RU2021274C1 - Process for preparing aminothiazolyl cephalosporin derivatives - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: the product: aminothiazole cephalosporin derivatives of the formula 1. Reagent 1: L- (2-aminothiazoline-4)-2-alkoxyiminoacetic acid. Reagent 2: a reagent resulting from dimethylformamide and thionyl chloride. Reaction conditions 273-233 K; cliphatic nitride. The compound 1 has the following structural formula (image). EFFECT: improved properties of the compounds. 2 cl

Description

в которой Х обозначает атом водорода, ацетоксильную группу, незамещенную N-пиридильную группу, 2-метило-5,6-диоксо-1,2,5,6-тетрагидро-1,2,4-триазинтиольную- -3 группу, R₁ обозначает метильную группу или алканокарбоксильную группу низших кислот с 1-4 атомами углерода, возможно в форме сложного эфира, желательно трет-бутилового, R₂ обозначает атом водорода, натрия или калия, аммониевую, силильную, алкильную или низшую алкиларильную группу.The invention relates to methods for producing aminothiazolyl derivatives of cephalosporin of General formula 1
H ₂ N

in which X represents a hydrogen atom, an acetoxyl group, an unsubstituted N-pyridyl group, a 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazintiol-3 group, R ₁ denotes a methyl group or alkanocarboxyl group of lower acids with 1-4 carbon atoms, possibly in the form of an ester, preferably tert-butyl, R ₂ denotes a hydrogen, sodium or potassium atom, ammonium, silyl, alkyl or lower alkylaryl group.

 Amintiazolyl derivatives of cephalosporin have a strong bactericidal effect and are used in medicine as modern antibiotics with a wide spectrum of action.

 A known method of producing derivatives of formula 1 by treating a carboxylic acid with phosgene, phosphorus pentachloride, phosphorus oxychloride or oxalyl chloride in the presence of an amide and subsequent condensation [1].

 The disadvantage of this method is the complexity of the process through the use of expensive reagents.

 The aim of the invention is to simplify the process.

 The goal is achieved by the proposed method for producing aminothiazolyl derivatives of cephalosporin of formula 1, which consists in the fact that the activation of Z-2- (2-aminothiazolyl-4) -2-alkoxyiminoacetic acid and the condensation of the active form with sodium, potassium, ammonium salts or silyl, alkyl or alkylaryl ethers with 1-20 carbon atoms of the derivative of 7-aminocephalosporin acid.

 A distinctive feature of the method is that activation is carried out in aliphatic nitrile by treatment with a reagent obtained from dimethylformamide and thionyl chloride at a temperature of 273-233K, after which the active form thus prepared is subjected to condensation.

 It is advisable to use acetonitrile as an aliphatic nitrile and activate at 253-248K.

 An advantageous variant of the method according to the invention for conducting the condensation process consists in adding an acetonitrile solution of activated Z-2 (2-aminthiazolilo-4-) 2-alkoxyiminacetic acid to an aqueous solution of a cephalosporic acid derivative, and the reaction of the solution does not go beyond 5 to 10 pH units at aid dosage of an aqueous solution of sodium hydroxide or potassium. In the process according to the invention, the degree of reaction is almost maximum, and the purity of the product is so high that it can be isolated from the mixture after condensation in the form of sodium or potassium salts used in medicine.

 PRI me R 1. Obtaining 7 [Z-2- (2-aminothiazolilo-4) -2-methoxyiminacetylamino] - cephalosporic acid.

The slurry Z-2- (2-amintiazolilo-4) - 2-metoksiiminuksusnoy acid (10.1 g, 0.05 mol) in dry acetonitrile (100 ml) cooled to -25 ^{° C} with stirring was added dropwise reagent prepared in benzene (50 ml) from thionyl chloride (11 ml, 0.15 mol) and dimethylformamide (15 ml). The resulting mixture was added portionwise to a solution of 7-amintsefalosporinovoy acid (13.6 g, 0.05 mol) in acetonitrile (100 ml) containing triethylamine (35 ml), while maintaining the temperature ^of -20 C. The resulting is stirred at -20 ^o C for 1 h, and then the solvent was filtered off and the solvent was evaporated. The residue was dissolved in water (50 ml) and 6 N was added while cooling. hydrochloric acid to a pH of 2.5. The title compound was salted out from the mixture with the addition of solid ammonium sulfate (40 g). A sample of the product was compared with ethanol. The identity of both samples was established using the following chromatography conditions: RP-18 250 x 4 mm, CH ₃ OH H ₂ O 1: 2, CH ₃ CO ₂ Na 0.4%, Bu ₄ NBr 0.4%.

 EXAMPLE 2. Preparation of the sodium salt of 7 [Z-2- (2-aminthiazolilo-4) -2-methoxyimine-cetylamino] cephalosporic acid.

In a mixture of acetonitrile (100 ml) and dimethylformamide (20 mL) cooled to ^-20 ° C, thionyl chloride (14 ml, 0.2 mol) and then portionwise Z-2- (2-amintiazolil-4) -2- methoxyiminacetic acid (20.1 g, 0.1 mol). The resulting solution was added dropwise with cooling in an ice bath in a mixture of water (300 ml) and acetonitrile (30 ml) containing 7-aminencephalosporic acid (27.2 g, 0.1 mol) neutralized with sodium hydrogen carbonate (42 g, 0.5 mol). The mixture obtained after the reaction was concentrated in vacuo to a volume of 150 ml and diluted with methanol (200 ml) and isopropanol (200 ml). The resulting suspension was filtered, and the filtrate was concentrated to a volume of 100 ml. The oily residue was dropwise added to isopropanol (500 ml). The precipitate was filtered off and dissolved in methanol (40 ml) with the addition of water (10 ml). The solution was filtered and added dropwise to a mixture of ethyl acetate (300 ml) and ethanol (100 ml). The precipitate formed was filtered and dried in vacuo, whereby the title compound was obtained, which was identified by the method described in Example 1.

 PRI me R 3. Obtaining the sodium salt of 7 [Z-2- (2-aminthiazolyl-4) -2-methoxyiminacetylamino] cephalosporic acid.

To a suspension of Z-2- (2-amintiazolilo-4) -2-metoksiiminuksusnoy acid (20.1 g, 0.1 mol) in dry acetonitrile (100 ml) cooled to -25 ^{° C,} with stirring was added dropwise reagent prepared in benzene (100 ml) from thionyl chloride (22 ml, 0.3 mol) and dimethylformamide (30 ml). The resulting solution was added in portions, cooling in an ice bath, and added to a mixture containing 7-aminencephalosporic acid, water (130 ml) and acetonitrile (20 ml), while maintaining a pH of 7.0-8.8 by dropwise administration of 5 n an aqueous solution of sodium hydroxide. The title compound was isolated from the mixture obtained after the reaction, as in Example 2.

 PRI me R 4. Obtaining 7 [Z-2- (2-aminothiazolyl-4) -2-methoxyiminacetylamino] - cephalosporic acid.

To a suspension of Z-2- (2-amintiazolilo-4) -2-metoksiiminuksusnoy acid (2g, 0.01 mol) in methylene chloride (15 mL) cooled to ^-20 ° C, was added a reagent prepared in benzene (15 ml ) from thionyl chloride (2.2 ml, 0.03 mol), and dimethylformamide (4 ml). The resulting solution was added dropwise to 7-aminencephalosporic acid (2.7 g, 0.01 mol) dissolved in a mixture of methylene chloride (25 ml) and triethylamine (7 ml). The resulting was stirred at 0 ^C for 1 h. The mixture obtained after the reaction, washed with a saturated aqueous solution of sodium hydrogen carbonate (3 x 50 mL). Aqueous solutions were combined, saturated with solid ammonium sulfate (100 g) and acidified with 6 N. hydrochloric acid to a pH of 2.5. The precipitate was filtered off, which was the title compound, the identity of which with the standard was established by a known method (see example 1).

 Example 5. Obtaining the sodium salt of 7- [Z-2- (2-aminthiazolyl-4) -2-methoxyimine-acetylamino] -3- (2-methyl-5,6-dioxo-1,2, 5,6-tetrahydro-1,2,4-triazintio-3) diacetoxy-cephalosporic acid.

In a mixture of acetonitrile (100 ml) and dimethylformamide (20 mL) cooled to ^-20 ° C, thionyl chloride (14 ml, 0.2 mol), then portionwise Z-2- (2-amintiazolilo-4) -2 -methoxyiminacetic acid (20.1 g, 0.1 mol). The resulting solution was added dropwise with cooling in an ice bath, to a mixture containing 7-amino-3- (2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazintio -3) diacetoxycephalosporic acid (37.2 g, 0.1 mol), water (130 ml) and acetonitrile (20 ml) while maintaining a pH of 6.5-7 by adding 5 N. an aqueous solution of sodium hydroxide. The mixture obtained after the reaction was concentrated to a volume of 200 ml, and then diluted with methanol (150 ml) and acetone (150 ml). The resulting was filtered and poured into methanol (500 ml). The precipitate was filtered and dried in vacuo, whereby the title compound was obtained.

¹ HNMR, 500 MHz (D ₂ O) ε: 3.48 (s, 3H), 3.33 and 3.59 ((q, 2H), 3.84 (s, 3H), 3.92 and 4, 22 (q, 2H), 5.06 (d, 1H), 5.64 (d, 1H), 6.86 (s, 1H).

 Example 6. Preparation of 7- [Z-2 (2-aminthiazolilo-4) -2- (α-t-butoxycarbo-α-methylethoxyiminacetylamino)] cephalosporic acid.

In a mixture of acetonitrile (100 ml) and dimethylformamide (20 mL) cooled to ^-30 ° C, was added thionyl chloride (14 mL) and then portionwise Z-2- (2-amintiazolilo-4) - -2 - (- α -t-butoxycarbo-α-methyl-ethoxyimino) -acetic acid (35.7 g). The resulting mixture was dropwise added to a solution of 7-aminencephalosporin acid (27.2 g) in water (130 ml) cooled with an ice bath and acetonitrile (20 ml), the pH of which was constantly maintained between 6.5-7.5 by adding a hydroxide solution sodium.

 After the completion of drip administration, the solution was acidified to pH 2.8 with hydrochloric acid and extracted repeatedly with ethyl acetate. The extracts were dried and concentrated, whereby the title compound was obtained.

¹ H NMR, 200 MHz, δ, 8.39 (d, 1H), 7.45 (s, 1H, H-tizol), 5.97 (dd, 1H, 7-H), 5.12 (d, 1H, 8-H), 5.09 (dd, 2H, 3-CH ₂ ), 3.52 (dd, 2H, 2-CH ₂ ), 2.10 (3H, COCH ₃ ), 1.61 and 1 60 (s and s, 6H, C (CH ₃ ) ₂ ), 1.42 (s, 9H, C (CH ₃ ) ₃ ).

 Example 7 Preparation of 7- [Z, 2- (2-aminothiazolyl-4) -2-methoxyiminacetylamino) 3- (pyridolo-1)] diacetoxycephalosporic acid.

In accordance with Example 7 and starting from Z, 2- (2-aminothiazolilo-4) -2-methoxyiminoacetic (20.1 g) and 7-amino-3-pyridyl-1) diacetoxycephalosporic (29.2 g) acids, get the title compound, the spectrum of which ¹ HNMR has the following signals: δ (DVSO-d ₆ , 500 MHz) 8.1-9.4 (m, 5H, pyridyl), 7.30 (s, 2H, NH ₂ ), 6 70 (s, 1H, H-thiazole), 5.64 (dd, 1H, 7-H), 5.69 and 5.11 (dd, 2H, 3 CH ₃ ), 5.07 (d, 1H, 6-H), 3.83 (s, 3H, OCH ₃ ), 3.53 and 3.04 (dd, 2H, 2-CH ₂ ).

 Example 8. Z, 7- [2- (2-aminthiazolilo-4) -2-methoxyiminacetylamino] cephalosporic acid methyl ester.

Proceeding in accordance with example 4 and starting from Z, 2- (2-aminothiazolilo-4) -2-methoxyimine acetic acid (20.1 g) and 7-aminocephalosporic acid methyl ester (28.6 g) acids, the title compound is obtained, a spectrum which ¹ H NMR has the following signals: 9.6 (d, 1H, CONH), 7.2 (s, 2H, NH ₂ ), 6.7 (s, 1H, H-thiazole), 5.8 (dd, 1H, H-H), 5.1 (d, 1H, 6H), 3.8 (s, 3H, N-CH ₃ ), 3.3 (s, 3H, COOCH ₃ ), 4.0 (dd, 2H, 3'-CH ₂ ), 3.4 (dd, 2H, 2-CH ₂ ), 2.0 (s, 3H, COCH ₃ ).

 PRI me R 9. Obtaining the sodium salt of 7- [Z-2- (2-aminthiazolyl-4) -2-methoxyimine-acetylamine] diacetoxycephalosporic acid.

To a slurry of Z-2- (2-amintiazolil-4) -2-methoxyimino acetic acid (20.1 g, 0.1 mol) in dry acetonitrile (100 ml) cooled to ^-25 ° C, with constant stirring, was added dropwise reagent prepared in gasoline (100 ml) of isothionyl chloride (22 ml, 0.3 mol) and dimethylformamide (30 ml). The resulting mixture was added in portions, cooling in an ice bath, to a solution of sodium salt of 7-aminodiacetoxycephalo-sporic acid (23.6 g, 0.1 mol) in water (130 ml) and acetonitrile (20 ml), maintaining the pH at the range of 7.5-8.5, by adding dropwise 5 N. caustic soda solution. The resulting mixture at the end of the reaction was brought in vacuo to a volume of 150 ml and dissolved in methanol (200 ml) with acetone (200 ml). The resulting mixture was filtered. The filtrate was concentrated in vacuo, and the precipitate was treated with anhydrous ethanol (300 ml). The resulting precipitate was washed with methanol and dried in vacuo to give the above compound.

¹ H NMR, 60 MHz (D ₂ O) δ: 1.75 (s, 3H), 3.4 (q, 2H), 3.8 (s, 3H) d, 4.9 (d, 1H), 5.5 (dd, 1H); 6.7 (s, 1H).

 Thus, the proposed method allows to simplify the process by using affordable and cheap reagents.

Claims (2)

1. METHOD FOR PRODUCING AMINOTIAZOLYL DERIVATIVES OF CEPHALOSPORIN of the General Formula
H ₂ N

where X is hydrogen, acetoxy, unsubstituted N-pyridyl group, 2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazintiol-3-group,
R ₁ is a methyl or alkanocarboxyl group of lower acids with 1 to 4 carbon atoms, possibly in the form of an ester, preferably tert-butyl;
R ₂ is hydrogen, sodium or potassium, ammonium, silyl, alkyl or lower alkylaryl group,
by activation of Z-2- (2-amino-thiazolyl-4) -2-alkoxyiminoacetic acid and condensation of the obtained active form of the acid with sodium, potassium, ammonium salts or silyl, alkyl or alkylaryl ethers with 1 to 20 carbon atoms of the 7-aminocephalosporin derivative acid, characterized in that, in order to simplify the process, the activation of Z-2- (2-aminothiazolyl-4) -2-alkoxyiminoacetic acid is carried out in aliphatic nitrile by treatment with a reagent obtained from dimethylformamide and thionyl chloride, at 273 - 233 K, after why cooked so Thus, the active form is subjected to condensation.  2. The method according to p. 1, characterized in that acetonitrile is used as aliphatic nitrile and activation is carried out at 253 - 248 K.