FI72123B - 7- / D (-) - alpha- (4-ethyl-2,3-DIOXO-1-PIPERAZINKARBOXIAMIDO) -alpha- (4-hydroxyphenyl) ACETAMIDO / 3- / 5- (1-methyl-1,2; 3,4-TETRAZOLYL) THIOMETHYL / -3-CEFEM-4-CARBOXYLSYRANS N, N-DIMETHYLACETAMIDADDUKTOCH - Google Patents

Description

72123 7- [D (-) - O (- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -o (.- (4-hydroxyphenyl) acetamido] -3- [5- (1-methyl- 1,2,3,4-Tetrazolyl) thiomethyl-N- (1,3-cephem-4-carboxylic acid N, N-dimethylacetamide adduct and process for its preparation

Divided separated from patent application 782 912.

The invention relates to 7 - / D (-) - jK of formula (I). - (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -N- (4-10 hydroxyphenyl) acetamide-3- [5- (1-methyl-1,2,3,4-tetrazolyl) ) N, N-dimethylacetamide adduct of thiomethyl-Z, 3-cephem-4-carboxylic acid and a process for its preparation.

C0Hc-N N-CONH-CH-CONH_N-S "15 2 5 V_ /! M] f |]. (CH3) 2N-C-CH3 (I) fo] COOH CH3

The acetamide adduct of formula (I) is used as an intermediate in the preparation of a therapeutically valuable 7- (D) - (C) (- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -β) of formula (II). (- (4-hydroxyphenyl) acetamido] -3-3-Z- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylic acid. ) for the preparation of a therapeutically valuable final product (II) is described in FI patent application 782 912.

V

C2H5-n '' n-CONH-CH-CONH — j— * j | 30 ^, Α, 'V »(II) (OJ 0 T ch2s i Y COOH CH3

OH

35 721 23 2 JP 10755/78 discloses that the bactericidal effect of the compound of formula (II) and its salt is excellent not only against gram-positive but also against gram-negative bacteria, their toxicity is low, and their bactericidal spectrum is wide.

According to JP 10,075/78, the compound represented by the formula (II) is obtained by condensing D (-) - c (- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -q (- (4-hydroxyphenyl) -10 acetic acid or a reactive derivative thereof such as acid chloride or acid anhydride with 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -Z23-cephem-4-carboxylic acid in neutral in the presence of a solvent such as methylene chloride or the like Such a reaction is commonly known as acylation of 7-aminocephalosporins and is often used.

According to JP 10 075/78, the acylation is carried out in one or more reaction-neutral solvents, such as water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, diethyl ether, diisopropyl , in the presence of benzene, toluene, methylene chloride, chloroform, ethyl acetate, and methyl isobutyl ketone.

The use of Ν, Ν-dimethylformamide and Ν, Ν-dimethylacetamide in the acylation as solvents is described in U.S. Patent 3,502,665 and the use of Ν, Ν-dimethylacetamide is described in JP Patent Application Kokai (published) 48,688/76. In the experiment of the inventor of the present invention, although N, N-dimethylformamide has been used in the reaction of the present invention, no precipitation of the compound of formula (I) from the reaction mixture has been observed.

The inventors of the present invention have therefore conducted extensive studies to find a simple method for preparing a compound of formula (II) and a pharmaceutically acceptable salt thereof in very pure and maximum yields. As a result, it has surprisingly been found that when 3 72123 is acylated in the presence of Ν, Ν-dimethylacetamide, the reaction proceeds uniformly and the compound of formula (I) crystallizes out in very pure and maximum yields and that upon treatment of the obtained compound of formula (I) with a solvent, The N, N-dimethylacetamide is easily cleaved off to give the compound of formula (II) in very pure form and in high yields, the preparation being sufficiently easy for technical production.

A compound of formula (I) is prepared according to the invention by administering a compound of formula (III)

HCl.H2N-j-r "^ h H

(III) O 1 CH2S 1

15 1 I

COOH CH3 reacts with a reactive derivative of a compound of formula (IV) 20 Λ COHc-N N-CONH-CH-COOH (IV)

2 5 v.V I

Φ

OH

In the presence of Ν, Ν-dimethylacetamide as solvent.

The reactive derivative of D (-) -? C- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -N- (4-hydroxyphenyl) -acetic acid of formula (IV) used as an acylating agent in the process of this invention can be prepared. from the corresponding acid essa, Ν-dimethylacetamide as solvent and the reaction mixture thus prepared can then be used in the acylation reaction, or the reactive derivative 35 can be prepared beforehand in a solvent other than N, N-721 23 4 dimethylacetamide and then used as such, or purified as such or . In addition to N, N-dimethylacetamide, a suitable co-solvent such as acetonitrile, acetone, methylene chloride or chloroform may be used in the preparation of the reactive derivative.

The remaining co-solvent in the reaction mixture does not interfere with the acylation of this invention.

Reactive derivatives of D (-) - oC- (4-ethyl-2,3-dioxo-1-piperizinecarboxyamino) -N- (4-hydroxyphenyl) -acetic acid of formula (IV) include acid halides of the compound of formula (IV) and reaction products with Vils-meier's reagent. These reactive derivatives are prepared by conventional methods. Halogenating agents used in the preparation of said acid halide or Vilsmeier's reagent include, for example, phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, trichloromethyl chloride, trichloromethyl chloride. The preferred reactive derivative of the compound of formula (IV) is the reaction product of the compound of formula (IV) with Vilsmeier's reagent.

The acylation of 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N-cephem-4-carboxylic acid hydrochloride of formula (III) is carried out using the above-mentioned formula of formula 25. A reactive derivative of a compound according to (IV). Although it is sufficient that the compound of formula (IV) and the compound of formula (III) are used in the acylation reaction in equimolar amounts, it is practically recommended that a slightly excess of the reactive derivative 30 of the compound of formula (IV) be used in order to obtain a difficult to obtain compound of formula (III). make it react effectively.

The acylation is carried out at a temperature of usually about 40 ° to about 30 ° C, preferably between about -30 ° to about 0 ° C, and the reaction is complete after about 15 minutes to about 23 hours. Since it is desirable to keep the reaction system dry, the reagents and solvents are thoroughly dried before use and the reaction is carried out under a nitrogen atmosphere. Any moisture present in the reaction system can be removed by adding a dehydrating agent such as trime-5-chlorosilane.

After the above acylation, a base such as sodium hydrogencarbonate or the like and water are added to the reaction mixture, and the mixture is stirred, whereby the Ν, Ν-dimethylacetamide adduct of formula (I) precipitates as crystals substantially free of by-products. Thus, these crystals are collected by filtration to easily obtain the N, N-dimethylacetamide adduct of formula (I) of this invention. At the end of the acylation, the amount of water added is 0.25-2.5 times, preferably 1.0-1.5 times, less than the amount of 15, Ν-dimethylacetamide used in the reaction. Since it is desirable that the pH of the reaction mixture is then between 1 and 3, the pH is adjusted accordingly by adding a base such as sodium hydrogencarbonate or the like.

The invention is illustrated in detail below with reference to Examples 20, but the invention is not limited thereto.

Example 1 In 16 ml of N, N-dimethylacetamide was dissolved 4.0 g of D (-) (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) (4-hydroxyphenyl) acetic acid. To a solution cooled to -20 ° to -22 ° C was added 2.02 g of phosphorus oxychloride over 10 minutes and the mixture was allowed to react at this temperature for 1 hour. To the above reaction mixture was added dropwise over 7 minutes, maintaining the temperature between -20 ° and 22 ° C, a mixture of 4.0 g of 7-amino-3- [5- (1-methyl-1,2,3,4 -tetrazolyl) thiomethyl-7-A-carboxylic acid hydrochloride, 12 ml of N, N-dimethylacetamide and 0.60 g of trimethylchlorosilane. The resulting mixture was allowed to react for 90 minutes at the same temperature. The reaction mixture was then warmed to room temperature, and 3.5 g of sodium hydrogencarbonate and 28.8 ml of water were added thereto, and the mixture was stirred for 2 hours to precipitate crystals. 1.4 ml of water was added to the mixture to dilute the mixture, and the mixture was stirred for 2 hours at room temperature and for 1 hour under ice-cooling. The crystals thus precipitated were collected by filtration, washed with 8 ml of aqueous N, N-dimethylacetamide (containing 80% by volume of water), and dried to give 6.85 g of 7- (JD (-) - (1- (4-Ethyl-2,3-dioxo-1-piperazinecarboxamido) -α- (4-hydroxyphenyl) acetamide-3- [3- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] N, N-dimethylacetamide adduct of .beta.-cephem-4-carboxylic acid, mp 161-163 ° C (dec.), yield 85.3%.

Δ IR (KBr) cm -1: 1 H 2 O = 0 1773, 1702, 1670 NMR (D 2 O-NaHCO 3) ppm: 1.20 (3H, t, -CH 2 CH 3), ch 3 2.11 (3H, s, - C-CH 2), 2.94 (3H, s, -CN 2),

15 "" X

O O

CH-λ CH 3 3.07 (3H, s, -CN 2), 3.20 - 4.20 (8H, m, CH 3, x 4), 2. U n \ 2.0, CH 3 3.97 ( 3H, s, (N, CHO), 4.94 (1H, d, C 1-6), 5.46 (1H, s, Ct-H),

f $ O

5.66 (1H, d, C-H), 7.09 (4H, AB, / q

Example 2

To a mixture of 8 ml of Ν, Ν-dimethylacetamide and 1 ml of acetonitrile was dissolved 2.0 g of D (-) - oi- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -oi- (4-hydroxyphenyl) vinegar-30 acid. To the resulting solution was added dropwise over 15 minutes at -20 ° C a mixture of 0.65 g of trichloromethyl chloroformate and 1 ml of acetonitrile. After the dropwise addition, the mixture was allowed to react at -20 ° C for one hour. A mixture of 2.0 g of 7-amino-3- [3- (1-methyl-3,712,13-1,2,3,4-tetrazolyl) was added dropwise to the reaction mixture over 10 minutes at -20 ° C. ) thiomethyl / N-cephem-4-carboxylic acid hydrochloride, 6 ml of N, N-dimethylacetamide and 0.3 g of trimethylchlorosilane. The resulting mixture was allowed to react at -20 ° C for 90 minutes. To remove acetonitrile, the reaction-5 mixture was concentrated in vacuo for 30 minutes (bath temperature 30 ° C; 15 mmHg). To the residue were added 1.2 g of sodium hydrogencarbonate and 14 ml of water, and the resulting solution was stirred to precipitate crystals for 2 hours at room temperature. The mixture was diluted again with 7 ml of water and stirred for 2 hours at room temperature and then for 1 hour under ice-cooling. The precipitated crystals were collected by filtration, washed with 4 ml of aqueous N, N-dimethylacetamide (containing 80% by volume of water), and dried to give 3.50 g of 7- / D (-) - dr (4-hydroxyphenyl). acetamide 7 -3-15 E- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl-N-cephem-4-carboxylic acid N, N-dimethylacetamide adduct; yield 87.1%. The melting point and IR and NMR values were consistent with those obtained in Example 1.

Example 3 To a suspension of 2.0 g of D (-) - d- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -α- (4-hydroxyphenyl) acetic acid in 20 ml of methylene chloride , 1.52 ml of trimethylchlorosilane was added. To the mixture was added dropwise and cooled at 10-15 ° C over 3 minutes, 1.58 ml of triethylamine, and the reaction was allowed to continue at the same temperature for one hour. The reaction mixture was cooled to -25 ° C, and 0.46 ml of N, N-dimethylformamide and 1.66 g of oxalyl chloride were added in this order, followed by allowing the reaction to continue for one hour at -20 to -25 ° C. The solvent was removed from the reaction mixture by distillation in vacuo. The residue was dissolved in 8 ml of N, N-dimethylacetamide, and the resulting solution was added dropwise over 4 minutes to a solution of 2.0 g of 7-amino-3- [5- (1-methyl) cooled to -20 to -22 ° C. - (1,2,3,4-tetrazolyl) thiomethyl-N-cephem-4-carboxylic acid 35 hydrochloride in 6 ml of N, N-dimethylacetamide. Reaction 8,721 23 was allowed to proceed at -20 to -22 ° C for 90 minutes. The reaction mixture was allowed to warm to room temperature and diluted with 14 ml of water, after which the pH of the diluted mixture was adjusted to 2 with sodium hydrogen carbonate. The mixture was stirred to precipitate crystals for 2 hours. To the mixture was again added 7 ml of water, and the mixture was stirred for 2 hours at room temperature and then for 1 hour under ice-cooling. The precipitated crystals were collected by filtration, washed with 4 ml of aqueous N, N-dimethylacetamide (containing 80% by volume of water) and dried to give 3.25 g of 7- / D (-) - <£ - (4- Ethyl 2,3-dioxo-1-piperazinecarboxamido) -N- (4-hydroxyphenyl) acetamido-3- [5 '(1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -N- the N, N-dimethylacetamide di adduct of cephem-4-carboxylic acid; yield 80.8%. The melting point and IR and NMR values were consistent with the values of the corresponding compound obtained in Example 1.

Il

Claims (3)

72123 A process for the preparation of 7- [p (-) - dr (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -O- (4-hydroxyphen-5-yl) acetamide] -3- For the preparation of the N, N-dimethylacetamide adduct of 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl-N-cephem-4-carboxylic acid, N, N-dimethylacetamide adduct, conh-ch-conh- | - ^ s ^ jj Ϊ. (CH3) 2N-C-CH3 (I) ro] ^ COOH 6h3 OH characterized in that SNN HCl * H N- of the compound of formula (III) is administered. React with (III) COOH ch 20 to react with a reactive derivative of a compound of formula (IV)> ° C-Hj. "N in the presence of N-CONH-CH-COOH (IV) N, OH-N, N-dimethylacetamide as solvent, 30 10 72123 Process according to Claim 1, characterized in that the reactive derivative of the compound of the formula (IV) is an acid halide of the compound of the formula (IV) or the reaction product of the compound of the formula (IV) and the Vilsmeier reagent. Process according to Claim 1 or 2, characterized in that the reactive derivative of the compound of the formula (IV) is the reaction product of the compound of the formula (IV) and the Vilsmeier reagent. 10 4. 7 - {[(-) -? - (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -o (- (4-hydroxyphenyl) acetamido] -3-Z5- (1-methyl- 1,2,3,4-Tetrazolyl) thiomethyl-7- [N-cephem-4-carboxylic acid β, Ν-dimethylacetamide adduct characterized in that it has the formula (I): 15 0 0 ° C 2 H 5 -V 7 "CONH- ? H "CONHTr" 1 ff F- (CH-) -NC-CH- 20 6h C00H CH3 (I) 11 72123