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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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  • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
  • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
  • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
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  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
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  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms
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  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• ABSTRACT Compounds represented by the following formula wherein A is a substituted or unsubstituted heterocyclic radical and T is a C C alkyl, alkenyl, cycloproplymethyl, cyclobutylmethyl or cyclopentyl group a process for their preparation and novel intermediates therefor are disclosed. These compounds are useful antibiotics.
• substituents include ethyl, n-propyl, isobutyl, n-pentyl, 3- methylbutyl, neopentyl, vinyl, allyl, methallyl, butenyl and pentenyl.
• the C to C alkyl, alkoxy, alkoxycarbonyl and alkanoylamino groups referred to herein are those wherein the alkyl moiety contains from one to three carbon atoms.
• Preferred 6 -aminopenicillanic acid compounds in accordance with the invention are those wherein A in the above formulas is 3-pyridyl, 2-methyl-4-pyridyl, 3- isoxazolyl, 4-oxazolyl, 2-oxo-2-pyrrolidinyl, pyrazinyl, tetrahydro-Z-furyl, 2-acetamido-4-thiazolyl, 1,5 dimethyl-Ii-pyrazolyl, tetrahydro-4-pyranyl, 1,2,3- thiadiazol-4-yl, 2-furyl or 4-pyridyl.
• the preferred compounds according to the invention are those wherein T is an alkyl or alkenyl group containing four or five carbon atoms.
• pounds is further demonstrated in vivo by establishing an oral CD in the mouse against S. aureous and E. coli.
• the corripounds represented by formula I are prepared by con- 1 35 densing 6-amino-penicillanic acid, the carboxyl group Minimum Inhibitory Concentration I mg/ml] CDQJper The Mouse [mg/kg] penicillin sodium Compound S. aureous FDA E. coli 1346 S. aureous (Schoch) E. coli 1346 [(R)-l-(2-furoyloxy-3-methyl-butyl1penicillin sodium 0.073 73 0.7 16
• rs m a protected form
• the 'riovl compounds represented by formula II or a functional deriv- the term ative thereof.
• Such functional derivatives are conventional and include, for example, halides, azides, anhydrides particularly mixed anhydrides with strong acids reactive esters such as the N- hydroxysuccinimide esters, amides, such as imidazolides and the like. After the reaction is completed, the protecting group is cleaved off and, if desired, the product is converted into a salt.
• Examples of methods whereby the carboxyl of 6- amino-penicillanic acid can be protected include conversion into a readily cleavable ester such as, for example, the benzyl ester, a p-bromophenacyl ester or a silyl ester such as the trimethyl silyl ester, or by salt formation with an inorganic or tertiary organic base such as,
• ester protecting group can be easily removed by methods known in the art.
• a benzyl ester can be easily removed by catalytic hydrogenation such as, for example, in the presence of a noble metal catalyst such as palladiumon-carbon, and a silyl ester can be cleaved by treating theproduct with water.
• the protecting group can be cleaved by treatment with acids such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and the like at low temperatures, e.g., O5C.
• the condensation of 6-aminopenicillanic acid, having a protected carboxyl group and the compound represented by formula II is carried out by methods well known in the art of peptide chemistry.
• the condensation is effected in the presence of a carbodiimide such as, for dicyclohexylcarbodiimide or an oxazolium salt such as, for example, N-ethyl-S- phenyl-isoxazolium-3'-sulfonate, in an inert solvent.
• Suitable solvents include, for example, ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene, dimethylformamide and the like.
• a salt of -aminopenicillanic acid such as, for example, a trialkylammonium salt
• a reactive functional derivative of a compound represented by formula II is condensed with a reactive functional derivative of a compound represented by formula II.
• the reaction of 6- aminopenicillanic acid having a protected carboxyl group and an acid compound represented by formula II, or a reactive functional derivative thereof, can conveniently be carried out at a temperature between about -40C. and C., preferably at about 0C.
• novel acid starting compounds represented by formula I] may be utilized as racemates or in an optically pure form. It is preferred to use the R- enantiomers in the practice of the invention. Specifically, the R configuration referred to pertains to the asymmetrical carbon atom marked with an asterisk in formula'lla.
• the acid compounds represented by formula II may be prepared by converting a compound represented by the general formula wherein A'and T" have the meaning given earlier and B represents a protected carboxyl group. H into the free acid form by cleaving. the protecting group.
• the protected carboxyl group represented by B in the above formula may be a readily cleavable ester group such as, for example, the benzyl or tert. butyl ester groups.
• the conversion of the protected carboxyl group into the free acid is readily effected in the case of the benzyl ester, for example, by catalytic hydrogenation in the presence of a noble metal catalyst. Where the protecting group is the tert.
• butyl ester cleavage may be accomplished by treatment with acid such as, for example, a mineral acid-hydrochloric acidor trifluoroacetic acid and the like.
• acid such as, for example, a mineral acid-hydrochloric acidor trifluoroacetic acid and the like.
• reactive functional derivatives thereof such as, for example, halides, azides, anhydrides, esters, amides and the like may be carried out by methods recognized in the art as being conventional.
• the compounds represented by formula III above may be obtained by conventional means such as, for example, utilizing known means such as described herein to protect the carboxyl group in a compound represented by the general formula OII IV wherein T has the meaning given earlier, and reacting the resulting product with a compound represented by the general formula ACOOI-I wherein A has the meaning given earlier, for example, in the presence of benzenesulfonyl chloride.
• Tire 6 am derivatives of 6-aminopenicillanic acid provided by the present invention possess a broad spectrum of activity against gram-positive microorganisms such as Staphylococcus aureus, Diplococcus pneumoniae and Streptococcus pyogenes and gram-negative microorganisms such as Escherichia coli, Proteus vulgaris, Proteus mirabilis and Salmonella typhi murium.
• Their antibiotic and bactericidal activity allows them to be utilized therapeutically and as disinfectants. It is preferred in accordance with the invention to administer the novel penicillin compounds described herein orally in view of their superior stability against gastric acid. It is contemplated, in the case of adults, that oral dosage forms each containing 200-600 mg.
• novel penicillin compounds of the invention may also be administered parenterally, rectally or topically in suitable dosage forms and may be administered in the form of their pharmaceutically acceptable salts or hydrates.
• Examples of the pharmaceutically acceptable salts of the penicillin compounds represented by formula I include salts with inorganic bases such as, for example, the alkali metal salts. e.g.. the sodium or potassium salt; ammonium salts; alkaline earth metal salts e.g.. the calcium salt and the like; and salts with organic bases such as amine compounds, for example, N-ethyl pipcridinc. procaine. dibenzylamine. N.N-dibenzylethylethylenediamine, alkylamines, dialkylamines or the like.
• the foregoing salts can also be hydrated. The hydration can be effected during the manufacturing process or can occur gradually as a consequence of the hygroscopic properties of an initially anhydrous salt.
• the compounds represented by formula l and their salts can exist as optically pure isomers and as diastereomer mixtures.
• the preferred compounds in accordance with the invention are those wherein the acyl group substituted on the amine group at position 6 of 6-aminopenicillanic acid has the R configuration.
• the R configuration referred to pertains to the asymmetrical carbon atom marked with an asterisk in the following formula wherein A and T have the meanings given above.
• novel 6-acyl derivatives of 6-aminopenicillanic acid of the present invention can be combined with conventional compatible organic or inorganic pharmaceutical carrier materials known in the art.
• Such materials include, for example, water, gelatin, gums, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and the like.
• Such pharmaceutical preparations may be in unit dosage form and may additionally contain other therapeutically valuable substances or conventional pharmaceutical adjuvants such as preservatives, stabilizing agents, wetting agents, emulsifying agents, buffers and the like.
• the pharmaceutical preparations can be in conventional solid dosage forms such as tablets, capsules, dragees and the like, conventional EXAMPLE 1 (R l 2-furoyloxy)-3-methylbutyl]penicillin sodium 264.0 g. of (R)-2-hydroxy-isocaproic acid were dissolved in 1.8 litres of absolute dioxan in a three-necked flask fitted with a stirrer, thermometer and reflux condenser with a calcium chloride tube. The solution was treated successively with 285 ml. of triethylamine and 236 ml. of benzyl chloride and heated at an internal temperature of 100 for 20 hours with stirring in an oilbath.
• the pyridine was then distilled off under reduced pressure at 30-50 and the residue dissolved in 600 ml. of 3-N hydrochloric acid with the addition of ice and extracted twice with 250 ml. portions of ethyl acetate.
• the ethyl acetate solutions were washed once with.l00 ml. of 3-N hydrochloric acid, twice with 100 ml. portions of water, twice with 100 ml. portions of 5 percent sodium bicarbonate solution and twice with 100 ml. portions of water and dried with magnesium sulphate.
• the ethyl acetate was distilled off under reduced pressure at 40 and the oil dried for 60 minutes under reduced pressure at 60. There was thus obtained benzyl- (R)-2-(2-furoyloxy)-isocaproate; [011 9.0 (C 4.0 in alcohol).
• a total of 55.5 g. of benzyl-(R)-2-(2-furoyloxy)- isocaproate were hydrogenated in 400 ml. of alcohol after the addition of 5 g. of palladium-on-charcoal (5 percent) until the theoretical amount of hydrogen had been taken up.
• the catalyst was filtered off by suction and the filtrate evaporated under reduced pressure at 40.
• the oil thus obtained was dissolved in 250 ml. of 8 percent sodium bicarbonate solution and the resulting solution washed twice with ml. portions of ether.
• the pH of the bicarbonate solution was adjusted to pH 2 with concentrated hydrochloric acid and extracted three times with ml. portions of ethyl acetate.
• the reaction mixture was kept for 20 hours at 0 and then evaporated under reduced pressure at 20.
• the residue was dissolved in 150 ml. of ice-water and extracted twice with 50 ml. portions of ether.
• the pH of the aqueous phase was adjusted to pH 2 at 0 with 3-N sulphuric acid and extracted three times with 80 ml. portions of ethyl acetate.
• the ethyl acetate solutions were collected and washed three times with 20 ml. portions of ice-cold 5 percent sodium chloride solution, dried with magnesium sulphate and evaporated under reduced pressure at 20.
• the residue was dissolved in 300 ml. of absolute ether, the solution filtered and treated with stirring with 50 ml.
• the decantation residue was taken up in 100 ml. of acetone and treated with 20 ml. of 2-M sodium-2- ethylcaproate in ethyl acetate, precipitated with petroleum ether-and decanted.- From methanol/isopropyl ether there crystallized (R)-3-methyl-1-[(S)-pyroglutamoyloxybutyllpenicillin sodium of melting point 180 (with decomposition); [04],, 187.0 (c 1.0 in water).
• EXAMPLE 4 sodium of melting point 205-206. (with decomposition); [01],, 189 (0 l in water).
• EXAMPLE 9 EXAMPLE [(S)-1(2-furoyloxy)-3-methylbutyl]penicillin sodium
• (S)-2-(2-furoyloxy)-isocaproic acid; [01],, 7 (0 4 in ethanol) was prepared via the corresponding benzyl ester.
• [(S)-1-(2-furoyloxy)-3-methylbutyllpenicillin sodium; mp 150 (with decomposition) [01],, +216 (c 2 in water) was prepared in accordance with the method of Example 1.
• EXAMP 14 [(R)-3-methyl- 1 1,2,3-thiadiazol-4-yl y]butyl]penicillin sodium
• a total of 13.0 g. of 1,2,3thiadiazol-4-carboxylic acid was suspended in m1. of pyridine and treated dropwise at 2535 over a period of 20 minutes with 12.8 ml. of benzene-sulphonyl chloride. The mixture was stirred at room temperature for an additional 30 minutes to yield a clear solution. 17.9 G. of tert. butyl- (R)-a-hydroxyisovalerate were then added over a period of 20 minutes with further stirring, the temperature rising to ca 40. After stirring for two hours at 60, the mixture was evaporated under reduced pressure, suspended in 200 ml.
• EXAMPLE 16 l' l yl-3-methylbutyl]penicillin sodium A total of 19.2 g. of 1,5-dimethy1pyrazole-3- carboxylic. acid was heated at reflux for 20-minutes with 80 ml. of thionyl chloride after which the excess thionyl chloride was removed under reduced pressure. The mixture was evaporated two additional times under reduced pressure with toluene, then taken up in 100 ml. of toluene and added dropwise at 0 with stirring to 22.4 g; of tert. butyl-(R)-a-hydroxyisocaproate in 80 m1. of pyridine.
• EXAMPLE l7 amide was brought into solution with 11.9 ml. of triethylamine. It was then treated slowly at 60 with strongstirring with 38.1 ml. of a 2.86 molar solution of phosgene in toluene and then a solution of 14.6 g. of tert. butyl-(R)-2-hydroxyisocaproate in 50 ml. of pyridine which has been previously cooled to ca 50, was added in one portion. After the mixture had reached room temperature, it was evaporated under reduced pressure and the residue taken up in ether and washed three times each with water and a 10 percent aqueous potassium bicarbonate solution, dried and once more evaporated under reduced pressure. There remained 26 g.
• the N-oxide of the above acid was obtained by dissolving 26.4 g. of it in ml. of glacial acetic acid by treating for three hours at 7080 with 11 ml. of 30 percent hydrogen peroxide. After the addition of an additional 8 ml. of 30 percent hydrogen peroxide, the mixture was left overnight at the same temperature. The mixture was then cautiously evaporated under reduced pressure and evaporated off twice with 50 ml. portions of water, care being taken to ensure that the mixture is never evaporated to dryness. This residue was taken up in chloroform, washed four times with water, dried and evaporated under reduced pressure.
• EXAMPLE 29 EXAMPLE 3O (RS l -[(2,G-dimethylisonicotinoyl )oxy]-3- methylbutyllpenicillin sodium (RS)-2-(2,6-dimethylisonicotinoyloxy)-isocaproic acid (mp. 9596) was prepared via its benzyl ester in a manner analogous to that described for the preparation of the starting material in Example 35. The resulting compound was treated with thionyl chloride to yield (RS)-2-(2,6-dimethylisonicotinoyloxy)- isocaproic acid hydrochloride.
• EXAMPLE 35 [(RS)-1-(isonicotinoyloxy)-3-methylbutyl]penicillin sodium A total of 29.5 g of benzyl-(RS)-a-bromoisocaproate was added dropwise at 60 with stirring over a period of 15 minutes to a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml. of dimethylformamide and 14.8 ml of triethylamine. The reaction mixture was stirred for 5 hours at 90. The triethylamine hydrobromide was then filtered off by suction and the filtrate evaporated under reduced pressure at 60.
• the ester formed above was dissolved in 10 ml of ethyl acetate and the resulting solution mixed with a solution of 19 g of p-toluenesulphonic acid in 35 ml. of ethyl acetate and crystallized for 2 hours at The resulting benzyl-(RS)-2- (isonicotinoyloxy)-isocaproate p-toluene-sulphonate was filtered off by suction, washed with 100 ml of ether and dried under reduced pressure at 60 to give a compound of melting point 136.
• EXAMPLE 36 [(RS l -(isonicotinoyloxy )butyl]penicillin sodium
• the (RS)-2-(isonicotinoyloxy)-valeric acid, melting point l52-153 was prepared via its benzyl ester in a manner analogous to that described for the preparation of the starting material in Example 35.
• EXAMPLE 43 [(R)- l-(5-methoxymethyl-2-furoyloxy)-3- methylbutyl]penicillin sodium (R)-2-(5-methoxymethyl-2-furoyloxy)-isocaproic acid (melting point 7374) was prepared via its benzyl ester in a manner analogous to that described for the preparation of the starting material in Example 1.
• Example 47 The following composition was prepared as follows and filled into gelatin capsules.
• the penicillin was homogeneously blended with the LUVISKOL and mannitol and compressed into slugs.
• the slugs were then passed through a suitable sieving machine and, after blendin with the tack and magnesium stearate, filled into suitable gelatin capsules.
• EXAMPLE 48 Reconstitutable injectable preparations were prepared by lyophilizing and hermetically sealing ampoules each containing 2 ml. of a sterile solution coni taining 263 mg. of [(R)-l-(2-furoyloxy)-3- methylbutyl]penicillin sodium, 1.1 mg. of methyl-phydroxybenzoate hydroxybenzoate.
• a compound of the formula OOH wherein A is selected from the group consisting of fu- I ryl', tetrahydrofuryl andthien l, and T is selected from the group; consisting'of C alke'ny-l, cyclopropylmethyl, cFclIobut-ylmethyl and cyclopentyl and pharmaceutical forms thereof.
• 25A compound selected from the group consisting of (R)-l-(2-furoyloxy)-3-methylbutyl-penicillin and harmaceutically acceptable salts and hydrated orms thereof.

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• 1971
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• 1972
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