SU440842A1 - - Google Patents

Description

(54) METHOD FOR OBTAINING DERIVATIVES 7- (o-AMINOMETHYLPHENYLACETAMIDO) -CEF-3-EM-4-CARBON

ACIDS

where R2 and Y are as defined,.

or with its soluble salt.

However, the method of obtaining 7-aminocephalosporanic acid derivatives, which are similar in structure to the known compounds, is not NH2O

// (..- C-NH, f

where or 1,

R is

N-CH,

N

ll ll or j I

,

or salts of these compounds. The COPE is that the compound of the formula

-CHN-S-R. (Ii) COOH

where R has the specified value

either the salt or the easily hydrolyzed ester of this compound is acylated with an acid of the general formula

CHjNHB

(Iii) (, S) -CHj-COOH,

where B is a protecting group, or a functional reactive derivative thereof, such as the corresponding hydrohalic acid, acid azide, anhydride ki-a} ota, mixed acid anhydride, in particular mixed anhydrides derived from stronger acids, such as lower aliphatic monoesters carboxylic acid, or alkyl- and aryl-sulfonic acid or more substituted acids, such as diphenylacetic acid, an active ester or thioether (for example, “-nitrophenol, 2,4-dinitrophenol, thiophenol, or thioux hydrochloric acid). Another acid III derivative is the corresponding azolide, for example the corresponding acid amide, in which the amide nitrogen is known, although these compounds have improved pharmaceutical properties.

A method for the preparation of compounds of the formula

J-CH2-S-fi

(I)

 looR

a quasi-aromatic five-membered ring containing at least two nitrogen atoms, such as imndazole, pyrazole, triazoles, benzimidazole, benzotriazole, or their substituted derivatives.

To maximize the yield of the product, it is necessary that the free amino group of the acylating acid III (or its functional aquivalent) be protected in the usual way with a protecting group of the type used either in the synthesis of peptides or in any of the syntheses of a-aminobenzylpenicillin from 2-phenylglycine. Examples of such protective or

the amine protecting groups are carbobenzoxy, p-nitrocarbobenzoxy, tert-butoxycarbonyl, 2-hydroxy-1-naphthocarbonyl, RoxoalkYLidene, furfuryloxycarbonyl, adamantyl-oxycarbonyl, and 2,2,2-trichloroethoxycarbonyl. The most preferred acylating agent is a hydrohalic acid salt, for example, a hydrochloric acid salt having the formula

IzNHz-HCl Q

V (S) ri-CH2-C-Cl

After the acylation reaction is completed, the protective amino group is removed in the usual way, resulting in the desired product of formula 1. Thus, the g-nitrocarbobenzoxy group is removed

catalytic hydrogenation, the tert-butoxycarbonyl group can be removed by treatment with formic acid, the 2-o, xi-1-naphthocarbonyl group by acid hydrolysis, the 2,2,2-trichloroethoxycarbonyl group -

treatment with zinc dust in glacial acetic acid.

The acylation reaction is usually carried out in an inert solvent. As such solvents, for example,

tetrahydrofuran, dimethylformamide, diethyl ether, methylene chloride, dichloroethane, chloroform, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, dimethylacetamide, nitromethane and acetonigril.

The most preferred temperature for the acylation reaction is from -20 to -7 ° C. However, as in

Most chemical reactions may use a temperature above or below the specified preferred limit. At higher temperatures, there is a tendency to decrease product yield as a result of decomposition and / or an increase in the number of side reactions, while at temperatures significantly below -20 ° C, a reduced reaction rate results in a decrease in product yield or a significant increase in the duration of the reaction. As a rule, acylation reactions proceed normally in the range of temperatures from about 0 to 30 ° C and the room temperature is the most accepted.

The ratio of reactants is not a critical factor and some reactions proceed regardless of the molar ratios of the reactants used. To achieve the maximum yield of the reaction product, at least an equimolar amount of the acylating agent is usually used, and it is sometimes desirable to use an excess amount of the acylirucidal agent. The resulting α-compounds are isolated in their free state or as salts.

Non-toxic, pharmaceutically acceptable salts of the compounds of Formula 1 include both carboxylic acid salts and salts formed by the addition of an acid to an amine. Typical non-toxic carboxylic acid salts are metal salts such as sodium, potassium, calcium, and aluminum, ammonium salts, and substituted ammonium salts, for example, salts of non-toxic amines such as trialkylamines, including triethylamine, procaine. Dibenzylamine, Nbenzyl- | p-phenethylamine, 1-ephenamine, M, .H-dibenzylethylenediamine, dehydroabiethylamine, N, N - bis - dehydroabiethylethylenediamine, N (lower) alkylpiperidine, such as N-ethylpiperidine, and other amines, are used to make up a mixture. together with benzylpenicillin. Typical non-toxic amine salts are acidic mineral (inorganic) salts, such as hydrochloride, hydrobromide, iodohydrate, sulfate, sulfamate and phosphate, as well as acidic organic salts, such as maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate (salt of malic acid), mandelate (salt of almond acid), ascorbate, etc.

Example 1. 7- (o-aminomethylphenylthioacetamido) -3- (1-methyl-5-tetrazolylthio) -methyl-ceph-3-em-4-carboxylic acid.

N,: N - Dicyclohexylcarbodiimide (2.06 g, 0.010 mol) was added to a solution (o-tertbutoxycarbonylaminomethylphenylthio) acetic acid (3.0 g, 0.010 mol) and 2,4-dinitrophenol (1.84 g, 0.010 mol) and 25 ml of ethyl acetate, cooled with ice. The reaction mixture was kept at 0 ° C for 30 minutes, then at 25 ° C for another 30 minutes. The precipitated N. / N-dicyclohexyl urea is removed

by filtration. The solvent is removed from the filtrate, whereby the crude ester is obtained as a yellow oily product. A solution of 7-amino-3- (1-methyl-5-tetrazolylthio) -methyl-cef-3-em-4-carboxylic acid (3.3 g, 0.010 mol) and tpiethylamine (2.0 g, 0.020 mol) in 25 ml of chloride methylene is added in one portion to the resulting ester, cooled to 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. A small amount of insoluble material is dropped by filtration and then the Ailtrath is diluted with ether. The oily residue is dissolved twice in methylene chloride (25 ml) and cooled with ether (200 ml), causing the precipitate to crystallize. Triethylammonium cephalosporanate is dissolved in 30 ml of methanol and this methanol solution is treated with 5 ml of a 2.3 M solution of potassium 2-ethylhexanoate in n-butyl alcohol, after which ether (200 ml) is added. 5.4 g of potassium cephalosporanate are recovered by filtration. A solution of this product in 100 ml of water is peeled off by adding 100 ml of ethyl acetate, cooled with ice while stirring, the pH adjusted to 2.5 by adding dilute hydrochloric acid. Cefalosporanic acid free (4.7 g) is obtained as a foam after drying the ethyl acetate solution and after removing the solvent. It is treated with 30 ml of trifluoroacetic acid at 0 ° C, kept at 0 ° for one hour and diluted with ether. The solid precipitate (3.6 g) is recovered, washed with ether and dissolved in a mixture of 30 ml of water and 30 ml of acetone. The pH of the solution was adjusted to 5.0 by the addition of 3N. ammonium hydroxide solution and evaporated under reduced pressure. The solid is recovered by filtration and washed with ice water, acetone and ether. It is finally dried in vacuum over PaOj, resulting in 1.8 g (38% of theoretical) of 7- (o-aminomethylphenylthioacetamido) -3- (1-methyl-5 - tetrazolylthio) - methyl cef-3-em-4. -carboxylic acid as a pale yellow solid.

   (r-lactamcarbonyl) and 1660 cm (amidcarbonyl). The NMR spectrum is also in accordance with the indicated structure.

Based on spectral analysis and thin layer chromatography, it was determined that the purity of the product is 80%.

Example 2. 7- (o-Aminomethylphenylthioacetamido) -3-G (5-methyl-1,3,4-thiadiazolylthio) -methyl-cef-3-em-4-carboxylic acid.

Cephalosporin was obtained in 21% yield according to the method described in Example 1, but using 7-amino-3- (5-methyl-1,3,4-thiadiazolylthio) -methyl-Cef-3-e-4-carboxylic acid; 7m x 3300 (NH) 1760 (B-lactamcarbonyl) and 1650 (amidcarbonyl) in the Nujol. The NMR spectrum in trifluoroacetic acid consisted of a seven-proton multiplet at t: 2.0–3.0 (phenyl and iNHs protons), a one-proton multiplet at t4.15–4.5 () and a one-proton doublet (, 5 HZ) at t 4, 85 (), four-proton multiplet with t of 5.15-5.6 (overlapping signals of amylmethylene and 3-CH2S-pootons), two-proton singlets with t of 6.00 (S-

SNGSO-) and 6.24 three-proton

SINGLET with t 6.88 (SNS). Based on the spectral analysis and thin layer chromatography data, it was established that the degree of the product is 90%.

Example 3. 7- (o-aminomethylphenylthio1cetamido) -3-S- (1,2,3-triazol-5-yl) -thiome yl-cef-3-em-4-carbo, nova acid.

Cephalosporin was prepared by the method described in Example 1, but using a uniform weight amount of 7-amino-3- 51, 2,3-triazol-5-yl) -thiomethyl-cef-3-it-4 carboxylic acid. The melting point of the product is 255-257 ° C (melting with decomposition); 7 max 1775 (p-lactamcarbonyl), 1670 (amidocarbonyl), 1590 and 1395 (carboxylate) in the nucleus.

Example 4. Suspension (in the form of amphoteric ions) 7 - (o - aminomethylphenylthioacegamido) -3- (1 - methyl-5 - tetrazolylthio) - methyl-ceph - 3 - it-4 - carboxylic acid (0.361 g) in 3 ml of methanol cooled with ice and treated with several drops of concentrated hydrochloric acid to obtain a clear solution. When added to the solution of the ester, 7- (oaminomethylphenylthio-aietamido) -3 - (1-methyl-5-tetrazolylthio) -methyl-cef-3-em-4-carboxylic acid hydrochloride is precipitated as a pale brown product. The product is removed by filtration and dried under vacuum over P2O5.

In the same way, chlorohydrates of 7- (o-am, nomethylphenylthioacetamido - 3- (5methyl-1, 3,4-thiadiazolylthio) -methyl-cef-3-4-carboxylic acid and 7- (o-aminomethylphenylthioacetamido) - (l, 2,3-trnazol-5-yl) -thiolsgil-cef-3-em - 4 - carboxylic acid.

Example 5. To a stirred suspension (in the form of an amphoteric ion) 7- (o-aminomethylphenylthioacetamido) -3- (1methyl-5-tetrazolylthio) methyl-cef-3-em - 4-carboxylic acid (0.361 g) is added 1N . an aqueous solution of sodium hydroxide at room temperature until a clear solution is obtained (pH 10.8). This solution is immediately dried at a temperature below 0 °, as a result of which pure sodium-7- (o-aminomethylphenylthioacetamido) -3- (1-methyl-5-tetrazolylthio) methyl-ceph-3-em-4- carboxylate.

Sodium salts of 7- (o-aminomethylphenylthioacetamido) -3- (5-methyl-1,3,4-thiadiazolyltno) methyl-cef: 3-em-4-carboxylic acid and 7- (o-amine-etnphenylthioacetamido) ( 1,2,3 - triazol-5-yl) thiomethyl-cef-3-4-ka | rboxylic acid was prepared in the same way.

Example 6. 7- (o-Ami "ohm; tylphenylacetamido) -3- (1 -methyl-1,2,3,4-tetrazole-5thio) -methyl-cef-3-em-4-carboxylic acid.

N, N-dicyclohexylcarbodiimide (1.44 g, 0.0070 mol) is added in one portion to an ice-cooled solution (o-tert-butoxycarbonylaminomethylphenyl) acetic acid (1.86 g 0.0070 mol) and 2.4 -dinitrophenol (1.29 g, 0.0070 mol) ethyl acetate. The mixture was kept at 0 ° C for 30 minutes, then at 25 ° C for 30 minutes. The precipitate is removed by filtration and the solvent is removed from the filtrate. At 0 ° C, a solution of 7-amino-3-G (1-methyl-1, 2,3,4-tetrazole-5-thio) methyl-ceph-3-em4-kaabonic acid f2.30 is added to the crude ester. g, 0,0070 mol) and

triethylamine (1.41 g, 0.014 mol) in 15 ml of chlorine methylene. The reaction mixture is stirred at room temperature for 2 hours. A small amount of the insoluble matter is removed by filtration.

the filtrate is diluted with ether. The resulting oily residue is twice dissolved in a small amount of methylene chloride and precipitated with ether. It is then dissolved in a small amount of methanol, and the solution

treated with 3.5 ml of a 2.3 M solution of potassium 2-ethylhexanate in n-butyl alcohol. The ester formed, the precipitate of the potassium salt of the protected cephalosporin (2.2 g) is removed by filtration. The aqueous potassium salt solution is peeled off with ethyl acetate and acidified to pH 2.5. The ethyl acetate layer is dried and evaporated, resulting in a cephalosporic acid as a foam (1.3 g). It is treated at 0 ° C for 10 hours with 10 ml of trfluoroacetic acid, after which ether is added to it. The precipitate is recovered, washed with ether and dissolved in a mixture of water (20 ml) and acetone (20 ml). The pH is adjusted to 5.0 by the addition of dilute ammonium hydroxide. The solution is evaporated under reduced pressure to a small volume and cooled. The product precipitates, it is removed by filtration and washed with ice water, methanol and ether, respectively, obtaining a yield of 0.45 g (14% of the theoretical). The IR spectrum and NMR spectrum were in full compliance with the indicated molecular structure of this product; product purity 85%.

Example 7. 7 - (o-aminomethylphenylacetamido) -3-G (5-methyl-1,3,4-thia-diaolylthio) methyl-cef-3-e-4-carboxylic acid. Cephalosporin was prepared as described in Example 6, but using 7-amino-3

(5 - methyl-1.3,4 - t aliazolylthio) - methyl cef-3-em-4 - carboxylic acid. The purity of the obtained product is 90%. Infrared spectrum: max (Nyjolmul) 3300 (NH) 1765 (p-lactamcarbokyl) and 1660 (amidocarbonyl).