SU953983A3 - Process for producing cephalosporin derivatives - Google Patents

Description

one

This invention relates to a process for the preparation of new cephalosporin derivatives, namely, 7- (4-halo-3-oxobutyramide) ceflosporin derivatives, which are intermediates 5 and for the synthesis of (2-exo-substituted-4-thiazolin-4-yl) acetamido cephalosporin derivatives with antimicrobial activity,

A known method of producing 7-acylamido cephalosporin derivatives by acylation of the corresponding 7-aminocephalosporin derivative with a reactive derivative of the corresponding carboxylic acid y1.

The aim of the invention is to obtain new compounds that expand the ar-JQ senate intermediates in the synthesis of cephalosporin antibiotics.

The goal is achieved based on the known N-acylation of 7-aminocephalosporins by the proposed method.

for preparing cephalosporin derivatives of the formula

V-CH2COCH2CONH-1soon

where W is a chlorine or bromine atom;

Y is acetoxy-, 1-methyltetrazol-4-ylthio- or 1-dimethylaminoethyl-tetrazol-5-ylthioradical,

interoperable with the formula

S

N

HgNN CHgY,

tu)

Cun

where Y is as defined above, with a compound of the formula

wcHgCocHaCow, (w)

where W has the indicated values, in the medium of the solvent at -60-10 C in the presence of a condensing agent, such as a secondary or tertiary amine.

U-C-halide-3-oxobutyrylamino) -cephalosporin derivatives, characterized by the formula (|), can be used in the form of free β-carboxylic acid or after conversion to the 5-salt using such non-toxic cation as sodium or potassium, or similar substances; or with the help of such basic amino acids as arginine, ornithine, lysine, histidine or acids similar to them, or with the help of such polyoxyalkylamines as N-methylglucamine, diethanolamine, triethanolamine, trioxymethylaminemethane or others.

PRI m e p1. Preparation of 7-A-chloro-5 -3 oxobutyramido | -3-acetoxymethyl-4carboxylic acid.

A solution of k, k-r diketene in 10 ml of methylene chloride is pre-cooled to -35 ° C and added to it. 20 3.92 g of chlorine. The resulting solution is stirred. 15 minutes. At the same time, 10.9 g of 7-aminocephalosporanic acid and 8.1 g of triethylamine are dissolved in 100 ml of methylene chloride and cooled to -30 ° C. The first solution is added to 25 to this solution, stirring and cooling it in such a way that the temperature of the mixture does not exceed -30 ° C. Then the mixture is gradually returned to room temperature for 1 hour, after which it is distilled under reduced pressure. . To the residue was added 100 ml of ethyl acetate and the mixture was stirred by stirring with 100 ml of 10% aqueous phosphoric acid solution. Then an aqueous layer saturated with sodium chloride is taken and extracted three times with ethyl acetate. The acetic acid ethyl ester layers are settled, washed with a saturated aqueous solution of sodium chloride, dehydrated, and their concentration is increased under reduced pressure to a final volume of 20 ml. The resulting concentrate is kept cold and the crystals of the target product which are recovered therewith are recovered by filtration.

Yield 6.3 g. Melting point 135-YO With dec. . IR fcM, KBG): 1790, 1750, 1655.

NMR (S, (j-dimethyl sulfoxide): 2.00 (S, COCH), 3, 3.6l (ABq, 3 55 18 Hz, 2-CH), 3.56 (S, COCHjCO), 4.50 ( S, C1CH2-) 1.67 and 5.00 (ABq, J 13 Hz, W-CH), 5.07 (d, D

 , 5 Hz, 6-H), 5.66 (dd, J A, 5 and 8 Hz, 7-H), 9, (d, J 8 Hz, CONH).

Elemental analysis.

Calculated for Cj HijCI SN-0 ,,%: C 43.03; H 3.87; N 7.17.

Found,%: C, 01; .N 3,89; N 7.18.

PRI mme R 2. Preparation of 7- (4-bromo-3-oxobutyrylamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid.

A solution of 3.4 g of the diquette in 10 ml of methylene chloride is pre-cooled before and a solution of 6.4 g of bromine in 10 ml of methylene chloride is added dropwise to it. At the same time, 10.9 g of 7-aminocephalosporanic acid and 8, .1 g of triethylamine are dissolved in 100 ml of methylene chloride and the resulting solution is cooled to. To this solution, add the solution of the first mixture, stirring and cooling it so that the temperature of the mixture does not exceed. The temperature is then gradually raised to room temperature over 1 hour, after which the resulting solution is distilled under reduced pressure. To the residue, 100 ml of ethyl acetate and 100 ml of a 10% aqueous solution of phosphoric acid are added and the mixture is stirred vigorously. Then, an aqueous layer saturated with sodium chloride is taken and it is double extracted with ethyl acetate. The layers of ethyl acetate are asserted, washed with a saturated aqueous solution of sodium chloride, dehydrated, treated with activated charcoal and their concentration is increased by drying under reduced pressure. Ether was added to the residue and allowed to stand for a while.

The crystals of the target product thus formed are recovered by suction filtration. The target compound contains a quarter molar fraction of ethyl acetate, which is the solvent for crystallization

Exit 8g.

IR (see KBG): 1780, 1735, 1650.

NMR ((9, d-dimethyl sulfoxide): 2.01 (S,), 3.54 (t, 2-CH4), 3.62 (S, COCHjCO), 4.37 (S, BrCHiCO), 4.67 and 5.01 (ABq, J 14 Hz, 3-CHg), 5.08 (d. J 4 Hz, 6-H), 5.66 (dd, l 4 and 8 Hz, 7-H); 9, 04 (d, l 8 Hz, CONH).

Claims (1)

Elemental analysis. Calculated for l / t SdNvO, I; C 39, Yu; H 3., 75; N 6.13. Found,%: C 39.20; H 3.63; Mb, 09. Example 3. Preparation of l-k-raloid-3-oxobuty ramido) -3-heterocyclic thiomethyl-4-carboxylic acids. Target compounds containing a 3-position heterocyclic thiomethyl substituent are prepared by one of the following methods. Method 1. 0) 10.7 g of V7.3n mmol) 7 acetoacetamido-3 acetoxymethyl-3-cephem-carboxylic acid, 30 mmol of the corresponding heterocyclic thiol and 5.08 g (60 mmol sodium hydrogencarbonate) are dissolved in 0 ml of water. the pH of the resulting solution was adjusted to 7.0 by adding a 10% aqueous solution of sodium hydroxide, after which the mixture was stirred at 60-b5 for t hours. After cooling, 2.31 g (GW mmol) hydroxylamine hydrochloride was added to the reaction mixture and the pH of the mixture obtained is a few d t up to 3,6-addition of 1N hydrochloric acid, after h its mixture is kept overnight at room temperature. Precipitated crystals of 7 amino-3 heterocyclic thiomet / 1L-3 Cephem-4-carboxylic acid are collected by filtration, washed with acetone and dried. (2) A solution of 1.05 g (13 mmol of diketene in 5 ml of methylene chloride is pre-cooled to -30 ° C and a solution of 1.05 g (15 mmol) of chlorine in 10 ml of carbon tetrachloride or a solution of 2.2 g (It mmol) of bromine in 5 ml of methylene chloride is added dropwise in the first solution. At the same time, 10 mmol of 7 amino-3-heterocyclic thiomethyl-3 cefem-β-carboxylic acid and 2.02 g (20 mmol) of triethylamine are dissolved in 20 ml of methylene chloride and the resulting solution is cooled to -20 ° C. The first solution is quickly added dropwise to this solution. As a result of the exothermic reaction taking place during this, the temperature in most cases rises to about 0 ° C. After the exothermic reaction stops, the temperature gradually rises to room temperature. After stirring for 15 minutes, the resulting solution was added to a mixture of 150 ml of ethyl acetate and 100 ml of an aqueous solution of phosphoric acid with vigorous stirring. The organic layer is separated, washed with water and dried, and then the solvent is evaporated. Ether was added to the residue and the mixture was for some time removed. The precipitate thus obtained, representing 7 (chlorine or bromo-3-oxobutyrylamido-3-heterocyclic thiomethyl-3-cephem-4-carboxylic acid, is recovered by filtration of the powder. Method 2. (1) A solution of 60 g (o, 2 mmol) 7-formamido-3-acetoxymethyl-3 cefem-carboxylic acid, 0.2 mol of the corresponding heterocyclic thiol and 33.6 g (0, t mol) of sodium hydrogen carbonate are dissolved in 200 ml of water and the pH of this solution is adjusted to to 7.0 by adding a 10% aqueous solution of sodium hydroxide, then this solution is stirred for tS h at 60-65 ° C and After this, 5.00 ml of methanol is added to it, the mixture is cooled with ice and 80 g of concentrated sulfuric acid is added to it, continuing to stir the mixture and maintaining its temperature no higher than 30 ° C, then keep it overnight in a refrigerator. 1000 ml of water and stirred by shaking with ethyl acetate (2 XX 400 ml). The combined aqueous layer is subjected to filtration by suction with 7, thereby removing the undissolved substances, and the pH of the resulting filtrate is adjusted to 3.8 by adding it's late Update aqueous ammonia, and then the resulting solution was allowed to stand for 3 hours at Oc. The precipitated crystals are collected by filtration and washed with cold water (100 ml), then with acetone (30% ml), then dried and 7-amino-3-heterocyclic thiomethyl-3-cephem-carboxylic acid is obtained, which is similar to paragraph (2) of the method 1 turn into the target product. Characteristics of the target compounds: WCH2COCHgCONH-, 0 Compound fP 1: GOOH II I Y -S-kj / CH2CH2N (CH5) Elemental analysis for NjO Calculated,%: €, 51; H, hO; N 19, A5. Found,%: C fO, 77; .H, 81; N I8,65v. .cm1773; -1b72, 1608, 1386,. NIIR (100 m. OM50) 8: 2.50 (5, N. / CH3 / 2. 3.17 (t, D 6H2, CHjWlCHA 3.5 and 3.76 (LVP, 7 l8H2, Z-Hz;,, 30 .. (brs, 3-CH),, 5b (p), C1CH2, 8 tetrazole CHi), 5.05 (d,: 3 5Н7, L – H). 5.6 / ((3d, D 558H- ,, 7-Н). Э, 07 (d, .1 8Н2 ;, CONH). Compound K 2 NY.;. Y-s4ij ..: CHs IR-с1 ektr, 1780, 1720,, 1390 124J17.0.700 cm -1. .YAIR HS1, d6) 3.57 and 3.79 (ABq, I i8H2; ie rH), 3.56 (s, 3.91 (s, tetrazole-CH3), t, 20, and 4.37 (ABq, J 13H, Сз-СН), 4.52 (S, С1СНг), 5.07 Id, О 5Hr, СЛ-Н), 5.6 (dd, .l 5t8H. VH), 9.05 (d, I 8HZ, CONH Compound f 3N-N 11 H. Y-S-4jfx.N NMR (lOOMHz. D, -DHSO) 5: 3.59 and 3.81 (ABq, l 18H, ZH), 3.63 (S, COGHgCO), 3.93 (S, tetrazole-CH3), t, 2 and i, 38 (ABq, I 13Hg ;. C — CH), t, 38. (. S. BrCH,), 5.07 (d, 1 5H2. 6-H ), 5.67 (dd; j 5b8H2. 7-H), 9.06 (d, J 8Hj. CONH). Claims for obtaining ceph derivatives osporin of the general formula 1-shnssosngsokn-N CHgY, where W is a chlorine or bromine atom; Y is an acetoxy, 1-methyltetrazol-5, Ilthio- or 1-dimethylaminoethyltetrazol-5 Il-thioradical, characterized in that , L-ili CHaY from where V has the indicated values, is reacted with a compound of the general formula III wcflgCOGHaCow where W has the indicated values in a solvent medium at a temperature of -60-10 ° C in the presence of a condensing agent, such as a secondary or retic Amine. : Priority for pr iz n and to and m 20,02,7 at U - acetoxy- or 1-methyltetrazol-5-ylthioradical; 13.11.7+ at the U-1-dimethylaminoyltetrazol-5thylthioradical. Sources of information taken IN attention during examination 1. US Patent GG, cl. .260-243, publ. 1972.