filtrate is triturated with 100 ml of n-hexane to

  
 <EMI ID = 129.1>

  
Light yellow amorphous solid.

  
Thin layer chromatography: Rf 0.34, support: gel of

  
 <EMI ID = 130.1>

  
"E. Merck", Darmstadt).

  
Developer: ethyl acetate / ethanol / acetic acid (25: 5: 1 by volume).

  
 <EMI ID = 131.1>

  
max
3.700-2.300, 1.770, 1.750-1.630, 1.560-1.470.

  
Nuclear magnetic resonance spectrum: (dimethylsulfoxide-

  
 <EMI ID = 132.1>

  
 <EMI ID = 133.1>

  
 <EMI ID = 134.1>

  
 <EMI ID = 135.1>

  
Chromogenic reaction with ferric chloride: positive
(dark blue).

Example 7

  
 <EMI ID = 136.1>

  
chloroethane, while stirring and cooling. The mixture is gradually heated to reflux temperature and reacted at reflux for 10 hours. Then, the solvent and the excess oxalyl chloride are separated off by distillation under reduced pressure to obtain the 2,3-diacean isocyanate.

  
 <EMI ID = 137.1>

  
anhydrous for the subsequent reaction.

  
(2) At room temperature, add dropwise to

  
 <EMI ID = 138.1>

  
mixture of 5.3 g of D (-) - phenylglycine in 100 ml of anhydrous dichloromethane at room temperature, then stirred until the mixture becomes clear. The solution obtained previously is added dropwise to the clear solution.

  
 <EMI ID = 139.1>

  
stirred the mixture for 1.5 hours at the same temperature, evaporated to dryness at room temperature

  
 <EMI ID = 140.1>

  
anhydrous and evaporated to dryness under reduced pressure. To the residue, 200 ml of cold dilute aqueous hydrochloric acid is added and the mixture is stirred for 5 to 10 minutes. By filtration, the white precipitates obtained are collected and dissolved in 250 ml of a cold aqueous solution of saturated sodium bicarbonate and the insoluble substances are removed.

  
 <EMI ID = 141.1>

  
ethyl tate and, after adjusting the pH to about 2.5

  
with cold 2N hydrochloric acid, the white precipitates obtained are collected by filtration, washed with water, then with diethyl ether and dried in air and 3 temperature ambient to obtain 4.5 g of acid D (-) - &#65533; - <EMI ID = 142.1>

  
 <EMI ID = 143.1>

  
(decomposition).

  
Analysis:

  

 <EMI ID = 144.1>


  
 <EMI ID = 145.1>

  
of methanol and, to the solution thus obtained, is added dropwise

  
 <EMI ID = 146.1>

  
health with ice water. The mixture is stirred at a temperature

  
 <EMI ID = 147.1>

  
ambient temperature and under reduced pressure. To the residue obtained, 50 ml of ethyl acetate and 100 ml of a cold aqueous solution of saturated sodium bicarbonate are added. The aqueous layer is separated and, after removing the insoluble substances by filtration, the pH is adjusted to about 2.5 with cold 2N hydrochloric acid. The white precipitate obtained is collected by filtration, washed with water, then with diethyl ether and dried in air to obtain

  
 <EMI ID = 148.1>

  
phenylacetic in the form of a white powder with a melting point of 211-212 [deg.] C (decomposition).

  
Analysis.

  

 <EMI ID = 149.1>


  
 <EMI ID = 150.1>

  
benztriazole in 100 ml of anhydrous tetrahydrofuran and, to the solution thus obtained, is added dropwise at a temperature of 0 to 5 [deg.] C, a solution of 0.75 g of N, N'-dicyclohexyl-

  
 <EMI ID = 151.1> the mixture while allowing its temperature to gradually rise

  
 <EMI ID = 152.1>

  
later, the dicyclohexylurea which precipitates is removed by filtration. For the subsequent reaction, the filtrate is used

  
 <EMI ID = 153.1>

  
 <EMI ID = 154.1>

  
mide 3 a suspension of 1.3 g of 6-aminopenicillanic acid in 50 ml of anhydrous dichloromethane, then stirred until 3

  
that the mixture becomes clear. To the clear solution thus obtained, the tetrahydrofuran solution obtained previously in (4) above is added dropwise while maintaining its temperature at 5-10 [deg.] C, then the mixture is stirred at the same. temperature for 2 hours. Then, the mixture is evaporated to dryness at room temperature and under reduced pressure, and to the residue is added anhydrous methanol, and again evaporated to dryness and under reduced pressure. To the residue, 150 ml of ethyl acetate and 100 ml of cold 1N hydrochloric acid are added, then the organic layer is recovered.

  
The organic layer is washed with a cold aqueous solution.

  
of saturated sodium chloride and extracted three times with

  
a cold aqueous solution of saturated sodium bicarbonate

  
 <EMI ID = 155.1>

  
obtained with 150 ml of ethyl acetate and, after adjusting the pH to about 2.5 with cold 2N hydrochloric acid,

  
it is extracted again with 150 ml of ethyl acetate. The organic layer is washed with cold aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. We treat

  
the residue with 80 ml of n-hexane to obtain 1 g of acid

  
 <EMI ID = 156.1> <EMI ID = 157.1>

  
Thin layer chromatography: Rf 0.37, support: gel of

  
 <EMI ID = 158.1>

  
"E. Merck", Darmstadt).

  
 <EMI ID = 159.1>
3.700-2.300, 1.770, 1.745-1.625, 1.560-1.450.

  
Nuclear magnetic resonance spectrum (dimethylsulfoxide-

  
 <EMI ID = 160.1>

  
4.23 (1H, s), 5.3-6.0 (3H, m), 6.6-7.7 (8H, m).

  
Ultraviolet ray absorption spectrum: (C2H50H) max (nm) 254, 322.

  
Chromogenic reaction with ferric chloride: positive
(dark green).

Example 8

  
(1) At room temperature, add dropwise to

  
 <EMI ID = 161.1>

  
Anhydrous dichloromethane to a solution of 15 g of N-methyl-3,4-diacetoxybenzamide and 6.49 g of trimethylsilyl chloride in 70 ml of anhydrous dichloromethane. After heating the mixture under reflux for 20 minutes, it is added

  
a solution of 42 ml of phosgene in 82 ml of dichloromethane! anhydrous at a temperature between -5 and 5 [deg.] C, then the temperature is allowed to rise gradually to room temperature. The excess phosgene and the solvent used are evaporated to dryness and under reduced pressure to obtain crude N- (3,4-diacetoxybenzoyl) -N-methylcarbamoyl chloride. The product is dissolved in 50 ml of cold anhydrous dichloromethane and, after removing the insoluble substances by filtration, this product becomes available for the subsequent reaction.

  
 <EMI ID = 162.1>

  
 <EMI ID = 163.1>

  
anhydrous methane and, to the mixture thus obtained, while stirring, the solution of N- (3,4-

  
 <EMI ID = 164.1>

  
anhydrous previously obtained in sub (1). After shaking at

  
at a temperature of 5 to 10 [deg.] C for 1.5 hours, the mixture is evaporated to dryness at room temperature and under reduced pressure and, after adding methanol

  
Anhydrous to the residue, the mixture is again evaporated to dryness at room temperature and under reduced pressure.

  
To the residue, 500 ml of ethyl acetate and 80 ml of cold 1N hydrochloric acid are added, then the organic layer is separated. This layer was washed with 500 ml of a cold aqueous solution of saturated sodium chloride and extracted three times with a cold aqueous solution of saturated sodium bicarbonate in a total amount of 700 ml. We wash three times

  
the aqueous layer separated using each time 100 ml of ethyl acetate and, after adjusting the pH to approximately

  
2.5 with cold 2N hydrochloric acid, extracted again with ethyl acetate. The separated organic layer was washed with cold aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain

  
 <EMI ID = 165.1>

  
pale yellow. Thin layer chromatography: Rf 0.51, support: gel of

  
 <EMI ID = 166.1>

  
E. Merck ", Darmstadt).

  
 <EMI ID = 167.1>

  
in volume).

  
 <EMI ID = 168.1> <EMI ID = 169.1>

  
 <EMI ID = 170.1>

  
 <EMI ID = 171.1>

  
5.23 (1H, d, J = 7Hz), 6.6-7.6 (7H, m), 9.50 (1H, d, J-7Hz). Chromogenic reaction with ferric chloride: positive.

  
 <EMI ID = 172.1>

  
acetic in 20 ml of methanol, added dropwise

  
 <EMI ID = 173.1>

  
ice water, then stir the mixture for 30 minutes

  
 <EMI ID = 174.1>

  
50 ml of cold 1N hydrochloric acid are added, the mixture is extracted with 100 ml of ethyl acetate. The organic layer is separated, washed with water and extracted with 70 ml of a cold aqueous solution of saturated sodium bicarbonate. The aqueous layer is separated and washed with 100 ml of ethyl acetate. After adjusting the pH to about 2.5 with cold 2N hydrochloric acid, the aqueous layer is extracted again with 200 ml of ethyl acetate. The separated organic layer is washed with cold aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness to obtain.

  
 <EMI ID = 175.1>

  
 <EMI ID = 176.1>

  
of anhydrous tetrahydrofuran containing 0.3 g of 1-hydroxybenztriazole. To the solution thus obtained, one adds drop <EMI ID = 177.1>

  
and under a nitrogen atmosphere. Stirring is continued while allowing the temperature to rise gradually to room temperature for 2 hours, then the mixture is removed.

  
 <EMI ID = 178.1>

  
later.

  
(5] Under a nitrogen atmosphere and at a temperature

  
 <EMI ID = 179.1>

  
in 50 ml of anhydrous dichloromethane, then the mixture is stirred until it becomes clear. To the clear solution is added drop &#65533; drops the solution in tetrahydrofuran previously obtained under (4), while maintaining the temperature

  
 <EMI ID = 180.1>

  
Then the mixture is evaporated at room temperature and under reduced pressure to dryness and, after adding anhydrous methanol to the residue, again evaporated to dryness under reduced pressure. To the residue, 100 ml of ethyl acetate and 80 ml of cold 1N hydrochloric acid are added, then the organic layer is separated. We wash this diaper

  
with cold aqueous saturated sodium chloride solution and extracted three times with cold saturated sodium bicarbonate in a total amount of 200 ml. The separated aqueous layer was washed with 150 ml of ethyl acetate and, after adjusting the pH to about 2.5 with cold ZN hydrochloric acid, it was again extracted with 150 ml of ethyl acetate. 'ethyl The organic layer is washed with a cold aqueous solution <EMI ID = 181.1>

  
anhydrous sodium and evaporated under reduced pressure. When

  
 <EMI ID = 182.1>

  
 <EMI ID = 183.1>

  
form of a pale yellow amorphous solid.

  
Thin layer chromatography: Rf 0.38, support: gel of

  
 <EMI ID = 184.1>

  
"E. Merck", Darmstadt).

  
Developer: ethyl acetate / ethanol / acetic acid (25: 5: 1 by volume).

  
 <EMI ID = 185.1>
3.700-2.300, 1.770, 1.750-1.620.

  
Nuclear magnetic resonance spectrum: (dimethylsulfoxide-

  
 <EMI ID = 186.1>

  
3.10 (3H, s), 4.20 (1H, s), 5.3-5.7 (3H, m), 6.5-7.4 (7H, m).

  
 <EMI ID = 187.1>

  
(nm) 275, 280 (protrusion), 290 (protrusion).

  
Chromogenic reaction with ferric chloride: positive (dark green).

Example 9

  
(1) The process adopted in Example 8 (2) is repeated, with

  
 <EMI ID = 188.1>

  
silica "60FZ54" (previously coated plate manufactured by

  
 <EMI ID = 189.1>

  
 <EMI ID = 190.1>

  
in volume).

  
 <EMI ID = 191.1> <EMI ID = 192.1>

  
The above compound is also prepared by the process described below. Has a mixture of 50 ml of tetrahydrofuran, 7 g of trimethyl-silyl chloride and 6.4 g of acid

  
 <EMI ID = 193.1>

  
 <EMI ID = 194.1>

  
thyl, 6.4 g of triethylamine are added dropwise at a temperature below 10 [deg.] C, while stirring. After the addition is complete, the mixture is stirred at 40-50 [deg.] C for 1 hour, then cooled to a lower temperature.

  
 <EMI ID = 195.1>

  
tion of 7.9 g of 3,4-diacetoxybenzoyl chloride in 20 ml of tetrahydrofuran, then the mixture is stirred at 50 [deg.] C for 2 hours. After cooling to a lower temperature

  
 <EMI ID = 196.1>

  
and the insoluble substances are removed by filtration. The filtrate is evaporated at room temperature and under reduced pressure to dryness, then the residue is purified by column chromatography on silica gel ("Wako-gel C-200", manufactured by "Wako-Junyaku KK", Japan) with 3-4% methanol in chloroform, to obtain 5 g of the product as a white powder.

  
(2) The process adopted in Example 8 (3) is repeated, with

  
 <EMI ID = 197.1>

  
mido) -penicillanic acid as a pale yellow amorphous solid.

  

 <EMI ID = 198.1>
 

  

 <EMI ID = 199.1>

Example 10

  
(1) At a temperature of 15 to 20 [deg.] C, 11.8 ml of

  
 <EMI ID = 200.1>

  
cillin to 3 molecules of water in 70 ml of anhydrous dichloromethane, then stirred until the mixture becomes clear. To the clear mixture is added dropwise 30 ml of a solution of N- (3,4-diacetoxybenzoyl) -N-methylcarbamoyl chloride in anhydrous dichloromethane, this chloride being prepared from

  
 <EMI ID = 201.1>

  
in Example 8 (1). After stirring for 1.5 hours at a

  
 <EMI ID = 202.1>

  
pickle and at room temperature until dry. To the residue is added anhydrous methanol and the mixture is again evaporated under reduced pressure to dryness. To the residue, we add

  
200 ml of ethyl acetate and 50 ml of cold IN hydrochloric acid, then the organic layer is recovered. The organic layer was washed with 200 ml of a cold aqueous saturated sodium chloride solution and extracted three times with cold saturated sodium bicarbonate in a total amount of 300 ml. The combined aqueous layer is washed twice, each time using
150 ml of ethyl acetate and, after adjusting the pH to about 2.5 with cold 2N hydrochloric acid, it is extracted again with ethyl acetate. The separated organic layer is washed with cold aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. When treating the

  
 <EMI ID = 203.1>

  
tamide) -pênicillanique in the form of a white powder.

  

 <EMI ID = 204.1>

Example 11

  
1 g of the white powder obtained in Example 10 is dissolved in 30 ml of ethanol and, to the solution thus obtained, <EMI ID = 205.1>

  
while cooling with ice water. After shaking at a

  
 <EMI ID = 206.1>

  
 <EMI ID = 207.1>

  
100 ml of ethyl acetate. The separated organic layer was washed with water and extracted with 50 ml of a cold aqueous solution of saturated sodium bicarbonate. The separated aqueous layer was washed with 50 ml of ethyl acetate and, after adjusting the pH to about 2.5 with cold 2N hydrochloric acid, again extracted with 100 ml of ethyl acetate. 'ethyl. The separated organic layer is washed with cold aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. When the residue is treated with 50 ml of n-hexane, one obtains

  
 <EMI ID = 208.1>

  
absorption of infrared rays, nuclear magnetic resonance and absorption of ultraviolet rays, the Rf value
(thin layer chromatography) and the result of the chromogenic reaction of the product with ferric chloride are the same as those of the product obtained in Example 8 (5).

Example 12

  
The process adopted in Example 10 is repeated, with the exception that 9.64 g of ampicillin containing 3 water molecules are used instead of 10 g amoxicillin containing 3 water molecules, for

  
 <EMI ID = 209.1>

  
dre white.

  

 <EMI ID = 210.1>
 

  

 <EMI ID = 211.1>

Example 13

  
To 5 ml of a methanolic solution of 1 g of acid

  
 <EMI ID = 212.1>

  
dropwise 3 ml of methanolic ammonia (0.07S g / ml), while stirring and maintaining its temperature between -15 [deg.] C and -10 [deg.] C, then stirring is continued at same temperature for 20 minutes. Then, the reaction mixture was poured into a mixture of 20 ml of 51 hydrochloric acid and 20 ml of ethyl acetate, while cooling with ice water and stirring. We separate the

  
 <EMI ID = 213.1>

  
duel with 20 ml of ethyl acetate, then the separated organic layer is combined with that which was previously separated. The combined layer is washed with water and extracted with
100 ml of a cold aqueous solution of saturated sodium bicarbonate. The separated aqueous layer is washed with acetate.

  
 <EMI ID = 214.1>

  
 <EMI ID = 215.1>

  
ethyl acetate. The separated organic layer is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to dryness. By treatment

  
 <EMI ID = 216.1> <EMI ID = 217.1>

  
cillanic. Infrared ray absorption, nuclear magnetic resonance, and ultraviolet ray absorption spectra, Rf value (thin layer chromatography) and

  
the result of the chromogenic reaction of the product with ferric chloride are the same as those of the product obtained in Example 9

  
(2).

Example 14

  
(1) The process adopted in Example 8 (1) is repeated, with the exception that 15.84 g of N-ethyl-3,4-diacetoxybenzamide are used instead of 15 g of N-methyl-3 , 4-diacetoxybenzamide,

  
to obtain N- (3,4-diacetoxybenzoyl) -N-ethylcarbamoyl chloride. The product is reacted with 14 g of D (-) - phenylglycine and treated as described in Example 8 (2), to

  
 <EMI ID = 218.1>

  

 <EMI ID = 219.1>
 

  
 <EMI ID = 220.1>

  
 <EMI ID = 221.1>

  
than as a white amorphous solid.

  

 <EMI ID = 222.1>


  
Chromogenic reaction with ferric chloride: positive <EMI ID = 223.1>

  
 <EMI ID = 224.1>

  
as a light red powder.

  

 <EMI ID = 225.1>


  
(2) By the method adopted in Example 8 (3) - (5), we treat

  
 <EMI ID = 226.1>

  
mido) penicillanic acid as a pale brown amorphous solid.

  

 <EMI ID = 227.1>
 

  

 <EMI ID = 228.1>

Example 16

  
 <EMI ID = 229.1>

  
of ampicillin to 3 molecules of water with 1.2 mole of N-methyl isocyanate, suspended in 40 ml of dichloromethane and then, while cooling in ice, 5 ml are added dropwise to the mixture obtained of N, 0-bis (trimethylsilyl) acetamide. After stirring the mixture at room temperature so as to make it clear, it is cooled to a temperature below 5 [deg.] C and 15 ml of a solution of 3.8 g of 3.4 chloride are added. -diacêtoxybenzoyl in dichloromethane, then stirred at room temperature for 5 hours. The reaction mixture is evaporated under reduced pressure to dryness and the residue is treated as described in Example 10, to obtain 3.5 g of 6- (D (-) - acid.

  
 <EMI ID = 230.1>

  
penicillanic. The infrared absorption and nuclear magnetic resonance spectra of the product are the same as those of the product obtained in Example 12.

Example 17

  
 <EMI ID = 231.1>

  
(1) suspended in 20 ml of dichloromethane and, to the suspension thus obtained, 1.4 ml of N-methyl- is added dropwise

  
 <EMI ID = 232.1>

  
Ethyl nate in dichloromethane. The mixture was stirred for 3 hours to obtain a solution of the mixed acid anhydride in dichloromethane. Separately, 5.3 g of triethylamine was added dropwise to a suspension of 5.8 g of 6-aminopenicillanic acid in 30 ml of dichloromethane, followed by stirring until the mixture became clear.

  
After cooling to -20 [deg.] C, the clear solution is mixed with the solution of the mixed acid anhydride in dichloromethane which was previously prepared above, then stirred for 1.5 hours. The reaction mixture is washed with

  
 <EMI ID = 233.1>

  
with an aqueous solution of saturated sodium chloride. The separated organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to dryness to obtain.

  
 <EMI ID = 234.1>

  
thin-layer matography), as well as the infrared ray absorption spectra and nuclear magnetic resonance of the product are the same as those of the product obtained in Example 12.

Example 18

  
 <EMI ID = 235.1>

  
(1) and 0.13 g of 1-hydroxybenzotriazole to 1 molecule of water in
10 ml of anhydrous tetrahydrofuran. To the solution thus obtained is added dropwise 5 ml of a solution of 0.29 g of N, N'dicyclohexylcarbodiimide in anhydrous tetrahydrofuran at 0 [deg.] C, on an ice bath and under an atmosphere of. 'nitrogen. Stirring is continued for 2 hours, while allowing the temperature of the mixture to rise gradually to room temperature and then, by filtration, the precipitate (dicyclohexylurea) deposited is removed. The filtrate containing the 1-benztriazolyl ester of

  
 <EMI ID = 236.1>

  
phenylacetic is made available for the subsequent reaction.

  
(2) At a temperature of 0 [deg.] C and under an azct atmosphere;

  
 <EMI ID = 237.1>

  
mixture of 0.50 g of 6-aminopenicillanic acid in 20 ml of dichloromethane, then stirred until the mixture becomes clear. To the clear solution, all

  
the tetrahydrofuran solution obtained under (1) above, while maintaining the temperature of the mixture between 5 and 10 [deg.] C, then stirred at the same temperature for 1.5 hours. The mixture is evaporated under reduced pressure and at room temperature to dryness and, after adding methanol to the residue, evaporated again under reduced pressure to dryness. To the residue are added 100 ml of ethyl acetate and 50 ml of hydrochloric acid.

  
 <EMI ID = 238.1>

  
layer with a cold aqueous solution of saturated sodium chloride and extracted three times with a cold aqueous solution of saturated sodium bicarbonate in a total amount of
150 ml. The separated aqueous layer was washed with ethyl acetate and, after adjusting the pH to about 2.5 with cold 2N hydrochloric acid, extracted again with 150 ml.

  
 <EMI ID = 239.1>

  
It was created with cold aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. When treating the residue

  
 <EMI ID = 240.1>

  
as a pale yellow amorphous solid. The Rf value (thin-layer chromatography), as well as the absorption spectra of infrared rays and nuclear magnetic resonance of the solid are the same as those of the product obtained in Example 12.

Example 19

  
 <EMI ID = 241.1>

  
d - (4-hydroxyphenyl) acetamido) penicillanic acid. Rf value
(thin layer chromatography), as well as the infrared ray absorption and nuclear magnetic resonance spectra of this product are the same as those of the product obtained in Example 10.

Example 20

  
 <EMI ID = 242.1>

  
ple 9 (1) in 50 ml of anhydrous dichloromethane and the solution thus obtained is cooled to a temperature below -15 [deg.] C.

  
To this solution is added dropwise 5.8 ml of chloride

  
of pivalyl, then 6.6 ml of triethylamine at this temperature, while stirring. After stirring for 1 hour, all

  
while stirring at a temperature below -15 [deg.] C, is added dropwise to the mixture, a solution of the triethylamine salt of 6-aminopenicillanic acid in dichloromethane, salt which was prepared in from 12.8 g of 6-aminopenicillanic acid. After continuing stirring for 1 hour, the reaction mixture is poured into 100 ml of a cold aqueous solution of sodium chloride containing 15 ml of concentrated hydrochloric acid. The separated dichloromethane layer was washed several times with cold aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to dryness. The residue is triturated in

  
 <EMI ID = 243.1>

  
(2) 26.7 g of the crude product obtained under (1) above are dissolved in 52 ml of dimethylformamide and, after adding

  
 <EMI ID = 244.1>

  
the mixture is stirred at a temperature between room temperature and 35 [deg.] C, for 2 hours. At the end of the reaction, this mixture is poured into a mixture of 300 ml of ice-cold water,

  
39 ml of concentrated hydrochloric acid and 140 ml of ethyl acetate. The ethyl acetate layer was collected, washed with water and, while cooling, extracted with 300 ml of a cold aqueous solution of saturated sodium bicarbonate. After washing the aqueous layer with ethyl acetate,

  
it is collected and poured into a mixture of 200 ml of ice-water and 100 ml of ethyl acetate. 6N hydrochloric acid is added dropwise to the mixture with stirring in order to adjust the pH to 3. The separated ethyl acetate layer is washed with water, dried over sulfate. of anhydrous magnesium and evaporated under reduced pressure to dryness.

  
The residue is treated with n-hexane, to obtain 16 g of a crude product which is purified by subjecting it to chromatography using a column filled with 480 g of "Sephadex LH-20".
(hydroxypropyl derivative of a crosslinked dextran gel manufactured by "Pharmacia Fine Chemicals", Sweden) and a mixture of dichlo-

  
 <EMI ID = 245.1>

  
 <EMI ID = 246.1>

  
of a white powder. The Rf (thin layer chromatography) value, infrared ray absorption, nuclear magnetic resonance and ultraviolet ray absorption spectra, as well as the result of the chromogenic reaction of the product with ferric chloride are the same as those of the product obtained in Example 9 (2).

I

Example 21

  
 <EMI ID = 247.1>

  
naked as described in example 7 (1) with 12.8 g of ampicillin to one water molecule and treated as described in example 1 (2),

  
 <EMI ID = 248.1>

  

 <EMI ID = 249.1>

Example 22

  
 <EMI ID = 250.1>

  
amorphous white. Infrared ray absorption, nuclear magnetic resonance and absorptior spectra. ultraviolet rays, the Rf value (thin layer chromatography), as well as the result of the chromogenic reaction of the product with ferric chloride are the same as those of the compound obtained in

  
 <EMI ID = 251.1>

Example 23

  
By the method adopted in Example 7 (1) - (3), we treat

  
 <EMI ID = 252.1>

  
corresponding benzotriazolyl ester in a manner analogous to that of Example 7 (4). This ester is reacted with 1.3 g of 6-aminopenicillanic acid in the same manner as in example

  
 <EMI ID = 253.1>

  
of a pale yellow amorphous solid. The spectra of infrared ray absorption, nuclear magnetic resonance and ultraviolet ray absorption, the Rf value (thin layer chromatography) and the result of the chromogenic reaction of the product with ferric chloride are the same as those of the compound obtained in Example 2.

Example 24

  
The 3,4-diacetoxybenzoyl isocyanate obtained in Example 1 (1) is reacted with D (-) - p-hydroxyphenylglycine from

  
the same way as in Example 7 (2), to obtain the acid

  
 <EMI ID = 254.1>

  
corresponding benzotriazolyl ester as described in Example 7

  
(4). This ester is reacted with 1.3 g of 6-aminopenicillanic acid as described in Example 7 (5), to obtain 1.02 g of acid.

  
 <EMI ID = 255.1>

  
phenyl) acetamido) penicillanic acid as a pale yellow amorphous solid. Infrared ray absorption, nuclear magnetic resonance and ultraviolet ray absorption spectra, the Rf value (thin layer chromatography) and the result of the chromogenic reaction of the product with chloru-

  
 <EMI ID = 256.1>

  
ple 4.

Example 25

  
The 3,4,5-triacetoxybenzoyl isocyanate obtained in Example 5 (1) is treated as described in Example 7 (2) - (3), to

  
 <EMI ID = 257.1>

  
phenylacetic which is converted into the corresponding benzotriazolyl ester. This ester is reacted with 1.3 g of 6-aminopenicillanic acid as described in Example 7 (S), to obtain

  
 <EMI ID = 258.1>

  
pale yellow amorphous. The infrared ray absorption, nuclear magnetic resonance and ultraviolet ray absorption spectra, Rf value (thin layer chromatography) and the result of the chromogenic reaction of the product with ferric chloride are the same as those of the compound of Example 6.

Example 26

  
N- (3,4-diacetoxybenzoyl) - chloride is reacted

  
 <EMI ID = 259.1>

  

 <EMI ID = 260.1>
 

  

 <EMI ID = 261.1>

Example 27

  
As described in Example 16, the derivatives are prepared

  
 <EMI ID = 262.1>

  
penicillanic acid as a pale yellow amorphous solid. The infrared ray absorption and nuclear magnetic resonance spectra, as well as the Rf value (thin layer chromatography) of the product are the same as those of the compound obtained in Example 1 (2).

  
 <EMI ID = 263.1>

  
mido) penicillanic acid as a pale brown amorphous solid. The infrared ray absorption and nuclear magnetic resonance spectra, as well as the Rf value (thin layer chromatography) of the product are the same as those of the compound obtained in Example 5 (2).

  
 <EMI ID = 264.1> phenylacetamido) penicillanic acid. The infrared absorption and nuclear magnetic resonance spectra, as well as the Rf (thin layer chromatography) value of the pro-

  
 <EMI ID = 265.1>

  
 <EMI ID = 266.1>

  
do) penicillanic. The absorption spectra of infrared rays and nuclear magnetic resonance as well as the Rf value (thin layer chromatography) of the product are the same as those of the compound obtained in Example 21.

Example 28

  
 <EMI ID = 267.1>

  
phenylacetic. This acid is reacted with 0.5 g of 6-aminopenicillanic acid as described in Example 18 (1), to obtain

  
 <EMI ID = 268.1>

  
amorphous pale brown. The infrared ray absorption and nuclear magnetic resonance spectra, as well as the Rf value (thin layer chromatography) of the product are the same as those of the compound obtained in Example 5 (2).

Example 29

  
 <EMI ID = 269.1>

  
0.50 g of 6-aminopenicillanic acid and treated as described in

  
 <EMI ID = 270.1>

  
penicillanic. Infrared ray absorption and nuclear magnetic resonance spectra, as well as the Rf value
(thin layer chromatography) of the product are the same as those of the compound obtained in Example 26.

Example 30

  
 <EMI ID = 271.1>

  
the acid to the corresponding mixed acid anhydride with pivalic acid, reacted with 1.3 g of 6-aminopenicillanic acid and treated as described in Example 20 (1), to obtain

  
 <EMI ID = 272.1>

  
this powder in ethyl acetate, treated with activated carbon and concentrated by evaporation at room temperature and under reduced pressure. The residue is treated with n-hexane, to obtain 2 g of a yellow amorphous solid.

  
 <EMI ID = 273.1>

  
nuclear magnetic resonance, as well as the Rf (thin layer chromatography) value of the product are the same as those of the compound obtained in Example 1 (2).

Example 31

  
3,4-Diacetoxybenzamide is processed as described in

  
 <EMI ID = 274.1>

  
the acid is converted into the corresponding mixed acid anhydride with pivalic acid, reacted with 1.3 g of 6-aminopenicillanic acid and treated as described in Example 20 (1), to

  
 <EMI ID = 275.1>

  
This powder is treated with activated charcoal as described in Example 30 to obtain 2.03 g of a pale yellow amorphous solid. Infrared ray absorption and nuclear magnetic resonance spectra, as well as the Rf value (chromatography

  
on a thin layer) of the product are the same as those of the compound obtained in Example 3.

Example 32

  
 <EMI ID = 276.1>

  
of the corresponding mixed acid with pivalic acid, reacted with 1.3 g of 6-aminop6nicillanic acid and treated as described in Example 20 (1), to obtain a crude product as a powder. This powder is treated with

  
 <EMI ID = 277.1>

  
 <EMI ID = 278.1>

  
acetamido) penicillanic acid. The infrared ray absorption and nuclear magnetic resonance spectra, as well as the Rf value (thin layer chromatography) of the product are the same as those of the compound obtained in Example 21.

Example 33

  
 <EMI ID = 279.1>

  
of a white amorphous solid. The spectra of infrared ray absorption, nuclear magnetic resonance and ultraviolet ray absorption, the Rf value (thin layer chromatography) and the result of the chromogenic reaction of the product with ferric chloride are the same as those of compound obtained in Example 14.

Example 34

  
 <EMI ID = 280.1>

  
mido) raw penicillanic acid in powder form. 0.76 g of this powder is subjected to the reaction and treatment described at <EMI ID = 281.1>

  
penicillanic acid as a pale brown amorphous solid. The spectra of infrared ray absorption, nuclear magnetic resonance and ultraviolet ray absorption, Rf value (thin layer chromatography) and the result of the chromogenic reaction of the product with ferric chloride are the same as those of the compound obtained in Example 15 (2).

CLAIMS

  
 <EMI ID = 282.1>

  

 <EMI ID = 283.1>


  
 <EMI ID = 284.1>

  
 <EMI ID = 285.1>

  
eg hydroxy; R3 represents a hydroxy group or a lower alkanoyl-oxy group; n is 2 or 3; at least two of the radicals R, are linked to adjacent carbon atoms, the position of the substituent R3 being chosen from positions 3 to 5

  
 <EMI ID = 286.1>

  
hydroxy, as well as from positions 2 to 6 when R- and R3, are other substituents, or a salt thereof.


    

Claims (1)

2. Compound according to claim 1, characterized in <EMI ID = 287.1> 3. A compound according to claim 2, characterized in <EMI ID = 288.1> 4. A compound according to claim 2, characterized in that R is a lower alkyl group. <EMI ID = 289.1> that the lower alkyl group is a methyl group or an ethyl group. 6. Compound according to claim 3, characterized in that R3 is a 2,3-dihydroxy group, a 3,4-dihydroxy group or a 3,4,5-trihydroxy group. 7. A compound according to any one of claims <EMI ID = 290.1> 8. A compound according to claim 1, characterized in! <EMI ID = 291.1> 10. A compound according to any one of claims <EMI ID = 292.1> 11. A compound according to any one of claims <EMI ID = 293.1> fior. 12. A compound according to claim 11, characterized in that the lower alkyl group is a methyl group. 13. A compound according to claim 10, characterized in that R3 is a 3,4-diacetoxy group or a 3,4,5-triacetoxy group. 14. A compound according to any one of the claims <EMI ID = 294.1> diacetoxy. <EMI ID = 295.1> tion 1. <EMI ID = 296.1> preparation, as described above.