DE1944379B2 - ALPHA-CARBOXYBENZYLPENICILLIN DERIVATIVES - Google Patents

Description

C = O O = C N-

OR ²

-CH-COOII

and their pharmaceutically acceptable salts, in which R ^{2 is} a monosubstituted phenyl radical, in which the substituent is a phenyl, lower carbalkoxyvinyl or lower carbalkoxy-lower alkyl radical

2. «-Carbo - ^ - biphenyloxyJ-benzylpenicillin and its pharmaceutically acceptable salts.

3. "-Carbo - ^ - carbomethoxymethylphenoxyJ -benzylpenicillin and its pharmaceutically acceptable salts.

4. Ä-Carbo- (4-carbomethoxymethylphenoxy) -benzylpenicillin and its pharmaceutically acceptable Salts.

The invention relates to Λ-carboxybenzylpenicillin derivatives the general formula

O H

CH-C-N-CH-CH

O = C-N-

QCHj) ₂

CH-COOH

and their pharmaceutically acceptable salts, in which R ^{2 is} a monosubstituted phenyl radical, in which the substituent is a phenyl, lower carbalkoxyvinyl or lower carbalkoxy-lower alkyl radical.

The acylation of 6-aminopenicillanic acid by 1) acid chlorides and 2) simple or mixed acid anhydrides is described in U.S. Patents 3,270,009, 3,142,673, and 3,173,916; and the one by 3) active derivatives of a substituted malonic acid for the preparation of various esters of oc-carboxyarylmethylpenicillins is described in British Patent 10 04 670. In addition, the manufacture such penicillins by acylation of 6-aminopenicillanic acid by means of aryl carboxy-ketene ester proposed in German patent application 19 00 195 been.

It has now been found that the acylation of 6-aminopenicillanic acid with a reactive Derivative of an aryl-substituted malonic acid runs easily and the economical production of esters of «-carboxy-benzylpenicillins, which are valuable as orally administrable antibiotics.

The compounds according to the invention can be by reaction of 6-aminopenicillanic acid or of a suitable derivative thereof in a reaction inert solvent at a temperature of about 0 to 50 ° C and a pH of about 5 to 8 with a phenylmalonic acid ester of the general formula

COX

COOR ₂

ίο in which X is a chlorine or bromine atom or -OCOR ₄ , in which R _{4 is} a benzyl or lower alkyl radical and R _{2 has the} above meaning.

As a derivative of 6-aminopenicillanic acid, for example, sodium, potassium or tri-loweral-5 Use kyl amine salt as the starting substance.

The degree of purity of the 6-aminopenicillanic acid is not critical for the success of the process.

The 6-aminopenicillanic acid can be used in pure, partially pure or crude form, as in the

ίο there is fermentation broth. When using water as the solvent, fermentation broths containing 6-aminopenicillanic acid are preferred from an economical point of view.
A reaction-inert solvent is understood here to mean a solvent which under reaction conditions does not undergo any noticeable reaction with either the reactants or the products. Aqueous and non-aqueous solvents can be used. The use of water as a solvent naturally involves some hydrolysis of the acid chloride. However, under the appropriate temperature and time conditions and the pH, the hydrolysis proceeds at a relatively slow rate compared to the desired N-acylation reaction. Suitable solvents for the manufacturing process are, for. B. methylene chloride, benzene, chloroform, dioxane, water, acetone, tetrahydrofuran, diethyl ether and dimethyl ether. Aqueous solvent systems, including those in which an emulsion is formed, e.g. B. water / water immiscible solvent can be used. Solvents that easily form emulsions with water are e.g. B. those water-immiscible solvents such as benzene, n-butanol, methylene chloride, chloroform, methyl isobutyl ketone and lower alkyl acetates such as ethyl acetate. The preferred water immiscible solvents are methyl isobutyl ketone and ethyl acetate.

The reaction is carried out in a pH range from about 5 to about 8, preferably from 6 to 7. The pH is adjusted to about neutral by adding a suitable acid acceptor, e.g. B. a Alkali metal or alkaline earth metal hydroxide. But you can also, and this is preferred, the Maintain pH by using a salt of 6-aminopenicillanic acid with an organic base. Any organic base which forms a salt with 6-aminopenicillanic acid can be used. Suitable organic bases are tri-lower alkylamines, Dibenzylamine, N, N'-Dibenzyläthylendiamine, N-low-Aikyl-piperidine, N-lower alkyl morpholines,

N-benzyl-ß-phenethylamine, N, N'-bis-dehydroabietylamine, Dehydroabietylamine or I-ephenamine.

However, it is advantageous to use a tri-lower alkyl amine, preferably triethylamine to be used as the organic base. Such bases have the advantage of being a salt with 6-aminopenicillanic acid, which is soluble in many of the aforementioned solvents. they are

especially advantageous if you have a non-aqueous Solvent system such as methylene chloride used

The reaction can be carried out within a wide temperature range, up to 50 ⁰ C. In order to avoid a decomposition of the products in the range of about 0, but preferably temperatures are employed from about 0 to about 30 ° C

The preferred form of the phenylmalonic acid ester as acylating agent is the respective acid monochloride due to the relatively easy production compared to the anhydrides.

The Phenylmalonsäuremonoester are in a known manner by reacting the appropriate Phenyichlorocarbonyl ketenes of the general formula

COCl

with the corresponding alcohols R ² OH, where R ^{2 has} the above meaning. The reaction is conducted at a molar ratio of 1: 1 carried out at a temperature of about -70 ⁰ C to about + 30 ° C, advantageously in a reaction inert solvent, which allows better mixing and better regulation of the reaction.

Suitable solvents are diethyl ether, dimethyl ether, Dioxane, methylene chloride and chloroform.

The reaction mixture is then treated with water and an alkaline reagent, e.g. B. sodium bicarbonate treated. The reaction mixture, if it still has a temperature below the freezing point of water, is ^{heated to at least 0 °} C., either before or after the addition of the water and the alkaline reagent. In order to neutralize the by-product hydrogen chloride and to form the salt of the phenylmalonic acid monoester, sufficient alkaline reagent, usually 2 to 3 equivalents, is added. The mixture is ^{stirred for about 1} hour and the organic solvent is stripped off ^{under reduced pressure below 35 ° C.} The remaining solution is extracted with ether, cooled to 10 to 15 ° C and adjusted to a pH of about 2. The acidic solution is mixed with a suitable solvent, e.g. B. methylene chloride, extracted, the extract dried and the solvent then removed under reduced pressure.

The phenylmalonic acid monoesters produced in this way are converted into their acid monochlorides Treatment with excess thionyl chloride converted, expediently in the presence of a reaction-inert Solvent such as benzene, diethyl ether or methylene chloride at a temperature of about 0 up to about 80 ° C, in a known manner.

The required phenylchlorocarbonyl ketene is prepared by reacting phenylmalonic acid with a halogenating agent such as PCl ₅ , PCl ₃ , POCl ₃ or SOCI ₂ at temperatures from about 0 to about 50 ° C. for one to about 10 hours. The reaction is carried out in the presence of a solvent system, preferably a reaction-inert solvent system. Suitable solvents are dialkyl ethers, e.g. B. diethyl ether, dipropyl ether, mono- and dimethyl ethers of ethylene glycol and propylene glycol, methylene chloride and chloroform.

The reaction time depends of course on the reaction temperature and the type of reaction participants addicted. A certain combination of reactants requires a lower temperature a longer reaction time than a higher temperature.

The molar ratio of the reactants, i.e. H. the phenylmalonic acid and the halogenating agent, can be used in wide areas, e.g. B. from 1:10 or higher, vary; however, for sufficient yields it should be at least stoichiometric. In practice a

ίο stoichiometric ratio of the reaction participants preferred.

The reaction participants can be added all at once or separately. When added separately is the order of addition is not critical. However, it seems that the implementation is going more smoothly and is subject to fewer side reactions when the phenylmalonic acid is added to the halogenating agent becomes, which results from the color of the reaction mixture, especially after the distillation under such conditions generally progresses the color of the reaction mixture from yellow to red. However, the color will progress with reverse addition, i.e. H. when adding the halogenating agent to the phenylmalonic acid, from yellow to black.

The phenylhalocarbonyl ketenes are isolated by distillation in vacuo. Because of their great They are usually under a nitrogen atmosphere at low temperatures and reactivity stored in the dark

The acid anhydride derivatives of the phenylmalonic acid half-esters are made by reacting the half-esters with a lower chloroalkyl carbonate in the presence of a Acid acceptor, such as pyridine, or a tri-lower alkylamine manufactured; (cf. J. Am. Chem. Soo, Vol. 75, pp.

637-639 [1953], and]. Org. Chem, Vol. 22, S, 248 [! 957]).

Instead of the lower chloroalkyl carbonates, other chlorocarbonates, e.g. B. chlorobenzyl carbonate or Use chlorophenyl carbonate.

The (X-Carboxybenzylpenicillin esters are well known Way isolated. A typical method when using water is to have the The pH of the reaction mixture is adjusted to about 2 to 3 and the product is extracted with ethyl acetate; the Ethyl acetate extract is washed with water, the product from this with 10% aqueous potassium bicarbonate extracted and then extracted again into ethyl acetate. The ethyl acetate extracts are again extracted with water, the aqueous extract brought to a pH of 2 to 3 and again with Ethyl acetate extracted. The product is obtained by removing the volatile components. That But product can also be dry by adding the appropriate inorganic or organic base Ethyl acetate extract can be isolated as an alkali metal or amine salt.

If an aqueous emulsion is used as the solvent, it is expedient to isolate the product by extracting the reaction mixture with a suitable water-immiscible solvent after adjustment to a pH of 2, ethyl acetate being particularly useful. The extract is then dehydrated and evaporated to dryness. The product turns into an amine or alkali metal salt by adding the appropriate base, e.g. B. N-ethylpiperidine or potassium ethylhexanoate, to a solution of the ester product in a suitable solvent such as ethyl acetate.

Another process that is then of value. if

the acylation reaction in a non-aqueous solvent, ζ. B. in methylene chloride, is carried out, consists in the addition of water to the reaction mixture and in the subsequent adjustment of the pH of the aqueous phase to about 2 to 3. The aqueous phase is separated, extracted with the non-aqueous solvent, and the combined non-aqueous Solvent layers dried. The products are removed from the non-aqueous solvent by addition of a ^gee: precipitated gnets organic base such as N-Äthylpeperidin or sodium or potassium 2-ethylhexanoate than their corresponding salts. However, the non-aqueous solvent can also be distilled off after drying at a low temperature, the residue taken up in a suitable solvent and the product precipitated therefrom by adding a suitable base. This alternative method offers greater latitude in terms of the choice of bases. The appropriate solvent will be determined by the solubility of the salt desired.

The esters are converted into the corresponding acids by known methods, for example by mild acid or alkali hydrolysis or enzymatically with an esterase such as liver homogenate.

The esters of the invention are effective antibiotics both in vivo and in vitro. You own for example, considerable effectiveness in treating gram positive and gram negative Infections in animals and humans. For this purpose, the pure substances or their mixtures can be used other antibiotics are used. They can be used alone or in combination with a pharmaceutical Carrier are administered from the point of view of the chosen route of administration and standard pharmaceutical practice is selected. They can also be taken orally in elixir or oral form Suspensions containing flavoring and / or coloring agents are administered or injected parenterally be, d. H. for example intramuscularly or subcutaneously. They can be used for parenteral administration on best used in the form of a sterile solution, which can either be aqueous, e.g. B. Solution in water or an isotonic saline, isotonic dextrose, or Ringer's solution, or which may be non-aqueous. In addition, compositions can advantageously be prepared which are suitable for immediate preparation of the solution prior to administration.

The oral and parenteral dosage for the present compounds is usually in Range of up to 200 mg / kg or 100 mg / kg of body weight per day.

The penicillin esters of the invention show improved absorption when administered orally versus those made from the corresponding free acids or alkali metal salts became. They therefore represent a common and effective dosage form of the -carboxybenzyl peniciliins.

In addition, many of the foregoing esters, while inherently inactive or of relative importance low activity against gram-negative organisms, due to the metabolism to the underlying

ίο lying acid, i.e. to a-carboxybenzylpenicillin degraded when given parenterally to animals or humans injected.

The antimicrobial spectrum of various claimed esters of «-Carboxybenzylpenicillin and some (used to prove the specific effect of the claimed esters) available as intermediates according to the method of BR-PS 10 04 670 (not mentioned there) esters and the known penicillin against Pseudomonas 1049 and in part also against Staphylococcus aureus 5 and Escherichia coli 266 is shown in Table I. The experiments were carried out under standardized conditions in which a nutrient broth containing different concentrations of the substance to be examined was inoculated with the particular organism concerned, and the minimum inhibitory concentration at which the growth of each organism no longer proceeded, observed and recorded. The substances examined were examined in the form of their sodium or potassium salts. The benzylpenicillin (potassium salt) investigated in this way gave values of 0.156 and> 100 for S. aureus and E. Coli, respectively.

Table II contains the in vivo values when administered orally and subcutaneously for many of the present invention Connections in the mouse.

The values were obtained under standardized conditions. The process consists (10- ⁶⁾ Culture of E. coli 266 in the formation of acute experimental infection with E. coli 266 in mice by intraperitoneal inoculation of mice with a standardized, which in 5% Schweinemagenmucin (hog mucin gatric) suspended was. The test compounds were administered in the form of their sodium or potassium salts to the infected mouse using a multiple dose regimen with the first dose being given 0.5 hour after inoculation and this dose being repeated 4.24 and 48 hours later. The percentage of surviving mice is then determined.

The LD 00 value of ₁ E. coli 266 (ie, the lowest concentration for a 100% mortality of the mice is required) is ΙΟ-. ⁷ In order to control a possible alteration in the virulence control animals received inoculations of ΙΟ- ^5, 10 ^-6 undlO-. ⁷

Table I.

In Vitro Spectra

Minimum inhibitory concentration y / ml

E. coli Pseudomonas S.

266 1049 aureus

4-carbomethoxyethylphenyl 6.2 0.78 - 4-carbomethoxymethylphenyl 12th 1.5 1.56 4-carbate ioxymethylphenyl 6.2 3.1 0.049 2-carbomethoxymethylphenyl 6.2 6.1 0.392 2-carbobutoxymethylphenyl 12th 12th -

continuation

2-biphenyl

4-carbomethoxy vinyl phenyl

2-carbomethoxyethylphenyl

For comparison:

n-octyl

n-butyl

t-butyl

methyl

Ampicillin (»Antibiotics Primer« [1965]

Pp. 118 to 123)

Minimum inhibitory concentration y / ml 1.6 Pseudomonas 3.1 S. E. coli 50 1049 12th aureus 266 3.1 0.012 0.195

50

2200

62

50

50

200

62

> 200

From the above test results, the superiority of the invention is Connections visible.

Table 11

In vivo values against E. coli 266 in the mouse

Orally 100 mg / kg Subcutaneous 100 mg / kg 200 mg / kg 100 200 mg / kg 80 ^c ) 2-biphenyl 100 20th 100 90 ^c ) 2-carbomethoxymethylphenyl 70 0 90 50 ^c ) 4-carbethoxymethylphenyl 80 0 90 70 4- (2-carbomethoxyethyl) phenyl 50 30th 80 100 4-carbomethoxymethylphenyl 90 100

^c ) = 50 mg / kg.

To demonstrate the superior effectiveness of the α-carboxylbenzylpenicillin esters claimed according to the invention The following comparative tests were carried out with respect to the known α-carboxybenzylpeniciliin employed.

_{The PD 50} value (the dose at which 50% of the test animals survive) was calculated from the percentages of surviving mice, as determined by the method described above and shown in Table II. The same thing happened with "-Carboxybenzylpenicillin".

The table below shows the PD50 values for the compounds according to the invention and for the comparison compound (R ² = H) for oral and subcutaneous administration.

Table III

PD50 values of the
α-Carboxybenzyl penicillin ester and des -carboxybenzyl penicillin vs. E. coli 266

PDso (mg / kg)

orally

subcutaneous

4- (carbomethoxymethyl) phenyl ^ 82 24
2-biphenyl 16 ") 11

H ^b ) (comparison compound)> 200 30-40

") The test was carried out with the potassium salt
^b ) The test was carried out with the sodium salt.

From the results given in Table ₅ O- PD values the effect of the esters of the invention as a pre-drug forms, ie substances which are converted by biological means in the final active form, can be seen. The ability of an ester to protect the test animal against E. Coli infection depends on the rate at which it is absorbed from the gastrointestinal tract and on the rate at which it converts to α-carboxybenzylpenicil-Hn, the chemotherapeutically active form hydrolyzed a ratio of oral to subcutaneous PD 50 PD ₅₀ that is greater than about 1: 1, a relatively poor absorption indicates the ester. A high subcutaneous PD ₅₀ value, ie a PD ₅₀ value which is greater than the subcutaneous PD 50 value of the -carboxybenzylpenicillin itself, indicates poor hydrolysis of the ester. Most of the esters given in the table have the same or even better effect than -carboxybenzylpenicillin and therefore represent orally, ie conveniently administered, effective dosage forms of-carboxybenzylpenicillin. The orally active esters according to the invention are easily absorbed after oral administration and what about therapy

table point of view is almost more important, too a-Carboxybenzylpenicillin hydrolyzed

The following experiment was carried out to support the above PD 50 values

Using blood serum tests, the extent of absorption and hydrolysis of an invention was determined Esters, namely the 4- (carbomethoxymethyl) phenyl ester of carbenicillin, determined in vivo. The determination was carried out after oral administration

709 508/444

preparation of the ester in dogs at a dose of 1000 mg / kg body weight. The drug was in Serum as carbenicillin, the hydrolysis product of the ester, in the following quantities.

amount of
Dogs

hours
0 0.5

1.0

2.0

4.0

3 0 0 4.2 6.3 l, 0 mcg / ml

The ratio of oral PDw to subcutaneous PD ₅₀ was 3.42. The subcutaneous PD ₅ o value (24) is lower than that of the Carbenicillins -, indicating a slight hydrolysis to carbenicillin in vivo (30 40).

Their advantage over «-carboxybenzylpenicillin lies consequently in that they are compounds to be administered orally, the action of which corresponds to the action of the subcutaneously administered «-carboxybenzylpenicillins is comparable.

example 1

A mixture of 3.74 g of 6-aminopenicillanic acid (17.3 mmol) in methylene chloride (50 ml) and 3.5 g of triethylamine (35 mmol) was stirred vigorously for 1.5 hours at room temperature and under nitrogen and then to 0 ° C chilled. A solution of 14.4 mmol of 2-phenyl-2- (2-carbomethoxymethylphenoxycarbonyl) acetyl chloride in 5 ml of methylene chloride was quickly added and the reaction mixture was stirred at room temperature for 1 hour. Then, the mixture was treated with 20 ml of water, stirred for 2 minutes, cooled to 1O ⁰ C and then adjusted by the addition of 6N hydrochloric acid, the pH of the mixture was stirred for 5 minutes, after which the methylene chloride layer was separated, dehydrated and evaporated to dryness, whereby the crude penicillin was obtained as an off-white foam (4.4 g).

550 mg of crude penicillin (1.12 mmol) in 1 ml of ethyl acetate was treated at room temperature with 147 mg of N-ethylpiperidine, stirred for 2 minutes, then cooled to 0 ° C., filtered and dried, the N-ethylpiperidine salt of «-Carbo- (2-carbomethoxymethylphenoxy) benzylpenicillin was obtained. Melting point 121 to 128 ⁰ C.

The N-ethylpiperidine salt was converted to the potassium salt in the following manner: 100 ml of benzene was placed in a 250 ml three-necked flask and 50 ml of benzene was distilled off. The refluxed benzene was admixed with 5 mmol of N-ethylpiperidine salt and then cooled to room temperature 3.2 ml of a 26% strength acetone solution of potassium ethyl hexanoate were added and the mixture was heated to 45 ° C. for 3 minutes. The mixture was kept to cool to room temperature, then to Quenched 0 ⁰ C, filtered and the potassium salt of <x -carbo- (2-carbomethoxymethylphenoxy) -benzylpeniciUin dried, melting point! 80 to 182 ° C

The sodium salt of a-Carbo- (2-carbomethoxymethylphenoxy) -benzylpenicil! In was prepared in a similar way by replacing the potassium ethyl hexanoate with sodium ethyl hexanoate, melting point 170 up to 72 ° C

Example 2

A stirred solution of 24 g of mono- (2-biphenyl) -phenylmalonat ΙΏπιΙ in dry acetone was cooled in an ice bath to 0 ⁰ C within 15 minutes

1.27 g of anhydrous triethylamine and then 900 mg of dry chloroethyl carbonate were added dropwise. A precipitate of triethylamine hydrochloride formed immediately. A solution of 1.8 g of 6-aminopenicillanic acid in 20 ml of a 5% solution of sodium bicarbonate and 5 ml of acetone was added to the mixed anhydride at the same time. The mixture was ^{stirred at 0 0} C for half an hour, then extracted with ether (3 × 50 ml) and mil

ίο concentrated hydrochloric acid acidified to pH 1.0. the acidic solution was extracted with ethyl acetate (3 × 50 ml). The extracts were combined with water saturated saline solution and dried over anhydrous sodium sulfate Solvent under reduced pressure gave the product as a yellow oil.

By dissolving in 1 ml of ethyl acetate and adding a slight excess of N-ethylpiperidine, the Product converted into the crystalline N-ethylpiperidine salt of «-Carbo - ^ - biphenyloxyJ-benzylpenicillin The salt was collected, washed with ethyl acetate and dried. Melting point 131 to 133 ° C (decomp.).

Example 3

In a similar way the a-Carbo- [4- (2-carbomethoxyethyl) -phenoxy] -benzylpenicillin, Melting point 94 to 96.5 ° C (decomp.), Prepared from the appropriate reactants.

Example 4
a) a-Carbo- (2-biphenyloxy) -phenylacetic acid

90 g phenylmalonic acid (0.5 mol), 85 g o-phenylphenol (0.5MoI), 0.8 ml Ν, Ν-dimethylformamide, 725 ml Isopropyl ether and 59.5 g thionyl chloride (0.5MoI)

were combined, stirred and refluxed on a steam bath for 2 hours.

The mixture was cooled to room temperature, then washed with water (3 × 50 ml) and washed with saturated aqueous sodium bicarbonate solution

(3 × 100 ml) extracted The combined aqueous extracts were washed with ether (2 × 25 ml), then acidified to pH 3 with 6N hydrochloric acid and extracted again with ether (3 × 50 ml). The ether extracts were first with water (2x15 ml) and then

washed with saturated aqueous salt solution (2 × 15 ml), then dehydrated over anhydrous sodium sulfate and evaporated to dryness. Yield: 90.3 g of -carbo (2-biphenyloxy) phenylacetic acid.

^b ) * - ^Carbo - (2-biphenyloxy) phenylacetic acid chloride

In a dry flask equipped with a condenser and drying tube was added 45 g of α-carbo- (2-biphenyloxy) phenylacetic acid (0.135 mol), 450 ml of methylene chloride, 0.1 ml of anhydrous N, N-dimethyl

formamide and 16.66 g of thionyl chloride (0.140 mol) The mixture was refluxed for 3 hours. The methylene chloride was reduced under reduced pressure Pressure removed, then the residue is treated with an additional 200 ml of the solvent and the

Repeated evaporation to give 48 g of a yellow oil.

cJa-Carbo-p-biphenyloxyI-benzylpenicillin

A slurry of 29.16 g of 6-aminopenicillan

acid (0.135 mol) in 800 ml of methylene chloride was at

Room temperature with rapid stirring at 27.27 g

Triethylamine (027MoI) added

The mixture was filtered, cooled to 5 ° C and stirred

48 g of (X-carbo- (2-biphenyloxy) -phenyl acetic acid chloride (0.135 mol) in 200 ml of methylene chloride were added, the rate of addition being kept so that the temperature did not rise above 10 ^° C. The mixture was then 1 hour stirred, diluted with 400 ml, adjusted to pH 2.0 and stirred vigorously.The methylene chloride phase was separated off, dehydrated over sodium sulfate and evaporated to dryness extracted with saturated aqueous sodium bicarbonate (3 × 150 ml) The aqueous extract was washed with ethyl acetate and then acidified to pH 2 in the presence of 300 ml of freshly distilled ethyl acetate.

The suspension was mixed vigorously, the ethyl acetate phase separated and successively with Washed with water (3 150 ml) and saturated saline solution (3 χ 150 ml). Then she was with dehydrated anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

The residue was dissolved in 400 ml of ethyl acetate, and 12 g of N-ethylpiperidine were added. The residue was vaccinated and left to stand overnight. The product was filtered, washed with ethyl acetate and air dried. Yield: 37.5 g; Melting point 131-133 ° C (decomposed).

Example 5

The above procedures were repeated but using phosphorus oxychloride instead of thionyl chloride for the production of the half-part of malonic acid with the following phenol derivatives instead of o-phenylphenol:

4-carbomethoxyethylphenol

4-carbethoxymethylphenol

4-carbomethoxymethylphenol

The following esters have been identified as their N-ethylpiperidine salts (NÄP) manufactured:

Penicillins (as NÄP salt)

Melting point ( ⁰ C)

<x-Carbo- (4-carbomethoxyathy! phenoxy ^ benzylpenicillin

a-Carbo - ^ - carbethoxymethylphenoxyJ-benzylpenicillin

oc-Carbo - ^ - carbomethoxyr-iethylphenoxyJ-benzylpenicillin 94-96.5 (decomp.)
104-106 (decomp.)
89-92 (decomp.)

Claims (1)

Patent claims: 1. α-CarboxybenzylpenicilIinderivate of the general formula OH S Il I / \ CH-CN-CH-CH C (CHj) ₂