BE609039A - - Google Patents

Description

       

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  "ANTIMICROBIAL COMPOUNDS AND COMPOSITIONS
THERAPEUTICS CONTAINING "

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The present invention relates to new compounds possessing valuable chemotherapeutic activity.



  More particularly, it relates to a new class of compounds possessing important antimiorobial properties, as well as to processes for their preparation.



   The compounds according to the present invention, more particularly, possess a high antimicrobial activity against microorganisms such as Micrococcus pyoenes, Proteus vularis and Diposlcous pneumoniae.



  In addition, these compounds possess certain other properties, such as prolonged stability, high titers in serum and low incidence of side effects.



   Some of the compounds in question possess, in addition, anti-microbial activity against certain microorganisms which have shown resistance to known penicillins, such as certain penicillin resistant strains of Staphylococcus aureus.



   The compounds according to the invention are, therefore, useful for the treatment of various microbial infections, allowing safe and effective therapy with minimal, if not no side effects.



  The administration of these compounds to the infected host can be in any of the usual forms, for example in the form of solutions, suspensions, creams, ointments, lozenges, capsules and the like, these compounds may be administered by the oral route, by injection or by the topical route, depending on the nature of the particular infection to be treated.

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   The compounds according to the present invention can be represented by the following structural formula:
 EMI3.1
      in which R is an isovaleric acid carbon-oxygen skeleton of the structure:
CH3
 EMI3.2
 M ^, C-CH3 C-CH2-A
3 or C-CH -CH-COOM -C-COOM where A denotes hydrogen or an alkanoyloxy, hydroxyl, benzoyioxy or pyridinium radical, A being able to denote, when considered with M, a monovalent carbon-oxygen bond, M denotes hydrogen, non-toxic pharmaceutically acceptable cations, an anionic filler or, in combination with A, a monovalent carbon-oxygen bond, B is hydrogen or a methyl radical,
X is hydrogen, halogen or an alkyl radical,

     lower alcoh or trifluoromethyl, Z is an atom with an atomic weight of less than 33, such as oxygen or sulfur and n is an integer equal to 0 or 1.



   The symbol is used in the present memo to orient the valence bonds of the carbon-oxygen skeleton of isovaleric acid which the radical R contains, with respect to the sulfur atom and to the nitrogen atom to which R is attached. This symbol is used for clarity only and in all other respects represents only a typical sulfur-carbon bond.



   More particularly, the isovaleric acid carbon-oxygen backbone designated by R is linked to the remainder of the molecule of the compounds in question in a vicinal ss-ss relation or in a Ór relation with respect to the backbone.

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 of isovaleric acid carbon. In the latter case, the compounds contain, in addition (1) an unsaturated bond between the a and p carbon atoms of the isovaleric group and (2) on the terminal carbon atom, a group denoted by A e / t chosen from hydrogen, alkanoyloxy, hydroxyl, benzoyloxy and pyridinium radicals or a carbon-oxygen bond with the carboxylic acid radical.

   In cases where A is a pyridinium radical, the cationic charge which this group possesses is balanced or compensated by the anionic charge of the carboxylic acid radical, the entire molecule being of Zwitter-ionic nature and M being an anionic charge. A can also denote a hydroxyl group or a lower alkanoic acid group having 1 to 6 carbon atoms, as well as the benzoic acid esters of this acid. The hydroxyl group represented by A can also be esterified internally with the carboxylic acid radical of the carbon-oxygen backbone of isovaletic acid, so as to form a lactone ring, when A and M taken together denote a monovalent carbon-oxygen bond.



   Also within the scope of the present invention are the pharmaceutically acceptable non-toxic salts of the above-mentioned carboxylic acid radical. Among the cations contained in these salts and defined by M, there may be mentioned, for example, the ions of alkali metals, such as, for example, the sodium ion, the potassium ion, the calcium ion, as well as the organic cations. amines, such as alkyl ammonium groups, such as the triethylammonium group.



   The compounds according to the present invention are therefore derivatives of thianaphthenecarboxylic and benzofuran carboxylic acids, which are prepared by treating certain heterocyclic amino rings; d formula:

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   H2N-CH - CH
 EMI5.1
 t C N 0
II in which R has the meaning indicated above, with a mixed anhydride of thianaphthenecarboxylic acid or benzofuran carboxylic acid, so as to form the desired carboxy amido compound. The necessary mixed anhydride is obtained, for example, by treating a thianaphthenecarboxylic acid or benzofuran carboxylic with a lower alkyl chloroformate, such as, for example, ethyl chloroformate / or with an acid chloride.

   The reactions of the process according to the invention can be schematized as follows:
 EMI5.2
 / B 0 0 K (CH) n-COH + ci-c-oc2H5 ##### Z / or III SO-C1 * fT ###? H2N-CH - CEyS h ¯¯¯¯¯ - (DB 0/3 ##### 1 Z (CH) n-C-Y, 5) IV II \ B n il "-co- B 0 't r' i

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0 where Y, in formula IV denotes a group OOCH25 in the case of treatment with ethyl chloroformate or -Cl in the case of thionyl chloride.



   Among the starting materials, the structures of which are represented by formula II, there may be mentioned, for example, 6-aminopenicillanic acid, 7-aminocephalosporanic acid and certain related derivatives of 7-aminocephalosporanic acid. This heterocyclic compound, 7-aminocephalosporanic acid, can be prepared from the antibiotic substance Cephalosporin C, whose physical and anti-microbial properties are known and whose structure is represented by the following formula:
 EMI6.1
 n M - "'"' CH- (CH2> 3-C-NH-CH - "CHS \ CHZ HOOC r r OC - NC HzOCOCH3 1 COOH v
By hydrolysis of Cephalosporin C, for example, by acid hydrolysis, α-aminoadipic acid and 7-aminocephalosporanic acid are formed, the structure of which can be represented by the formula:

   
 EMI6.2
 NH2-CH ----- H -, S, - CH ôC r "-l,) - CH20COCH t COOH
VI
In addition to the formation of 7-aminocephalosporanic acid during the acid hydrolysis of Cephalosporin C, it is also formed by hydrolysis of an acetyloxy group and subsequent internal esterification, the lactone corresponding to the formula

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 EMI7.1
 H2N-CH ---- CH "-S N - ', H2 H2N-f H --- CH 1 1 1 N" -cC \ C-0 If 0 VII
The two products represented by formula VI and by formula VII can be easily separated, due to their different physical properties, for example by chromatographic techniques.



   The Applicant has observed, moreover, that it is possible to modify the structure of 7-aminocephalosporanic acid by enzymatic cission of acetyloxy croup, without subsequent formation of lactone. 3-hydroxymethyl-7-aminodecephalosporanic acid is thus formed corresponding to the formula:
 EMI7.2
 H2N-CH CU CH2 / C ---- N,: -, - CH20H COOH VIII
The name "decephalosporanic acid" is used in the present specification for simple nomenclature reasons and it designates the core of the basic heterocyclic acid corresponding to the formula:

   
 EMI7.3
 CHZ - r CH r CH9 t2 t '- 0 C --ß "pH r COOH
IX
This cleavage of the acetyloxy group, to form 3-hydroxymethyl-7-aminodecephalosporanic acid without subsequent formation of lactone can be effected by employing enzymatic means, for example, by the action

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 an acetylesterase. Suitable enzyme preparations can be obtained, for example, from citrus fruits, such as oranges, grapefruits, lemons and the like, as described by Jansen et al.



  Arch. Biochem., 15,415 (1947). The preparations of such an enzyme advantageously ensure the hydrolysis of the acetyloxy side chain, without subsequent formation of lactone.



  The hydroxyl group then obteneut to be further modified, for example by re-esterification with a radical of a lower alkanoic acid or a radical of benzoic acid, so as to form the lower alkanoates homologous to the acetate present in natural cephalosporin C. or the corresponding benzoate.



   Since the conditions and reagents employed for acylation of hydroxyl groups are similar to those employed for acylation of amino group, it is generally desirable in practice to perform acylation of the group. hydroxymethyl in position 3 of deccephalosporanic acid, after formation of the carboxy amido group in position 7. Deacetylation of cephalosporin C or of 7-aminocephalosporanic acid according to the enzymatic techniques set out in this specification, followed by 'Re-acylation of the resulting hydroxyl group usually results in an unwanted concomitant acylation of the amino group of the α-aminoadipic side chain acid of Cephalosporin C or of the amino group in the 7-position of the 7- acid. aminocephalosporanic respectively.

   Thus, in practice, Cephalosporin C is cleaved by acid hydrolysis, as described above, to form 7-aminocephalosporanic acid which is, in turn, subjected to the treatments according to the present invention, to form derivative 7. -carboxyamide of cephalosporanic acid. This compound can then be

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 treated with acetyl esterase as described herein, to form the corresponding compound containing a hydroxy methyl group in the 3-position, this compound being, in turn, re-acylated, by methods analogous to those known in the art, for example using an acyl halide or an acid anhydride.



   Treatment of cephalosporin C with a tertiary base such as, for example, pyridin, quinoline or collidine, before acidic hydrolytic cleavage of the aminoadipic acid side chain, forms a salt derivative. quaternary of Cephalosporin C which, on hydrolysis, gives a nucleus to which, in the case of pyridine, has been assigned the name of 3-pyridinium-methyl-7-aminodecephalosporanic acid internal salt responding to frmole
 EMI9.1
 H2N-CH - CH J} H2 0, --- N 1 - C, H2 \ =. X 000 x
Catalytic reduction of Cephalosporin C with palladium on charcoal, followed by acid hydrolysis as described herein provides the nucleus of 3-methyl-7-amino-decephalosporanic acid which,

   when reacted with the acid chloride or mixed anhydrides of benzofuran carboxylic and thianaphthene carboxylic acids employed in the process according to the present invention, provides the 3-methyl substituted 7-carboxyamidodecephalosporanic acids. These reactions can be schematized as follows:

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 EMI10.1
 NH2 ,,, S CH 'H2 CH (CH2) 3-C-NH-CH - CH CH2 H2 HOOC / C ### N C-CHZOCOCH3 COOH v NH2 0 \ CH (CHZ) 3 CTH-CH-CH CH, NH -GH-CH CH / Gli (CH 2) 3 t lH2 NH 2 T t CH 2 HOOC, Ç - TC% H-CH3. ## N / CH-CH3 0 1 COOH COOH XI XII B 0 B 0 ti # ## t 'X -H- (CN) CC1 X il 4j- (CH2) nC-NH-CH-CH CH2 7' 7 t cl-at COOH
XIII
Many of the necessary thianaphthene carboxylic and benzofuran carboxylic acids employed as starting materials are readily available.

   Those which are not can be prepared from appropriate thianaphthene by methods analogous to those known in the art and described below.



   The following examples will further illustrate the invention. These examples should not be considered as limiting the scope of the invention, this scope being defined only by the claims terminating this specification.

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   EXAMPLE 1
270 g (2.02 moles) of anhydrous aluminum chloride are added to 1.8 l of carbon disulfide. The suspension is cooled to 5 ° C. and a mixture of 210 g (1.57 mol) of thianaphthene, 107 g (1.36 mol) of acetyl chloride and 200 ml of carbon disulfide are added dropwise. drop and at a rate such that a temperature below 100C is maintained. When this addition is complete, the reaction mixture is left to stand for 2 hours, after which 10% hydrochloric acid is added, so as to decompose the reaction mixture. The layers that form are then separated. The aqueous layer is extracted three times with ether and the ethereal extracts are then combined with the organic layer.

   This solution is dried over magnesium sulfate, after which the solvents are removed in vacuo and the residue obtained is subjected to fractional distillation, so that 3-acetylthianaphthene boiling at 135-137 / 3 mm is obtained.



   A solution of 34 g (0.825 mol) of sodium hydroxide in 280 ml of water is cooled to 0 C .; 48.0 g (154 ml., 0.3 mol) of bromine are added dropwise to the solution obtained, so as to maintain a temperature below 10 C. The solution is again cooled to 0 and 17 6 g (0.1 mol) of 3-acetylthianaphthene are added dropwise while maintaining a temperature of 0 ° C. After decolourization of the reaction mixture, stirring is continued for 3 hours. At the end of this period, the reaction mixture is distilled in the presence of water vapor, so as to drive off the bromoform and the carbon tetrabromide. The residue is then cooled to 50 ° C. and acidified by adding 40 ml of concentrated sulfuric acid.

   The solid material which thus forms is collected by filtration, washed with water and recrystallized.

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 read in hexane, so that thianaphthene-3-carboxylic acid is obtained.



   EXAMPLE 2
A solution of 12.3 g (0.086 mole) of thia-naphthene-3-carboxylic acid in 200 ml of acetone is cooled in an ice bath at 0 ° C. The solution is cooled, 10.2 g (0, 1 mole) of triethylamine in 100 ml of acetone. The temperature of the reaction mixture is maintained at -10 C and a solution of 12.5 g (0.11 mol) of ethyk chloroformate in 45 ml of acetone is added dropwise, while stirring, so maintaining a final reaction temperature of -5 C. To this mixture is then added slowly, while stirring, a solution of 23.8 g (0.1 mol) of 6-aminopenicillanic acid in 40 ml of water and 15 ml of triethylamine.

   When the addition is complete, the mixture is stirred and allowed to come to room temperature, after which it is further stirred for a further 30 minutes. The mixture is extracted with three fractions of 300 ml of ether and the resulting aqueous solution is brought to a pH of 2.0 using 6N sulfuric acid, maintaining a temperature below 10 C. At a pH of 2, the solution is extracted with 250 ml of butyl acetate and then twice, each time with 75 ml of butyl acetate.



   To the combined butyl acetate extracts, 250 ml of water are added and the pH is adjusted to 8.0 by the addition of solid potassium bicarbonate while stirring. The layers are separated and the aqueous layer is brought to a pH of 2.0 by the addition of 6N sulfuric acid at a temperature below 10 C. The acidic aqueous mixture is then extracted with 200 ml of butyl acetate. and the organic extract is then washed once with water and dried over sodium sulfate. With the butyl acetate solution,

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 a solution of potassium hydroxide in N-butanol (40 g / l) is added while stirring vigorously until the pH of the reaction mixture is 8.4 The mixture is cooled until it occurs crystallization.

   The crystals are then collected by centrifugation, washed with a small amount of acetone and dried. The dried crystals are recrystallized from butanol and dried.
 EMI13.1
 so as to obtain 6- / ¯ (3-thianaphthenyl) - carboxyamid27-penicillanic acid in the form of potassium salt. Alternatively, 3.5 g (0.02 mole) of thianaphthene-3-carboxylic acid is reacted with 11 ml of thionyl chloride at room temperature overnight. The solution obtained is evaporated in vacuo at 35 ° C. and the oil obtained is added with 25 ml of benzene, after which the mixture is again evaporated.

   After adding a further 25 ml of benzene and repeating the treatment described above, the residual oil is kept under vacuum, to remove any traces of thionyl chloride, after which 4 g of the oil are dissolved in 50 ml. of dried acetone. The resulting solution is added slowly, while stirring, to 4.3 g of 6-aminopenicillanic acid in 190 ml of a 3% aqueous solution of sodium bicarbonate and 120 ml of acetone.



  The reaction mixture is maintained at 25 C for 11/2 hours and then extracted twice with 150 ml of ether. To the residual aqueous solution is added 40 ml of butyl acetate. The mixture obtained is cooled to a temperature below 10 ° C., after which its pH is adjusted to 2.4 by means of 20% phosphoric acid and the phases obtained are separated. The aqueous phase is extracted with 15 ml of butyl acetate and the combined butyl acetate extracts are washed with 10 ml of water, the pH of which has been adjusted to 3. The washed organic solution is then dried over sulfate. magnesium and filtered. To the filtrate is added

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 9.6 ml of a 30% isopropanolic solution of potassium 2-ethylhexanoate.

   After addition of one volume of ether, while stirring, the crystals which form on cooling are collected by filtration, washed with a mixture (1: 1) of ether and butyl acetate, then with ether, the crystals being finally dried.
 EMI14.1
 6 (3-Thianaphthenyl) -carboxyamidJ penicillanic acid as a potassium salt.



   By treating the potassium salt with HCl and extracting with ether, the acid 6 - [(3-
 EMI14.2
 thianaphthenyl) -carboxyamid27-penicillanic free.



     EXAMPLE 3
Equivalent amounts of the following substituted thianaphthenes are subjected to the procedure of Example 1: 4-bromothianaphthene, 7-bromothianaphthene, 5-chlorothianaphthene and 6-chlorothianaphthene.



   The correspondingly substituted thianaphthene 3-carboxylic acids thus obtained are then treated in the manner described in Example 2. The
 EMI14.3
 following compounds: 6- (4-Bromo 3-thianaphthenyl) - carboxyamido-7-penicillanic acid, 6- (7-bromo 3-thianaphthenyl) -carboxyamido7-penicillanic acid, 6 - / ** ( 5- chloro 3 -thianaphthenyl) -carboxyamid-penicillanic and 6 - (6-chloro-3-thianaphthenyl) -carboxyamid21-penicillanic acid.



    EXAMPLE 4
As described in Example 3 equivalent amounts -, / of the following thianaphthenes are treated as described in Examples 1 and 2: thianaphthene, 5-methoxythianaphthene, 5-ethlthianaphthene, 5-butylthianaphthene and 5-trifluoromethylthianaphthene. The following compounds are thus obtained respectively: acid
 EMI14.4
 6 C (6-methßl-3-thianaphthenyl) -carbcxyamid-penicillanic acid, 6 - [(5-methoxy-3-thianaphthenyl) -carboxyamido7-penicil-

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 EMI15.1
 Lanic acid, 6-C (5-ethyl 3-thianaphthenyl) -carboxyamid penicillanic acid, 6 (5-butyl 3-thianaphthenyl) -carboxy-amid2! -penicillanic acid and 6 (5-trifluoromethyl 3-thianaphthenyl) -carboxyamid21-penicillanic acid.



   EXAMPLE 5 To a boiling solution of 152.5 g (1 mole) of
 EMI15.2
 2-Chlnrobenzaldehyde in 700 ml of ethanol, a molten mixture of 120 g of sodium sulfide and 16 g of sulfur is added dropwise with stirring over the course of 2 hours.



  The mixture is then cooled and combined with a solution of 60 g of potassium hydroxide and 60 g of sodium sulfide in 300 ml of water. The mixture is heated for 15 minutes and brought to a boil. To this mixture is then added, while stirring, a solution of 140 g of chloroacetic acid in 250 ml of water which has been neutralized by adding sodium bicarbonate. The mixture is left for 15 hours. At the end of this period, a crystalline mass forms. This is collected by filtration and dissolved in a dilute aqueous solution of sodium hydroxide. On acidification a solid material forms which is collected by filtration, dried and recrystallized from hexane to form thianaphtse-2-carboxylic acid.

   This compound is then used instead of thianaphthene -3-carboxylic acid in the procedure of Example 2, and 6 - [(2
 EMI15.3
 thianaphthenyl) -carboxyamido7 "-penicillanic acid.



   Similarly, equivalent amounts of the following substituted benzaldehydes are used instead of 2-chloro-4-methylbenzaldehyde, 2-chloro-4-m ethoxy-benzaldehyde and 2-chloro-4-ethoxybenzaldehyde.



  The following compounds are respectively obtained: 6-methylthianaphthene-2-carboxylic acid, 6-methoxythianaphthene-2-carboxylic acid, 6-ethoxythianaphthene-2-carboxylic acid. By using equivalent amounts of these

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 compounds in the procedure of Example 2, the following compounds are obtained respectively: acid 6 - [(6-methyl-2
 EMI16.1
 thianaphthenyl) -carboxyamido 7 -penicillanic acid, 6-r (6-methoxy-2 thianaphthenyl) -carboxyamidJ penicillanic and 6- / 6-erhoxy-2-thianaphthenyl) -carboxyamid penicillanic.



   EXAMPLE 6
A cooled solution of 29.5 g (0.217 mole) of N-butyl bromide in 40 ml of anhydrous ether is added dropwise to a cooled suspension of 3.6 g (0.535 mole) of lithium in the form of wire. finely cut from 70 ml of anhydrous ether. The reaction mixture is cooled in an ice bath during this addition and, when this is complete, this mixture is heated under reflux for 1 hour, while stirring. The reaction mixture is then filtered and cooled in an ice bath. 19.3 g (., 0.044 mol) of thianaphthene in 30 ml of anhydrous ether are then added. When this addition is complete, the mixture is heated at reflux for 45 minutes.



   To this ethereal solution of thianaphthene lithium was slowly added 22.5 g (5.0 moles) of acetaldehyde in 500 ml of cooled anhydrous ether. The mixture is heated at reflux temperature for 1 hour, then it is poured into 5 liters of ice water saturated with ammonium chloride.



  The organic layer is then separated and the aqueous layer is extracted three times with ether. The combined organic layers are dried over sodium carbonate and distilled in vacuo, whereby 1- (2-thianaphthenyl) -etanol is obtained.



   A mixture of 35.6 g (0.20 mol) of 1- (2-thianaphthenyl) -ethanol and 29.7 g (0.25 mol) of thio- chloride; nyle is heated to reflux for 90 minutes. The mixture is then distilled and recrystallized from hexane, sour

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 te which is obtained from 2- (a-chloroethyl) -thianaphthene.



   A mixture of 14.9 g (0.076 mole) of 2- (a-chloro-ethyl) -thianaphthene, 7.8 g (0.12 mole) of potassium cyanide, 125 ml of dioxane and 65 ml of water is stirred under reflux for 3 hours. The mixture is then cooled, then added with water, after which the organic layer is separated. The aqueous layer is then extracted three times with benzene and the benzene extracts are then combined with the organic layer. The combined organic solutions are then washed, dried and freed from solvents under reduced pressure. By vacuum distillation of the residue, 2- (a-cyanoethyl) -thianaphthene is obtained.



   A mixture of 14.9 g (0.06 mole) of 2- (a-cyano-ethyl) -thianaphthene, 10 g of sodium hydroxide (0.25 mole), 50 ml of water and 50 ml of ethanol is heated under reflux for 18 hours. The mixture is then cooled, after which about 17 ml of concentrated hydrochloric acid is slowly added, until the mixture is only weakly basic. The mixture is then filtered and the filtrate is heated to boiling to drive off excess ethanol. After addition of water, the basic aqueous solution is washed with ether. the washed solution is then clarified with charcoal and filtered, after which the filtrate is acidified.

   The solid material which thus forms is collected by filtration, dried and recrystallized from carbon tetrachloride, whereby α- (2-thianaphthenyl) -propionic acid is obtained.



   The o .- (2-thianaphthenyl) -propionic acid is then treated in the manner described in Example 2. At the end of the operating stages described in this example, one obtains
 EMI17.1
 6- / ¯a- (2-thianaphthenyl) -propior.atnido7 * -penicillanic acid. 1 acid e j EXAMPLE 7 #######
Working in a similar fashion, but employing formaldehyde instead of acetaldehyde during the initial stages.

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 -tiaux of the procedure of Example 6, 2-thianaphthenylmethanol is obtained, which, after having been treated in the manner described for the remaining stages in Example 6,
 EMI18.1
 provides 6 (r2-thianaphthenyl) acetamid penicilla- nic acid.



   EXAMPLE 8
By employing the substituted thianaphthenes mentioned in Examples 3 and 4 in the procedure of Example 6, the following compounds are obtained: acid 6- [Ó- (4-
 EMI18.2
 bromo-2-thianaphthenyl) 3ropionamid pencillanic, 6a- (5-chloro-2-thianaphthenyl) -propionamid penicillanic acid, 6- ± -a- (6-ohloro-2-thianaphthenyl) -propionamido7- penicillanic acid, 6a - (7 bromo - tfiia.aphthenyl) - propionamid2l-penicillanic acid, b "a- (b-methyl-2-thia- naphthenyl) -propionamido7-pneicillanic acid, 6 - (5-methoxy -2-thianaphthenyl) propionamid > -pneicillanic acid, 6-La- (5- ethyl-2-rhianaphthenyl) propionamid7-penicillanic acid, 6 ra- (5-butyl-2-thianaphthenyl) propionamid penicillanic acid and 6-Ca- (5-trifluoromethyl-2- thianaphthenyl) -propiona- midoj-pdnicillanique.



   Similarly, employing these substituted thianaphthenes in the procedure / of Example 7, in which formaldehyde is employed instead of acetaldehyde, the following compounds are obtained: 6 - [(4-bromo-2 -
 EMI18.3
 thianaphthenyl) acetamid ± 7-penicillanic acid 6 (5- chloro-2-thianaphthenyl) -acetamidoJ-penieillanic acid, 6- ± - (6-chloro-2-thianaphthenyl) -acetamioJ-penicillanic acid, 6- ± - (7 -bromo-2-thianaphthenyl) acetamidoj-penicillanic acid, 6--6-methyl-2-thianaphthenyl) -acetamid21-penicillanic acid "6 5-methoxy-2-thianaphthenyl) -acetamidoepenicillaniqz acid, 6-5-ethyl-2- thianaphthenyl) -acetamidJ -penicillanic acid, 6-L5-butyl-2-thianaphthenyl) -acetamid> penicillanic acid, 6 - (5-trifluoromethyl-2-thianaphthenyl) -acetamid27- penicillanic acid.

   

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   EXAMPLE 9
A stream of chlorinated hydrogen is passed through a solution of 372 g (4.6 moles) of 372 aqueous formaldehyde and 153 ml (4.2 moles) of concentrated hydrochloric acid and 500 g of thianaphthene. , until the solution is saturated with chlorinated hydrogen. During this time the temperature rises to about 5 ° C. and is held there for 1 hour, while the slow bubbling of chlorinated hydrogen is continued. At the end of this period, the mixture is cooled and poured into 350 ml of ice water. The mixture is then extracted with benzene and the benzene extracts are successively washed with water, with a 10% aqueous solution of sodium bicarbonate and finally again with water. The washed bezene solution is then dried and the solvents are driven off under reduced pressure.

   The residue is distilled off in vacuo, so that 3-chloromethyl-thianaphthene is obtained.
 EMI19.1
 



  By using an equivalent amount of acetaldehyde instead of formaldehyde in the procedure described above, 3- (a-chloroethyl) -thianaphthene is obtained.



   3-Chloromethylthianaphthene (13.9 g, 0.076 mole) is combined with 7.8 g (0.12 mole) of potassium cyanide, 125 ml of dioxane and 65 ml of water. This mixture is stirred under reflux for 3 hours, after which it. is cooled. The organic layer is separated and the aqueous layer is extracted three times with benzene. The benzene extracts are then combined with the organic layer and the total organic solution obtained is then washed with water, dried and freed from solvents under reduced pressure. By distillation of the residue under vacuum, 3-cyanomethylthianaphthene is obtained.



   A mixture of 13.7 g (0.08 mole) of 3 -cyanomethyl-thianaphthene, 10 g of sodium hydroxide (0.25 mole), 50 ml of water and 50 ml of ethanol is heated at reflux during

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 before 6 p.m. The mixture is then cooled and about 17 ml of concentrated hydrochloric acid is added slowly until the mixture is only weakly basic.



  The mixture is then filtered and the filtrate is heated to boiling to remove excess ethanol. Water is then added to the basic aqueous solution, and this dilute solution is then washed with ether and clarified with charcoal. After filtration, the filtrate is acidified and the solid material which forms is again collected by filtration, dried and recrystallized from carbon tetrachloride, so that (3-thianaphthenyl) -acetic acid is obtained.



   By subjecting 3- (α-chloroethyl) -thianaphthene prepared in the manner described above to the treatment described above, α- (3-thianaphthenyl) - propionic acid is obtained.



   By subjecting equivalent quantities of a- (3-thianaphthenyl) -propionic acid and (3-thianaphthenyl) - acetic acid to the procedure described in Example 2, one obtains
 EMI20.1
 contains 6α- (3-thianaphthenyl) -propionamidJ-penicillanic acid and 6 r (3-thianaphthenyl) acetamido7-penicillanic acid, respectively.



   EXAMPLE 10
4 g of Cephalosprin C in the form of the sodium salt are dissolved in 60 ml of water and the pH is adjusted to 2.5 by adding the acid form of the Dowex 50 resin (X $).



  The resin is filtered and washed with 20 ml of water. 20.5 ml of 0.1N hydrochloric acid are added to the combined filtrate and washings. The mixture is left to stand for 72 hours at 20 ° C., after which it is poured onto a column of Dowex-1 resin (in the form of acetate), 2 cm × 10 cm. The initial percolating solution is collected in 10 ml fractions and when the twelfth fraction has been collected the column is eluted with water, until

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 that a total of 34 fractions were collected. The column is then eluted with 0.5N acetic acid and 65 additional fractions are collected.



   Fractions 36-45 are combined and concentrated by freeze drying to give 7-aminocephalosporanic acid.



   Fractions 2 to 16 are combined and conentrated in vacuo to give the lactone of deacetyl cephalosporin C which, when again subjected to the above-described acid hydrolysis treatment, gives the lactone of acid 3- hydroxymethyl-7-aminocephalosporanic.



   By increasing the concentration of the acid in the procedure described above, so that this concentration changes from 0.1N to 1.0N and by increasing the duration of the reaction to 4 days, the quantities of Cephalosporin C deacetyl acid lactone and acid lactone
 EMI21.1
 3-hydroxymethyl =? - aminocephalosporanic.



   EXAMPLE 11 A. - 1 g of Cephalosporin C in the form of sodium salt is dissolved in 50 ml of water. A sufficient quantity of Dowex-50 (X8) resin in hydrogenated form is then added to adjust the pH to 2.6. The resin is then separated by filtration, and the filtrate is added with 3.8 ml of pyridine, the pH rising to about 6.5. The solution is maintained at 37 ° C. for 48 hours in a glass container. At the end of this period the solution is freeze-dried and the residue is triturated twice with 50 ml of acetone and re-dried. The solid material is then dissolved in 10 ml of water and the solution obtained is poured onto a column of Dowex 1 resin; (X10) as acetate, 2cm x 10cm. The column is eluted with water and 10 ml fractions are collected.



  Fractions 2 to 4 are then combined and dried by dongé

 <Desc / Clms Page number 22>

 lation. The residue is stirred with acetone and dried to give the pyridinium internal salt of desacetyl Cephalosporin C.



  B. - This material is then subjected to the acid hydrolytic treatment described in Example 10. After chromatographic separation as described therein. For example, the first fractions collected are combined and evaporated until a residue is obtained consisting of the internal salt of 3-pyridiniummethyl-7-aminodecephalosporanic acid. The last fractions are combined and concentrated until the internal pyridinium salt of deacetyl cephalosporin C is obtained which can be subjected to the hydrolytic treatment again, to provide an additional quantity of material.



   EXAMPLE 12
A solution of 1.52 g (0.086 mole) of thia-naphthene-3-carboxylic acid in 20 ml of acetone is cooled in an ice bath at 0 C. To the cooled solution, 1.02 g (0 0.1 mole) of triethylamine in 10 ml of acetone. The temperature of the reaction mixture is kept at 0 and a solution of 1.25 g (0.011 mol) of ethyl chloroformate in 4.5 ml of acetone is added dropwise with stirring. The reaction mixture is stirred for 30 minutes and allowed to gradually come to room temperature, after which it is filtered. The filtrate thus obtained is added slowly to a solution of 2.72 g (0.01 mol) of 7-aminocephalosporanic acid in 90 ml of a 3% aqueous solution of sodium bicarbonate and 50 ml of acetone.

   When the addition is complete, the mixture is allowed to come to room temperature and stirring is continued for a further 90 minutes. The mixture is then extracted three times with fractions of 30 ml of ether and the aqueous solution obtained is adjusted to a pH of 2.5 by addition of concentrated sulfuric acid, During

 <Desc / Clms Page number 23>

 This pH adjustment, the temperature is maintained at a value below 10 ° C. When a pH of 2.5 has been reached, the solution is extracted with 25 ml of butyl acetate and then twice again with 10 ml of butyl acetate. The butyl acetate extracts are washed once with water, then an additional 25 ml of water is added and the pH is adjusted to 8.0 by adding solid potassium bicarbonate, while stirring.

   The aqueous layer is separated, filtered and adjusted to a pH of 2.0 by adding concentrated sulfuric acid at a temperature below 10 C. The acidic aqueous mixture obtained is extracted twice with 20 ml of butyl acetate, washed with water and dried over sodium sulfate. To the dried butyl acetate solution is added, with vigorous stirring, a solution of potassium hydride in n-butanol (40 g / l) until the pH of the reaction mixture is 8.4 The mixture is cooled until crystallization occurs and the crystals formed are collected by centrifugation, washed with a small amount of acetone and dried. The dried crystals are dissolved in a minimum amount of a mixture (9: 1) of acetone and water and precipitated by adding anhydrous acetone.

   These crystals are collected and dried, so that one obtains
 EMI23.1
 7 L "(3-Thianaphthenyl) -carboxyamid-cephalospora- nic acid as the potassium salt.



   By treating an aqueous solution of the potassium salt with chlorinated hydrogen and extracting with
 EMI23.2
 ether, 7- ± - (3-thianaphthenyl) -carboxy-amido7-cephalosporanic acid is obtained
In a similar fashion, using an equivalent amount of thianaphthene-2-carboxylic acid instead of thianaphthene-3-carboxylic acid in the procedure
 EMI23.3
 from this example, 7 C (2-thianaphthenyl) - carboxyamido / -cephalosporanic acid is obtained.

 <Desc / Clms Page number 24>

 



   Likewise, by using equivalent amounts of a- (2-thianaphthenyl) -propionic acid, a- (3-thia-
 EMI24.1
 naphthényD-propionique, acid (2-thianaphthényl) -ï.o <3tique and 3 -thianaphthényl acetic acid, one obtains by operating in the manner described in this example, acid 7- [Ó- (2 -thia naphthenyl) -propionamido7-cephalosporanic acid
 EMI24.2
 7 Ca- (3-thianaphthenyl) propionamid-cephalosporanic acid, 7 r (2 thianaphthenyl) acetam.id cephalosporanic acid and 7 (3 thianaphthenyl) -acetamido, -cµphalo9pora: ic acid
EXAMPLE 13
3-Hydroxy-methyl-7-aminodecephalosporanic acid lactone (2.28 g) is reacted with ethyl formate mixed with thianaphthene-3-carboxylic acid anhydride, according to the initial procedures of Example 12.

   The reaction mixture is extracted with butyl acetate and the organic extracts are then concentrated until a residue consisting of
 EMI24.3
 3-hydroxymethyl-7 (3-thianaphthenyl) acid lactone. carboxyamido / -deephalosporanic acid, which is further purified by recrystallization from ether.



   In a similar fashion, the other thianaphthene-carboxylic acids described in the present specification can be used in place of thianaphthene-3-carboxylic acid, to form the 7-carboxy amido cor- f derivatives.
 EMI24.4
 responders to the 3 - hydroxymethyldecephalosporanic acid lactone. EXE1 <1PLE
EXAMPLE 14
Analogously, equivalent amounts of the internal salt of 3-pyridiniummethyl-7-aminodecephalosporanic acid are employed instead of 7-aminocephalosporanic acid in the procedure of Example 12. This gives rise to the invention.
 EMI24.5
 thus the internal salt of 3-pyridiniummethyl-7 - (3-thianaphenyl) -carboxyamid> deccephalosporanic.

 <Desc / Clms Page number 25>

 



   EXAMPLE 15
An acetyl esterase preparation obtained from the peels of 72 oranges by the method of Jansen et al., Arch. Biochem. 15 415 (1947) is added to 1 g of 7- (3-thianaphthenylcarboxyamido) -cephalosporanic acid dissolved in 15 ml of water. The pH is set to 6 and maintained at this value or higher for 15 hours. At the end of this period, the solution is passed through a column of IR 4B resin (in acetate form) and eluted with a 0.1M aqueous solution of acetic acid, the pH of which has been adjusted by addition. of pyridine, to 5.5.

   The solutions collected by development of column i. Are brought to a pH of 8 by adding sodium hydroxide and the alkaline mixture is evaporated in vacuo, until 3-hydroxymethyl-7- (3- thianaphthenylcarboxyamido) -decephalosporain in the form of sodium salt.



   To 1 g of 3-hydroxymethyl-7- (3-thianaphthenylcarboxyamido) -deephalosporanic acid in 10 ml of collidine, 15 ml of propionyl chloride is added. The mixture is left to stand for 10 hours and is then poured into 25 ml of ice water. The solid material which thus forms is collected by filtration, recrystallized from dimethylformamide and dried, whereby one obtains
 EMI25.1
 3-propionyloymethyl-'J- (3-thianaphthenyl) -carboxyami-i do7-decephalosporanic acid.

   Similarly, other lower alkanoyl chlorides, such as butanoyl chloride or pentanoyl chloride can be employed instead of propionyl chloride. We obtain the cor-
 EMI25.2
 respondents: 3-butaroyloxymethyl-7 (3.-thionaphthenyl) - carboxyamido7-decéphalosporan-i.que acid and 3-pentanoyloxy-methyl-7 - / "(3-thianaphthenyl) -carboxyamido / -decephalosporanic acid;
Similarly, benzoyl chloride is employed instead of these lower alkanoyl chlorides. We

 <Desc / Clms Page number 26>

 
 EMI26.1
 obtains 3-benzoyioxymethyl-7-Z- (3-thianaphthenyl) - carboxyamido7-decephalosporanic acid.



  Using 7-y (2-Thianaphthenyl) -car- boxyamidil-cephalosporanic acid 7-ra- (2-thianaphthenyl) -propionamido7-cephalosporanic acid and 7-LrJ-thianaphthenyl) carboxyamid21- cephalosporanic acid, the following compounds are respectively obtained by treating them as described in the present example: 3-proino acid
 EMI26.2
 oxymethyl 7 r (2-thianaphthenyl) -caW oxyamid-.d.ecephalosporanic acid, 3-propionyloxymethyl-7-Za- (2-Ghianaphthenyl) - propionamido7-decephalosporanic acid and 3-propionyloxy-methyl 7 r (2) thianaphthenyl acid -acetamidoT-decephalosporanic.



   In a similar fashion, the corresponding benzoates of the above compounds are prepared using benzoyl chloride;
EXAMPLE 16
To 500 ml of anhydrous ether, 18.6 g (0.49 mol) of lithium aluminum hydroxide are added. The mixture is stirred and rinsed with nitrogen, after which is added dropwise, so as to produce a moderate reflux, 48.6 g (0.31 mol) of benzofuran 3-carboxylic acid. The mixture is then stirred for a further 90 minutes at room temperature and the excess lithium aluminum hydroxide is decomposed by the subsequent addition, with caution, of 19 ml of water, 57 ml. of a 10% aqueous solution of sodium hydroxide and 57 ml of water.

   The resulting mixture is filtered and the collected solid is mixed with additional water, then stirred and filtered again. The filtrates are combined and the layers are separated. The aqueous layer is then extracted with ether and the combined organic layer is dried over magnesium sulfate and concentrated under reduced pressure until an oil is obtained. This oil is then distilled under vacuum, so that one obtains

 <Desc / Clms Page number 27>

 
3-hydroxymethyl-benzofuran.



   To 88.1 g (0.74 mol) of thionyl chloride, 45 g of 3-hydroxymethylbenzofuran are slowly added, while cooling. When this addition is complete, the mixture is heated under reflux on a steam bath for 90 minutes and the excess thionyl chloride is driven off under reduced pressure. The residue is rinsed twice with anhydrous benzene and the solvents are driven off, after each addition, under reduced pressure. The residue thus obtained is then distilled under vacuum, so that one obtains
3-chloromethylbenzofuran.



   34.3 g (0.22 mol) of 3-chloromethylbenzofuran are added to 40 ml of dimethylformamide. To this solution is added 20 g (0.41 mol) of sodium cyanide in 40 ml of dimethylformamide. The solution is cooled in a water bath, until no more heat is given off. The mixture is then stirred for 15 minutes at room temperature and finally heated to 60 ° C. for 2 hours. The mixture is then cooled and filtered and the filtrate is concentrated in vacuo. The residue is then distilled, which makes it possible to obtain 3-cyanomethylbenzofuran.



   2 g of 3-cyanomethylbenzofuran are dissolved in
30 ml of alcohol 30 To this solution is then added a solution of 0.6 g (0.015 mol) of sodium hydroxide in
10 ml of water. The mixture is heated under moderate reflux for 18 hours, cooled, brought to a pH of 9.3 using concentrated hydrochloric acid and filtered. The filtrate is evaporated to remove solvents and the residual solution is diluted with water to about 50 ml, then extracted with two 50 ml portions of ether. The residual aqueous phase is then decolorized with 0.25 g of
Norit and filtered. On adjusting the pH to 2.9 with concentrated hydrochloric acid, a solid is formed which is collected by filtration and dried.

 <Desc / Clms Page number 28>

 so as to produce (3-benzofuryl) -acetic acid.



   EXAMPLE 17
To 150 g of carbon disulphide, 39.2 g (0.47 mol) of benzofuran are added. The mixture is stirred vigorously, while cooling, after which 75 g (0.47 mol) of bromine in 150 g of carbon disulfide are added dropwise. The rate of addition is controlled so that the temperature does not exceed -5 C. When the addition is complete, the solution is filtered and the solid material thus collected is recrystallized from chloroform, so that benzofuran dibromide is obtained.



   A total of 27.8 g (0.1 mole) of benzofuran dibromide is added in several portions to a cooled solution of 12 g of potassium hydroxide in absolute ethanol. When the addition is complete, the mixture is allowed to come to room temperature, after which it is heated to reflux, with stirring, for 2 hours.



  At the end of this period, the mixture is distilled in the presence of water vapor and the organic layer is separated from the distillate. This distillate is washed once with water and dried over sodium sulfate to give 3-bromobenzofuran.



   A mixture of 19.9 g (0.1 mole) of 3-bromobenzofuran, 9.8 g (0.11 mole) of cuprous cyanide and 20 ml of pyridine is heated for 18 hours at 215-240 C The reaction mixture is then treated with aqueous ammonium hydroxide and extracted with benzene. The benzene extracts are then evaporated until a residue is obtained at the temperature of the steam bath and this residue is recrystallized from cyclohexane. This gives 3-cyanobenzofuran, m.p. 93 C.



   To a solution of 25.0 g of methyl magnesium iodide in anhydrous ether is added 14.5 g (0.1 mole) of 3-cyanobenzofuran dropwise. During the addition,

 <Desc / Clms Page number 29>

 the reaction is controlled as needed by cooling. When the addition in question is complete, the mixture is heated under reflux for 1 hour. The solution is then cooled and added with an aqueous solution of ammonium chloride. The reaction mixture is then extracted with ether and the ethereal extracts are washed with 10% sulfuric acid and with water, after which they are dried over magnesium sulfate. The solvents are evaporated and the residual material distilled, to provide 3-benzofurylmethyl ketone.



   A solution of 16.2 g (0.1 mol) of 3-benzofuryl-methyl ketone in 20 ml of anhydrous ether is added dropwise to a suspension of 1.9 g (0.05 mol) of hydride. lithium and aluminum in 50 ml of anhydrous ether. The mixture is then heated under reflux for 30 minutes.



  Then carefully add 2 ml of water, to decompose the reaction mixture. The mixture obtained is filtered and the filtrate is extracted with ether, the ethereal extracts obtained being dried over magnesium sulfate. Evaporation of the dried ethereal solution and distillation of the residue gives 3- (α-hydroxyethyl) -benzofuran.



   3- (α-hydroxyethyl) -benzofuran is treated with thionyl chloride, sodium cyanide and aqueous sodium hydroxide according to the procedure described in Example 16, so that 'we successively obtain 3- (Ó-
 EMI29.1
 chloroethβ1) -benzofuran, 3- (a-cyanoethyl) -benzofuran and a- (3-benzofuryl) -propionic acid.



    In a similar manner by employing 5-chloroben zofuran in the procedure / present example, one obtains
 EMI29.2
 finally α- (5-ehloro-3-ben-ofuryl) -propionic acid. tK Likewise, when 6-methylbenzofuran and 5-methoxybenzofuran are treated as described in the present example, a- (6-methyl-3-benzofuryl) - propionic acid and a- (5-methoxy-3-benzofuryl) -propionic.

 <Desc / Clms Page number 30>

 



     EXAMPLE 18
One mole of salicylaldehyde (122 g) is dissolved in 400 ml of ethanet heated to reflux with 56 g of potassium hydroxide until a solution is obtained.



   This solution is then added slowly, while being stirred, with 92.5 g (1 mole) of chloroacetone. When the reaction has ceased, an equivalent volume of water is added and the resulting mixture is distilled to remove excess ethanol. The residual material is extracted with ether and the ethereal solutions are dried over magnesium sulfate. By removing the solvents under reduced pressure, a residue which is recrystallized from ethanol is obtained. In this way 2-acetylbenzofuran is obtained.



   To a suspension of 19 g (0.5 mole) of lithium aluminum hydride in 500 ml of anhydrous ether is added dropwise 160 g (1 mole) of 2-benzofurylmethyl ketone in 200 ml of anhydrous ether. The mixture is heated under reflux for 1 hour, then decomposed by adding dropwise and successively, 17 ml of water, 17 ml of a 10% aqueous solution of sodium hydroxide and 57 ml of sodium hydroxide. water.



   The precipitated salts are removed from the solution by filtration and the filtrate is concentrated until an oil is obtained which, on vacuum distillation, gives 2- (Ó-hydroxyethyl) -benzofuran.



   In a manner analogous to that described in Example 16, 2- (a-hydroxyethyl) -benzofuran is subjected to chlorination, cyanidation and hydrolysis, using equivalent amounts of the benzofuran compounds. - ques. This gives α- (2-benzofuryl) -propionic acid.



     In a similar fashion, employing 5-bromo-salicylaldehyde, 4-fluorosalicylaldehyde, 5-methylsalicylaldehyde and 4-methoxysalicylaldehyde, in the procedure; -toire of the present example, one obtains the acid a- (5-bromo-

 <Desc / Clms Page number 31>

 2-benzofuryl) -propionic, a- (4-fluoro-2-benzofuryl) -propionic acid, a- (5-methyl-2-benzofuryl) -pro- pionic acid and α- (6-methoxy-2-benzofuryl) -propionic acid.



   EXAMPLE 19
A solution of 15.2 g (0.086 mol) of 2-benzofuryl acetic acid in 200 ml of acetone is cooled in an ice bath to 0. To the cooled solution, 10.2 g (0.1 mol) of triethylamine in 100 ml of acetone are added.



  The temperature of the reaction mixture is maintained at -10 and a solution of 12.5 g (0.11 mol) of ethyl chloroformate in 45 ml of acetone is added dropwise while stirring, so as to maintain a final reaction temperature of -5 C. To this mixture is then slowly added, while stirring, a solution of 23.8 g (0.1 mol) of 6-aminopenicillanic acid in 40 ml of water and 15 ml of triethylamine. When the addition is complete, the mixture is stirred and allowed to come to room temperature, after which it is stirred for a further 30 minutes.



  The mixture is extracted with three fractions of 300 ml of ether and the resulting aqueous solution is brought to a pH of 2.0 using 6N sulfuric acid, maintaining a temperature below 10 C. At a pH of 2, the solution is extracted with 250 ml of butyl acetate, then twice more with 74 ml of butyl acetate each time.



   To the combined butyl acetate extracts, 250 ml of water are added and the pH is adjusted to a value of 8.0 by addition of solid potassium bicarbonate, while stirring. The layers are separated and the aqueous layer is brought to a pH of 2.0 by adding 6N sulfuric acid at a temperature below 10 C. The acidic aqueous mixture is then extracted with 200 ml of butyl acetate and the organic extract is then washed with water and dried over sodium sulfate. With the butyl acetate solution, we

 <Desc / Clms Page number 32>

 while stirring vigorously, add a solution of potassium hydroxide in n-butanol (40 g / l until the pH of the reaction mixture is 8.4. The mixture is cooled until 'crystallization occurs.



  The crystals are then collected by centrifugation, washed with a small amount of acetone and dried. The dried crystals are recrystallized from butanol and dried in
 EMI32.1
 so that 6-r (2er.zofryi) acetamid27-penicillanic acid is obtained as the sodium salt.



   Similarly, by employing 16.3 g of Ó- (2-benzofuryl)) - propionic acid instead of 2-benzofuryl acetic acid in the procedure of the present example, one obtains
 EMI32.2
 holds 6 a- (2-benzofuryl) -propionamid penicillanic acid. Likewise, using a- (5-bromo-2-
 EMI32.3
 benzofuryl) -propionic acid, a- (5-fluor-o-2-benzofuryl) propionic acid, a- (5-methyl-2-benzofuryl) -propionic acid and a- (6 -methoxy-2-benzofuryl) -propionic, we
 EMI32.4
 obtains 6 a- (5-bromo-2-benzofuryl) -propionamid- acid. penicillanic acid, 6 - / "m- (5-fluoro-2-benzofuryl) - propionamid27-penicillanic acid, 6 - /" a- (5-methyl- h 2-henzofuryl) propionamid penicillanic acid and 6- α- (6-methoxy-2-benzofuryl) -propionamid pericillanic acid.



   EXAMPLE 20. -
11 ml of thionyl chloride are combined with 3.52 g (0.02 moles) of 3-benzofuryl acetic acid and the mixture is left to stand at room temperature overnight. The solution obtained is evaporated under vacuum at 35 and the oil obtained is added with 25 ml of benzene. After re-evaporating the mixture, an additional 25 ml of benzene is added and the treatment is repeated. The residual oil is kept under vacuum, to remove any traces of thionyl chloride. 4 g of the oil thus obtained are then dissolved in 50 ml of dried acetone and the solution obtained is added slowly, while stirring, to 4.3 g.

 <Desc / Clms Page number 33>

 6-aminopenicillanic acid in 190 ml of a 3% aqueous solution of sodium bicarbonate and 120 ml of acetone.



  The reaction mixture is kept at 25 ° C. for 90 minutes, extracted twice with 150 ml of ether, after which the residual aqueous solution is added with 40 ml of butyl acetate. The mixture obtained is cooled to a temperature below 10 ° C. then its pH is adjusted to 2.4 using 20% phosphoric acid and the phases are separated. The aqueous phase is extracted with 15 ml of butyl acetate, and the combined extracts of butyl acetate are washed with 10 ml of water and adjusted to a pH of 3. The washed organic solution is then dried over sodium sulfate. magnesium and filtered. To the filtrate was added 9.6 ml of a 30% solution of potassium 2-ethylhexanoate in isopropanol.

   A volume of ether is then added with stirring and the crystals which form on cooling are collected by filtration, washed with a 1: 1 mixture of ether and butyl acetate, then with water. ether.



  After final drying, 6- [3 (benzofuyrl) - acetamindopendillanic acid is obtained in the form of a potassium salt.



   By treating an aqueous solution of this potassium salt with chlorinated hydrogen and extracting with ether,
 EMI33.1
 free penicillinic acid 6 (3benzofuryl) acetamid is obtained.



   Similarly, 3.24 g of benzofuran 3-carboxylic acid and 3.8 g of α- (3-benzofuryl) -propionic acid are employed in the procedure of the present example.



  6 - [(3-benzofuyrl) car-
 EMI33.2
 boxyamido7-penicillanic and 6-Ca- (3benzofuryl) propionamido-penicillanic acid.



   Likewise, a- (6-methyl-3-benzofuryl) -pro-
 EMI33.3
 pionic acid and a- (5-methoXY-3-benzofuryl) -propionic acid: are used in equivalent amounts in the operating mode
 EMI33.4
 4-- cover of this example. We obtain respectively the com ..

 <Desc / Clms Page number 34>

 
 EMI34.1
 posed: 6-Ca- (6-methyl-3-benzofuryl) -propionamid ± 7-penicillanic acid and 6-ra- (5-methoxy-3-benzofuryl) -propionamid21-penicillanic acid
EXAMPLE 21
Sodium Cephalosporin C dihydrate (0.75 g) in sufficient water to dissolve it is added to an aqueous suspension of 2.0 g of 10% palladium on charcoal in 30 ml of water. water which has been previously saturated with hydrogen. The mixture is hydrogenated, while being stirred, at atmospheric pressure for 1 hour.



   The catalyst is separated by centrifugation and the supernatant liquid is stored. The catalyst is then extracted with an 80% aqueous solution of methanol at a pH of 8 and the extracts are adjusted to a pH of 6 by adding hydrochloric acid. The total extract is evaporated to a small volume and added to the original reaction solution. The total solution is then brought to a pH of 6 by means of sodium hydroxide and then lyophilized, so that the product is obtained in the form of sodium salt.



   The product obtained (0.3 g) is dissolved in 7 ml of water containing 0.25 g of anhydrous sodium bicarbonate.



  To this stirred solution, 0.25 g of 1-fluoro-2,4-dinitrobenzene in 7 ml of ethanol is added. The mixture is stirred in the dark at room temperature for 2.5 hours. The pH of the solution is then brought to 5 by adding concentrated hydrochloric acid and the alcohol is driven off under reduced pressure.



   The mixture is brought to a pH of 7 by adding sodium bicarbonate and extracted with ether, to remove the excess 1-fluoro-2,4-dinitrobenzene, so that a clear aqueous solution is obtained. . The pH is brought to 2.5 by adding concentrated hydrochloric acid and the solution is extracted several times with ethyl acetate. The ethyl acetate extracts are washed with water

 <Desc / Clms Page number 35>

 dried over anhydrous sodium sulfate and evaporated to dryness.



   The solid material obtained (1 g) is dissolved in 10 ml of acetonitrile and 10 ml of 1N hydrochloric acid. This solution is stored in the dark, at a temperature of 37 C under nitrogen, for 64 hours.



   At the end of this period, 20 ml of water are added to the solution and the latter is then extracted five times using 10 ml fractions of ethyl acetate. The residual solution is then brought to a pH of 6 with 1N sodium hydroxide and added or poured onto a column of Dowex-1 (X8) resin (in the form of acetate, 3 cm x 5 cm). When all the solution had been poured onto the column it was washed with 60 ml of water, after which the product was eluted with 2N acetic acid. Lyophilization of the eluate with acetic acid gives the product which is 3-methyl-7-aminodecephalosporanic acid as a solid.



     EXAMPLE 22
A solution of 13.9 g (0.086 mole) of benzofuran 3-carboxylic acid in 20 ml of acetone is cooled in an ice bath to 0 C. To the cooled solution, 1.02 g is added. (0.01 mole) of triethylamine in 10 ml of acetone. The temperature of the reaction mixture is maintained at 0 ° C. and a solution of 1.25 g (0.011 mol) of ethyl chloroformate in 4.5 ml of acetone is added dropwise with stirring. The reaction mixture is stirred for 30 minutes and allowed to gradually come to room temperature, after which it is filtered. The filtrate thus obtained! slowly added to a stirred solution of 2.72 g (0.01 mole) of 7-aminocephalosporanic acid in 90 ml of a 3% aqueous solution of sodium bicarbonate and 50 µl of acetone.

   When this addition is complete, the mixture is allowed to come to room temperature and con-

 <Desc / Clms Page number 36>

 continue to stir for 30 minutes. The mixture is then extracted three times with 30 ml fractions of ether and the aqueous solution obtained is brought to a pH of 2.5 by adding concentrated sulfuric acid. During the addition of this acid, the temperature is kept below 10 C. When the pH of 2.5 is reached, the solution is extracted first with 25 ml of butyl acetate and then again at twice with 10 ml of butyl acetate. The total extracts are washed with water and, after addition of a further 25 ml of water, the pH is adjusted to 8.0 by adding solid potassium bicarbonate, while stirring.

   The aqueous layer is separated, filtered and brought to a pH of 2.0 by adding concentrated sulfuric acid at a temperature below 10 ° C. The acidic aqueous mixture obtained is extracted twice with 20 ml of butyl acetate. , washed with water and dried over sodium sulfate. To the dried butyl acetate solution is added, with vigorous stirring, a solution of potassium hydride in n-butanol (40 m / l) until the pH of the reaction mixture is 8.4. The mixture is cooled until crystallization occurs and the crystals formed are collected by centrifugation, washed with a small amount of acetone and dried. The dried crystals are dissolved in a minimum quantity of 9: 1 acetone and water and precipitated by adding anhydrous acetone.

   These crystals are collected and dried, so that one obtains
 EMI36.1
 7 C (3 benzofuryl) -carboxyamid-cephalosporanic acid in the form of potassium salt.



   By treating an aqueous solution of the potassium salt with chlorinated hydrogen and extracting with
 EMI36.2
 from ether, 7-Z- (3-benzofuryl) -carboxya- mido] -cephalospranic acid is obtained

 <Desc / Clms Page number 37>

 
Similarly, using an equivalent amount of benzofuran 2-carboxylic acid instead of benzofuran 3-carboxylic acid in the procedure herein
 EMI37.1
 example, 7 (2benzofuryl) -carboxyamide] -cephalosproanic acid is obtained
Likewise, by employing equivalent amounts of a- (2-benzofuryl) -propionic acid, a- (3-benzofuryl) - propionic acid, (2-benzofuryl-acetic acid and (3benzofuryl) -acetic acid, we obtains, following the same mode
 EMI37.2
 operative, 7 a- (2 benzofuryl) -propionamid cephalosporanic acid, 7 - a- (3-benzofuryl) acid

  -propionamid21- cephalosporanic acid, 7 (2-henzofuryl) -acetamido'- cephalosporanic acid and 7 (3-benzofuryl) -acetamid> cephalosporanic acid.



     EXAMPLE 23
Benzofuryl 3-carboxylic acid is used with the acid
 EMI37.3
 Instead of 3-thianaphthene-3-carboxylic acid in the procedure of Example 13. 3-hydroxymethyl 7-r (3-benzofuryl) -carboxyamid-decephalosporanic acid lactone is obtained.



   EXAMPLE 24
An equivalent amount of the inner salt of 3-pyridiniummethyl-7-aminodecephalosporanic acid is used instead of 7-aminocephalosporanic acid in the example: of Example 22. The internal salt of 3- acid is obtained.
 EMI37.4
 pyriâiniummethyl-7 r (3 benzofuryl) -carboxyamid-decéphalosporanique.
 EMI37.5
 



  EXAMPLE
EXAMPLE 25 -3-methyl-7-aminodecephalo- acid is used.
 EMI37.6
 sporanic acid (2.34 g) instead of 7-aminocephalosporanic acid è in the process of Example 22, and acid is obtained
 EMI37.7
 3-methyl-7- (3-benzofurylcarboxyamido) -deephalo :: boranic. CI F- Similarly, by operating as described in Example 22, 3-methyl-7- (2-

 <Desc / Clms Page number 38>

 benzofurylcarboxyamido) -decephalosporanic acid, 3-
 EMI38.1
 methyl-7- ± -a- (2-benzofuryl) -propionamidoj-decephalosporanic acid, 3-rnethyl-.7 a- (3-benzofuryl) -propionamid-decephalosporanic acid, 3-methyl-7- Z- (3-benzofuryl) - acetamirl27-decephalosporanic.



   By using 3-methyl-7-aminodecephalosporanic acid in the procedure of Example 12, similarly obtained 3-methyl-7- (3-thianaphthenylcarboxoxyamido) -decephalosporanic acid, 7- (2-Thianaphenylcarboxy-amido) -deephalosporanic acid, 3-methyl-
 EMI38.2
 7 ra- (z-thianaphthenyl) -propionamid-decephalosporanic acid, 3-methyl-7-ra- (3-thianaphthenyl) -propionamidJ decephalosporanic acid,) -methyl-7 - \ 2-thianaphthenyl) -acetamido7-decephalosporanic and 3-methyl-7- (3-thianaphthenyl) -acetamid-decephalosporanic acid.



   EXAMPLE 26
3-Hydroxymethyl-7- (3-benzofurylcarboxyamido) -decephalosporanic acid was prepared as described in Example 15, using 1 g of 7- (3-benzofuryl-carboxyamido) -cephalosporanic acid in instead of 7- (3-thianaphtenylcarboxyamido) -cephalosporanic acid. From the compound thus obtained, 3-propionyloxymethyl -7- (3-benzofurylcarboxyamido) -deephalosporanic acid, 3-butanoyl-oxymethyl-7- (3) are prepared by the process described in Example 15 -benzofurylcarboxyamido) -decephalosporanic acid 3-pentanoyloxymethyl-7- (3-benzoyfurylcarboxyamido) -deephalosporanic and 3-benzoyl-oxymethyl'-7- (3-benzofurylcarboxyamido) -decephalosporanic acid.



   EXAMPLE 27
1 g of 6- (2-thianaphthenylcarboxyamido) -penicillanic acid is dissolved in an excess of amyl acetate and the solution is added with 10 g of N-ethylpiperidine. The

 <Desc / Clms Page number 39>

 The solution is stirred for 30 minutes and the crystals formed on standing are collected by filtration and dried to constitute the N-ethylpiperidine salt of 6- (2-thianaphenylcarboxyamido) -penicillanic acid.



     EXAMPLE 28
Using triethylamine instead of N-ethylpiperidine in the procedure of Example 27 and
 EMI39.1
 6- / ¯a- (3-thianaphthenyl) -propiO''namido7-penicilla- nic acid instead of 6- (2-thianaphthenylcarboxyamido) -penicillanic acid, the triethylamine salt of acid
 EMI39.2
 6 - (3-thianaphthenylj-propionamid-penicillanic acid.
CLAIMS 1.- Compounds corresponding to the formula:
 EMI39.3
 zut \ t NH-CH - 1s {b-B 0 CH 1/1 X 1 c ------ N3 o 1 in which -R is an isovaleric acid carbon-oxygen backbone having the following structures:
 EMI39.4
 CH3 "ICH2 'L.'

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

C-CH or C-CH2-A -CH-COOM -C-COOM in which A denotes hydrogen or an alkanoyloxy, hydroxyl, benzoyloxy or pyridinium group, or alternatively, in combination with M, a carbon bond- monovalent oxygen, M denotes hydrogen, non-toxic pharmaceutically acceptable cations, an anionic charge when A denotes a pyridinium group or, in combination with A, a monovalent carbon-oxygen bond, B denotes hydrogen or a methyl radical, Z denotes oxygen or sulfur, X denotes hydrogen, a halogen atom or an alkyl, alkoxy or trifluoromethyl radical, and n is equal to 1 or 2. <Desc / Clms Page number 40> 2. - Compounds corresponding to the formula: EMI40.1 F! ###! 1 / S \ / CH3 X # L. # jf-fCHpJ-CH-CH-CH w CH3 ZC ## N ### CH-COOH 0 / in which Z denotes oxygen or sulfur, X denotes hydrogen, a dtahlogene atom or an alkyl, alkoxy or trifulormiethyl group, M denotes hydrogen or a non-toxic pharmaceutically acceptable salt and n is equal to 0 or 1. 3. - Compounds corresponding to the formula: EMI40.2 5>, 1 - (CH n X # h "j (CH2) nc-THfH-CHScHz 0 1-11 C t N -e U - (; 112A 0 W 2 COOM in which Z denotes oxygen or sulfur , X denotes hydrogen, a halogen atom, an alkyl, alkoxy or trifluoromethyl group, A denotes hydrogen, or an alkanoyloxy, hydroxyl, benzoyloxy, pridinium group or, in combination with N, a carbon-oxygen bond monovalent, M denotes hydrogen, a non-toxic pharmaceutically acceptable cation, an anionic charge when A denotes a pyridinium radical or, in combination with M. a monovalent carbon-oxygen bond, and n is equal to 0 or 1. 4.- Compounds corresponding to the formula: EMI40.3 e / S \ / CH3 X 'T, (CH 2) n C-NH-CH-CH 1 1 11, CCH3 X \ s / / C ## N ### CH-COOH goose <Desc / Clms Page number 41> in which X denotes hydrogen, a halogen atom or an alkyl, alkoxy or trifluoromethyl radical, and M denotes hydrogen or a non-toxic pharmaceutically acceptable cation, n being equal to 0 or 1. 5.- Compounds corresponding to the formula: EMI41.1 fN. / go3 X-- 5 C-NH-OH. {) o- 0/0 - // CN ---, CH-: qOOM in which X denotes hydrogen, a halogen atom or an alkyl, alkoxy or trifluoromethyl group and M denotes hydrogen or a a pharmaceutically acceptable non-toxic cation, n being equal to 0 or 1. 6. - Compounds corresponding to the formula: EMI41.2 r j1 ### Tî // 8 "X Il # H- (CH) ¯C-NH-CH-CH H2" -S /. / -N "C C-CH2A c é, / p -N 1 -CH2A COOM in which X denotes hydrogen, a halogen atom or an alkyl, alkoxy or trifluoromethyl group, A denotes hydrogen or a alkanoyloxy, hydroxyl, benzoyloxy, pyridinium or, in combination with M, a monovalent carbon-oxygen bond, M denotes hydrogen, -ment 4-a non-toxic pharmaceutical / acceptable cation, an anionic charge when A denotes a pyridinium radical or, in combination with M, a monovalent carbon-oxygen bond and n is 0 or 1. <Desc / Clms Page number 42> 7. - Compounds corresponding to the formula: EMI42.1 W 0 CUL, <: nr 0 'COOM in which X denotes hydrogen, a halogen atom, or an alkyl, alkoxy or trifluormethyl radical A denotes hydrogen, or an alkanoyloxy, hydroxyl, benzoyloxy or pyridinium radical . orin combination with M, a monovalent carbon-oxygen bond, M denotes hydrogen, a non-toxic pharmaceutically acceptable cation, an anionic charge, when A denotes a pyridinium group, in combination with M, a monovalent carbon-oxygen bond - slow and n is equal to 0 or 1. EMI42.2 8.- 6 - (2-Thianaphthenyl) -carboxyamidi! -Penici1-lanic acid. 9.- 6- ± ¯ (2-Benzofuryl) -carboxyamido7-penicilla- nic acid. 10.- 6 (3-Thianaphthenyl) -carboxyamid penicillanic acid. 11.- 6-Z- (3-Benzofuryl) -carboxyamidoT-penicilla- nic acid. 12.- .. 3-Methyl -, ^ - r (2-thianaphthenyl) -carboxyamide 7-decephalosporanic acid. 23.- 3-Methyl-7 (3-thianaphthenyl) -carboxya! I-d-decephalosporanic acid. 14'- 3-Methyl-7- ± - (2-benzofuryl) -carboxyamidoj-decephalosporanic acid. 15'- 3ethyl-7- (3-benzofuryl) -carboxyamid7-deccephalosporanic acid. 16.- 3-cano acid; Tlox; r..thyl-7- (2-thianaphthenyl) - <Desc / Clms Page number 43> EMI43.1 carboxyamidoj-decephalosporanic. 17.- 3-Alkanoyloxycaethyl-7- (3-thianaphthenyl) - carboxyamidoj-decephalosporanic acid. 18.- Internal salt of 3-pyridiniummethyl-7- C (2-thianaphthenyl) -carboxyamid-decephalosporanic acid 19.- Internal salt of 3-pyridiniummethyl -? - C (3-thianaphthenyl) -c2rboxyamido, 7 decépèalosporanique. 20. Pharmaceutically acceptable non-toxic salts of any of the compounds according to any one of claims 8 to 17. 21. - Antimicrobial pharmaceutical composition, characterized in that it contains a compound according to one or the other of claims 1 to 20, as well as a pharmaceutical vehicle. 22. - New compounds and processes for their preparation, in substance, as described above, in particular in the examples.