SU1516013A3 - Method of producing thermally stable crystalline sulfuric acid-additive salts of 7-/-alpha-(2-aminothiazol-4-yl)-alpha-(z)-methoxyiminoacetamido/-3-/(1-methyl-1-pyrrolidinio)-methyl/-3-cephem-4-carboxylate - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular to the preparation of a thermally stable crystalline addition salt with 7- [α- (2-aminothiazol-4-yl) -α- (Z) methoxyiminoacetamido] -3 - [(1-methyl -1-pyrrolidinio) -methyl] -3-cephem-4-carboxylate, having a diffraction X-ray lattice, removed for powder on a copper tube with a nickel filter (CU: NI) with specific values of interplanar spacing D and relative intensities 1 / 1 °, which can be used in medicine. The goal is to develop a method for obtaining a new crystalline form of a cephalosporin antibiotic. The production of the target product is carried out by the reaction of amphoteric 7- [α- (2-aminothiazol-4-yl) -α- (Z) -methoxyiminoacetamido] -3 - [(1-methyl-1-pyrrolidinio) methyl] -3-cephem- 4-carboxylate with a concentration of 100-200 mg / ml with H ₂ SO ₄ (1-2 mol. Eq.) In an aqueous medium. The crystallization of the desired product from the reaction mixture is then initiated and recovered. 1 tab.

Description

1.5 g of amphoteric ions are slowly added to 10 ml of energetically stirred 1 N, sulfuric acid solution (1.59 mol eq) at 20-26 ° C. A solution is obtained. Then, the crystallization is initiated by means of a seed using a crystalline sulfuric acid addition salt, and the crystalline mass is held in the form of a slurry for 0.5 h. Next, the crystals are separated by vacuum filtration, washed with 3 ml of acetone: water (1: 1 by volume) and two servings of 5 ml of acetone; then vacuum sugoku is performed at 40-50 ° overnight,

The yield is 1.3 g of the sulfuric acid addition salt.

Elemental analysis

Calculated,%: C 39-, 44; And 4.53; N 14.52; S -16.62; - not detected

.

Found,%: C 38.91; H 4.57; N 14.64; S 16.71; 1.42.

Example 2. Obtaining additive sulfuric acid,

1.5 g of amphoteric ions are dissolved in 5 ml of water; B, the resulting solution is added with stirring 5 ml of 1 M solution of HjiSO4. Then, the crystallization is initiated by priming the crystalline acid addition salt, then the crystals are incubated in hplame for 0.5 h. Then the crystals are separated by vacuum filtration, washed with 3 ml of a mixture of acetone: water (1: 1 by volume) and two portions 5 ml of acetone; then dried under vacuum at 40-50 ° C overnight.

The yield is 1.3 g of the sulfuric acid addition salt.

X-ray diffraction grating of crystalline sulfate salt (- (2-aminothiazol-4-yl) -o / - (E) -methoxyminoacetamido D-3 (1-methyl-1-pyrrolidino) -methyl -: Z-cepham-4- the carboxylate prepared according to examples 1 and 2 was determined using a diffractometer for powdered Rigaku materials using a copper tube, a nickel filter and a sample contained in a glass cup as x-ray targets. The scan rate was 2 / min in the field of change from

four

40, while mechanically recording

0

five

0

five

0

five

0

five

The diagram was drawn in order to fix the angles with the maximum diffraction. On the basis of these data, the intervals (d) and relative intensities (1/1 °) were determined. These data are given below, d-intercept | А 1/1 °,%

9,20100

6.8950

5.5028

5.0922

4.5038

4,4144

4.1964

3.7838

3.6444

3.3925

3.3131

3.1547

Example 3. The study of stability at elevated temperatures.

The thermal stability was determined by storing the compositions in dry containers at different temperatures, and the change in efficiency was determined using HPLC,

The results are presented in the table. (The increase in efficiency is indicated by a plus sign in front of a number; a loss of efficiency of less than 10% for 2-4 weeks at 45-56 C generally indicates a decrease in efficiency of less than 10% for 2-3 years with room temperature)

Example 4, Testing physical mixtures.

Physical mixtures were obtained from a crystalline sulfuric acid addition salt with trisodium orthophosphate, sodium bicarbonate, L (+) - lysine and L () - arginine. The bases were added in such proportions as to ensure that the pH of the mixture was diluted with water until amphoteric ions activity was 250 mg / kg (as determined by HPLC) in the following limits: trisodium orthophosphate (pH 6.0); sodium bicarbonate (pH 6.0); Lr - (- f) - lysine (pH 6.0); L - (+) - arginine (pH 6.0 /,

Injection compositions of wages using sterile water to bring amphoter5 activity 1516013, 6

ions up to 250 mg / ml, which op-d, A

Determined by HPLC, Difficulties. 9.20 100

with solubility was not 50

Injections were performed (at a dose of 100 mg / kg) 5.50 28

by intramuscular method to rabbits, 5.09 22

while the pain was 4.50 38

allowable limits. Minimum4,44 A4

pain sensations observed at 4,19 63

the use of a composition containing ar-S 3.78 38

ginin, 3.64 4A

Claims (1)

Claim 3 3,39 25 The method of obtaining thermally Sta-3,31 31 bil crystalline additive3,15, 47 salts with sulfuric acid. - (2-ami-15 characterized in that notiazol-4-yl) -o (- (2) -methoxyimino-in the aquatic environment of amphotsrgay 7-CC / - (2-acetamido-3- (1-methyl-1-pyrrolidi-aminothia-4-yl) (7) -methoxyimino -methyl-3-cephem-4-carboxylate, noacetamido / -3-C (1 -methyl-1-pyroreuting the following. X-lidinio-methyl-3-cephem-4-carboxygen diffraction grating, taken for powder 20 lats with a concentration of 100-200 mg / ml on a copper tube with a nickel filter (Cu: Ni) with the following values of interplanar distances d and relative intensities Comparative data on thermal stability of amorphous and crystalline additive salt with sulfuric acid Loss Form at storage (%) at a temperature, ° С 4556 100 week days 112G41b ll2 | 4 1 Amphoteric ions 3751 71 - 57 - - 100 H ZO-salt 2.43 +5 1.4 5 + 3 O 0-10 Up to + 5 + 6 + 6 Compiled by Z. Latypova Editor L. Veselovska Tehred A. Kravchuk Corrector L. Patay  - .. ",.". ".-.----" ...------- .------ ------------------ I Order 6299/59 Circulation 352Subscription BHHHTPi State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, 4/5 Raushsk nab. Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101 enter into interaction with sulfuric acid, taken in an amount of 1–2 mol eq, then initiate the crystallization of the target product from the reaction mixture and isolate it.