KR810000101B1 - The process of 6 methoxy-6-( -carboxy thienyl acetamido)-penicillins - Google Patents

Abstract

Title compds. [I; R = 2 or 3-thienyl; R1 = H or solting ion, R2 = H, solting ion or ester, Rx = H or carboxyl protecting group were prepd. by reaction of II and III followed by hydrolysis or alcoholysis. Thus, 6α-methoxy, 6β-aminopenicillate and pyridine were treated with methylene chloride to give benzyl 6α-methoxy, 6β-(2'-phenoxycarbonylthie-3-yl-acetamido) phenicillate(III). III was treated with N-sodium bicarbonate to give 6α-methoxy, 6β-(2'-phenoxycarbonylthiene-3-yl acetamide) penicillanic acid.

Description

Method for producing 6-methoxy-α-carboxy penicillins

The present invention relates to a process for the preparation of 6-methoxy-α-carboxy penicillin compounds useful for the treatment of a wide range of Gram-negative bacteria in animals including humans and poultry.

The 6-substituted acylamino penicillins of general formula (A) are already known.

Wherein R _A represents an acyl group and R _B represents hydroxy or mercapPto, substituted or unsubstituted methoxy, ethoxy, methyl, ethyl, methylthio, or ethylthio group, carbamoyloxy, carba Moylthio, C _1-6 alkanoyloxy C _1-6 alkanoylthio, cyano or a carboxyl group or a derivative of a carboxyl group such as carbamoyl.

R _C is a hydrogen atom or an esterification group or cation which may be used in medicine.

The known α-carboxy substituted acyl group R _A was 2-carboxyphenylacet amido, and a specific example of such side chains is exemplified by the following R _B. : Methyl, cyano, aminomethyl, 2-carboxy-2-amino ethoxy.

6-methoxy substituted penicillins with α-carboxy-substituted acyl side chains are not shown.

6-αmethoxy-6β- (2-carboxyphenyl acet amido) peniclanic acid, which is simply 6-methoxy penicillin in the above formula (A), is known.

We have now found 6-methoxy α-carboxy penicillins with superior antimicrobial activity compared to previously known compounds and 6α-methoxy-6β- (2-carboxyphenyl acet amido) peniclanic acid.

According to the present invention there is provided a compound of formula (I).

In the common sense

R is 2- or 3-thienyl,

R ¹ is hydrogen or salting ion (Saltingion) that can be used as a drug R ² is hydrogen or salting ion that can be used as a drug or an ester group that can be hydrolyzed in vivo.

Suitable salt ions for the R ¹ and R ² groups are from alkali metal ions such as aluminum, sodium or potassium, alkaline metal ions such as calcium or magnesium, ammonium or substituted ammonium ions such as lower alkylamines such as triethylamine ,

Hydroxy-lower alkyl amines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri (2-hydroxyethyl) -amine, cycloalkyl amines such as bicyclohexylamine, or furokane , Dibenzylamine, N, N-dibenzylethylenediamine, 1-ephenamine, N-ethyl piperidine, N-benzyl-β-phenethyl amine, dehydroabiethylamine, N, N'-bis-de From hydroaviethyl ethylene diamine,

Or bases such as pyridine, collidine or quinoline, or other amines that have been used to make salts with benzylpenicillin.

Ester groups that can be used as drugs that can be hydrolyzed in vivo for R ² are those that can be hydrolyzed in the human body to produce the acid of the parent nucleus.

Suitable examples include acetoxymethyl and acyloxyalkyl groups such as pivaloyloxy-methyl, α-acetoxyethyl, α-acetoxybenzyl and α-pivaloyloxyethyl groups: ethoxycarbonyloxymethyl and α-ethoxy Alkoxycarbonyloxyalkyl groups such as carbonyloxyethyl: lactones, thiolactones, dithiolactone groups, for example ester groups of the following structural formulas.

In the above formula, X 'and Y' are oxygen or sulfur and Z 'is an ethylene group (optionally substituted with lower alkoxy, halogen or nitro), 2-phenylene group.

Suitable ester groups are esters of phthalide and 5,6-dimethoxy phthalide.

Specific compounds of the present invention are as follows.

6-β- (2-carboxy-2-thiene-3'-ylacetamido) -6-α-methoxy-penicsilane acid;

6-β- (2-carboxy-2-thiene-2'-ylacetamido) -6-α-methoxy-phenicsilane acid

The compound of formula (I) is prepared by reacting a compound of formula (III) or its Nsilin or N-phosphorylated derivative with an N-acylated derivative of acid of structure (N).

Where R ^X is hydrogen or a carboxyl protecting group.

In the common sense

R is as defined in the formula (I).

Then perform one or more of the following steps, if necessary.

(i) Removal of silyl or phosphoryl groups by hydrolysis or alcohol degradation

(ii) removal of carboxyl protecting groups

(iii) converting the product to a salt or ester

The term “N-silyl derivative” of compound (III) refers to a product in which the 6-amino group of compound (III) is reacted with a silylating agent such as halosilane or silazane of the following general formula;

L ₃ Si u; L ₂ Si U ₂ ; L ₃ Si NL ₂ ;

L ₃ Si NH Si L ₃ ; L ₃ Si.NH, COL; L ₃ Si.NH.CO.NH.Si L ₃ ;

L₃;L.NH.CO.NH.SiL ₃ ;

L ₃ ;

Where U is halogen, and the same or different L represents hydrogen or alkyl, alkoxy, aryl or aroalkyl, respectively.

Better silylating agents are silyl chloride, in particular trimethyl chloro silane.

The term “N-phosphorylated” derivative of compound (III) is intended to include compounds in which the 6-amino group of formula (III) is substituted with the following general formula.

-P _a R _b

Ring R _a is alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, an alkyloxy or dialkylamino group, R _b is R such as _a or halogen, or R _b and R _b together from gastroesophageal form a ring.

Suitable carboxy-protecting derivatives for -CO ₂ R ^X in the formulas (III) and (IV) include salts, esters and anhydride derivatives of carboxylic acids. Derivatives are preferably easily degraded in the next step of the reaction. Suitable salts include salts of tertiary amines such as tri-lower alkylamines, N-ethyl-piperidine, 2,6-lutidine, pyridine, N-methylpyrrolidine, salts of N-dimethylpiperazine. .

Better is a salt with triethylamine.

Suitable ester groups for the structural formula CO ₂ R ^X are as follows.

(i) -COOCR _d R _e R _c wherein at least one of R _c and R _d · R _e is P--methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy, methoxy Electron donors such as methoxymethyl, benzyl or hur-2-yl.

Remainder R _c , R _d

-메톡시벤질옥시 카르보닐, 2,4,6-트리메틸벤질옥시카르보닐, 비스-(

-에톡시 페닐) 메톡시카르보닐, 3,5-디-t-부틸-4-하이드록시벤질옥시카르보닐, 메톡시톡시카르보닐과 벤질옥시카르보닐이 있다.R _d and R _e groups are hydrogen or an organic substituent. Suitable ester groups of this type are

-Methoxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, bis- (

-Ethoxy phenyl) methoxycarbonyl, 3,5-di-t-butyl-4-hydroxybenzyloxycarbonyl, methoxyoxycarbonyl and benzyloxycarbonyl.

(ii) -COOCR _d R _e R _c wherein at least one of R _c and R _d · R _e is benzoyl, P- nitrophenyl, 4-pyridyl, Trojan chloromethyl, tribromo methyl, urethra methyl, cyanomethyl , Ethoxycarbonylmethyl, arylsulfonylmethyl, 2-diethylsulfoniumethyl, 0-nitrophenyl or cyano. The remaining R _c , R _d and R _e are hydrogen or an organic substituent. Suitable esters of this type include benzoyl methoxy carbonyl, P-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribro Moethoxy carbonyl.

(iii) -COOCR _c R _d R _e where at least two of R _c and R _d R _e are hydrocarbons such as alkyl such as methyl or ethyl, aryl such as phenyl and the remaining R _c , R _d and R _e groups If it is, it becomes hydrogen. Suitable esters of this type include t-butyl oxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl.

(iV) -COORf where Rf is adamantylphenyl, alkyl-substitutedphenyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, penta chlorophenyl ;

(V) The silyloxy carbonyl group obtained by making the above-mentioned silylating agent react with carboxylic acid.

(Vi) CO ₂ P · R _a R _b where R _a and R _b are as defined above.

(Vii) an ester group capable of hydrolysis in vivo as defined above.

The carboxyl groups from the above esters are usually regenerated by methods such as hydrolysis of acid or alkali catalysts or hydrolysis of enzyme-catalysts.

Alternative decompositions are as follows:

Reaction with Lewis acids such as trifluoroacetic acid, formic acid, hydrochloric acid in acetic acid, zinc bromide of benzene solvent, aqueous solution or suspension of mercury compounds. (The reaction of Lewis with acid is facilitated by the addition of nucleophiles such as anisole):

Reduction with reagents such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohol, zinc / pyridine, palladium treated charcoal and hydrogen, sodium and liquid ammonia: containing nucleophilic oxygen or sulfur atoms such as alcohol and malcaptan or water Attack by a nucleophile; Oxidative methods, such as those involving the use of hydrogen peroxide and acetic acid, irradiation.

Reactive N-acylated derivatives of acid (IV) are used in the above process. The choice of reactive derivatives is of course influenced by the chemical nature of the substituents of the acid.

Suitable N-acylated derivatives include acid halides, with acid chlorides or acid bromide being preferred.

Acylation with acid halides may include, for example, tertiary amines (such as triethylamine or dimethyl alanine), inorganic bases (such as calcium carbonate or soda bicarbonate) and hydrogen halides liberated in acylation reactions such as oxiranes. It is influenced by the presence of the binding acid binder. Oxirane is desirably an ethylene oxide to propylene oxide, such as sodium (C ₂ -6) -1,2- alkylene oxide. The acylation reaction using an acid halide is preferably water-soluble acetone, ethyl acetate, dimethyl acetamide, dimethylformamide, acetonitrile and dichloro in the temperature range of -50 ° to + 50 ° C, preferably at -20 ° to + 30 ° C. In water-soluble or water-insoluble solvents such as metals, 1,2-dichloroethane, or mixtures thereof.

Other reactions include solvents that do not mix with water, especially in unstable emulsions of ketones or aliphatic esters such as methyl isobutyl ketone or butyl acetate.

Acid halides are prepared by reacting an acid (IV) or a salt thereof with a halogenating agent (eg chloroated or brominated) such as phosphorus pentachloride, thionylchloride, oxaryl chloride.

Alternatively, the N-acylated derivatives of acid (IV) are symmetrical or mixed accompaniments. Suitable mixed anhydrides include alkoxy formic anhydrides or for example monocarbonates of carbonic acid, trimethyl acetate, thioacetic acid, diphenylacetic acid, benzoic acid, phosphoric acids (such as phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfones (P-toluene Anhydrides with sulfonic acids). Mixed or symmetric anhydrides can be produced on site.

For example, mixed anhydrides are produced using N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline.

If symmetric anhydride is used the reaction is carried out in the presence of 4-lutidine as catalyst.

Substitutable N-acylated derivatives of acid (IV) include acid azide or cyanomethanol, P-nitrophenol, 2,4-dinitrophenol, thiophenol, pentachlorophenol, monomethoxyphenol, or 8 '. Activated esters such as esters with halophenols including hydroxyquinoline; Or amides such as N-acyl saccharin or N-acylphthalimide; Or alkylidene amino esters prepared by reacting acid (N) with oxime; Or a direct α-carboxy compound is a cationic acid chloride of malonic acid (IV).

Some activated esters, for example esters formed with 1-hydroxybenztriazole ana N-hydroxy succinimide, are prepared by reacting a suitable hydroxy compound with an acid in the presence of a carbodiimide, preferably dicyclohexyl carbodiimide. Manufactured on the fly.

Other reactive N-acylated derivatives of acid (IV) include reaction intermediates formed by in situ reaction with a condensing agent, such as carbodiimide, such as N, N-diethyl-dipropyl- or di Isopropyl carbodiimide, NN-dicoxyhexyl carbodiimide or N-ethyl-N'-γ-dimethyl aminopropyl carbodiimide; For example, there are suitable carbonyl compounds such as N, N'-carbonyl diimidazole or N, N'-carbonyldi triazole; For example, N-ethyl-5-phenylisoxazolinium-3-sulfonic acid salt or isoxazolium salt such as N-t-butyl-5-ethyl isoxazolinium and chlorate; Or N-alkoxycarbonyl-2-alkoxy-1,2-dihydro quinoline, such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydro quinoline.

Other condensing agents include Lewis acids (eg BBr ₃ -C ₆ H ₆ ); Or phosphoric acid condensing agents such as diethyl phosphoryl cyanide. The condensation reaction is preferably carried out in an organic reaction medium such as methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxane or tetrahydrofuran.

Compound (III) is prepared by a known method, for example, from esters of compounds of the following structural formula.

Compounds in the above formula are prepared by known from the corresponding 6-isocyano compounds.

In order to administer the antibiotic according to the present invention, it is necessary to make it in a convenient form for use as a medical or veterinary medicine as with other antibiotics. Therefore, the present invention can be used as a medicine with the compound of formula I above. Pharmaceutical compositions, including carriers or excipients.

Oral administration is good, but the composition may be formulated according to the route of administration. The compositions are in the form of solutions such as capsules, powders, granules, lozenges, oral or sterile injectable solutions or suspensions.

Tablets and capsules for oral administration are in unit dose dosage form and include binders such as syrup, acacia, geladine, sorbitol, tragacanth, polyvinylpyrrolidone, diluents such as lactose, sucrose, corn starch, calcium phosphate Sorbitol, glycine: tablet lubricants such as magnesium stearate, talc, polyethylene glycol or silica; Disintegrants such as potato starch; Or conventional excipients such as suitable wetting agents, such as sodium urirylsulfate. Purification can usually be avoided by methods well known in the practice of pharmaceuticals. Oral medications may be, for example, in the form of water-soluble or oily suspensions, solutions, emulsions, syrups or elixirs, or may be provided dry to be formulated with water or a suitable solvent prior to use.

Such solutions may include suspending agents such as solitals, syrups, methyl cellulose, glucose syrups, gelatin, hydroxyethylcellulose, carboxy methylcellulose, aluminum stearate gels or hydrogenated edible fats, emulsifiers such as lecithin, sorbitan, Monooleates or acacias: non-aqueous solvents (including cooking oils), for example, ton oil, fractionated coconut oil, oily esters such as glycerin or polylene glycol, or ethyl alcohol: preservatives such as methyl or propyl P-hydroxy benzo Ate or sorbic acid and, if desired, conventional additives such as fragrances or colorants.

Suppositories contain conventional suppository bases, such as cocoa, butter or other glycerides.

For administration by injection, liquid unit dosage forms are prepared using the compound and sterile media and water is the preferred sterile media. The compound may be suspended or dissolved in the solvent, depending on the solvent and the concentration used.

In preparing solutions, the compounds can be dissolved in water for injection and filtered sterilized before filling and sealing in appropriate vials or ampoules. It is convenient to dissolve additives such as local anesthetics, adjuvants and buffers in the medium. After filling the vial to increase stability, the composition may be frozen and moisture removed under vacuum. The lyophilized dry powder is then filled and sealed in vials and attached vials with distilled water for injection before use. Injectable suspensions are prepared in substantially the same way except that the compounds are suspended in the media instead of dissolved and are not accompanied by sterilization by filtration. Compounds can be sterilized by exposure to ethylene oxide prior to suspension in sterile media.

It is convenient to include surfactants or wetting agents in the composition to promote uniform dispersion of the compound. The composition is preferably 10-60% by weight, containing 0.1-99% by weight of active substance, depending on the method of administration. When the composition comprises dosage units, each unit preferably contains 50-500 mg of the active ingredient. The therapeutic dose in adults ranges from 100-3000 mg per day, for example 1500 mg per day and depends on the route and frequency of administration.

The side chain of penicillin of formula (I) can have a member carbon atom. The present invention includes not only mixtures of compound (I) but also all possible epimers.

The compounds of the present invention are opportunistically stable against gram-negative β-lactabene and have activity against all important gram negative pathogens except Pseudomonasaeraginosa.

The following examples illustrate the preparation of the compounds of the present invention.

Example 1

(a) benzyl 6α-methoxy, 6β-amino penicillate

The corresponding 6α-methylrio derivatives were converted to the title compound.

(d) benzyl 6α-methoxy, 6β- (2'-phenoxycarbonylthien-3-yl-acetamido) penicilanate

A solution of benzyl 6α-methoxy, 6β-amino penicilanate (1.6 mmol) and pyridine (02 milliliters) dissolved in alcohol-free methylene chloride (15 milliliters) was phenyl hydrogenthiene- at 0-5 °. Treated with a methylene chloride (4 milliliter) solution of acid chloride prepared from 3-yl malonate (2 mmol). After 2.5 hours the solution was washed with water, dilute hydrochloric acid and dilute sodium bicarbonate, dried and concentrated by evaporation. Chromatography with silica gel gives the desired di-ester at a yield of 52.2%.

Nmr (CDcl ₃ ) δ = 1.35 (6H, S, gem dimethyls), 3.55 (3H, S, OCH ₃ ), 4.52 (1H, S, proton), 5.09 (1H, S, 2'-proton, 5.27 (2H , S, OCH ₂ Ph), 5.69 (1H, S, C ₅ protons), 7.09-7.88 (13H, m, phenyl and thienyl protons)

(C) 6α-methoxy, 6β- (2'-phenoxy carbonylthien-3-yl acetamido) penicilanic acid

Di-ester (150 milligrams) obtained in (b) was dissolved in anhydrous alcohol (10 milliliters), and a solution of water (3 milliliters) and N-sodium bicarbonate (1 equivalent) at 50 P.Si for 10 hours or more at 10% Pd Treated with / C (200 milligrams). Lyophilization gave the title compound in 62% yield as its sodium salt.

Nmr (D ₂ O) δ = 1.4 and 1.6 (6H, 2S, gem dimethyls), 3.45, 3.60 (3H, 2S, OCH ₃ ) 4.35 (1H, S, C ₃ protons), 5.1 (1H, S, 2 ' -Protons), 5.6 (1H, S, C ₅ protons), 7-7.7 (8H, m, phenyl and thienylprotons).

(d) 6-β- (D, L-2-carboxy-2-thien-3'-yl acetamido) -6-α-methoxyphenicylanic acid

Sodium 6-α-methoxy-6-β- (D, L-2-phenoxycarbonyl-2-thien-3'-yl-acetamido) phenylanate (0.460, 0.9 mmol) with sodium tetraborate Methahydrate (0.7 grams) dissolved in water (15 milliliters) was stirred at room temperature for 4 hours. The solution was then acidified to PH 4.0, washed with ethyl acetate (2 x 10 milliliters), acidified to pH 1.5 and extracted with ethyl acetate (2 x 20 milliliters). The extract was washed with water and extracted with dilute soda soda to pH 6.5. This water-soluble extract was washed with ether and freeze-dried to obtain 0.240 gram of disodium salt of 58.2% of the title compound. t. l. (S ₁ O ₂ : Chloroform / Acetone / Acetic acid; 7: 7: 1) Rf-0.25; mmr (D ₂ O, δ = 1.55 (6H, S, gemdimethyls), 3.65, 3.75, (3H, 2 × S, OCH ₃ ), 4.5 (1H, S, C ₃ proton, 5.7 (1H, S, C ₅ Protons), 7.2-7.8 (3H, m, thienyl protons).

Example 2

(a) benzyl-6α-methoxy, 6β- (2'-benzyloxycarbonylthien-3-yl acet amido) penicilanate

A solution of benzyl 6α-methoxy, 6β-aminophenicilanate (1.6 mmol) and pyridine (0.2 milliliter) dissolved in alcohol-free methylene chloride (15 mls) was added to methylene chloride (4 milliliters) at 0-5 °. Treated with acid chloride of dissolved monobenzyl 3-thienylmalonate (2 mmol).

After 2.5 hours, the reaction proceeded as above. Chromatography using silica gel afforded the desired pure diester (0.64 grams, 66%) in the foam.

ν max (CHCl ₃ ) 3250, 1770, 1735, 1685, 1495 cm ⁻¹ .

), 4.50(2S, 1H, C2'-H), 4.85(S 1H, C₃-H), 5.28(2S, 4H, CH₂O), 5.63 (S, 1H, C5-H) 7.5(m, 8H, Ar-H), 7.74 및 7.91(2bs, 두 경우에 있어서 다

의 1H).S (CDCl ₃ ) 1.33 (bS, 6H, C ₂ -CH ₃ ), 3.43 and 3.47 (2S, 3H,

), 4.50 (2S, 1H, C2'-H), 4.85 (S 1H, C ₃ -H), 5.28 (2S, 4H, CH ₂ O), 5.63 (S, 1H, C5-H) 7.5 (m, 8H, Ar-H), 7.74 and 7.91 (2bs, both cases)

Of 1H).

(b) 6α-methoxy, 6β-2'-carboxy-thien-3-yl acetamido peniclanic acid

-및 중탄산 소다(0.5밀리리터)의 용액을 10％ Pd/C(200밀리그람)으로 상온, 상압에서 4시간 이상 처리했다. 여과하고 증발 농축한후 생성물을 PH 2에서 에틸 아세테이트와 물 사이에 분배 되었다.Dibenzyl ester (200 milligrams) obtained in 1 (a) was dissolved in anhydrous alcohol (10 milliliters), water (milliliters) and

And a solution of soda bicarbonate (0.5 milliliter) was treated with 10% Pd / C (200 milligrams) at room temperature and atmospheric pressure for 4 hours or more. After filtration and evaporation, the product was partitioned between ethyl acetate and water at PH 2.

The low acid ethyl acetate phase was dissolved in aqueous methanol and lyophilized with pH adjusted to 6.5 to afford the title compound converted to disodium salt.

The product (140 milligrams) was essentially pure by TLC.

) 3.45 및 3.52(2S, 3H, OCH₃), 4.26 (S, 1H, C3-H), 5.52 (S, 1H, C5-H) 및 7.1-7.6(m, 3H, Ar-H).KBr 1760, 1670, 1500, 1365 cm ^-1 ; δ (D ₂ O) 1.4 (bs, 6H,

) 3.45 and 3.52 (2S, 3H, OCH ₃ ), 4.26 (S, 1H, C3-H), 5.52 (S, 1H, C5-H) and 7.1-7.6 (m, 3H, Ar-H).

The C ₂ '-H signal was obscured by HOD.

Example 3

6, α-methoxy-6β- (D, L-2-carboxy-2-thien-2'-yl acetamido) peniclanic acid

In sodium 6, α-methoxy-6, β- (D, L-2-phenoxycarbonyl-2-thien-2'-yl acetamido) penicilanate (0.65 grams) and water (50 milliliters) Dissolved sodium tetraborate decahydrate (1.0 gram) was stirred at room temperature for 2.5 hours. The solution was then acidified to pH 4.0, washed with ethyl acetate (3 x 50 milliliters), acidified to pH 2.0, extracted with ethyl acetate (2 x 50 milliliters), dried over anhydrous MgSO ₄ and concentrated by evaporation in vacuo. 0.49 grams (93%) of pale yellow foam was produced.

tl C (SiO ₂ : chloroform / acetone / acetic acid, 50: 50: 7)

Rf = 0.21; NMR [(CD ₃ ) ₂ CO]

), 4.50(1H, d, 3-H), 5.32 (1H,S, ＞

), 4.50 (1H, S, 3-H), 5.32(1H, S,

CONH-), 5.65(1H, S, 5-H), 7.3-(3H, m, 티에닐 방향족) 8.88(1H, d,

), 9.28(2H, S, -CO₂H).S = 1.50 (6H, m, gemdimethyl ₃ ) 3.52 (3H, d,

), 4.50 (1H, d, 3-H), 5.32 (1H, S,>

), 4.50 (1H, S, 3-H), 5.32 (1H, S,

CONH-), 5.65 (1H, S, 5-H), 7.3- (3H, m, thienyl aromatic) 8.88 (1H, d,

), 9.28 (2H, S, -CO ₂ H).

Biological data:

Comparison with 6α-methoxy-6β- (2-carboxyphenyl acet amido) peniclanic acid

6α-methoxy-6β- (2-carboxyphenylacet amido) peniclanic acid [6-methoxy carbenicillyl] and 6-α-methoxy 6-β- (2-carboxy-thien-3'-yl Acetamido) Table 1 shows the results of the microbiological evaluation of penicilanic acid [6-methoxy tisilsilyl], which shows the two compounds for Gram-negative bacteria and Sfrep Faecalis. Minimum stop concentrations (system dilution prior to culture limit).

It can be seen from Table 1 that the 3-thienyl compound (6-methoxy ticarcillin) is consistently twice as active as the corresponding phenyl compound (6-methoxy carbenicillin).

TABLE 1a

[Minimum stop concentration ^* (μg / ml)]

TABLE 1b

Claims (1)

Reacting a compound of formula (III) or an N-silyl or N-phosphorylated derivative thereof with an N-acylated derivative which is an acid of formula (IV) and removing the silyl or phosphoryl group by hydrolysis or alcoholysis or a carboxyl protecting group Method for producing 6-methoxy-α-carboxy penicillins of the general formula (I) characterized by removing the.

In the common sense R is 2- or 3-thienyl, R ¹ is hydrogen or salting ion, R ² is hydrogen or salting ion or ester group which can be hydrolyzed in vivo and R ^X is hydrogen or carboxyl protecting group.