FI62834B - BUTTER PROCESSING OF ANTIBACTERIA WITH PENICILLIN AND OTHERS - Google Patents

Description

1,62834 2,3-Dioxopiperazine derivatives used as intermediates in the preparation of antibacterial penicillin and cephalosporin derivatives and process for their preparation 5 Separated from patent application No. 780330

This invention relates to novel 2,3-dioxopiperazines and to a process for their preparation.

The compounds of the invention are novel and can be represented by the general formula (I):

O O

A —— C — NH CH — B (I) is ws r5 R2 2 5 wherein R is a hydrogen atom or a methyl group, R is a methyl, phenyl, hydroxyphenyl, cyclohexadienyl or thienyl group, A is a C1-12 alkyl group, and B is a carboxyl group, a salt thereof or a reactive derivative thereof.

The novel compounds of formula I according to the invention are useful intermediates in the preparation of penicillins and cephalosporins having broad and effective antibacterial activity against gram-positive and gram-negative bacteria, in particular the microorganisms Pseudomonas aeruginosa, Klebsiella pneumoniae and against which micro-organisms are clinically very significant. These penicillins and cephalosporins have good resistance to bacterial β-lactamase.

The compounds of the formula I according to the invention are not previously known. The new compounds of formula II and their non-toxic salts disclosed in the same applicant's earlier patent application (Finnish patent application No. 751,340) were found to have the above-mentioned properties and very valuable therapeutic effects: 2,62834 oo) - \ AN NC-NH-CH-CONH— - (^ S \ \ - (ok5. A? <xi>

• v Y

COOH

where Z is or C-CH 2 R 4, where R 4 is a hydrogen atom, a quaternary ammonium group or an organic, O, n,. 2 5 A group attached via N or S, and R, R, R and A are as defined above.

15 The particularly good properties of the compounds of the formula II and their non-toxic salts are due to the part in the molecule: 20 Λ

O O

M

A-N N-C- M /

25 R

2 wherein R and A are as defined above. The compounds of formula I are thus quite useful intermediates in the preparation of the compounds of formula II and their acid addition salts. Particularly preferred are compounds of formula I wherein A is an ethyl group.

The compounds of formula I are prepared in such a way that the amino acid or a salt thereof having the general formula: 35 H, N - CH - COOR4 (III) R5 3 62834 4 ς

wherein R is a hydrogen atom or a salt-forming cation, and R

is as defined above, is reacted with a compound of the general formula: wherein B 'is a reactive derivative of a carboxyl group, and 2 R and A are as defined above, optionally in an inert solvent in the presence of a binding agent at a temperature in the range from -30 to + 40 ° C, and then, if desired, the product obtained is converted into a salt or the reactive derivative of the carboxyl group is converted into another reactive derivative in a manner known per se.

In the above formulas, A is a C 1-4 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, dodecyl and the like.

In the general formula I, the carboxyl group B can be represented by the formula -COOM, wherein M is a salt-forming cation.

These salt-forming cations are of the type common in penicillin and cephalosporin compounds. Salts include, for example, alkali metal salts such as sodium, potassium salt, etc., alkaline earth metal salts such as calcium, magnesium salts, etc., ammonium salts and salts with nitrogenous organic bases such as procaine, dibenz-ylamine, N-benzyl- / 3-phenethylamine, 1-Ephenamine, Ν, Ν-dibenzylethylenediamine, trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorethylamine, N-methylmorphoamine salts.

4,62834

In the general formula, the Htt salt-forming cation comprises the above-mentioned cations.

In the general formula I, the reactive derivative of the carboxyl group B is an acid halide, an acid anhydride, a mixed anhydride with organic or inorganic acids, an active ester, an active acid amide or an acid cyanide, etc. In particular, B is an acid chloride, a mixed anhydride or an active acid ester. Examples of mixed anhydrides include mixed anhydrides with substituted acetic acids, alkylcarboxylic acids, arylcarboxylic acids and aralkylcarboxylic acids; examples of active esters include cyanomethyl ester, trichloromethyl ester, trichlorethyl ester, substituted phenyl ester, substituted benzyl ester, substituted thienyl ester, etc., and examples of active acid amides include acid amides of saccharines, N-amoylamides, benzoyl, imidazolides, benzidyl , with sulfonamides, etc.

The carboxylic acid reactive derivative B 'in the compound of formula IV is one commonly used in the preparation of acid amides. Examples are acid halides, acid azides, acid cyanides, mixed anhydrides of organic or inorganic acids, active esters, active amides, etc. Particularly preferred are acid halides such as acid chlorides, acid bromides, etc., active esters such as cyanomethyl ester, trichloromethyl ester, etc.

A compound of formula IV can be readily prepared by reacting a compound of formula 30 (0)

A-N NH

2,3-dioxopiperazine according to formula V and R 2 s 62334, wherein A and R are as defined above, to react with phosgene, trichloroester of chloroformic acid or the like.

Examples of reactive derivatives of formula (IV) are given in Table I.

6 6 2 S 3 4

Table 1 Compound__Physical Properties I.R. (Cm ^)

5 ^ £ sp. 94-95 ° C

(CH 2 Cl 2 -Et 2 O) CH 3_N 2 N-COCl (decomposes) y) Q = Q 1790.1680

ID O .O

10 \ S

CH3COOCH2CH2-N2 and N-COCl 0 c = 0 1790 '1720 oily 1670

O O

15 [CH3CH2-N] -N-COCl. mp. 95-96 ° C (AcOBu) JC = 0 1780 '1660' / (decomposes) 20 oo V- (CH, CH, CH, -N /, N-COCl 1) c = 0 1780, 3 2 \ / 1710-1640 25

O O

\\ / CH3 (CH2) 2CH2-N N-COCl \) c = 0 1780 '1660 ^^ oily

30 O O

V-f (CH3), CH-N N-COCl v) c = 0 1780 '1660 w

mp. 130-131 ° C

35 OO (decomposes) w DUCH.-n 'N-COOCCl, m.p. 115-117 ° C i) C = 0 1810 '1710 ^ (decomposes) * G75 7 OO \ // * ^ \ 1790 CH-j (CH_) N-COCl Oily VC = 0 3 ^ J \ _ / 1720-1665 5

O O

V ”(CH, (CH-) ÄCH - N N-COCl oily \) c = 0178 ° '3 * _ / 1720-1640 10

O O

^ // t \ \ T7R0 CH, (CH-) cCHp-N N-COCl oily \ Jc = Ox 'u' J z ^ \ _ / 1720-1640 15

O O

/ CH, (CH -), CH9-N N-COCl oily l) C = 0 1780 '20 / ö2 ^ _ / 1720-1640 O O 25 \ / CH, CH., ~ N N-COCl m.p. 65-70 ° C l) C = 0 1785 '1680 3 1 \ / -v (decomposes) CH3 30

O O

\ / CH3CH2-N2K-COK3 m.p. 191-193 ° C l) 2150 35 (dec.) 0 C = 0 1750, 1655

Note: Et 2 O «CH 3 CH 2 OCH 2 CH 3

AcOBu = CH 3 COO (CH 2) 3 CH 3 8 62834

The implementation of the method according to the invention is described in more detail below.

In the process, a compound of formula HI is dissolved or suspended in an inert solvent or solvent mixture, such as water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, ethyl acetate, methyl ethyl ketone, methylene ketone, methylene ketone, -dimethoxyethane, etc. The compound of formula III in the form of a solution or suspension is then reacted with a compound of general formula (IV), preferably in the presence of a base. Examples of bases include inorganic bases such as alkali hydroxides, alkali metal bicarbonates, alkali carbonates, etc., organic bases such as trimethylamine, N-methylpiperidine, diethylamine, etc.

Compounds of formula I in which B is a salt of a carboxyl group can be readily prepared by conventional methods from compounds of formula I in which B is a carboxyl group.

Compounds of formula I wherein B

is a reactive derivative of a carboxyl group, can be prepared by conventional methods from compounds of formula I wherein B is a carboxyl group or a salt thereof.

The invention furthermore relates to D-isomers and L-isomers of the racemates of the formula I.

Examples of compounds of formula I wherein B is carboxyl: of - (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid, OC- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) no) phenylacetic acid, oC- (4-n-propyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid,

Of- (4-n-butyl-2,3-dioxo-1-piperazinecarbonyl-35-amino) phenylacetic acid,

Of- (4-Isopropyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetic acid, 9,632334

Of- (4-n-pentyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid,

Of- (4-n-hexyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid, Of- (4-n-heptyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid,

Of- (4-n-octyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid,

Of- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino-10-one) -p-hydroxyphenylacetic acid,

Of- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) -p-hydroxyphenylacetic acid,

Of- (6-methyl-4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid, Of- (4,6-dimethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid,

Of- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -1,4-cyclohexadienylacetic acid,

Of- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino-20-amino) -1,4-cyclohexadienylacetic acid,

Of- (4-n-propyl-2,3-dioxo-1-piperazinecarbonylamino) -1,4-cyclohexadienylacetic acid,

Of- (4-n-butyl-2,3-dioxo-1-piperazinecarbonylamino) -1,4-cyclohexadienylacetic acid, Of- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -2 -tienyylietikkahappo,

Of- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) -2-thienylacetic acid,

Of- (4-n-propyl-2,3-dioxo-1-piperazinecarbonyl) -30 2-thienylacetic acid,

Of- (4-n-butyl-2,3-dioxo-1-piperazinecarbonylamino) -2-thienylacetic acid.

The following examples illustrate the preparation of the compounds of the invention: Example 1 1) To a solution of 8.7 g of the sodium salt of D (-) - OC-phenylglycine in 50 ml of water were added 50 ml of ethyl acetate and 5.05 g of triethylamine. 9.5 g of 4-methyl-2,3-dioxo-1-piperazinecarbonyl chloride was gradually added to the mixture over 15 minutes at 0-5 ° C, then the mixture was allowed to react at 5-15 ° C for 30 minutes. After completion of the reaction, the aqueous layer was separated, washed with diethyl ether and adjusted to pH 1.5 by adding dilute hydrochloric acid, whereupon crystals precipitated. The crystals were filtered, washed with water and dried to give 14.1 g of O (-) - O (- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenyl-10-acetic acid, mp 138-141 ° C ( decomposition), yield 87% Crystallization from aqueous butanol gave white crystals, mp 140-142 ° C (dec.).

Analysis (C ^ H ^ N ^ O, .- ^ O):

Calculated: C 52.01 H 5.30 N 13.00% 15 Found: C 52.24 H 5.32 N 12.87% IR (KBr) cm-1 C = Q 1710, 1700, 1660, NH 3280 NMR (d 6 -DMSO) δ values: 0.1 (1H, d), 265 (5H, s), 4.60 (1H, d), 6.10 (2H, bs), 6.50 (2H, bs) ), 7.0 (3 H, s).

In the same manner as above, the following compounds of the invention were prepared.

D (-) - O- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid, m.p. 130-132 ° C, yield 84%. Analysis * H 2 O):

Calculated: C 53.40 H 5.68 N 12.46% Found: C 53.73 H 5.69 N 12.28% IR (KBr) cm -1: 1 NR NR 3280,> c = 0 1710, 1700, 1660, (-CON <1, -COOH) NMR (d 6 -DMSO) δ values: 0.1 (1H, d), 2.65 (5H, s), 4.60 (1H, d), δ, Δ (2H, bs), 6.50 (2H, bs), 6.65 (2H, q), δ 8.90 (3H, t).

D (-) - O- (6-methyl-4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid, m.p. 129-130 ° C, yield 80%.

Analysis (C 18 H 28 N 2 O 2 O 3): 35 Calculated: C 54.70 H 6.02 N 11.96%

Found: C 55.00 H 6.05 N 11.78% IR (KBr) cm -1: 0C = Q 1705, 1670, NR NR 3400, 3260.

n 62834 2) To a stirred solution of 10 g of the above-obtained D (-) -? - (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid in 200 ml of acetone was added dropwise a solution of 5.2 g of the sodium salt of 2-ethylhexanoic acid in 50 ml of acetone. The precipitated crystals were filtered and washed with acetone to give 9.6 g of the sodium salt of D (-) - (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid, m.p. 165 ° C (decomposes), yield 95%.

Preparation of a compound of formula II from a compound of the invention:

To a suspension of the sodium salt of D (-) - α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid (8.8 g) obtained above in methylene chloride was added 20 mg of N-methylmorpholine. 3.1 g of ethyl chlorocarbonate dissolved in 20 ml of methylene chloride were then added dropwise to the mixture over 5 minutes at -20 to -50 ° C, and the mixture was allowed to react for one hour with D (-) - <X- (4-methyl-2, To form 3-dioxo-1-piperazinecarbonylamino) phenylacetic acid mixed anhydride. A solution of 9.4 g of 6-aminopenicillanic acid triethylamine salt in 40 ml of methylene chloride was added dropwise to this reaction mixture over 10 minutes at -40 to -30 ° C, and the mixture was allowed to react at -40 to -20 ° C for one hour. I drive. The reaction mixture was then allowed to slowly warm to 0 ° C over 1 hour, then the mixture was extracted with 100 ml of water. The aqueous layer was separated and the methylene chloride layer was re-extracted with 50 mL of water. The resulting aqueous layers were combined, adjusted to pH 2 by the addition of dilute hydrochloric acid while cooling with ice to give a crystalline precipitate. The crystals were filtered off, washed with water, dried and then dissolved in 200 ml of acetone. A solution of 4 g of the sodium salt of 2-ethylhexanoic acid in 40 ml of acetone was added dropwise over 10 minutes. The precipitated crystals were filtered, washed with acetone and dried to give 55.4 g of the sodium salt of 6- [b (-) - α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetamido] penicillanic acid, m.p. 170 ° C (decomposes), yield 80.8 g. The structure of the compound was determined by IR and NMR spectra.

12 62 834

When the above procedure was repeated, D (-) - OC- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -phenylacetic acid was replaced by D (-) - Of- (4-ethyl-2,3-dioxoacetic acid). -1-piperazinecarbonylamino) phenylacetic acid gave the final product of formula D (-) -

0 O

s / ch

10 CH0CH0-N N — CONHCHCONH — S

2 2 \ _ / X I ^^ 3 o * - - ^ COONa

15 Sp. (decomposes) 183-185 ° C

Example 2

To a solution of 10 g of the sodium salt of D (-) -? - phenylglycine in 50 ml of water were added 50 ml of ethyl acetate and 7 g of triethylamine. 12.6 g of 4-n-propyl-2,3-dioxo-1-piperazinecarbonyl chloride were then added to the mixture over 15 minutes at 0-15 ° C, and the mixture was allowed to react at 5-15 ° C for 30 minutes. The aqueous layer was then separated and 150 ml of ethyl acetate was added. The pH of the mixture was adjusted to 1.5 with dilute hydrochloric acid, the ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 16 g of D (-) - OC- (4-n-propyl-2,3-dioxo- 1-piperazinecarbonylamino) -30 phenylacetic acid, m.p. 90-93 ° C (decomposes), yield 83%.

In a similar manner, D (-) -OC- (4-n-butyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid, m.p. 86-89 ° C, 84% yield.

Example 3 To a suspension of 2 g of D (-) - O-β-hydroxyphenylglycine in 7 ml of water was added 1.8 g of potassium carbonate to give a solution. To this solution was added 2.5 g of 4-methyl-2,3-dioxo-1-piperazinecarbonyl chloride over 15 minutes at 5-10 ° C, and the reaction was allowed to proceed at this temperature for one hour. After completion of the reaction, the pH of the reaction mixture was adjusted to 5.5 with dilute hydrochloric acid, and the precipitated oily substance was separated and crystallized from isopropyl alcohol to give 2.3 g of D (-) - Ct- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino). β-hydroxyoxyphenylacetic acid, m.p. 160-165 ° C (decomposes), yield 60%.

10 IR (KBr) cm -1: V) c = 0 1710, 1700, 1660.

In the same manner as above, D (-) - O- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) -p-hydroxyphenylacetic acid, m.p. 138-142 ° C (decomposes), yield 53%.

Example 4 1) To a solution of 2.28 g of D (-) - O-amino-1,4-cyclohexadienylacetic acid in 15 ml of 1N NaOH were added 20 ml of ethyl acetate and 2.1 ml of triethylamine, and the resulting mixture was cooled to 0 ml. ° C. To this mixture was slowly added 1.69 g of 4-methyl-2,3-dioxo-1-piperazinecarbonyl chloride over 10 minutes. The reaction mixture was cooled with ice, and the reaction was allowed to proceed for 30 minutes, then the aqueous layer was separated and 20 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 25 by the addition of 2N hydrochloric acid under ice-cooling. The ethyl acetate layer was separated, washed with sufficient water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Isopropyl alcohol was added to the residue to give 2.5 g of white crystalline D (-) - Ot- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -1,4-cyclohexadienylacetic acid, m.p. 140-145 ° C (decomposes), yield 74%.

IR (KBr) cm -1: 0NR 3300, 0C_Q 1715, 1660 NMR (D 6 -DMSO) δ values: 0.57 (1H, d), 4.26 (1H, s), δ 4.36 (2H, s), 5.29 (1H, d), 6.07 - 6.18 (2H, m), 6.38 - 6.49 (2H, m), 7.05 (3H, s), 7.35 (4H, s).

14 62834

Preparation of a compound of formula II from a compound of the invention:

To a suspension of 0.45 g of the above D (-) - N- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -1,4-5 cyclohexadienylacetic acid in 15 ml of anhydrous methylene chloride was added with stirring 0 , 24 ml of N-methylmorpholine. The resulting solution was cooled to -10 ° C, dropped into the solution. 3 ml of anhydrous methylene chloride solution containing 0.24 g of ethyl chloroformate, and the reaction was allowed to continue at the same temperature for 90 minutes for D (-) - Of- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -1 To prepare a mixed anhydride of 4-cyclohexadienyl-acetic acid. The reaction mixture was then cooled to -20 ° C, and 5 ml of a methylene chloride solution containing 0.70 g of triethylamine salt of 6-aminopenicillanic acid and 0.31 ml of triethylamine was gradually added dropwise. The mixture was allowed to stand at -20 ° C for one hour at -20 to 0 ° C for one hour and at 0-5 ° C for one hour. The solvent was removed by distillation under reduced pressure, the residue was dissolved in 10 ml of water, and the solution was washed with 10 ml of ethyl acetate. To the aqueous layer was again added 15 ml of ethyl acetate, the pH was adjusted to 2.0 with 2N hydrochloric acid while cooling with ice. The ethyl acetate layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 0.74 g of white crystalline 6- / D (-) -Cc- (4-methyl-2,3- dioxo-1-piperazinecarbonylamino) -1,4-cyclohexadienylacetamide-7-penicillanic acid, m.p. 84-87 ° C (decomposes), yield 87%. The structure of this compound was confirmed by IR and NMR spectra.

30 Example 5

To a suspension of 0.9 g of D (-) - O-alanine in 15 ml of water was added 2.05 g of triethylamine, whereby D (-) -? -Alanine was dissolved, and the solution was cooled to 0 ° C. To the solution was added 2.3 g of 4-methyl-2,3-dioxo-1-piperazin-35-carbonyl chloride over 15 minutes, after which the reaction was allowed to continue for 30 minutes under ice-cooling. Dilute hydrochloric acid was then added to the reaction mixture to adjust the pH to 2.0. The water was removed by distillation under reduced pressure, 30 ml of acetone was added to the residue, followed by filtration of the insoluble matter. To the resulting acetone solution was added 10 ml of an acetone solution containing 1.6 g of the sodium salt of 2-ethylhexanoic acid, and the precipitated crystals were filtered and dried to give 2.1 g of D (-) - <K- (4-methyl-2,3-dioxo). -1-piperazinecarbonylamino) propionic acid sodium salt, m.p. 115-118 ° C (decomposes), yield 78.5%.

IR (KBr) cm -1: c = 0 1700, 1680, 1600 (-CONCl 2, COO ').

Example 6 1) To a solution of 2.2 g of DL-O-amino-2-thienylacetic acid in 14 ml of 1N sodium hydroxide solution was added at 0 ° C 2.2 g of triethylamine. At the same temperature, 3.6 g of 4-methyl-2,3-dioxo-1-piperazinecarbonyl chloride were then gradually added. The reaction was then allowed to proceed at 150 ° C for 30 minutes and at room temperature for 30 minutes. The pH of the reaction mixture was then adjusted to 1.0 by the addition of dilute hydrochloric acid. The precipitated crystals were filtered, washed with water and dried to give 3.5 g of DL-OG- (4-methyl-2,3-dioxo-1-piperazinecarbonyl-20-amino) -2-thienylacetic acid, m.p. 214-215 ° C (decomposes), yield 80.5%.

IR (KBr) cm-1: * Oc = 0 1710, 1680-1660.

2) To a solution of 3.5 DL-Ct- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -2-thienyl-25-acetic acid obtained above in 100 ml of acetone was added dropwise 1.86 g of the sodium salt of 2-ethylhexanoic acid. dissolved in 50 ml of acetone, whereupon crystals precipitated. The crystals were filtered and washed with acetone to give DL-O- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -2-thienylacetic acid sodium salt, m.p. 175-176 ° C (decomposes).

Preparation of a compound of formula II from a compound of the invention:

To a suspension of 3.3 g of the sodium salt of DL-α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) -2-35 thienylacetic acid obtained above in 50 ml of methylene chloride was added 30 mg of N-methylmorpholine, and the obtained the mixture was cooled to -20 to -15 ° C. To the resulting mixture was added dropwise over 5 minutes 1.3 g of ethyl chlorocarbonate in 20 ml of methylene chloride, and the mixture was stirred at the same temperature for 90 minutes to give DL - <* - (4-methyl-2,3- dioxo-1-piperazinecarbonylamino) -2-thienylacetic acid mixed anhydride. A solution of 3.3 g of the triethylamine salt of 5-aminopenicillanic acid in 50 ml of methylene chloride was then added dropwise to the mixture over 20 minutes at -50 to -40 ° C, and the resulting mixture was stirred at -40 to 30 ° C for 30 minutes. At -30 to -20 ° C for 30 minutes and then at -20 to 0 ° C for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in water. The pH of the aqueous solution was adjusted to 2.0 by adding dilute hydrochloric acid under ice-cooling to give a crystalline precipitate. The crystals were filtered, washed sufficiently with water and dried to give 4.1 g of 6- [b] -Oc- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino-15-one) -2-thienylacetamide <2-penicillanic acid, m.p. 185 ° C (decomposes), yield 80.5%. The structure of the compound was confirmed by IR and NMR spectra.

Example 7

To a solution of 3.2 g of D (-) - O- (4-ethyl-2,3-di-20-oxo-1-piperazinecarbonylamino) phenylacetic acid in 20 ml of anhydrous methylene chloride and 5 ml of dimethylformamide, 1.33 g of N, N-dimethylaniline were added.

The mixture was cooled to -15 to -10 ° C and 1.14 g of ethyl chlorocarbonate in 5 ml of anhydrous methylene chloride was added dropwise over 5 minutes. The reaction was allowed to proceed at the same temperature for 60 minutes to form D (-) - QC- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid mixed anhydride.

Preparation of a compound of formula II from a compound of the invention:

To a suspension of 3.28 g of 7-amino-3- [5- (1- (ethyl-1,2,3,4-tetrazolyl) thiomethyl] -2'-cephem-4-carboxylic acid in 65 ml: in anhydrous acetonitrile, 3.04 g of Ν, Ο-bis (trimethylsilyl) acetamide was added to give a solution. The solution was cooled to -20 ° C and poured into the reaction mixture obtained above. The reaction was allowed to proceed at -10 to -5 ° C for 60 minutes. Then, 5 ml of methanol was added to the reaction mixture, and the insoluble matter was filtered off.

The solvent was then distilled off under reduced pressure.

17 62 834 The residue was dissolved in a solvent mixture of 100 ml of water and 50 ml of ethyl acetate, and the pH of the resulting solution was adjusted to 7.5 to 8.0 with sodium hydrogen carbonate. To the aqueous layer were added 80 ml of ethyl acetate and 20 ml of acetone, and the pH of the resulting solution was adjusted to 1.5 by adding dilute hydrochloric acid. The organic layer was separated, washed with sufficient water, and the solvent was distilled off under reduced pressure. The residue was dissolved in 15 ml of acetone, and 60 ml of 2-propanol was added to the solution with stirring, whereupon white crystals precipitated. The crystals were filtered, washed with 2-propanol and dried to give 5.26 g of 7- [D (-) -? - (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetamide] -3- / 5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl-1H-cephem-4-carboxylic acid, m.p. 163-165 ° C (ha-15), yield 83.6%.

The structure of the compound was determined by IR and NMR spectra. When the above procedure was repeated, D (-) - OC- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetic acid was replaced by D (-) -Of- (4-methyl-2,3-dioxoacetic acid). -20 1-piperazinecarbonylamino) phenylacetic acid, the final product of formula D (-) -

Ov O

25 y— ^

CH3-N N-CONHCHCONH —- ^ SN N-N

N '^ γλλί ch2s- ^ nn J

COOH I

30 CH3

OH

Sp. (decomposes) 147-149 ° C.

35 Example 8

To a solution of 0.63 g of D (-) - OC- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid 18 62834 in 10 ml of anhydrous methylene chloride was added 0.5 g of oxalyl chloride and a droplet Ν, Ν-dimethylformamide, and the mixture was allowed to react at room temperature for 30 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was washed with anhydrous benzene to give 0.6 g of D (-) - CC- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetyl chloride, m.p.

112-116 ° C (decomposes), yield 88.8%.

IR (KBr) cm-1: i) NH 3280, Vc = 0 1790, 1695.

Preparation of a compound of formula II from a compound of the invention:

To a suspension of 0.27 g of 7-aminocephalosporanic acid in 6 ml of anhydrous methanol was added 0.24 g of triethylamine. The resulting solution was cooled to -40 ° C, and a solution of 0.34 g of D (-) - O- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) dissolved in 5 ml of anhydrous methylene chloride was added thereto. ) phenylacetyl chloride, and the temperature of the reaction mixture was then allowed to gradually rise to room temperature over one hour. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was added 20 ml of water, and the resulting solution was washed twice with 5 ml of ethyl acetate. To the aqueous layer was added 20 ml of ethyl acetate, and the pH of the resulting solution was adjusted to 1.5 with 2N HCl with stirring. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, then the solvent was removed by distillation under reduced pressure to give 453 mg of D (-) - O - (4-ethyl-2,3-dioxo-1-piperazinecarbonyl) carbonylamine. phenylacetamido-3-acetoxymethyl-A-cephem-30 4-carboxylic acid, m.p. 165-166 ° C (decomposes), yield 79.0%. The structure of this compound was confirmed by IR and NMR spectra.

However, the procedure of step (2) above was repeated using the following reactive derivatives instead of D (-) - O- (4-ethyl-2,3-dioxo-1-piperazine-35-carbonylamino) phenylacetyl chloride to give 7-D (- ) -CC- (4-Ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacet-3-amino] -3-acetoxymethyl-A-cephem-4-carboxylic acid: 19 <834

Reactive Yield of a Compound of Formula I Derivative D (-) - Of (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetyl azide / prepared D (-) - O (- (4-ethyl-2 From 3-dioxo-1-piperazinecarbonylamino) phenylacetyl chloride and sodium azide 7 68% p-nitrophenyl-D (-) - O- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetate 10 / prepared from D (-) -OC- (4-ethyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid-Posta and di (p-nitrophenyl) sulfite7 62% N- / D (-) - CC- (4-ethyl-2,3- dioxo-1-piperazinecarbonylamino) phenylacetyl] imidazole 15 / prepared from D (-) - O- (4-ethyl-2,3 ** dioxo-1-piperazinecarbonylamino) phenylacetic acid Posta and N, N'-carbonyldiimidazole 65%

Example 9 1) To a solution of the sodium salt of D (-) - O-phenylglycine (28.2 g) in 150 ml of water were added 200 ml of ethyl acetate and 18.2 g of triethylamine, and the mixture was cooled to 0 ° C. 34.3 g of 4-methyl-2,3-dioxo-1-piperazinecarbonyl chloride were added to the mixture over 15 minutes, and the reaction was allowed to proceed at 5-10 ° C for 15 minutes. The aqueous layer was separated, adjusted to pH 0.5 with 2N HCl while cooling with ice. The precipitated crystals were filtered off and dried, yielding 42 g of white crystalline D (-) - Of- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenyl-30-acetic acid.

Preparation of a compound of formula II from a compound of the invention D (-) - α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid (0.31 g) in a suspension of anhydrous methylene chloride (15 ml) was added with stirring. , 11 g of N-methylmorpholine, and the resulting solution was cooled to -20 ° C. A solution of ethyl chlorocarbonate (0.13 g) in anhydrous methylene chloride (3 ml) was added to the solution, and the mixture was allowed to react at -10 ° to -20 ° C for 60 minutes. To the resulting mixed anhydride solution was added dropwise a solution obtained by adding 0.50 ml of triethylamine 7-amino-3- [2- (5-methyl-1,3,4-thia-3-diazolyl) thiomethyl To a suspension of -A-cephem-4-carboxylic acid (0.41 g) in 5 ml of methanol. After the addition was complete, mixture 5 was allowed to react at -50 to 30 ° C for 30 minutes, at -30 to -20 ° C for 60 minutes, at -20 to 0 ° C for 60 minutes, and then at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, water (10 ml) was added to the concentrated reaction mixture, the solution was washed with 5 ml of ethyl acetate, a new portion (15 ml) of ethyl acetate was added, and the pH was adjusted to 1.5 with 2N hydrochloric acid under ice-cooling. The separated insoluble matter was filtered off and the ethyl acetate layer was separated, washed successively with water and saturated NaCl solution, dried over magnesium sulphate and evaporated under reduced pressure to give 0.58 g (91%) of 7- / b (-) - O-C (-) - 0 as pale crystals. 4-Methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetamide-3- [2- (5-methyl-1,3,4-thiadiazolyl) thiomethyl] -4-cephem-4-carboxylic acid, m.p. 160 ° C 20 (decomposes).

IR (KBr) cm -1: 0p_q 1780 (lactam), 1650-1720 (-CONCl 2, -COOH) 1 H-NMR (d 6 -DMSO) δ values: 0.2 (1H, d), 0.6 ( 1H, d), 2.60 (5H, s), 4.35 (1H, q), 4.40 (1H, d), 5.0 (1H, d), 5.70 (2H, q) , 6.10 (2H, broad s), 6.25 - 6.55 (2H, 2H, broad s), 7.0 (3H, s), 7.30 (3H, s).

The procedure described above was repeated using the compounds of formula I shown in Table 2 below to replace D (-) - Of- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid to give the cephalosporin derivatives shown in Table 2. Their structure was determined by IR and NMR spectra.

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By repeating the procedure described in Example 9 above, starting from D (-) -? - (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid (0.3 g) and 7-amino-3-ol / 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N-cephem-5 4-carboxylic acid gave 0.5 g of 7- (T) (-) - O- (4-methyl-2,3 -dioxo-1-piperazinecarbonylamino) phenylacetamide-2- [3- (5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylic acid, m.p. 161-163 ° C (decomposes), yield 76%.

IR (nujol) cm -1: λ max = 0 1775 (lactam, 1720-1660 δ (-CON δ, -COOH) NMR (d 6 -DMSO) δ values: 0.02 (1H, d), 0.34 (1H, d), 2.48 (5H, s), 4.17 (1H, q), 4.26 (1H, d), 4.92 (1H, d), 5.66 (2H, s) , 6.01 (5H, s), 6.35 (4H, s), 7.0 (3H, s).

The procedure described above was repeated using the compounds of formula I shown in Table 3 instead of 15 D (-) - α- (4-methyl-2,3-dioxo-1-piperazinecarbonylamino) phenylacetic acid to give the cephalosporin derivatives shown in Table 3. Their structure was determined by IR and NMR spectra.

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Claims (4)

24 62834 1. 2,3-Dioxopiperazine derivatives of the formula: OOM AN NC-NH-CH-B (I) 10 v_ (5 έ5 R2 2 5 wherein R is a hydrogen atom or a methyl group; R is used as intermediates in the preparation of antibacterial penicillin and cephalosporin derivatives; a methyl, phenyl, hydroxyphenyl, cyclohexadienyl or thienyl group, A is a C 1-4 alkyl group, and B is a carboxyl group, a salt thereof or a reactive derivative thereof. A process for preparing a compound according to claim 1 having the general formula: O O M A-N N-C-NH-CH-B (I) 25 V_ / 5 r5 k2 2 5 wherein R is a hydrogen atom or a methyl group; R is a methyl, phenyl, hydroxyphenyl, cyclohexadienyl or thienyl group; A is a C 1-4 alkyl group; and B is a carboxyl group, a salt thereof or a reactive derivative thereof, characterized in that the amino acid or a salt thereof of the general formula H2N-CH-COOR4 (III) R5 35 25 6 2 8 3 4 • 4. 5 wherein R is a hydrogen atom or a salt-forming cation, and R is as defined above, is reacted with a compound of general formula: wherein O 'is a carboxyl group reactive derivative, 2 and R and A are as defined above, in an inert solvent, optionally in the presence of an acid scavenger at a temperature between -30 and + 40 ° C, and then, if desired, the product obtained is converted into a salt or a carboxyl group reactive derivative into another reactive derivative. 26 62834