CS242018B1 - Method of beta-lactam antibiotics' production - Google Patents

Abstract

The invention relates to a new preferred method production of beta-lactam antibiotics of formula (I) by acylating the core nuclei compounds of formula III, for example 6-aminopeniclanic acid, 7-aminodesacetoxycephalosporanic acid or 7-aminocephalosporan syn-form of the hydrochloride 2-alkoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride of formula IV. Compared to prior art methods, it is solved at least two degrees shorter since there is no introduction and removal amino-protecting groups in the 2-position starting thiazote derivative of Formula IV.

Description

The present invention relates to a novel preferred process for the preparation of the beta-lactam antibiotics of the formula I by acylating the starting core compounds of the formula III, e.g. amino-1,3-thiazol-4-yl) acetyl chloride of formula IV. Compared to the prior art, the process is at least two degrees shorter, since the introduction and removal of the amino protecting group at the 2-position of the starting thiazole derivative of the general formula IV is eliminated.

The invention relates to a process for the preparation of beta-lactan antibiotics of the formula I c-co-nh-a it

N-OY (,) wherein Y represents alkyl of 1 to 0 carbon atoms, cyclic alkyl of 3 to 6 carbon atoms, A

benzyl, formyl, tert-butyloxycarbonyl or chloroethyl groups were used for this purpose. The antibiotics thus obtained contain a protecting group which must be removed again at the end of the synthesis. This extends the schemes of all syntheses of aminothiazole antibiotics by at least two unpleasant and loss reaction steps. An example of such a complicated procedure is the preparation of 6- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) penicillanic acid (DOS 2,826,482).

The above-mentioned disadvantages and disadvantages are eliminated by the process for the preparation of the beta-lactam antibiotics of the formula I according to the invention, which consists in the fact that the compound of the formula IV

HCi · H ^ N

C-COCP

N-OY (IV) wherein Y denotes the same as in formula I reacts with a compound of formula III wherein X is hydrogen or acetoxy, or tautomeric forms thereof.

These so-called aminothiazole beta-lactam piolosynthetic antibiotics are a very interesting group in which several compounds with a broad spectrum of activity, all of which have been classified into higher generations, have been found and put into practice. In addition, the aminothiazole residue has been successfully introduced into the side chain of the monolactam antibiotics of the azthreonam type.

To date, beta-lactam antibiotics of formula I have been prepared by amino acid of formula

N-C-COOH li

N-OY (II) in which Y denotes the same as the protecting group in formulas I and Z, converts it into a reactive carboxyl derivative, which is then acylated with a compound of formula III

H2NA (III), in which A denotes the same as in formula I. As follows from the above scheme, it is first necessary to protect the amino group at position 2 of the amino acid of formula II. TO

H2NA (III), in which A denotes the same as in formula I.

Compound (IV) is a novel, highly preferred starting material for the synthesis of beta-lactam antibiotics; it is the syn-form of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride hydrochloride (US Patent No. 238,950), which can be directly acylated, for example, with 6-aminopenicillanic acid (6-APK) 7-Aminodesacetoxycephalosporane (7-ADCKi, 7-aminocephalosporane and derivatives thereof) directly to produce the desired antibiotics without the need to introduce and remove protecting groups.

A preferred method of acylation according to the invention is to first convert the compound of formula III in an inert solvent such as methylene chloride to the corresponding silyl derivative, which in the presence of a hydrogen chloride binding agent, which may be urea, acetamide and the like (formed in the reaction mixture during silylation of the compounds of formula H2NA).

The resulting antibiotic is isolated in a conventional manner after completion of the reaction. In some cases, isolation is further facilitated by the crystallization of very pure antibiotic disilyl derivative hydrochloride from the reaction medium, which is readily isolated and decomposed to the desired antibiotic.

The following examples illustrate the process according to the invention but do not limit it in any way.

Example 1

6- (2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] penicillanic acid and its sodium salt.

To a suspension of 10.0 g of O-aminopenicillanic acid in 100 ml of methylene chloride was added 8.0 g of hexamethyldisilazane and 4 drops of conc. sulfuric acid. The reaction mixture was heated at reflux for 6 hours with a chloro-calcium cap. Filter the resulting cloudy solution through diatomaceous earth. 6.0 g of dimethylaniline was added to the filtrate and cooled to -30 ° C. 12.5 g of 2-methoixyimino-2- (2-amino-1,3-thiazol-4-yl) acetyl chloride hydrochloride syn-form were added and the reaction mixture was stirred without cooling for 20 minutes. Stir for 30 minutes, cool with ice water, dilute with 50 mL of anhydrous benzene, filter the precipitated crystals with suction and wash with anhydrous ether. The crystals are filtered off with suction, washed with 2 X 100 ml of water, 15 ml of ethanol and 100 ml of ether and dried under vacuum at 40 DEG C. 16.6 g of the title acid of m.p. 193 DEG C. (decomposition) are obtained. 212 [deg.] C. (decomposition) The NMR spectrum was consistent with the literature data (DOS 28 26 482).

Preparation of sodium salt:

3.0 g of the previous non-crystallized acid was dissolved in 15 ml of isopropyl alcohol and 1.3 g of a 41.4% solution of sodium alpha-ethyl caproate in butanol, which was diluted with 15 ml of isopropyl alcohol, was added. The desired sodium salt precipitates and is filtered off with suction after 1 hour, washed with 50 ml of isopropanol and 30 ml of ether. After drying, 2.7 g of crystalline sodium salt is obtained. This salt can be further purified by boiling in a small amount of isopropyl alcohol.

Example 2

3-Methyl-7- [2- (2-amino-1,3-thiazol-4-yl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid and its sodium salt.

To a suspension of 10.0 g of 7-aminodesacetoxycephalosporanic acid in 180 ml of anhydrous methylene chloride was added 8.5 g of hexamethyldisilazane, 4 drops of conc. sulfuric acid and the reaction mixture was refluxed with a chloro-calcium cap for 8 hours. The resulting cloudy solution was filtered through diatomaceous earth, and 5.9 g of dimethylaniline was added to the filtrate and cooled to -30 degrees Celsius. 12.5 g of the previous chloride hydrochloride were added with stirring, and the reaction mixture was stirred for 15 minutes without cooling. Crystalline disilyl derivative hydrochloride is separated. After 30 min stirring the precipitated crystals were sucked off, washed with 50 ml of methylene chloride and ether, dried in vacuo at 40 C. Yield ⁿ 18.5 g. A suspension of 6.0 g of this product in 100 ml of a dy was adjusted to pH 3 The precipitated product is filtered off with suction, washed with 100 ml of water and dried under vacuum at about 40 DEG C. for 24 hours. 3.7 g of the title acid are obtained. The IC and NMR spectra are consistent with those in the literature. Preparation of sodium salt

3.1 g of the previous acid are stirred in 30 ml of acetone, dissolved while stirring by the addition of 5 ml of dimethylformamide, the solution is decolorized with charcoal, dried over magnesium sulphate, filtered off with suction through kieselguhr and washed with a little acetone. 3.2 g of a 41.4% solution of sodium alpha-ethyl caproate in butanol diluted with 20 ml of acetone are added to the filtrate with stirring. After stirring for 10 minutes, the precipitate is filtered off with suction, washed with 2 X 10 ml of acetone and dried in vacuo. Yield 3.0 g of sodium salt with a content of 97%. The IR and NMR spectra were consistent with those in the literature.

This antibiotic has been prepared before, but with the need to introduce and remove protecting groups.

Example 3

3-Acetylmethyl-7- (2-amino-1,3-thiazol-4-yl) -2-methoxyiminoacetamide-O] -ceph-3-em-4-carboxylic acid

To a suspension of 2.56 g of 7-aminocephalosporanic acid in 20 ml of anhydrous tetrahydrofuran was added 5.4 ml of N, O-bis-trimethylsilylacetamide, and after stirring for 5 minutes a clear solution was formed which was cooled to -20 ° C. Then 2.8 g of the previous chloride hydrochloride are added, cooling is discontinued, after 15 minutes the solution is cooled again to -10 ° C and 2 ml of methanol are added. 30 ml of water are added to the precipitated solid, the pH is adjusted to 6.5 with sodium bicarbonate solution and the solution is lyophilized. The crude sodium salt is obtained almost on a quantitative scale. A portion was dissolved in a small amount of water, adjusted to pH 3. The precipitated solid acid, when compared to an authentic preparation, yielded corresponding values for both NMR and thin layer chromatography in three systems.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of beta-lactam antibiotics of the general formula I wherein X is a hydrogen atom or an acetoxy group, or tautomeric forms thereof, characterized in that the compound of the general formula IV C-CO-NH-A (,) in which Y represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, A C-COCI li N-OY (IV) in which Y denotes the same as in formula I, reacts with a compound of formula III HNNA (III) in which A denotes the same as in formula I. Severography, n. P., Plant 7, Most Price 2,40 Kčs