FI56840C - FOERFARANDE FOER FRAMSTAELLNING AV SAOSOM ANTIBACTERISKA AEMNEN ANVAENDBARA 6- (2-PHENYL-2- (AMIDINO-OCH IMIDOYLAMINO-ALKANOYLAMINO) ACETAMIDO) PENICILLAN SYROR - Google Patents

Description

I- ^ r- \, -, ... v ADVERTISEMENT rrn ** (11) UTLÄGGNI NGSSKRIFT 56840 C (45) Pc1 'r.tti f'y ini;>. · Ty 13: .1 ^ (51) Kv .ik. * / int.ci. · c 07 D 499/68? U05 / 7 ^ FINLAND - FINLAND (21) Pttenttlhekemui - P »tenttn» 5knlng (22) Haksmlipiivi - Ansöknlngidsi 31 · 07 · 7 3 ^ ^ (23 ) Alkuptlvl — Glltighetsdag 31 · 07.7 3 (41) Has become public - Bllvlt offentlig 03.02.7¾

National Board of Patents and Registration (44) Nihtivikeipwon f, kuul.julksl.un pvm.- .. 10_0

The Patent and Register Office of the Patent Office and the Public Procurement Act are published. id. l y (32) (33) (31) Claim claimed — Begird prlorltet 02.08.72 USA (US) 277061; (71) Pfizer Inc., 235 East l + 2nd Street, New York 17, N.Y., USA (72) Ernest Seiichi Hamanaka, Groton, Conn., John Gerritt Stam,

Lyme, Conn., USA (US) (7¾) Oy Kolster Ab (5¾) Method for the preparation of 6- / 2-phenyl-2- (amidino- and imidoylamino-alkanoylamino) acetamide / penicillanic acids for use as antibacterial agents - Förfarande för framställning av säsom antibakteriska The present invention relates to a process for the preparation of compounds of formula ♦ / X -CHCONH ^ v- / CH_ for use as antibacterial agents.

\ = J NH Ί-1 TcH

c = 0 N 2 CO 2 H

(CHp) 1 2 n

Z

For the preparation of 6- [2-phenyl-2- (amidino- and imidoylamino-alkanoylamino) -acetamide] penicillanic acids and their pharmaceutically acceptable base salts according to formula 2 56840, wherein Z is XC-NH- or y-

V H2N

n is 1 or 2, and is pyridyl or phenyl substituted with fluorine, chlorine, bromine, trifluoromethyl, 3,4-dichloro or 3,5-dichloro.

The process according to the invention is characterized in that the formula V 'y-CHCONHn. / S CH3

\ = y NH I CH3 II

The compound of the N-S: o 2h or a salt thereof is reacted with the formula

Z- (CH_) -CO-X III

with a compound of formula n, wherein Z and n are as defined above, and X is -OH or -Cl, in the presence of a compound that binds the formed HX, and, if desired, forming a pharmaceutically acceptable base salt of the resulting compound. Penicillins have a general formula

O

"1 R-C-NH

"f — r 1¾

? -ko2H

The pharmacodynamic properties and the antibiotic activity spectrum of penicillins depend to a large extent on the nature of the group R. The most commonly used penicillins are those in which the group R is a benzyl, phenoxymethyl or n-phenoxyethyl group. Although these well-known analogs have a very strong effect against gram-positive microorganisms, their activity against gram-negative microorganisms is limited. Thus, penicillins that resist the growth of gram-negative bacteria, e.g., E. coli, Pseudomonas, or Klebsiella species, are valuable drugs.

3,56840

Recent efforts to improve the range of activity of penicillins have led to the synthesis of several new agents, oi-carboxybenzylpenicillin (U.S. Pat. No. 3 lU2,673), a broad-spectrum antibiotic, is reported to be more potent against gram-negative bacteria in gastrointestinal, but limited to aminoarylmethylpenicillins and related compounds (U.S. Patent Nos. 2,985,6 ^ 8, 3,100,282, 3,373,156, 3,308,023, and 3,326,677) are known, but have a limited range of activity against certain gram-negative microorganisms; .

Both gram-negative and gram-positive activity are claimed for 6-ureidopenicillanic acid derivatives in U.S. Patent Nos. 3,180,863, 3,120,512 and 3,118,877 and for α-ureidopenicillins in U.S. Patent No. 3,352,851. Activity against gram-negative bacteria, especially Pseudomonas of? -carbamoylureidopenicillins (U.S. Pat. No. 3,838,118) and? -alkoxycarbonylureidopenicillins (U.S. Pat. No. 3,180,882). More recently, ot-guanylureidopenicillins (U.S. Pat. No. 3,579,501) and ot-imidoyl-ureopopenicillins (U.S. Patent No. 3,633 to U05) have been reported to be useful against infectious diseases, especially those caused by the genus Pseudomonas.

In the penicillins prepared according to the invention, the t-carbon atom of the penicillin side chain to which the amidino or imidoylaminoalkanoylamino moiety is attached is an asymmetric carbon atom which allows the existence of two optically active isomers, the D- and L-diastereoisomers, D-formate, D racemate. According to previous observations concerning the activity of such penicillins having asymmetric carbon atoms, the compounds of formula I having the D-configuration are more active than the compounds of the L-configuration and are therefore preferred compounds, although the L- and DL forms are also considered to be within the scope of this invention.

According to the invention, the compounds of formula I are prepared by reacting oi-aminobenzylpenicillin or a salt thereof with a reaction in an inert, aprotic solvent in the presence of an acid scavenger such as a tertiary amine at -30 to 0 ° C. In general, it is preferable to use an excess of acid chloride of up to 100-200%. Under these conditions, it is necessary to add a sufficient amount of a tertiary amine, preferably triethylamine, to neutralize the hydrochloride of the acid chloride as well as the hydrogen chloride formed by the action of the acid chloride on the α-amino group of penicillin.

11 5 G Θ4 O

The reaction-inert solvent which forms the liquid phase of said reaction mixture should be one which does not react appreciably more with the reagents of said reaction than with the product. Preferred solvents should be anhydrous, aprotic, polar solvents such as dimethylformamide or hexamethylphosphoramide.

Although the coupling of the reagents is initially performed at ice bath temperature, it is often desirable to allow the reaction mixture to warm to room temperature after stirring for a few minutes to reduce the presence of by-products until the reaction is complete or nearly complete. The reaction time, which varies depending on the temperature and the concentration of the starting reagents and the inherent reactivity, is usually 0.5 to 12 hours.

Upon completion of the above reaction, any insolubles are filtered off and the product is precipitated by adding the filtrate to a large amount of diethyl ether or some other solvent in which the product is insoluble. The crude product is isolated by suction filtration and drying. The methylene chloride suspension of the crude product is triturated to remove the starting t-aminobenzylpenicillin by adding a small amount of triethylamine, which converts the starting penicillin to a methylene chloride-soluble triethylamine salt. The pure product is then filtered and dried.

The starting materials used in the process of the invention are readily prepared by methods known to those skilled in the art, α-aminobenzylpenicillins are known and are described in U.S. Patent Nos. 2,985,6k8 and 3,3b 6JJ and Long et. ai., J. Chem. Soc., 1920 (1971), while hydrochlorides of acid chlorides are easily synthesized from the corresponding acids using thionyl chloride or phosphorus pentachloride. The corresponding acids, in turn, are prepared by synthetic methods well known to those skilled in the art. Of note in this regard are the preparations presented by Ried, et. et al., Ann., 661, 76 (1963) s Ried et. et al., Chem. Ber., 95, 728 (1962), McElvain, et. ai., J. Am. Chem. Soc., 71, ^ 0 (19 ^ + 9), Bauer, et. ai., J. Org. Chem., 27, 3882 (1962) and Cardellini, et. ai., Ann. Chim. (Rome) 58, 183, 1199 (1958).

The acidic compounds of the invention form salts with bases. The compound in acid form is converted into a salt by reacting the acid and a suitable base in an aqueous or non-aqueous medium. Suitable basic reagents for use in the preparation of salts include, for example, organic amines, ammonia, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, and alkaline earth metal hydroxides, hydrides, 5,56840 alkoxides and carbonates. Such bases are represented by ammonia, primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethylamine, octylamine, secondary amines such as dicyclohexylamine, and tertiary amine, N-ethylanine, such as diethylamine and 1,5-diazobicyclo- (U, 3,0) -5-noneene; sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydride and barium hydroxide.

The compounds of this invention are sufficiently basic to form acid addition salts due to the amidino and imidoylamino moieties; they, especially pharmaceutically acceptable acid addition salts, are also considered to be within the scope of this invention.

When utilizing the chemotherapeutic activity of the compounds of the invention which form basic salts, it is, of course, preferable to use pharmaceutically acceptable salts. Although insolubility in water, high toxicity, or lack of crystalline nature may make some salt species unsuitable or less desirable for use as such for a particular pharmaceutical use, water-insoluble or toxic salts may be converted to the corresponding acids to any pharmaceutically acceptable salt. Preferred pharmaceutically acceptable salts include sodium, aluminum, potassium, calcium, magnesium, ammonium and substituted ammonium salts, e.g. procaine, dibenzylamine, N, N-bis (dehydroabietyl) ethylenediamine, 1-efenamine, N-ethylpiperidine, N-benzyl-β-phenethylamine, Ν, Ν'-dibenzylethylenediamine, triethylamine and salts with other amines used to form salts with benzylpenicillin.

Several of the penicillins described herein have in vitro activity against a wide variety of microorganisms, including both gram-positive and gram-negative bacteria. Their useful activity can be readily demonstrated in in vitro experiments against a variety of organisms in a cerebrospinal infusion medium by the standard two-fold serial dilution technique. The in vitro activity of the compounds described herein makes them useful for topical use in the form of ointments, ointments, etc., or, e.g., for sterilizing patient room supplies.

These new penicillins are also potent bactericidal agents in vivo in animals, including humans, not only in parenteral therapy, but also in oral therapy.

6 56840

It will be appreciated that the physician will ultimately determine the dosage which will be most suitable for an individual and will vary with the age, weight and reactions of the patient, the nature and extent of the symptoms, the nature of the bacterial infection being treated and the pharmacodynamic properties of the particular agent. It is often found that when administered orally, larger amounts of active ingredient are required to achieve the same level produced by a small amount when administered parenterally.

Taking full account of the above factors, it is considered that an effective daily oral dose of the compounds of this invention in humans is about.

10-100 mg / kg / day with a recommended range of 50-75 mg / kg / day in single or divided doses, and an extra-gastrointestinal dose of 25-100 mg / kg / day with a recommended range of about 20-75 mg / kg / day effective infection symptoms. These values are illustrative and there may, of course, be individual instances where higher or lower dosage ranges are merited.

As mentioned above, the penicillins of the present invention are broad-spectrum antibiotics which, in contrast to many penicillin analogs, are very potent against gram-negative microorganisms, especially E. coli, Pseudomonas and Klebsiella species. Furthermore, they prove to be more resistant than most penicillins to the degrading effect of penicillinase, an enzyme produced by certain bacteria that breaks down penicillin into inactive penicillanic acid.

The antimicrobial activity ranges of several compounds of this invention are shown in the following tables. Table I compares the in vitro properties of 6- (D-2-phenyl-2- (amidinopropionamido) acetamido) penicillanic acid (PAP) to ampicillin (AMP) and carbenicillin (CAE). The experiments were performed under standard conditions in which each of the organisms shown was inoculated into a nutrient solution containing different concentrations of the test material and the minimum inhibitory concentration (MIC) was determined.

Table I

In vitro comparison results for PAP, AMP and CAR (MIC; μg / ml)

Organisms PAP AMP CAR

E. coli 51 A 266 1.56 3.12 3.12 E. coli 51 A 002 200 200 200

Ps. Aeruginosa 52 A 490 1.56 0.78 0.6

Ps. Aeruginosa 52 A 10U 12.5 200 50

Ps. Aeruginosa 52 A 173 0.78 38 75

Kleb. pneumoniae 53 A 009 25 100 200

Kleb. pneumoniae 53 A 015> 200 250> 200 A. aerogenes 55 A 002 100 100 25 A. aerogenes 55 A 004 6,25 5 50

Ser. marcescens 63 A 001 3.12 200 25 (continued) 7,56840

Organisms PAP AMP CAR

P. mirabilis 57 C 015 6.25 1.56 1.25 P. vulgaris 57 A 059 1.56 6 12.5 S. aureus --- 0.09 1.56

Table II shows the in vivo test results for the three compounds listed in Table I against several test infections in mice.

Values (% survivors) are obtained under standard conditions known to those skilled in the art. In the case of E. coli, the test compound is administered to infected mice in a multiple dosing series, with the first dose administered 0.5 hours after infection and repeated four and twenty-four hours later.

Table II

% Protection XX

Organism Route of administration Dose (mg / kg) PAP AMP CAR

E. coli 51 A 266 PO 200 30 90 70 50 20 80 10 E. coli 51 A 266 SC 200 80 90 90 50 80 80 90 5C) PO = oral; SC = subcutaneous route% of survivors.

Table III shows additional in vitro test results for compounds of formula I.

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Table IV shows the in vivo comparison results for the three compounds of Table III against E. coli infections in mice.

The results expressed as the percentage of survivors are obtained under standard conditions familiar to those skilled in the art. The test compound is administered to infected mice in a multiple dosing series, with the first dose administered 0.5 hours after infection and repeated four and twenty-four hours later.

Table IV

Y

Organism Method of administration Dose (mg / kg)

K? H2 H

NH NH NH

C = NH C = NH C = NH

000 F Cl Br E. coli 51 A 266 PO 200 10 0 0 50 0 0 0 25 10 0 10 E. coli 51 A 266 SC 200 90 JO 90 50 70 60 60 25 50 50 50

The following examples illustrate the invention.

Example 1 6- (D-2-Phenyl-2- (amidinoacetamido) acetamido) penicillanic acid To 10 ml of dry dimethylformamide is added, at room temperature and under nitrogen, 810 mg (6 mmol) of p-nitrophenol, 1.2 kg of (6 mmol) ) dicyclohexylcarbodiimide and 8.30 mg (6 mmol) of amidinoacetic acid hydrochloride, and the mixture is stirred for 2 hours. The triethylamine salt of D-α-aminobenzylpenicillin (1.8 g, U mmol) is added to the yellow suspension and the mixture is stirred overnight at ambient temperature. The solids are filtered and the clear filtrate is poured into 200 ml of diethyl ether. The precipitated yellow product is filtered off and suspended in 100 ml of methylene chloride to which 2 ml of triethylamine have been added. After stirring for 1 hour, the purified product is filtered and dried in vacuo, 910 mg (52.5 # yield).

10 56840

Infrared spectrum peaks (λ and; KBr): 3.0 (b), 3, * +, 5.6, 6.0, 6.25, 6.6, 6.85, 7.15, 7, · k, 8.1 and 8.85.

Nuclear Magnetic Resonance Spectrum (ppm; DMSO-D 6): 1.1 * 8 (d, 6H), 3.95 (s, 2H), U, U (1H), 5.2-5.8 (c, 3H) , 7.36 (7H) and 8-9 (b, 3H).

Example 2 6- (D-2-Phenyl-2- (3-amidinopropionamido) acetamido) penenylacetic acid

To a suspension of 1.35 g (3 mmol) of the triethylamine salt of D-ec-aminobenzylpenicillin in 15 ml of dimethylformamide under nitrogen is added 0.63 ml (it, 5 mmol) of triethylamine, and the mixture is cooled to 0 ° C in an ice bath. 3-Amidino-propionyl chloride hydrochloride (770 mg, 5 mmol) is added and the mixture is stirred for 15 min. At 0 ° C and for another hour at room temperature. The mixture is then cooled to 0 ° C and an additional 237 mg (1.5 mmol) of this mixture is added. acid chloride hydrochloride and 0.21 ml (1.5 mmol) of triethylamine, and the reaction mixture is stirred for 1 hour at room temperature. The solids are filtered and the filtrate is added dropwise with stirring to 200 ml of diethyl ether. The crude, dried product (1.2 g) is suspended in 200 ml of methylene chloride and treated with 1 ml of triethylamine. After stirring for 30 minutes, the purified product is filtered off and dried under reduced pressure, 6Uo mg (Uj, 1 *% · .η yield).

Infrared spectrum peaks (μm; KBr): 3.0 (b), 3.35, 5.6, 6.0, 6.2, 6.6, 6.85, 7.15, 7.65, 8, 0, 8.15 and 8.85.

Nuclear Magnetic Resonance Spectrum (ppm; DMSO-D 6): 1.5 (d, 6H), 2.55 (b, 4H), 1 +, 0 (s, 1H), 5.2U-5.85 (c, 3H) , 7.1 * (7H) and 9.0 (b, 3H).

Example 3 6- (D-2-Phenyl-2- (p-chlorophenylformimidoylaminoacetamido) acetamido) penicillanic acid

To a mixture of 13.5 g (0.03 mol) of the triethylamine salt of D-ef-aminobenzylpenicillin and 3 g (0.03 mol) of triethylamine in 20 ml of dry dimethylformamide cooled to -30 ° C is added U, 0 g (0.015 mol) of p-chlorophenylformimidoylaminoacetyl chloride hydrochloride. After the mixture has been stirred in the cold for 1.5 minutes, a further U.0 g (0.015 mol) of this mixture are added. acid chloride, followed by 1 * 5 min. after which 3 g (0.03 mol) of triethylamine are added. The alternations are continued for 1 * 5 min. at intervals until 16.0 g (0.06 mol) of acid chloride and 9.09 g (0.09 mol) of triethylamine are added to the penicillin salt. The reaction mixture is allowed to warm to room temperature, filtered and the filtrate is poured into 2.5 l of chloroform.

The precipitate obtained is filtered off, washed successively with chloroform and ether and dried in vacuo. The crude product is then dissolved in 50 ml of dimethylformamide,

5 G 8 4 O

containing U g of triethylamine. A small amount of insoluble matter is filtered off, the filtrate is added to 100 ml of chloroform and the precipitated product is filtered off with suction. The product is further purified by trituration twice with 80 ml of methylene chloride containing 2 g of triethylamine and finally by trituration with methylene chloride alone. The pure product is dried in vacuo, yield 12%.

Nuclear Magnetic Resonance Spectrum (ppm; DMSO-D 6): 1.3 (d, 6H), 3.8 (s, 1H), U, 1 (s, 2H), 5.2 (s, 2H), 5.62 (b, 1H), 5.8-7.0 (s, 3H), 7.0-7.8 (m, 9H) and 8.35 (s, 2H).

Example U

Using the procedure of Example 3, and starting from the triethylamine salt of D-et-aminobenzylpenicillin and the appropriate acid chloride, the following compounds are synthesized:

f »II

C HcCHCONH. / S vO 3

6 m Ί-OH

C = 0 r N CO H

I ^ ^

NH

C = NH

K

Yield% NMR + x p-CF C 9 H 8 - 6.8 X 1, U (d, 6H), U, 0 (s, 1H), U, 2 (s, 2H), 5.25 (s, 2H), 5.7 (b, 1H) and 6.8-8 (m, 1H).

p-FCgH 2 - 16.0 1, U (d, 6H), 1 »(s, 1H), U, 3 (s, 2H), U-5.3 (s, 6H), 5.3 (s , 2H), δ.8 (s, 1H), 7-7.6 (s, 7H) and 7.6-8 (m, 2H).

p-BrCl 2 H 2 - 8.5 1, U 5 (d, 6H), 3.9 (s, 1H), U, 2 (s, 2H), 5.25 (s, 2H), U, U-5, Δ (s, 7H), 5.8 (s, 1H), 7-8 (2xs, 12H) and 9.0 (s, 2H).

m-ClCl 2 H 2 - 8.7 1.0 (U, d, 6H), 3.9 (s, 1H), 1.2 (s, 2H), δ 6.6 (m, 8H), 7-8 (m, 11H) and 9.05 (t, 2H).

3, U-C 12 C 6 H 3 - 6.5 x 1, MdtfH), 3.9 (s, 1H), 1 », 1 (b, 2H), k, 8-6 (m, 11H), 7.2 (s, 7H), 7.7 (b, 2H) and 8.0 (s, 1H).

3,5-Cl 2 C 8 H 7 7.1 * X 1, U (d, 6H), U, 0 (partially covering s, 3H), 5.0-7.0 (m, 9H), 7, Ms, 5H), 7.8 (s, 3 H) and 9.0 (t, 2 H).

+ Peaks of the nuclear magnetic resonance spectrum - ppm; DMSO-Dg X ·

Not scanned above 500 Hz.

56840

Example 5 6- (D-2- (3-Amidinopropionamido) acetamido) penicillanic acid triethylamine salt

A slurry of 1.7 g (3.8 mmol) of 6- (D-2-phenyl-2- (3-amidinopropionamido) acetamido) penicillanic acid in 20 mL of water is treated with 0.5 mL (3.8 mmol) of triethylamine. After stirring for 5 minutes, a small amount of insoluble matter is filtered off and the filtrate is lyophilized.

In a similar manner, ammonium salts of the penicillin described above and the other penicillins described herein and salts of pharmaceutically acceptable organic amines are prepared.

Example 6 6- [D-2-Phenyl-2- (U-pyridoimidoylaminoacetamido) acetamide] penicillanic acid A. U-Pyridoimidoylaminoacetyl chloride dihydrochloride

A mixture of 21.1+ g of glycine and 97 g of methyl 1 * -pyridyl imidate in 100 ml of amyl alcohol is heated under reflux for 3 hours. The solid is filtered while the reaction mixture is still hot, then washed successively with amyl alcohol (2 x 100 mL) and diethyl ether (U x 100 mL). Drying overnight under nitrogen gives 51 g of the desired compound U-pyridoimidoylaminoacetic acid, m.p. 223_226 ° C.

10 g of H-pyridoimidoylaminoacetic acid in 50 ml of diethyl ether are treated with a sufficient amount of hydrogen chloride gas to give the dihydrochloride salt, 13.8 g, m.p. II + 5-150 ° C.

To 350 ml of methylene chloride are added 10.1 g of 1-pyridoimidoylaminoacetic acid dihydrochloride, 9.2 g of phosphorus pentachloride and 3.5 ml of dimethylformamide, and the resulting mixture is stirred at room temperature overnight. The yellow solid is filtered, washed successively with chloroform (1 x 300 mL) and hexane (1 x 300 mL). The desired U-pyridoimidoylaminoacetyl chloride dihydrochloride is dried under nitrogen gas, m.p. 150 ° C (dec.).

B. 6- [2-Phenyl-2- (ii-pyridoimidoylaminoacetamido) acetamide] 2-penicillanic acid in a flask cooled to -30 ° C with a 150 ml magnetic stirrer, a drying tube and a low temperature thermometer, containing U, 03 g D -cf-aminobenzylpenicillin trihydrate in 60 ml of dimethylformamide and 2.72 ml of triethylamine, 1.35 g of U-pyridoimidoylaminoacetyl chloride dihydrochloride are added. After stirring for 30 minutes at a temperature between -30 and -6 DEG C., a further 1.36 ml of triethylamine are added and, after 5 minutes, a further 1.35 g of acid chloride. Stirring is continued for 30 minutes at -30 to -1 ° C, after which 5 ml of triethylamine are added and then, after 5 minutes, 2.7 g of acid chloride. After stirring for 5 minutes in the cold, H.08 ml of triethylamine are added and then, after 10 minutes, 1.3 g of acid chloride. Stirring is continued in the cold for 30 minutes, then the reaction mixture is allowed to warm to room temperature over U5 minutes. The insoluble material is filtered off and washed with 20 ml of dimethylformamide. The solid is discarded and the washings are combined with the filtrate and added to 1 liter of chloroform. The precipitated solid (900 mg) is filtered and discarded, and the filtrate is diluted with 2 liters of hexane. The precipitate obtained, consisting of a mixture of D-ofc-aminobenzylpenicillin and the desired product, is filtered and imaged to give 2.87 g. The crude product is added to 80 ml of methylene chloride and 1 ml of triethylamine is added to this suspension with stirring. The suspension is stirred for 30 minutes, then filtered to give 1.31 g. The pure product is obtained by crystallization at room temperature from methanol and water to give 325 mg.

Nuclear Magnetic Resonance Spectrum (ppm; DMSO-D 6 -D 2 O): 1.5 (d, 6H), U, 2 (m, 3H), U, 8-6.0 (111.1 ^), 7, Δ (s, 5H), 7.9 (d, 2H) and 8.6-9.3 U, Uh).

X

as an impurity in water.

Claims (1)

1U - 56840 Claim: A process for the preparation of 6- (2-phenyl-2-) compounds of the formula (CHCONH 2 / CH 2 / NH 2 / NH 3 IC = O 0>> for the preparation of (amidino- and imidoylamino-alkanoylamino) -acetamido-7-penicillanic acids and their pharmaceutically acceptable base salts, in which Z is JC-NH- or XC-R 1 -HNN 2 k 2 n is 1 or 2, and is pyridyl or phenyl fluorine, chlorine, bromine, trifluoromethyl, 3, U-dichloro or 3,5-dichloro, characterized in that a compound of the formula < with a compound of formula Z- (CH 2 -CO-X III 2 n, wherein Z and n are as defined above, and X is -OH or -Cl, in the presence of a compound which binds the formed HX, and, if desired, forms a compound a pharmaceutically acceptable base salt.