CH622798A5 - Process for the preparation of 6-(D-2-acylamido-2-phenylactamido)- penicillanic acids - Google Patents

Description

The present invention relates to a process for the preparation of 6- (D-2-acylamido-2-phenyl-acetamido) -penicillanic acids of the formula wherein R1 is hydrogen or a hydroxyl group, R2 is a group of the formula -CO-CH (NH2) - CH2COR3 or -COCHa-CH (NH2) -COR3 and R3 represents a hydroxy, lower alkylamino, di-lower alkylamino, lower alkoxy or a hydroxy- 25 lower alkylamino group or R3 can mean an amino group if R1 represents a hydroxy group.

U.S. Patents 3,268,513 and 3,340,252 disclose the preparation of 6- [D-2- (DL-2-aminoglutaramido) -2-phenylacetamido] penicillanic acid by reacting 6- (D-2-amino-2- phenyl- 30 acetamido) -penicillanic acid described with DL-glutamine and the glutaramido derivative mentioned shows antimicrobial activity against both gram-positive and gam-negative bacteria. On the other hand, DT-AS 1,934,783 describes the preparation of 6- [D-2- (L-2-amino-3- 35 carbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid by condensing 6-aminobenzylpenicillin with Biphenylisopropyloxycarbonyl-L-asparagin and subsequent removal of the protective group.

The 40 new penicillins obtained by the process according to the invention can be used as antibacterial substances, for. B. as additives to animal feed and as chemotherapeutic agents for poultry and mammals, as well as for humans and they can be used in the treatment of infectious diseases caused by gram-positive or gram-negative bacteria. The penicillanic acid compound (I) shows a strong antimicrobial activity against a large number of microorganisms and can be rapidly absorbed by both oral and parenteral administration in humans and animals. In particular, the penicillanic acid compounds of the formula (I) show a strong antimicrobial activity against bacteria of the types Pseudomonas and Staphylococcus. So z. B. 6- [D-2- (D-2-Amino-3-N-methyl-carbamoyl-propionamido) -2-p-hydroxyphenylacetamido] - 55 penicillanic acid a minimal inhibitor concentration (MI C) (agar dilution method, cardiac infusion agar) of approximately 12.5 ßg / ml compared to Pseudomonas aeruginosa A3. On the other hand, the MIC of sulbenicillin (ie dinarium 6- (D-2-sulfonyl-2-phenylacetamido) penicillanate), A0 is 6- [D-2- (DL-2-aminoglutaramido) -2-phenylacetamido] -penicillanic acid and 6- [D-2- (L-2-amino-3-carbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid compared to the above-mentioned microorganisms 12.5, 50 and more than 100 i.ig / ml The antimicrobial activity of 6- [D-2- (D-2-amino-3-N-methylcarbamoyl-propionamido) -2-p-hydroxyphenylacet-amido] -penicillanic acid, as obtained by the process according to the invention, is opposite Staphylococcus aureus ATCC 6538P and St. epidermidis 10131R 2 to 4 times sulbenicillin and 6- [D-2- (L-2-amino-3-carbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid. The penicillanic acid compounds (I), as obtained by the process according to the invention, also have strong antimicrobial activity against other gram-positive and gram-negative bacteria, such as. B. against those of the species Streptococcus, Escherichia, Klebsiella, Salmonella and Bacillus. Furthermore, the toxicity of the compounds of formula (I) is remarkably low. So z. B. with intravenous administration of 6- [D-2- (D-2-amino-3-N-methylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid in mice in a dose of 10,000 mg / kg for a period Survival of all test animals was observed 14 days after administration.

The penicillanic acid compounds of the formula (I) prepared by the process according to the invention can be used for pharmaceutical use either as free acids or as salts thereof. Pharmaceutically usable, non-toxic salts of the compounds of formula (I) are e.g. B. non-toxic metal salts such as sodium, potassium, calcium, aluminum, ammonium and substituted ammonium salts, salts of non-toxic amines such as trialkylamines, e.g. B. triethylamine, procain, dibenzylamine, N-benzyl - /? - phenäthyiamin, 1-ephenamine, N, N'-dibenzylethylenediamine, dehydroabiäthylamin, iN, N'-bis-dehy-droabiäthyläthyläthamin, and other amines as they for the preparation of salts with benzylpenicillin can be used. The penicillanic acid compounds (I) are readily water-soluble and can be administered orally or parenterally (e.g. intravenously, intramuscularly, subcutaneously). A daily dose of compound (I) is 0.25 to 20 g, in particular 0.5 to 10 g and very particularly preferably 1-4 g for adult patients. Furthermore, compounds (I) can be administered in the form of pharmaceutical compositions containing the named compound together with pharmaceutical auxiliaries. Suitable auxiliaries are e.g. B. gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talc, vegetable oils or other known auxiliaries. The pharmaceutical compositions can be in solid form as tablets, as coated tablets, as pills, or capsules, or in soluble form as solutions, suspensions or emulsions. They can be sterilized and / or contain other additives such as stabilizers, wetting agents or emulsifiers.

622 798

4th

The process according to the invention for the production of 6- (D-2-amino-2-phenylacetamido) -penicillan-penicillanic acid compounds (I) consists of a condensed acid of the formula:

R1 -V ^ VCH-COKH

w Ìh2 o. I »I

wherein Y1 represents hydrogen or a protective group, with an N-protected amino acid of the formula:

R2 '_ OH

(III)

15

wherein R2 'is a group of the formula: -CO-CH (NHZ) -CH2CORs'

receives from which the protective group (s) is or are split off.

Examples of the protective group Y1 are benzyl, succinimidomethyl, phthalimidomethyl, phenacyl, trimethylsilyl and 2,2,2-trichloroethyl groups. On the other hand, the benzyl group is suitable as a protective group for a hydroxyl group R3 '. Examples of the protective group Z are o-nitro-phenylsulfenyl, benzyloxycarbonyl and 1-methyl-2-lower alkoxycarbonylvinyl. The penicillanic acid compounds (II) in which Y1 is hydrogen can be used for the process according to the invention in the form of their free acid or a salt thereof. Examples of these salts are alkali metal salts such as sodium and potassium salts and lower trialkylamine salts such as trimethylamine and triethylamine salts. 40

The condensation reaction of the penicillanic acid compound (II) with the amino acid (III) can be easily carried out. It is preferably carried out in the presence of diphenylphosphoric acid azide (i.e. NsPCKOCaHs ^) in a solvent. The reaction is suitably carried out at -20 to 20 ° C, especially at -10 to 5 ° C. The presence of an organic tertiary amine such as trimethylamine or triethylamine and the use of dimethylformamide, dimethyl sulfoxide or dichloromethane as a solvent is particularly preferred. In an alternative, the acid (III) can be converted into corresponding reactive derivatives prior to the condensation reaction. Suitable examples of the reactive derivatives of these acids mentioned are the corresponding mixed anhydrides (e.g. lower alkoxycarbonyl esters such as ethoxycarbonyl, 55 isobutoxycarbonyl, tert.-butoxycarbonyl and tert.-amyloxycarbonyl esters, lower alkanoyl esters such as pivaloyl ester),

active esters (e.g. esters with p-nitrophenol and N-hydroxy-succinimide) and azides. The mixed anhydrides of the acid (III) can be obtained in a conventional manner, e.g. B. 60 by reacting said acids with a lower alkoxycarbonyl halide (e.g. bromide or chloride) or a lower alkanoyl halide (e.g. bromide or chloride) at -40 to 5 ° C and in the presence of an acid acceptor in a solvent. Suitable solvents are 65

Chloroform, dichloromethane, dimethyl sulfoxide and dimethylformamide, while as suitable acid acceptors N, N-dimethylaniline, N-methylmorpholine, pyridine or the like

45

50

or -COCH «-CH (NHZ) -COR3 ', R3' has the same meaning as R3, and if R3 'represents a hydroxyl group, which may also be protected, Z represents a protecting group, or with a reactive derivative thereof, wherein a 6- (D-2-acylamido-2-phenylacetamido) -penicillanoic acid compound of the formula:

(IV)

come into question. On the other hand, the active esters of acid (III) can be reacted with p-hydroxyphenol or N-hydroxysuccinimide at -10 to 30 ° C in the presence of a dehydrating agent (e.g. dicyclo-hexylcarbodiimide) in a solvent (e.g. Tetrahydrofuran, dioxane, diglyme) can be obtained. The azides are obtained by reacting the hydrazides of the acid mentioned with sodium nitrite in a dilute mineral acid (e.g. sulfuric acid). The condensation reaction of the penicillanic acid compound (II) with the reactive derivative of the amino acid (III) thus obtained takes place at a temperature from -30 to 40 ° C., in particular from -15 ° to 5 ° C. in a solvent. Dimethylformamide, chloroform, tetrahydrofuran and methylene chloride are suitable for this.

The protective group can be split off from the 6- (D-2-acylamido-2-phenylacetamido) -penicillanic acid compound (IV) in a suitable manner and depending on the nature of the protective groups. So z. B. an o-nitrophenylsulfenyl group as substituent Z can be eliminated by reacting the compound of formula (IV) with 2-3 molar equivalents of a thioamide in a solvent. Examples of the thioamides mentioned are thioacetamide, thiobenzamide, thiourea and 2-mercapto-5-methyl-1,3,5-thiadiazole. The reaction is preferably carried out at 0-40 ° C and especially at 10-20 ° C. Ethyl ether, tetrahydrofuran, dioxane, lower alkanol (e.g. methanol, ethanol) or a mixture of the solvents mentioned are suitable reaction media. If Z represents a benzyloxycarbonyl group and / or each of the protective groups Y1 and for R3 '= hydroxy-xybenzyl, the protective groups mentioned are cleaved off by shaking the compound (IV) in hydrogen gas and in the presence of a catalyst. This catalytic hydrogenation is preferably carried out at 0 to 40 ° C, in particular at 10 to 20 ° C and at atmospheric pressure. Preferred examples of the catalyst mentioned are palladium-BaCOs, palladium-activated carbon and palladium-black. Lower alkanols such as methanol and ethanol are suitable reaction media. On the other hand, if the protecting group Z is 1-methyl-2-lower alkoxycarbonylvinyl and / or the protecting group Y1 is trimethylsilyl, the said group (s) can be obtained by treatment with dilute mineral acid (e.g. 0.5-1) ° / o hydrochloric acid) at a temperature of 5-10 ° C in a solvent (e.g. methyl ethyl

5

622798

ketone, methyl isobutyl ketone, dioxane) are split off. Furthermore, when phenacyl, phthalimidomethyl or succinimidomethyl is used as the protecting group Y1, the above group can be split off by reacting with an alkali metal salt of a thiol compound or thiophenol. This reaction is preferably carried out at -10 to 10 ° C in a solvent (e.g. tetrahydrofuran, isopropanol). The preferred thiol compound is

2-ethylhexyl ester of 2-mercaptoacetic acid used.

When the protecting group Y1 is 2,2,2-trichloroethyl, this group can be split off by reducing the compound (IV) with 90% formic acid zinc powder in the conventional manner. This reaction is preferably carried out at -5 to 10 ° C.

The compound (III) used as a starting product can be easily obtained in a conventional manner. So z. B. the N-protected amino acids (III) by reacting an amino acid of the formula R3'COCH2-CH (NH2) -COOH or R3'CO-CH (NH2) -CH2COOH with a compound of the formula ZX, in which X is a halogen, receive. This reaction is carried out at 0-40 ° C and in the presence of an acid acceptor (e.g. sodium carbonate, potassium carbonate, sodium hydroxide) in a solvent (e.g. water, tetrahydrofuran, dioxane or a mixture thereof).

The following examples describe embodiments of the process according to the invention which are easy to carry out and accordingly preferred. In the present description and in the claims, the terms “lower alkyl” and “lower alkoxy” mean straight-chain or branched alkyl and alkoxy having 1-6 carbon atoms.

example 1

(1) A solution of 1.5 g (11.8 mmol) of DL-2-amino-3-N-methylcarbamoyl-propionic acid hydrochloride (ie DL-N'-methylasparagin.HCl) in 16 ml of water was neutralized with potassium carbonate and then mixed with 5 ml of tetrahydrofuran. Then 2.5 g of o-nitrophenylsulfenyl chloride was added to the solution at 5-10 ° C, and the mixture was stirred at the same temperature for 2 hours. During the reaction, the mixture was kept at slightly alkaline pH (pH 8) by adding potassium carbonate. 10 ml of water were then added to the reaction medium and the insoluble solids were filtered off, whereupon the filtrate was washed twice with ethyl acetate, acidified with citric acid and then extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate extracts were washed with water, dried and concentrated in vacuo to remove the solvent. 2.8 g of DL-2- (o-nitrophenylsulfenyl-ammo) -3-N-methylcarbamoyl-propionic acid with mp 151-152 ° C. were obtained.

(2) 1.5 g (5 mmol) of DL-2- (o-nitrophenylsulfenylamino) -

3-N-methylcarbamoyl-propionic acid was dissolved in 30 ml of tetrahydrofuran. 1.14 g (5.5 mmol) of dicyclohexylcarbodiimide and 632 mg (5.5 mmol) of N-hydroxysuccinimide were added to the solution at 0-5 ° C and the mixture was stirred at the same temperature for 16 hours. The insoluble constituents were then filtered off and the filtrate was added

Concentrated at 20 ° C under reduced pressure and the crystalline precipitate thus obtained washed with benzene / ether. 1.2 g of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionyloxy] succinimide were obtained in the form of crystals of mp 133-135 ° C.

(3) 450 mg (1.13 mmol) of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionyloxy] succmimide and 6.05 mg (1.3 mmol) of 6- [ D-2-amino-2- (p-hydroxyphenyl) acetamido] -penicillanoic acid triethylamine salt were combined in one

Mixture of 10 ml chloroform and 15 ml dimethylformamide dissolved and the solution stirred at 0-5 ° C for 16 h. The solvent was then removed at about 30 ° C. and under reduced pressure, whereupon ether was added to the residue and the precipitate thus obtained was filtered off. 700 mg of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoylpropion-amido) -2-p-hydroxyphenylacetamido] -penicillanic acid were obtained in the form of a yellow caramel-like mass, io IR spectrum :

v Nujoi: 3270.1775.1720.1645 cm- *

Max.

(4) 710 mg (1.1 mmol) 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid and 450 mg (3.3 mmol) of thiobenzamide were dissolved in a mixture of 20 ml of ethanol and 5 ml of tetrahydrofuran. The solution was stirred at room temperature for 30 minutes, after which the solvent was removed at about 30 ° C. and under reduced pressure. The residue thus obtained was mixed with 20 ml of tetrahydrofuran and the precipitate obtained was filtered off. This precipitate was redissolved in 10 ml of aqueous tetrahydrofuran and 30 ml of ethyl acetate were added, and the aqueous phase was then separated off. After washing twice with tetrahydrofuran and ethyl * 25 acetate, the aqueous phase was freeze-dried. 450 mg of 6- [D-2- (DL-2-amino-3-N-methylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid were obtained in the form of a colorless powder with a melting point of 195-198 ° C. (Dec.).

IR spectrum:

v Nujoi; 3280, 1760, 1650, 1595 cm- '

Max. 7 '7

Thin layer chromatography:

Rf = 0.43 (silica gel, solvent: n-butanol-vinegar-35 acid-water (4: 1: 1))

IR spectrum of the Na salt:

15

20th

30th

40

45

V Nui01: 3300.1760.1650.1555 cm- »

Max. 7

Example 2

(1) 3 g (23.6 mmol) of D-2-amino-3-N-methylcarbamoyl-propionic acid hydrochloride (ie D-N'-methyl-asparagin.HCl), 5 g of o-nitrophenylsulfenyl chloride, 30 g Water, 10 ml of tetrahydrofuran and 12 g of potassium carbonate were treated in the same manner as described in Example 1 (1). 5 g of D-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionic acid of mp 134-136 ° C. were obtained.

(2) 1.57 g (5.2 mmol) of D-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionic acid, 1.3 g of dicyclohexyl-

50 carbodiimide, 788 mg N-hydroxysuccinimide and 15 ml tetrahydrofuran were treated as described in Example 1- (2). 1.8 g of N- [D-2- (o-nitrophenylisulfenylamino) -3-N-methylcarbamoylpropionyloxy] succinimide, mp 126-128 ° C., were obtained.

5S (3) 800 mg (2 mmol) of N- [D-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionyloxy] succinimide and 932 mg (2 mmol) of 6-IT> -2-amino -2- (p-hydroxyphenyl) acetamidoj-penicillanic acid triethylamine salt were dissolved in 15 ml of dimethylformamide. The solution was stirred at 0-5 ° C for 60 h after which it was treated in the same manner as described in Example 1- (3). 1.15 g of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-p-hydroxy-phenylacetamido] -penicillanic acid were obtained in the form of a yellow powder 65 mp 165-167 ° C (dec.).

(4) 1.10 g (1.7 mmol) of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] penicillanic acid and 830 mg

622 798

6

(6.0 mmol) of thiobenzamide were dissolved in a mixture of 15 ml of methanol and 5 ml of tetrahydrofuran. The solution was stirred at room temperature for 45 minutes, after which the reaction mixture was further treated in the same manner as described in Example 1- (4). Man 5

received 700 mg of 6- [D-2-amino-3-N-methylcarbamoyl-propion-amido) -2-p-hydroxyphenylacetamido] -penicillanic acid as a colorless powder, mp. 198-201 ° C. (dec.).

IR spectrum:

v Nujoi; 3280, 1760, 1660 cm-1 10

mas. t; f --V f. .

Thin layer chromatographië:

Rf = 0.43 (silica gel, solvent: n-butanol-acetic acid-water (4: 1: 1)

IR spectrum of the Na salt:

v Nujoi; 3300.1760.1660.1600 cm-1

Max.

15

35

Example 3

(1) 4.5 g (36 mmol) of L-2-amino-3-N-methylcarbamoyl-propionic acid hydrochloride (ie L-N'-methyl-asparigin.HCl), 20 7.6 g of o-nitrophenylsulfenyl chloride, 40 g of water, 20 ml of tetrahydrofuran and 18 g of potassium carbonate were processed as described in Example 1- (1). 7 g of L-2- (ö-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionic acid of mp 132-135 ° C. were obtained. 25th

(2) 3.2 g (11 mmol) of L-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionic acid, 2.6 g of dicyclohexylcarbodiimide, 1.6 g of N-hydroxysuccinimide and 35 ml of tetrahydrofuran were made as processed in Example 1- (2). 3.5 g of N- [L-2- (o-nitrophenylsulfenyl-30 amino) -3-N-methylcarbamoyl-propionyloxy] -succinimide of mp 127-129 ° C. were obtained.

(3) 792 mg (2 mmol) of N- [L-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionyloxy] succinimide and 932 mg (2 mmol) of 6- [D-2-amino- Triethylamine salt of 2- (p-hydroxyphenylacet-amido] -pemcillanoic acid was dissolved in 15 ml of dimethylformamide. The solution was stirred at 0-5 ° C for 16 hours, after which it was processed in the same manner as described in Example 1- (3) 1.05 g of 6- [D-2- (L-2- (o-nitrophenylsulfenylamino) -3-N-40 methylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid were obtained in the form of a caramel-like mass .

IR spectrum:

v Nujoi: 3260.1775.1720.1635 cm-i max. ^

(4) 1.00 g (1.55 mmol) of 6- [D-2- (L-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido-penicillanic acid and 740 mg (5.4 mmol) of thiobenzamide were dissolved in a mixture of 40 ml of methanol and 10 ml of tetrahydrofuran. The solution was stirred at room temperature for 40 min, after which it was processed as described in Example 1- (4). 620 mg of 6- [D-2- (L-2-amino-3-N-methylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid of mp 197-200 ° C. (destroyed. ). 55

IR spectrum:

v Nujoi; 3250.1760.1650 cm-1

Max.

Thin layer chromatography:

Rf = 0.43 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

Example 4

(1) 2.10 g (10 mmol) of D-2-amino-3-N-isopropylcarbamoyl-propionic acid (ie D-N'-isopropyl-asparagine), 2.2 g of fi5 o-nitrophenylsulfenyl chloride, 20 ml of water , 20 ml of tetrahydrofuran and 2.0 g of potassium carbonate were processed as described in Example 1- (1). 2.3 g of D-2- were obtained

60

(o-Nitrophenylsulfenylamino) -3-N-isopropyl-carbamoyl-propionic acid, mp. 146-147 ° C (dec.).

(2) 981 mg (3 mmol) of D-2- (o-nitrophenylsulfenylamino) -3-N-isopropylcarbamoyl-propionic acid, 639 mg of dicyclohexyl-carbodiimide, 356 mg of N-hydroxysuccinimide and 20 ml of tetrahydrofuran were prepared as in Example 1- (2 ) processed. 1.13 g of N- [D-2- (o-nitrophenylsul-fenylamino) -3-N-ispropylcarbamoyl-propionyloxy] -succinimide were obtained in the form of crystals of mp 144-145 ° C. (dec.).

(3) 699 mg (1.5 mmol) of 6- [D-2-amino-2- (p-hydroxy-phenyl) -acetamido] -penicillanoic acid-triethylamine alz were dissolved in 10 ml of dimethylformamide at 3-5 ° C. 636 mg (1.5 mmol) of N- [D-2- (o-nitrophenylsulfenylamino) -3-N-iso-propylcarbamoyl-propionyloxyj-succinimide was added to the solution and the resulting mixture was stirred at the same temperature for 2 hours. After the reaction had ended, the mixture was poured into 50 ml of ice / water, whereupon this aqueous mixture was washed twice with 30 ml of ethyl acetate, acidified with citric acid and then extracted three times with 30 ml of ethyl acetate each time. The combined extracts were washed three times with 20 ml of water, dried and concentrated at a temperature lower than 25 ° C and under reduced pressure to remove the solvent. 950 mg of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-N-isopropyl-carbamoyl-propionamido) -2-p-hydroxyphenyl-acetamido] -penicillanic acid were obtained in the form of crystals of mp. 152-154 ° C (dec.).

IR spectrum:

v Wujoi: 3275.1780.1730.1640.1620 cm-i max.

(4) 920 mg (1.36 mmol) of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-N-isopropylcarbamoyl-propionamido) -2-p-hydroxy-phenylacetamido] -penicillanic acid were dissolved in a mixture of 20 ml of ethanol and 5 ml of tetrahydrofuran. 616 mg (4.5 mmol) of thiobenzamide was added to the solution at room temperature and the mixture was then stirred at the same temperature for 1 hour. The reaction solution was then concentrated at a temperature below 25 ° C. and under reduced pressure. Ether was added to the residue and the crystalline precipitate obtained was filtered off. After washing this precipitate with tetrahydrofuran, it was dissolved in 50 ml of water, the aqueous solution twice with tetrahydrofuran / ethyl acetate (3: 1), and washed with ether and then freeze-dried. Ether was added to the freeze-dried powder and the crystalline precipitate obtained was filtered off. 620 mg of 6- [D-2- (D-2-amino-3-N-isopropylcarbamoyl-propionamido) -2-p-hydroxy-phenylacetamido] -penicillanic acid were obtained in the form of crystals of mp. 198-200 ° C. ( Dec.).

IR spectrum:

v: 3250.1760, 1650 cm- '

Max. -

Thin layer chromatography:

Rf = 0.38 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

Example 5

(1) 2.5 g (11 mmol) of D-2-amino-3-Nn-butylcarbamoyl-propionic acid hydrochloride (ie D-N'-n-butyl-asparagin.KCl), 2.2 g of o- Nitrophenylsulfenyl chloride, 25 ml of water, 25 ml of tetrahydrofuran and 1.2 g of sodium hydroxide were processed in the same manner as described in Example 1- (1). 2.6 g of D-2- (o-nitrophenylsulfenylamino) -3-N-n-butylcarbamoyl-propionic acid of mp 143-144 ° C. (decomp.) Were obtained.

(2) 1.023 g (3 mmol) of D-2- (o-nitrophenylsulfenylamino) -3-N-n-butylcarbamoyl-propionic acid, 639 mg (3.1 mmol)

7

622798

Dicyclohexylcarbodiimide, 356 mg (3.1 mmol) of N-hydroxysuccinimide and 20 ml of tetrahydrofuran were processed in the same manner as described in Example 1- (2). 1.04 g of N- [D-2- (o-nitrophenylsulfenylamino) -3-N-n-butylcarbamoyl-propionyloxy] -succinimide of mp 135-136 ° C. (dec.) Were obtained.

(3) 699 mg (1.5 mmol) 6- [D-2-amino-2- (p-hydroxyphenyl) acetamido] penicillanoic acid triethylamine salt, 657 mg (1.5 mmol) N- [D- 2- (o-Nitrophenylsulfenylamino) -3-Nn-butylcarbamoyl-propionyloxy] -succinimide and 10 ml of dimethylformamide were processed as described in Example 4- (3). 1010 mg of 6- [D-2- (D-2- (o-nitro-phenylsulfenylamino) -3-N-n-butylcarbamoyl-propionamido) - were obtained.

2-p-hydroxyphenylacetamido] -penicillanic acid in the form of a caramel-like mass.

IR spectrum:

v: 3275, 1770, 1725, 1640 cm-i max.

(4) 980 mg (1.42 mmol) 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-Nn-butylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid, 616 mg (4.5 mmol) of thiobenzamide and 15 ml of ethanol were as in Example

4- (4) processed. 570 mg of 6- [D-2 ~ (D-2-amino-3-Nn-butylcarbamoyl-propionamido) -2-p-hy-droxyphcnylacetamidoj-penicillanic acid were obtained in the form of crystals of mp. 188-191 ° C. (dec .).

IR spectrum:

v Nujoi; 3270, 1760, 1650 cm- '

"lax.

Thin layer chromatography:

Rf = 0.45 (silica gel, solvent: n-butanol-acetic acid-water (4: 1: 1)).

Example 6

(1) 2.7 g (11 mmol) of D-2-amino-3-Nn-hexylcarbamoyl-propionic acid hydrochloride (ie D-N'-hexylasparagin.HCl), 2.2 g of o-nitrophenylsulfenyl chloride, 30 ml of water, 25 ml of tetrahydrofuran and 1.2 g of sodium hydroxide were processed in the same manner as described in Example 1- (1). 2.8 g of D-2- (o-nitrophenylsulfenylamino) -3-N-n-hexylcarbamoylpropionic acid of mp 115-116 ° C. (decomp.) Were obtained.

(2) 1.11 g (3 mmol) of D-2- (o-nitrophenylsulfenylamino) -

3-N-n-exylcarbamoyl-propionic acid, 639 mg (3.1 mmol) of dicyclohexylcarbodiimide, 356 mg of N-hydroxysuccinimide and 20 ml of tetrahydrofuran were processed in the same manner as described in Example 1- (2). 1.23 g of N- [D-2- (o-nitrophenylsulfenylamino) -3-N-n-hexylcarbamoyl-propionyloxyj-succinimide of mp 128-129 ° C. (dec.) Were obtained.

(3) 699 mg (1.5 mmol) 6- [D-2-amino-2- (p-hydroxyphenyl) acetamido] penicillanoic acid triethylamine salt, 699 mg (1.5 mmol) N- [D- 2- (o-Nitrophenylsulfenylamino) -3-Nn-hexylcarbamoyl-propionyloxyj-succinimide and 10 ml of dimethylformamide were processed as described in Example 4- (3). 980 mg of 6- [D-2- (D-2- (o-nitrophenylsulfylamino) -3-N-n-hexylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid were obtained in the form of a caramel-like mass.

IR spectrum:

v Nujoi; 3275, 1770.1725.1635 cm- '

Max.

(4) 714 mg (1 mmol) 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-Nn-hexylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid, 472 mg ( 3.5 mmol) of thiobenzamide and 10 ml of ethanol were processed in the same manner as described in Example 4- (4). You got

390 mg of 6- [D-2- (D-2-amino-3-Nn-hexylcarbamoyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid in the form of crystals of mp. 186-189 ° C (dec. ).

IR spectrum:

v: 3250, 1770, 1655 cm -i max.

Thin layer chromatography:

Rf = 0.53 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

Example 7

(1) 5 g (33 mmol) of D-2-amino-3-carbamoyl-propionic acid (ie D-asparagine), 8.5 g of o-nitrophenylsulfenyl chloride, 40 ml of water, 20 ml of tetrahydrofuran and 5.5 g of potassium carbonate were processed as described in Example 1- (1). 6.7 g of D-2- (o-nitrophenylsulfenylamino) -3-carbamoyl-propionic acid of mp 163 ° C. (dec.) Were obtained.

(2) 2.85 g (10 ml mol) of D-2- (o-nitrophenylsulfenylamino) -3-carbamoyl-propionic acid, 2.28 g of dycyclohexylcarbodiimide, 1.27 g of N-hydroxysuccinimide and 50 ml of tetrahydrofuran were prepared in the same manner as processed in Example 1- (2). 3 g of N- [D-2- (o-nitrophenylsulfenylamino) -3-carbamoyl-propionyloxy] -succinimide of mp 135-136 ° C. (dec.) Were obtained.

(3) 380 mg (1.00 mmol) of N- [D-2- (o-nitrophenylsulfenylamino) -3-carbamoyl-propionyloxy] succinimide and 500 mg (1.07 mmol) of 6- [D-2- Amino-2- (p-hydroxyphenylacetamido] -penicillanoic acid triethylimine salt were dissolved in a mixture of 4 ml of chloroform and 4 ml of dimethylformamide. The solution was stirred at 0-5 ° C. for 26 hours.

after which the solvent was removed at about 30 ° C. and under reduced pressure. 10 ml of an aqueous 5% citric acid solution were added to the residue and the mixture obtained was extracted with a mixture of 10 ml of ethyl acetate and 10 ml of tetrahydrofuran. The extract was washed with water, dried and then concentrated at about 30 ° C. and under reduced pressure to remove the solvent. 800 mg of 6- [D-2- (D-2- (o-nitrophenylsulfe-nylamino) -3-carbamoyl-propionamido) -2-p-hydroxyphenyl-acetamido] -penicillanic acid were obtained as crude product. This crude product was redissolved in a mixture of 2 ml of tetrahydrofuran and 8 ml of ethanol. 410 mg (3 mmol) of thiobenzamide were added to the solution obtained and the mixture was stirred at room temperature for 15 minutes, after which the solvent was removed at about 30 ° C. and under reduced pressure.

The residue thus obtained was mixed with 20 ml of tetrahydrofuran and the pale yellow precipitate formed was filtered off. This precipitate was dissolved in 30 ml of water, the insoluble constituents were separated off by filtration and then the filtrate was freeze-dried. The colorless amorphous powder obtained was suspended in 3 ml of methanol, and 100 mg (1.0 mmol) of triethylamine and 180 mg (1.0 mmol) of potassium 2-ethylhexanoate were added to the suspension. 20 ml of ether were then added, and the colorless precipitate formed was filtered off. 370 mg of potassium 6- [D-2- (D-2-amino-3-carbamoyl-propionamido) -2-p-hydroxyphenyl-acetamido] -penicillanate of mp. 213-215 ° C. (dec.) Were obtained.

IR spectrum:

v Nujoi; 3300, 1760, 1660, 1590 cm- »

Max. '

Thin layer chromatography:

Rf = 0.30 (silica gel, solvent: n-butanol-vinegar-

acid-water (4: 1: 1)).

Example 8

(1) 594 mg (1.5 mmol) of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionyloxy] succinimide and 900 mg (2.0 mmol) of da-aminobenzylpenicillin triethyl- amine salt were mixed in a mixture of 25 ml of chloroform

5

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35

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55

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622 798

8th

and 10 ml of dimethylformamide dissolved. The solution was stirred at 0-5 ° C for 17 hours, after which the mixture was processed in the same manner as described in Example 1- (3) after the reaction was completed. 870 mg of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained as yellow crystals of mp 135-140 ° C. (Dec.).

IR spectrum:

v Nujoi: 3280.1780.1730.1635 cm-!

Max.

(2) 860 mg (1.35 mmol) 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid and 547 mg ( 4.05 mmol) of thiobenzamide were dissolved in a mixture of 50 ml of methanol and 10 ml of tetrahydrofuran. The solution was stirred at room temperature for 15 minutes, after which it was processed as described in Example 1- (4). 580 mg of 6- [D-2- (DL-2-amino-3-N-methylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained as a colorless powder with a melting point of 193-195 ° C. (dec.).

IR spectrum:

v Nujoi: 3250.1760.1645.1590 cm- *

Max.

Thin layer chromatography:

Rf = 0.45 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

Example 9

(1) 1.19 g (3 mmol) of N- [D-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionyloxy] succinimide and 1.35 g (3 mmol) of da-aminobenzylpenicillin-triethylamine- salt was dissolved in a mixture of 25 ml of chloroform and 15 ml of dimethylformamide. The solution was stirred at 0-5 ° C for 15 hours, after which it was processed as described in Example 1- (3). 1.81 g of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-N-methyl-carbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained in the form of yellow needles of mp 145-147 ° C (dec.).

IR spectrum:

v Nujoi: 3250, 1780, 1725, 1630 cm- '

Max.

(2) 1.80 g (2.86 mmol) of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-phenyl-acetamido] -penicillanic acid and 1.23 g (8.98 mmol) of thiobenzamide were dissolved in a mixture of 30 ml of methanol and 5 ml of tetrahydrofuran. The solution was stirred at room temperature for 20 min, after which it was processed as described in Example 1- (4). 1.23 g of 6- [D-2- (D-2-amino-3-N-methylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained as a colorless powder, mp. 193-195 ° C. (dec.) .

IR spectrum:

v Nujoi: 3275.1760.1650 cm- '

Max.

Thin layer chromatography:

Rf = 0.45 (silica gel, solvent: n-butanol-acetic acid-water (4: 1: 1)).

IR spectrum of the potassium salt:

v Nujoi; 3290, 1765, 1650, 1600 cm-1

Max.

Example 10

(1) 1.60 g (4 mmol) of N- [L-2- (o-nitrophenylsulfenyl-

amino) -3-N-methylcarbamoyl-propionyloxy] succinimide and

1.80 g (4 mmol) of D-a-aminobenzylpenicillin triethylamine salt were dissolved in 25 ml of dimethylformamide. The solution was stirred at 0-5 ° C for 16 hours, after which the reaction obtained was further processed as described in Example 1- (3). 2.45 g of 6- [D-2- (L-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamyol-propionamido) -2-phenylacetamido] -penicillanic acid were obtained as yellow needles, mp 144-146 ° C (dec.).

IR spectrum:

V Nuiol; 3250.1770.1730.1635 cm-1

Max. ''

(2) 2.40 g (3.81 mmol) of 6- [D-2- (L-2- (o-nitrophenylsulfenylamino) -3-N-methylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid and 1 , 80 g (13.14 mmol) of thiobenzamide were dissolved in a mixture of 30 ml of methanol and 25 ml of tetrahydrofuran. The solution was stirred at room temperature for 30 min, after which it was worked up in the same manner as described in Example 1- (4). 1.51 g of 6- [D-2- (L-2-amino-3-N-methylcarbamoyl-propionamido) -2-phenylacetamidb) -2-phenylacetamido] -penicillanic acid were obtained in the form of a colorless powder of mp 191- 193 ° C (dec.).

IR spectrum:

v Nujoi; 3270.1760.1650 cm- '

Max.

Thin layer chromatography:

Rf = 0.45 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

IR spectrum:

v Nujoi: 3300.1765, 1650, 1600 cm- '

Max.

Example 11

(1) 1.6 g (10 mmol) of DL-2-amino-3-N-ethylcarbamoyl-propionic acid (ie DL-N'-ethyl-asparagine, 2 g of o-nitro-phenylsulfenyl chloride, 20 ml of water, 8 ml of tetrahydrofuran and 1.9 g of potassium carbonate were processed in the same manner as described in Example 1- (1) to obtain 1.7 g of DL-2- (o-nitrophenylsulfenylamino) -3-N-ethylcarbamoyl-propionic acid, mp 178-180 ° C (dec.).

(2) 850 mg (2.7 mmol) of DL-2- (o-nitrophenylsulfenylamino) -3-N-ethylcarbamoyl-propionic acid, 577 mg of dicyclohexylcarbodiimide, 322 mg of N-hydroxysuccinimide and 20 ml of tetrahydrofuran were prepared in the same manner as in Example 1- (2) implemented. 850 mg of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N-ethyIcarbamoyl-propionyl-oxy} -succinimide were obtained in the form of a yellow caramel-like mass.

(3) 820 mg (2 mmol) of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N-ethylcarbamoyl-propionyloxy] succinimide and 900 mg (2 mmol) of da-aminobenzylpenicillin triethylamine salt were added in 15 ml of dimethylformamide dissolved. The solution was stirred at 0-5 ° C for 16 h after which it was worked up in the same manner as described in Example 1- (3). 1.19 g of 6- [D-2- (DL-2- (o-nitrophenyl-sulfenylamino) -3-N-ethylcarbamoyl-propionamido) -2-phenyl-acetamido-penicillanic acid were obtained in the form of a caramel-like mass.

IR spectrum:

v Nujoi; 3270.1770.1720.1640 cm- '

Max.

(4) 1.15 g (1.78 mmol) of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-ethylcarbamoyl-propionamido) -2-phenyl-acetamido] -penicillanic acid and 822 mg (6 mmol) of thiobenzamide were mixed in a mixture of 20 ml of methanol and

2 ml of tetrahydrofuran dissolved. The solution was stirred at room temperature for 20 minutes, after which the reaction solution was worked up in the same manner as described in Example 1- (4). 600 mg of 6- [D-2- (DL-2-amino-3-N-ethylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid of mp 190-193 ° C. (dec.) Were obtained.

IR spectrum:

v Nujoi; 3270.1760.1650 cm-1

mnv 7 7

s

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50

55

60

65

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622 798

Thin layer chromatography:

Rf = 0.475 (silica gel, solvent: n-butanol-vinegar-

acid-water (4: 1: 1)).

IR spectrum:

v Nujoi; 3280.1765, 1650, 1600 cm-1

Max. -

Example 12

(1) 1.75 g (10 mmol) of DL-2-amino-3-Nn-propylcarbamoyl-propionic acid (ie DL-N'-n-propyl-asparagine), 2.2 g of o-nitrophenylsulfenyl chloride, 20 ml Water, 10 ml of tetrahydrofuran and 2.2 g of potassium carbonate were worked up in the same manner as described in Example 1- (1). 2.2 g of DL-2- (o-nitrophenylsulfenylamino) -3-N-n-propylcarbamoyl-propionic acid with a melting point of 200-205 ° C. (decomp.) Were obtained.

(2) 1.9 g (6 mmol) of DL-2- (o-nitrophenylsulfenylamino) -3-N-propylcarbamoyl-propionic acid, 1.3 g of dicyclohexylcarbodiimide, 700 mg of N-hydroxysuccinimide and 20 ml of tetrahydrofuran were prepared in the same manner processed as described in Example 1- (2). 2.4 g of N- [DL-2- (o-nitro-phenylsulfenylamino) -3-N-n-propylcarbamoyl-propionyloxy] succinimide were obtained in the form of a yellow caramel-like mass.

(3) 450 mg (1.06 mmol) of N- [DL-2- (o-nitrophenylsulfenylamino) -3-Nn-propylcarbamoyl-propionyloxy] succinimide and 495 mg (1.1 mmol) of da-aminobenzylpenicillin triethyl -amine salt were dissolved in 15 ml of dimethylformamide. The . Solution was stirred at 0-5 ° C for 16 h after which it was worked up in the same manner as described in Example 1- (3). 230 mg of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-n-propylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained in the form of a caramel-like mass.

IR spectrum:

v Nujoi; 3280, 1770, 1725, 1645 cm-1

Max.

(4) 210 mg (0.31 mmol) 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-Nn-propylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid and 137 mg ( 1.0 mmol) of thiobenzamide were dissolved in 10 methanol. The solution was stirred at room temperature for 20 minutes, after which it was worked up in the same manner as described in Example 1- (2). 75 mg of 6- [D-2- (DL-2-amino-3-N-n-propylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid of mp 175-178 ° C. (dec.) Were obtained.

IR spectrum:

v Nujoi; 3250.1765, 1650 cm-1

Max.

Thin layer chromatography:

Rf = 0.55 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

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15

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25th

Example 13

(1) A solution of 13.5 g of DL-N- (o-nitrophenylsulfenyl) aspartic anhydride in 20 ml of tetrahydrofuran and 30 ml of methanol was heated to 50-60 ° C for 30 minutes. The solvent was then removed under reduced pressure, whereupon the residue obtained was dissolved in 100 ml of tetrahydrofuran and 5.1 g of N-hydroxysuccinimide and 9.1 g of dicyclohexylcarbodiimide were added. The mixture was then left at room temperature for 17 hours, whereupon the precipitated urea was filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. 14.2 g of N- [DL-3- (o-nitrophenyl-sulfenylamino) -3-methoxycarbonyl-propionyloxy] -succinimide of mp 158-160 ° C. (dec.) Were obtained.

(2) A solution of 2.4 g of N- [DL-3- (o-nitrophenylsulfenylamino) -3-methoxycarbonyl-propionylox.y] succinimide and 1.5 g of n-butylamine in 25 ml of tetrahydrofuran was added at room temperature left standing for 2 days. The solution was then concentrated under reduced pressure to give 1.8 g of methyl DL-2- (o-nitrophenyisub fenylammo) -3-Nn-butylcarbamoyl propionate, mp 104-105 ° C . '' ..

(3) 'To a solution of. 1.7 g of methyl DL-2- (o-ritro-: phenylsulfenylamino) -3-N-n-butyIcarbamoyl-prionion in 30 ml of methanol were added to 2 ml of hydrazine hydrate. The yellow crystals formed after one hour were filtered off, giving 1.2 g of DL-2- (o-nitrophenylsulfenylamino) -3-N-n-butylcarbamoyl-propionylhydrazide, mp. 180-182 ° C. "" "- ■ - ••

(4) To a solution of 888 g of DL-2- (o-nitrophenyl-sulfenylamino) -3-Nn-butylcarbamoyl-propionyl-hydrazide in 15 ml of tetrahydrofuran, containing 5 ml. 10% sulfuric acid and 5 ml acetic acid, were added 345 mg sodium nitrite Added in portions at a temperature of -5 to -10 ° C. After 20 min, 20 ml of cold water were added to the reaction mixture, whereupon it was extracted with 20 ml of ethyl acetate. The extract was dried and then concentrated under reduced pressure, util dias solvent was removed. 700 mg of DL-2- (ö -Nitrophenylsulfenylamîno) -3-Nnb "utylcarbainoyl-propiônyl-azide in the form of a yellow karaniel-like mass. "* '•

(5) 700 mg (1.9 mmol) DL-2- (o-nitrophenylsulfenyl-amino) -3-N-n-butylcarbamoyl-propionyl2id and 900 mg

(2 mmol) D-a-aminobenzylpenicillin triethylamine Salt were dissolved in 15 ml of chloroform. The solution was stirred at 0-5 ° C for 30 h, after which it was worked up in the same manner as described in Example 1- (1). 210 mg of 6- [D-2- (DL-2- (o-Nitrophëylsulfenylamino) -3-Nn-butylcarbamoyl-propionamido) -2-phenylaoetamido] -peni-cillanic acid in the form of a yellow caramel-like mass.

v Nujoi; 3300.1780.1725.1640 cm-i max. •

(6) 200 mg (0.3 mmol) 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-Nn-butylcarbamoyl-propionamido) -2-phe-nylacetamido] -penicillanic acid and 300 mg (2.19 mmol) of thiobenzamide was dissolved in a mixture of 10 ml of methanol and 1 ml of tetrahydrofuran. The solution was stirred at room temperature for 30 minutes, whereupon the reaction mixture obtained in the same manner as in Example

1- (4) was worked up. 85 mg of 6- [D-2- (DL-2-amino-3-N-n-butylcarbamoyl-propionamido) - were obtained.

2-phenylacetamido] -penicillanic acid in the form of a colorless powder, mp. 190-193 ° C. (dec.).

IR spectrum:

5 »V Nujoi; 3375, 1665, 1645 cm-1

Max. .

Thin layer chromatography:

Rf = 0.51 (silica gel, solvent: n-butanol-acetic acid)

acid-water (4: 1: 1)).

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55

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65

Example 14;

(1) 1.76 g (10 mmol) of DL-2-amino-3-N - /} - hydroxyethyl-carbamoyl-propionic acid (i.e., DL-N '- /? - hydroxyethyl-aspa-ragin), 2 , 2 g o-nitrophenylsulfenyl chloride, 20 ml water,

10 ml of tetrahydrofuran and 2.2 g of potassium carbonate were processed in the same manner as described in Example 1- (1). 2.1 g of DL-2- (o-nitrophenylsulfenyiami-no) -3-N-yS-hydroxyethylcarbamoyl-propionic acid of mp 123-125 ° C. were obtained. ...

(2) 1.64 g (5 mmol) of DL-2- (o-nitrophenylsulfenylamino) -3-N - /? - hydroxyethylcarbamoyl-propionic acid, 1.13 g of dicyclo-hexylcarbodiimide, 633 mg of N-hydroxysuccinimide and 40

ml of tetrahydrofuran were prepared in the same way as in.

622798

10th

game l- (2) described processed. 1.7 g of N- [DL-2- (o-nitrophenyisulfenylamino) -3-N - /? - hydroxyethylcarbamoyl-propionyloxy] -succinimide were obtained in the form of a yellow caramel-like mass.

(3) 852 mg (2.0 mmol) of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N- / 3-hydroxyethylcarbamoyl-propionyloxy] succinid and 675 mg (1.5 mmol) Da-aminobenzylpenicillin triethylamine salt was dissolved in 30 ml of chloroform. The solution was stirred at 0-5 ° C for 16 h after which it was worked up in the same manner as described in Example 1- (3). 550 mg of 6- [D-2- (DL-2- (o-nitro-phenylsulfenylamino) -3-N - /? - hydroxyethylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained in the form of a yellow caramel-like mass .

IR spectrum:

v Nujoi; 3270.1770, 1720.1650 cm- '.

Max.

(4) 500 mg (0.76 mmol) of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-β-hydroxyethylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid and 390 mg (2.8 mmol) of thiobenzamide were dissolved in a mixture of 10 ml of methanol and 2 ml of tetrahydrofuran. The solution was stirred at room temperature for 20 minutes, after which it was worked up in the same manner as described in Example 1- (4). 280 mg of 6- [D-2- (DL-2-amino-3-N- / 5-hydroxyethylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained in the form of a colorless powder with a melting point of 177-180 ° C. ( Dec.).

IR spectrum:

v Nujoi; 3260.1760.1655 cm- '

Max.

Thin layer chromatography:

Rf = 0.49 (silica gel, solvent: n-butanol-vinegar-

acid-water (4: 1: 1)).

Example 15

(1) 1.61 g (10 mmol) of DL-2-amino-3-N-dimethylcarbamoyl-propionic acid (i.e. DL-N'-dimethyl-asparagine), 2.1 g

0-nitrophenylsulfenyl chloride, 20 ml of water, 15 ml of tetrahydrofuran and 2.1 g of potassium carbonate were processed in the same manner as described in Example 1- (1). 1.9 g of DL-2- (o-nitrophenylsulfenylamino) -3-N-dimethyl-carbamoyl-propionic acid of mp 144-146 ° C. were obtained.

(2) 1.39 g (4.3 mmol) of DL-2- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyl-propionic acid, 936 g of dicyclohexylcarbodiimide, 518 mg of N-hydroxysuccinimide and 40 ml of tetrahydrofuran were used in the same manner as in example

1- (2) processed. 1.6 g of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyl-propionyloxy] -succinimide of mp 126-128 ° C. (dec.) Were obtained.

(3) 820 mg (2 mmol) of N- [DL-2- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyI-propionyloxy] succinimide and 900 mg (2 mmol) of da-aminobenzylpenicillin triethylamine salt were added to a mixture of 15 ml of chloroform and 13 ml of dimethylformamide. The solution was stirred at 0-5 ° C for 16 h after which it was worked up in the same manner as described in Example 1- (1). 1.22 g of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyl-propionamido) -2-phenyl-acetamido] -penicillanic acid were obtained in the form of a yellow caramel-like mass.

IR spectrum:

v Nujoi; 3200.1780.1730.1630 cm-1

Max.

(4) 1.21 g (1.88 mmol) of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid and 1 , 03 g (7.50 mmol) of thiobenzamide were dissolved in a mixture of 30 ml of methanol and 10 ml of tetrahydrofuran. The solution was stirred at room temperature for 20 min, after which it was run in the same manner as in Example. l- (4) has been worked up. 660 mg of 6- [D-2- (DL-2-amino-5 3-N-dimethylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid of mp 192-194 ° C. (dec.) Were obtained.

IR spectrum:

v Nujoi; 3240, 1770, 1630 cm-1

Max.

10 thin layer chromatography:

Rf = 0.451 (silica gel, solvent: n-butanol-vinegar-

acid-water (4: 1: 1)).

IR spectrum:

v Nujoi: 3240, 1760, 1640, 1590 cm-1.

15 max.

Example 16

(1) 720 mg (2 mmol) DL-2-benzyloxycarbonylamino-3-2i benzyloxycarbonyl-propionic acid and 210 mg (2 mmol) tri-

Ethylamine was dissolved in 7 ml of dichloromethane and a solution of 270 mg (2 mmol) of isobutyl chlorocarbonate in 2 ml of dichloromethane was added to the former solution at a temperature of -20 to -15 ° C. 10 minutes after this addition, a solution of 740 mg (2 mmol) of D-a-aminobenzylpenicillin triethylamine salt in 4 ml of dimethylformamide was added dropwise. The mixture was stirred at -15 to -10 ° C for 30 minutes and then further stirred at -10 to 0 ° C for 30 minutes. 30 After the reaction was completed, the mixture was concentrated at about 30 ° C and under reduced pressure to remove the solvent. 5 ml of a 5% aqueous solution of citric acid and 10 ml of ethyl acetate were added to the residue obtained, and the organic phase was separated off. This organic phase was then washed with water, dried and then mixed with 200 ml of triethylamine (2 mmol). The mixture obtained was concentrated at about 30 ° C. and under reduced pressure to remove the solvent. 970 mg of 6- [D-2-40 (DL-2-benzyloxycarbonylamino-3-benzyloxycarbonyl-pro-pionamido) -2-phenylacetamido] -penicillanoic acid-triethylamine salt were obtained in the form of colorless crystals of mp 110-113 ° C (dec.).

IR spectrum:

45 v Nuioi; 3300, 1775, 1735, 1690, 1660, 1610, 1520 cm-1.

(2) 200 mg (0.3 mmol) of 6- [D-2- (DL-2-benzyloxycarbonyl-amino-3-benzyloxycarbonyl-propionamido) -2-phénylacet-amidoj-penicillanic acid triethylamine salt were dissolved in 6 ml of etha-

50 noi dissolved and 300 mg of 30% palladium BaCOs were added to the solution. The mixture was shaken at room temperature in hydrogen gas for 4 hours and at atmospheric pressure. After the reaction had ended, undissolved portions were filtered off and the filtrate was concentrated at about 30 ° C. 55 and under reduced pressure to remove the solvent. 5 ml of ether were added to the residue obtained, a white precipitate being obtained, which was filtered off, washed with chloroform and dried. 60 mg of 6- [D-2- (DL-2-amino-60 3-hydroxycarbonyl-propionamido) -2-phenylacetamido] -penicillanoic acid triethylamine salt of mp 189-191 ° C. (dec.) Were obtained.

IR spectrum:

v Nujoi; 3300.1750, 1665.1595.1540 cm-1

^ max.

Thin layer chromatography:

Rf = 0.36 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

IL

622 798

Example 17

(1) 9.2 g (50 mmol) of DL-2-amino-3-methoxycarbonyl-propionic acid hydrochloride (i.e., O-methyl-aspartic acid, HCl), 10.5 g of o-nitrophenylsulfenyl chloride, 50

ml of water, 70 ml of tetrahydrofuran and 24.3 g of potassium carbonate were processed in the same manner as described in Example 1- (1). 9.8 g of DL-2- (o-nitro-phenylsulfenylamino) -3-methoxycarbonyl-propionic acid, mp. 108-109 ° C., were obtained.

(2) 9 g (30 mmol) of DL-2- (o-nitrophenylsulfenylamino) - 10 3-methoxycarbonyl-propionic acid, 6.7 g of dicyclohexylcarbodiimide, 4 g of N-hydroxysuccinimide and 80 ml of tetrahydrofuran were prepared in the same manner as in Example 1- (2) described processed. 11 g of N- [DL-2- (o-nitro-phenylsulfenylamino) -3-methoxycarbonyl-propionyloxy] - 15 succinimide, melting point 125-127 ° C., were obtained.

(3) 794 mg (2 mmol) of N- [DL-2- (o-nitrophenylsulfenylamino) -3-methoxycarbonyl-propionyloxy] succinimide and 900 mg (2 mmol) of da-aminobenzylpenicillin triethylamine salt were mixed in a mixture of 25 ml of chloroform and 4 ml of 20 dimethylformamide dissolved. The solution was stirred at 0-5 ° C for 15 hours, after which the reaction mixture obtained was worked up in the same manner as described in Example 1- (3). 1.2 g of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-methoxycarbonyl-25-propionamido) -2-phenylacetamido] -penicillanic acid were obtained in the form of a yellow caramel-like mass.

IR spectrum:

Nujoi; 3300, 1790, 1725, 1650 cm-i max. 30th

(4) 1.20 g (1.90 mmol) of 6- [D-2- (DL-2- (o-nitrophenylsulfenylamino) -3-methoxycarbonyl-propionamido) -2-phenyl-acetamido] -penicillanic acid and 800 mg (5.84 mmol) of thiobenzamide was dissolved in a mixture of 20 ml of methanol and 3 ml of tetrahydrofuran. The solution was stirred at 35 room temperature for 45 min, whereupon it was worked up in the same manner as described in Example 1- (4). 1.51 g of 6- [D-2- (DL-2-amino-3-methoxy-carbonyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained as a colorless powder, mp. 185-188 ° C. (dec .). 40 IR spectrum:

v Nujoi; 3250, 1760, 1730, 1660 cm->

Max.

Thin layer chromatography:

Rf = 0.453 (silica gel, solvent: n-butanol-acetic acid-water (4: 1: 1)).

IR spectrum of the potassium salt:

v Nujoi; 3280.1760.1730.1650.1595 cm-1

Max.

The following connection was made in the same manner as described above: 50

6- [D-2- (D-2-Amino-3-methoxycarbonyl-propionamido) -2-p-hydroxyphenylacetamido] -penicillanic acid: mp 170-173 ° C (dec.).

IR spectrum:

v Nujoi; 3300.1760.1720.1650.1600 cm-1 55

Max.

Thin layer chromatography:

Rf = 0.42 (silica gel, solvent: n-butanol-vinegar-

acid-water (4: 1: 1)).

60

Example 18

(1) 18.4 g (100 mmol) of D-2-amino-3-methoxycarbonyl-propionic acid hydrochloride, (ie D-aspartic acid-O-methyl ester.HCl), 20 g of o-nitrophenylsulfenyl chloride, 80 ml of 6J water, 80 ml of tetrahydrofuran and 26 g of potassium carbonate were processed in the same manner as described in Example 1- (1). 18 g of D-2- (o-nitrophenylsulfenyl-

amino) -3-methoxycarbonyl-propionic acid, mp 86-87 ° C.

(2) 3 g (10 mmol) of D-2- (o-nitrophenylsulfenylamino) -3-methoxycarbonyl-propionic acid, 2.3 g of dicyclohexylcarbodiimide, 1.35 g of N-hydroxysuccinimide and 30 ml of tetrahydrofuran were prepared in the same manner as in Example 1 - (2) worked up described. 3.5 g of N-fD-2- (o-nitro-phenylsulfenylamino) -3-methoxy-carbonyl-propionyloxy] -succinimide were obtained, with a melting point of 133 ° C. (dec.).

(3) 794 mg (2 mmol) of N- [D-2- (o-nitrophenylsulfenylamino) -3-methoxycarbonyl-propionyloxy] succinimide and 900 mg (2 mmol) of da-aminobenzylpenicillin triethylamine salt were dissolved in 25 ml of chloroform . The solution was stirred at 0-5 ° C for 16 h after which it was worked up in the same manner as described in Example 1- (3). 1.15 g of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-methoxycarbonylpropionamido) -2-phenylacetamido] -penicillanic acid were obtained in the form of a caramel-like mass.

IR spectrum:

v Nujoi; 3270, 1775, 1720, 1640 cm-1

Max. 7

(4) 1.10 g (1.74 mmol) of 6- [D-2- (D-2- (o-nitrophenylsulfenylamino) -3-methoxycarbonyl-propionamido) -2-phenyl-acetamido] -penicillanic acid and 835 mg (6.1 mmol) of thiobenzamide were dissolved in a mixture of 30 ml of methanol and 5 ml of tetrahydrofuran. The solution was stirred at room temperature for 40 min and then worked up in the same manner as described in Example 1- (4). 680 g of 6- [D-2- (D-2-amino-3-methoxy-carbonyl-propionamido) -2-phenylacetamido] -penicillanic acid with mp. 185-188 ° C. (dec.) Were obtained.

IR spectrum:

v Nujoi; 3250.1765.1725 (ester), 1655 cm-1

Max.

Thin layer chromatography:

Rf = 0.453 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

Example 19

(1) 720 mg (2 mmol) of benzyl-DL-3-benzyloxycarbonylamino-3-carboxy-propionate and 210 mg (2.1 mmol) of triethylamine were dissolved in 7 ml of dichloromethane and a solution of 270 mg (2 mmol) of isobutyl chloroformate in 2 ml of dichloromethane was added at -20 to -15 ° C. A solution of 990 mg (2.2 mmol) of D-a-aminobenzylpenicillin triethylamine salt in 5 ml of chloroform was added dropwise 10 min after the addition. The mixture obtained was then worked up in the same manner as described in Example 16- (1). 1.30 g of 6- [D-2- (DL-3-benzyloxycarbonylI-amino-3-benzyloxycarbonyl-propionamido) -2-phenylacetamido] -penicillanic acid triethylamine salt were obtained in the form of a colorless powder of mp 115-119 ° C (dec.).

IR spectrum:

v Nujoi; 3300.1775.1730.1660.1610.1500 cm-1

Max.

(2) 660 mg (0.83 mmol) of 6- [D-2- (DL-3-benzyloxycarbononylamino-3-benzyloxycarbonyl-propionamido) -2-phenyl-acetamido] -penicillanoic acid triethylamine salt were dissolved in 20 ml of ethanol and 500 mg of 30% palladium BaCOs were added to the solution. The mixture obtained was shaken at room temperature in hydrogen gas for 2 h at atmospheric pressure and then worked up in the same manner as described in Example 16- (2). 220 mg of 6- [D-2- (DL-3-amino-3-hydroxycarbonyl-propionamido) -2-phenylacetamido] -penicilanoic acid triethylamine salt were obtained in the form of a pale gray powder with a melting point of 185-188 ° C. (dec .).

622798

12th

IR spectrum::. -

v Nujoi; 3250.1770.1650.1600.1530 cm- '

Max.

Thin layer chromatography:

Rf = 0.28 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

Example 20

(1) 1.6 g (10 mmol) of DL-3-amino-3-N-ethylcarbamoyl-propionic acid (ie DL-N'-ethyl-iso-asparagine), 2.2 g of o-nitrophenylsulfonyl chloride, 20 g of water, 20 ml Tetrahydrofuran and 2.3 g of potassium carbonate were processed in the same manner as described in Example 1- (l). Mail received 2.0 g of DL-3- (o-NitröphenylsulfenyIamino) -3-N-äthylcarbä-moyl-propionic acid of mp. 165-167 ° C (dec.).

(2) 1.05 g (3.35 mmol) of DL-3- (o-nitrophenylsulfenyl-amino) -3-N-ethylcarbamoyl-propionic acid, 700 mg of dicyclohexylcarbodiimide, 391 mg of N-hydroxysuccinimide and 40 ml of tetrahydrofuran were used in the same manner like in example "

1- (2) processed. 1.2 g of N- [DL-3- (o-nitrophenylsulfenylamino) -3-N-ethylcarbamoyl-propionyl-oxy] succinimide of mp 157-158 ° C. were obtained.

<3) .820 mg (2 mmoles) of N- [DL-3- (o-nitrophenylsulfenyl-amino) -3-N-ethylcarbamoyl-propionyloxy] succinimide and 900 mg (2 mmoles) of da-arainobenzylpenicillin-triethylamine salt dissolved in 15 ml of dimethylformamide. The resulting solution was stirred at 0-5 ° C for 16 hours, after which it was worked up in the same manner as described in Example 1- (3). 1.09 g of 6- [D-2- (DL-3- (o-nitro-phenyIsulfenylamino) -3-N-ethylcarbamoyl-propionamido) - were obtained.

2-phenylacetamido] -penicillanic acid in the form of a caramel-like product. •:

IR spectrum:

v Nujoi: 3260.1775.1725.1620cm-i. '

Max. ^. ... »;

(4) 1.05 g (1.63 mmol) of 6- [D-2- (DL-3- (o-nitrophenylsulfenylamino) -3-N-ethylcarbamoyl-propjonamjdo) - 2 ~ phenyl-acetamido] - Penicillanic acid and 781 mg (5.7 mmol) of thiobenzamide were dissolved in a mixture of 30 ml of methanol and 5 ml of tetrahydrofuran. The resulting solution was stirred at room temperature for 45 minutes, after which it was worked up in the same manner as described in Example 1- (4). 730 mg of 6- [D-2- (DL-3-amino-3-N-ethyl-carbamoyl-propionamido) -2-phenylacetamido] -penicillan were obtained.

Acid of mp. 200-203 ° C (dec.).

IR spectrum:

v Nujoi; 3290.1765.1655 cm- '

Max. .

Thin layer chromatography:. ,.

Rf = 0.475 (silica gel, solvent: n-butanol-vinegar-

acid-water (4: 1: 1)).

Example 21

(1) 1.75 g (10 mmol) of DL-3-amino-3-Nn-propylcarbamoylpropionic acid, (ie DL-N'-n-propyl-iso-asparagine), 2.2 g of o-nitrophenylsulfonyl chloride, 20 ml of water , 20 ml of tetrahydrofuran and 2.3 g of potassium carbonate were processed in the same manner as described in Example 1- (1). 2.8 g of DL-3- (o-nitrophenylsulfenylamino) -3-N-n-propylcarbamoyl-propionic acid of mp 148-150 ° C. (decomp.) Were obtained.

(2) 981 mg (3 mmol) of DL-3- (o-nitrophenylsulfenylamino) -3-Nn-propylcarbamoyl-propionic acid, 618-mg of dicyclohexylcarbodiimide, 345 mg of N-hydroxysuccinimide and 40 ml of tetrahydrofuran were prepared as in Example l- ( 2) described processed. 1.1 g of N- [DL-3- (o-nitrophenyl-; sulfenylamino) -3-N-n-propylcarbamayl-propionyloxy] - were obtained. : succinimide in the form of a yellow caramel-like mass -. * ■ '

(3) 848 mg (2 mmol) of N- [DL-3- (o-nitrophenylsulfenylamino) -3-Nn-prQpylcarbamoyl-propionyloxy] succinimide and 900 mg (2 mmol) of Da-ammobenzylpemcillin-triethylamine salt were added in 20 ml of dimethylformamide dissolved. The resulting solution was stirred at 0-5 ° C for 16 hours, after which the reaction was worked up in the same manner as described in Example 1- (3) after the completion of the reaction. 800 mg of 6- [D-2- (DL-3- (o-nitro-phenylsulfenyiamino) -3-N-n-propylcarbamoyl-propionamido-2-phenylacetamido] -penicillanic acid were obtained in the form of a caramel-like mass.

IR spectrum: '

v Nujoi 1-3275.1775, -1725.1635 cm-1.

Max. 7. 7. 7

(4) 780 mg (1.17 mmol) 6- [D-2- (DL-3- (o-Nftrophenyl-sulfenyIamino) -3-Nn-propylcarbamoyl-propionamidó] -penicillanic acid and 561 mg (4.1 mmol) Thiobenzamide was dissolved in a mixture of 15 ml of methanol and 2 ml of tetrahydrofuran .. The solution was stirred at room temperature for 20 minutes, after which it was worked up in the same manner as described in Example 1- (4). 390 mg of 6- [ D'-2- (DL-3-Ammo-3-Nn-propylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid, mp. 181-184 ° C (dec.).

IR spectrum:

v Nujoi; 3280.1770.1660 cm ~ i max. ''

Thin layer chromatography:

Rf = 0.55 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

Example 22

(1) 1.6 g (10 mmol) of DL-3-amino-3-N-dimethylcarbamoyl-propionic acid (ie DL-N'-dimethyl-isoasparagine), 2.2 g of o-nitrophenylsulfenyl chloride, 20 ml of water, 20 ml of tetrahydrofuran and 2.2 g of potassium carbonate were processed as described in Example 1- (1). Men contained 1.9 g of DL-3- (o-nitro-phenylsulfenylamin0) -3-N-dimethylcarbämoyl-prapionic acid of mp. 144-146 ° C: _. '

(2) 1.88 g (6 mmol) of DL-3- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyl-propionic acid, 1.24 g of dicyclohexylcarbodiimide, 748 mg of N-hydroxysuccinimide and 40 ml of tetrahydrofuran were prepared in the same manner as processed in Example 1- (2). 900 mg of N- [DL-3- (o-nitrophenylsulfenylammo) -3-N-dimethylcarbamoyl-propionyloxy] succinimide, mp. 171-172 ° C., were obtained.

(3) 820 mg (2 mmol) of N-0> L-3- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyl-propionyloxy] -succinimide and 900 mg (2 mmol) of D-a-aminobenzylpenicillin-triethylamine. , amine salt were in one. Mixture of, 25 ml of chloroform and 12 ml of dimethylformamide dissolved. The solution was stirred at 0-5 ° C for 18 h after which the reaction was worked up as described in Example 1- (3). 1.25 g of 6- [D-2- (DL-3- (o-nitrophenylsulfenylamino) -3-N-dimethylcarbamoyt-propionanlido> f2-phenylacetamido] -penicillanic acid were obtained in the form of a yellow caramel-like mass.

IR spectrum:

v Nujoi; 3270.1780.1725.1630 cm- '.

Max. '7

(4) 1.20 g (1.86 mmol) 6-tD-2- (DL-3- (o-nitrophenylsulfenylamino) -3-N-dimethylearbamayl-propionamido) -2-phenylacetamide oil-penicillanic acid and 800 mg ( 5.80 mmol) of thiobenzamide were dissolved in a mixture of 20 ml of methanol and 3 ml of tetrahydrofuran. The solution obtained was stirred at room temperature for 30 minutes, after which the work-up was carried out after the reaction had ended

5

IQ

15

20th

25th

30th

35

40

45

50

55

60

65

13

as described in Example 1- (4). 810 mg of 6- [D-2- (DL-3-amino-3-N-dimethylcarbamoyl-propionamido) -2-phenylacetamido] -penicillanic acid were obtained in the form of a colorless powder of mp. 207-210 ° C. (decomp.) .

IR spectrum: 5

v Nujoi; 3250.1760.1645 cm- »

mar '7

622 798

Thin layer chromatography:

Rf = 0.392 (silica gel, solvent: n-butanol-vinegar

acid-water (4: 1: 1)).

IR spectrum of the potassium salt:

V Nujoi; 3260.1760.1640.1595 cm- ».

TT1HT 7 7 7

M

Claims (7)

622 798 1. Process for the preparation of a compound of formula CD ^ ^ -CH-CONH NH I 2 " R wherein Ri is hydrogen or a hydroxyl group, E2 can mean a grappe if R1 is a hydroxyl group Group of the formula: -CO-CH (NHa) -CHoCORä or -COCH2-, and pharmaceutically acceptable salts thereof, CH (NH2) -COR3, and Rs is a hydroxy-, lower alkylamino-, characterized in that in a first step Diniederaikylamino-, Niederalkoxy- or a hydroxy- 15th represents lower alkylamino group and R3 is also an amino A) a compound of the formula: R1- / CH-001H "1 MBU wherein Y1 represents hydrogen or a protective group with an N-protected amino acid of the formula R2 '- OH (III), wherein R2' is a group of the formula -CO-CH (NHZ) -CH2CORs' or -COCHj-CH (NHZ) -COR3 'represents R8' has the same meaning as R3, and if R3 'is a hydroxy group beGH-COKH' MH indicates that this can also be protected, and Z represents a protective group, or is brought to condensation with a reactive derivative of the amino acid of the formula III mentioned, a compound of the formula: (IV) R get what B) the protective group (s) mentioned is split off from the compound of the formula IV, and finally C) the product obtained is converted into a pharmaceutically acceptable salt thereof as required. 2. The method according to claim 1, characterized in that said condensation reaction of the compound of formula II with the compound of formula III is carried out in the presence of diphenylphosphoric acid in a solvent. 2nd PATENT CLAIMS 3rd 622 798 the protecting group or groups from the compound of formula IV (i) by treatment with 2-3 molar equivalents of a thioamide in a solvent when Z is o-nitrophenylsulfenyl, (ii) by shaking in hydrogen gas in the presence of palladium BaCOs, palladium Activated carbon or palladium black if Z is benzyloxycarbonyl and / or Y1 or the protective group for the hydroxyl group R3 'in compound of the formula III benzyl, (iii) by treatment with a dilute mineral acid in a solvent if Z is 1-methyl-2-lower alkoxycarbonylvinyl or Y1 trimethylsilyl, (iv) by treatment with an alkali metal salt of a thiol compound or thiophenol when Y1 is phenacyl, phthalimidomethyl or succinimidomethyl, or (v) by reduction with 90% formic acid zinc powder when Y1 is 2,2,2-trichloromethyl. 3. The method according to claim 1, characterized in that said reactive derivative of the compound of formula III is a lower alkoxycarbonyl ester, a lower alkanoyl ester, a p-nitrophenyl ester, a succinimido ester or an azide and that said condensation reaction of the reactive derivative with the compound of formula II is carried out at a temperature of -30 to 40 ° C in a solvent. 4. The method according to claim 1, characterized in that the protective group Z is an o-nitrophenylsulfonyl, a benzyloxycarbonyl or a 1-methyl-2-lower alkoxycarbonylvinyl group that Y1 is hydrogen or the benzyl, succinimidomethyl, phthalimidomethyl -, Phenacyl, trimethylsilyl or 2,2,2-trichloroethyl group means and that the protective group for the hydroxy group R3 'in the compound of formula III is benzyl. 5. The method according to claim 4, characterized in that the removal of the protective group or groups from the compound of formula IV (i) by treatment with 2-3 molar equivalents of thioamide 40 45 50 55 60 65 in a solvent when Z is o-nitrophenylsulfyl, (ii) by shaking in hydrogen and in the presence of palladium-BaCOs, palladium-activated carbon or palladium black when Z is benzyloxycarbonyl and / or Y1 or the protecting group for the hydroxy group Ra 'in the compound of the formula III are benzyl, (ni) by treatment with a dilute mineral acid in a solvent if Z is 1-methyl-2-lower alkoxycarbonylvinyI and / or Y1 is trimethylsilyl, (iv) by treatment with an alkali metal salt of a thiol compound or of thiophenol when Y1 is phenacyl, phthalimidomethyl or succinimidomethyl or (v) by reduction with 90 "/ 0 formic acid zinc powder when Y1 is 2,2,2-trichloroethyl. 6. The method according to claim 1, characterized in that when in the compound of formula II Y1 is hydrogen or a protective group such as benzyl, succinimidomethyl, phthalimidomethyl, phenacyl, trimethylsilyl or 2,2,2-trichloroethyl, the protective group Z in the compound of Formula III represents o-nitrophenylsulfenyl, benzyloxycarbonyl or l-methyl-2-lower alkoxycarbonylvinyl, the protective group for the hydroxyl group R3 'in the compound of the formula III is benzyl; the compound of formula III is used in the form of a reactive derivative such as a lower alkoxy-carbonyl ester, a lower alkanoyl ester, p-nitrophenyl ester or a succinimido ester, and that the condensation reaction of the compound of formula II with the reactive derivative of the compound of formula III at a temperature from -30 to 40 ° C in a solvent and that further the cleavage 7. Compound of formula 1 prepared by the process according to claim 1.