SU541437A3 - Method for preparing 3-thiolated 7-acylamino cephalosporanic acid derivatives, their salts or esters - Google Patents

Description

OR its salt, or hydrolysable ester, is reacted with an acylating agent, an acid derivative having formula III

Ci-l, -lIHB

111

, p-soon

and (where B is an amino-protecting group, for example, commonly used in peptide synthesis, such as gret-butoxycarboyl, 1-carbethoxy-1-propenyl-2, carbobenzyloxy, formyl, o-itrophenylsulphenyl, p, p, p-trichloroethox-15

 O Y (CH ,, g-C-Zsicarbonyl, 4-oxo-2-pentenyl-2-, etc., and n has the above values, such as acid halide, mixed anhydride or activated ester and others, preferably compound formulas

- Ш, Жг-НС {. // about

; N-IN 1

1T - N

, and with it (CH,) „- C-C1 where n has the above values, the formation of compound 1 11 of formula IV

where B and / g are as defined above, or a salt thereof, or an easily hydrolyzable ester, followed by removal of the amino-protecting group B by known methods. After wrapping reactions of acylation and 20

, -S-.Q which, if necessary, can be converted to sodium dimethanesulfonate salts by known methods, preferably according to the method comprising reacting the zwitterion of formula V with sodium formaldehyde bisulfite or its source, such as, for example, sodium formalin bisulfite, and water in the presence of a strong sodium base such as sodium 2-ethylhexanoate. According to the invention, the starting compound of formula II or its salt or easily hydrolyzable ester is obtained by reacting 7-amino cephalosporanic acid or its salt with a thiol of formula VI or it) and thus need the compound thus obtained

-N

The coo® release mentioned above gives the desired products of formula I, having a zwitterionic nature, corresponding to formula V II, are converted by known methods into the corresponding salt or ester. Hence it is clear that compounds of formula I can also be obtained by first acylating 7-aminocephalosporanic acid or its salt, followed by reacting the resulting 7-acylaminocephalosporanic acid with a thiol of formula VI, which leads to the replacement of the 3-acetoxy group of 7-acylaminocephalosporanic acid with b- mercaptoterazolo-4,5-bis-pyridazine to obtain the desired product of formula I. Example 1. 7-Amino-3 - (tetrazolo 4,5-b pyridazine - 6ylthiomethyl) -3-cephem-4-carboxylic acid (compound of formula P) . A. To a hot solution (50-60 ° C) of 9.65 g (0.062 mol) of 6-mercaptotetrazolo 4,5-B pyridazine and 10.42 g (0.124 mol) of sodium bicarbonate and 300 ml of water are added carefully 16 80 (0.062 mol) 7-ACC and the mixture is heated

at 80-85 ° C for 30 minutes About 7 g of sodium bicarbonate is added to the reaction mixture to dissolve the insoluble material. The solution is treated with activated carbon, filtered, and the filtrate is acidified to pH 5 with dilute hydrochloric acid. The precipitate is separated by filtration, washed with water, dried in air, and finally in vacuum over P2O5, 14.17 g (64%) of the product are obtained; T. pl. 248-250 ° С (with splitting).

B. A stirred solution of 16.8 g (0.11 mol) of 6-mercaptotetrazolo 4,5-b of niridazine and 18.48 g (0.22 mol) of MANSO 3 in 1 l of 0.1 M phosphate buffer solution (pH 6.4 ) is heated at 50 ° C and 30 g (0.11 mol) of 7-ACC is added in portions to the solution.

The mixture is heated at 80 ° C for 2.5 hours, during which time all of the remaining undissolved material remains. The reaction mixture is cooled to room temperature and the precipitated compound of formula P is collected by filtration, washed with 200 ml of water and dried in air. An additional amount of the product of formula II is obtained from the filtrate and washes during acidification to pH 5 with dilute HC1. The total yield is 32.9 g (83%); m.p. 245-250 ° С (with decomposition of Kenyom).

IR spectrum:, isQO, 1615, 1538, 1360 cM-i.

UV spectrum: 3237 nm (e 19,500), 275 im (e 12000), 310 nm (acute) (e 5700).

NMR spectrum:, - ;, 3.35 1H, dv, 18 Hz, 2-I (3.76) 1H, dv, 18 Hz, 2H, 4.00 1H, dv, 10 Hz, 3-СНз, 4 , 48 1H, dv, 10 Hz, 3-CH., 4.93 IH, dv, 4 Hz, 6-H, 5.32 1P, dv, 4 Hz, 7H, 7.46 IH, dv, 10 Hz, tshridazinovy N, 8.18 IH, dv, 10 Hz, pyridazine HI.

Calculated for C, 2HnC7Oz52,%: C 39.44; H 3.03; N 26.83; S 17.55.

Found,%: C 39.19, H 2.71, N 26.84, S 17.35.

Example 2

7- (o-tert-Butoxycarbonylaminomethylphenylacetamido) -3 - (tetrazolo 4,5 -b pyridazin-6-ylthiomethyl) (compound of formula IV, B-gret-B, and OCO-) -3-cephem-4-carboxylic acid.

To a solution of 20.26 g (0.047 mol) of 2,4-dinitrophenyl (o-tert-butoxycarbonylaminomethyl) phenyl acetate in 150 ml of tetrahydrofuran, a solution of 14.40 g (0.039 mol) of the compound of formula II and 19.19 g (0 , 19 mol) TEA in 150 ml of 50% aqueous tetrahydrofuran at O-5 ° C. The reaction mixture is stirred for 18 hours and concentrated under reduced pressure to remove tetrahydrofuran below 30 ° C. The aqueous concentrate is washed with two portions of 200 ml of ether, acidified to pH 2 with dilute hydrochloric acid and extracted with five portions of ethyl acetate each with 200 ml. The combined extracts are washed with two 100 ml portions of water, dried with anhydrous sodium sulfate, treated with activated carbon to f; ltru1ot. Evaporation solvent gives a slightly yellow l; A liquid that was rubbed with ether to obtain 3.89 g (58% of TV compound (B-greg-ViOSO); mp 166-173 ° C (with salting).

IR spectrum: 1770, 1710, 1690, 1535, 1370, 1255, 1170.

Calculated for

with.

C-HosNsOgSo-HoO, 70

WITH

49.51; H4.79; N 17.77; S 10.17.

Found,%: C 49.58; 49.65; H 4.19; 4.59; N 17.41, 17.66; S 10.14. 7- (o-aminomethylphenylacetamido) -3- (tetrazolo 4, 4-6 pyridazine-6-ylthiomethyl) -3 cefem-4-carboxylic acid (compound of formula I).

13.80 g (0.022 mol) is added in one portion to 20 ml of trit fluoroacetic acid

Compound IV (B-GOST-UOSO) and the mixture is stirred at 45 pps at O-10 ° C. 300 ml of ether is added to the reaction mixture to obtain the compound of formula I () as trifluoroacetate, which is collected by filtration and washed with ether. Tr 1 fluoroacetate is dissolved in 20 ml of water and adjusted to pH 5 with hydroxide. to obtain zwitterionic in the form of a gummy oil, which is separated by decanting and zattrayut with water. The solid product is collected using flitra; 1 W, washed with 20 liters of water H 200 ml of p otonyl one by one and dried in BaKvvNic under P; O5 with a uisis-. 5.10 g (45%). pure, io amorphic.

Amorphous 11 roda kt in the form of toroia (3.50 g) is dissolved in 400 ml of 50% aqueous solution of tetrahydrpfuran irp heated to 60--70 ° C with ruiTeicioniiiioM mixing. The solution is treated with a small amount of activated carbon. The filtrate is cooled, mashed and incubated overnight in a refrigerator to obtain 2.27 g of the product as fine needles; t, pl. 190-193 ° C (with decomposition).

 Calculated for D, Ccc, 5.-1.5,%: C, 46.74; H 4.30; N 20.77; S 11.89,

Found,%: C 47.18, 47.37: H 4.08, 3.88; N 20.23; 20.93; S 12.03. PM 3.

7-Go-Kch-Bis- (iatriisulfomethyl) - aminomethylphenyl-petamido-3 - (tetoazolo 4,5-T

pyridazine - 6 - ilthiomethyl) - 3 - cephem - 4carboxylate natrt.

A mixture of 1 g (1.95 mol) 7- (o-aminomethylphenylacetamido) - 3 - (tetrazolo 4,5-b pyridazine - 6 - ylthiomethyl) - 3-cephem-4-carboxylic acid, 1.52 g (10 mmol) sodium hydroxymethanesulfonate monohydrate, About ml

(6 mol) 1M solution of sodium 2-ethylhexanoate in ethyl acetate, 10 ml of isopropanol and 10 ml of water are stirred at room temperature for 30 minutes to obtain a crystalline product, which is collected by filtration, washed with three portions of absolute ethanol in 50 ml and dried over,

at 45-52 ° C) pressure of 1 mm Hg. Art. over 20 teas to obtain 1.5 g of 7-.oN, N-6HC (sodium sulfamethyl) -amyomethylphenylacetamido-3- (tetrazolo 4,5-b pyridazin-6ylthiomethyl) -3-cephem-4-carboxylate sodium, which is readily soluble in water (above 1 g / ml); m.p. above 270 ° C.

IR spectra: 1760, 1660-1620, 1604, 1540, 1400, 1200, 1040 cm-H

UV spectrum: vcc 242 nm (e 18000), 271 nm (e 11600, acute) 312 nm (e 5100, acute).

NMR Spectrum: b 4% ™ 3.34: 1H, dv, 18 Hz, S-CHg, 3.76 1H, dv, 18 Hz S-CH3 3.85 2H, acute, CO-CH-, 4.04 4H, N-CHg- and 3-CHg-S, 4.30 4H, acute, N-CHg-SOsNa, 4.92 1H, dv, 4.5 Hz, 6-H, 5.42, 1H, dv, 4.5 HZ 7-N, 7.05-7.30 {4H, hair dryer H, 7.40 1H, dv, 10 Hz pyridazine H, 8.11 1H, dv, 10 Hz, pyridazine N.

H e and me 4.

A. (og og-butoxycarbonylaminomethylphenyl) -propionamido-3- (tetrazolo 4,5- & pyridazin-6-ylthiomethyl) -3-cephemcarbopic acid.

N, N - dicyclohexylcarbodiimide (0.41 g, 2 mmol) is added to a mixture of (3- (o-greg-butoxycarbonylaminomethylphenyl) - propionic yolism (0.56 g, 2 mmol) and 2,4-dinitrophenol (0.37 g, 2 mmol) in 5 ml of THF and the mixture is stirred for 1 hour at room temperature. The precipitated urea is filtered off. A 7-amino-3- (tetrazolo | 4.5-6 pyridazine-6-ylthiomethyl) -3-solution is added to the filtrate cefem - 4-1,31-carboxylic acid (0.73 g, 2 mmol) and triethylamine (0.81 g, 8 mmol) in 100 ml of 50% aqueous THF, and the mixture is stirred for 18 hours at room temperature. The reaction mixture p The mixture was washed with ether (2X20 ml) and the aqueous layer was acidified to pH with diluted HC1 and extracted with ethyl acetate (3X50 ml). The combined extracts were washed with water (30 ml), treated with activated charcoal, dried over anhydrous sodium sulfate and evaporated under reduced pressure to an oil. with 50 ml of ether to obtain 7 (o-tert-butoxycarbonylaminomethylphenyl) propionamido-3- (tetrazolo 4,5 - 6 pyridazin-6-ylthiomethyl) -3-cephem-4-carboxylic acid as a colorless solid, which is collected during filtration and dried in vaCHiMj about

(CHiJn-c-m

0

where - 1 or 2

Cuume over phosphorus pentoxide. Yield 0.33 g, 26%); m.p. 110-120 ° C (with decomposition). IR spectrum: v qy jygo, 1710, 1690, 1530,

 MdKLg7j

1370, 1250 cm. UV spectrum: 240 nm (e 19400),

270 nm (acute) (el2500), 310 nm (acute) (e 5000).

NMR spectrum: b4 ° / 1 ° 1.37 9H, acute, t / (yy-but.yl-H, 4.96 1H, dv, 4 Hz, 6-H, 5.55, 1H, dv, 4 and 8 Hz 7-H, 6.99 4H, acute, phenyl H, 7.5 1H, dv, 10 Hz, pyridazine H, 8.38 | 1H, dv, 10 Hz, pyridazine H, 8.69 H, dv, 8 Hz CONH.

Calculated for Ca7H3oN8O6S2-0.5H2O,%: C, 51.02; H 4.91; N 17.63.

Found,%: C 51.74; H 4.83; N 17.88.

B. 7 - p- (o-aminomethylphenyl) -propionamido-3- (tetrazolo 4,5-6 pyridazine-6-ylthiomethyl) -3-carboxylic acid.

Trifluoroacetic acid (0.5 ml) and (o-tert-butoxycarbonylaminomethylphenyl) propionamido - 3 - (tetrazolo 4,5-p pyridazin-b-pltiomethyl) - 3 - cephem - 4 - carboxylic acid (0.28 g 0.46 mmol) is mixed while cooling at 0 ° C and stirred for 30 minutes. Ether (50 ml) is added to the mixture to obtain stratacetate (o-aminomethylphenyl) -propionamido-3- (tetrazolo 4,5-pyridazip-6-ylthiomethyl) -3-cephem-4carboxylic acid, which is separated by decanting, washed with ether, the solution in water (1 ml) and adjusted to pH 6 with diluted NH4OH. The product obtained (oamminomethylphenyl) -propionamido-3- (tetrazolo 4, 5-6 pyridazine-8-ylthiomegyl) -3 cefem-4-carboxylic acid is collected by filtration and dried in vacuo over P-Discharge is 0.10 g (42%); m.p. 190-197C (with decomposition).

IR spectrum: 1760, 1665, 1600,

1535 cm-1.

Calculated for Cr2H2gH8O45g-1 / 2H2O,%: C 49.33; H 4.33; N 20.92; S 12,18.

Found,%: C 49.04; H 4.26; N 20.17; S 11.96.

The formula of the invention

The method of obtaining derivatives of 3-thiolated 7-acylaminocephalosporanic acid general, it of formula I

X

Cho-s

salts or esters thereof, characterized in that the compound of formula II -NxClL-g or its salt, or easily hydrolyzable ester, is reacted with aciCHjNEB O (where the Vil has the above values, or its salt and this lightly hydrolysable 15 ester, -with subsequent removal

L1iruyuschey agent derived acid formula III 10

1T-

-1T LsNg8-CO OH (IC) p-COOH where B is an amino-protective group, for example, G | 0 -t-butoxycarbonyl- or 1-carbethoxy-1 propenyl-2, and p is as defined above, to form a compound of formula IV , ityoy group B and isolation of the desired product as a free compound, sol, or an ester.