Method of extraction of the potassium salt of phenoxymethylpenicillin
(57) Abstract:The invention relates to a method of extraction of the potassium salt of phenoxymethylpenicillin, including the first butylacetate extraction and soda reextraction, where soda reextract besieged phenoxymethylpenicillin at pH 1.5 to 1.7, followed by separation of the crystalline phenoxymethylpenicillin, which is dissolved in an organic solvent, and the obtained concentrated solution precipitated potassium salt of phenoxymethylpenicillin using potassium acetate solution at the rate of 0.3 to 0.35 l to 1 billion UNITS of dentists contained in the concentrated solution. The technical result is an improvement of the method of receipt. 2 C.p. f-crystals. The invention relates to biotechnology and relates to a method of obtaining biologically active substances, namely to receive the dentists used as an intermediate product to obtain a semi-synthetic lactam antibiotics and chemotherapy of bacterial infections.Known methods for producing dentists, consisting in the extraction of the antibiotic from native solution of organic solvents,and potassium or potash, followed by separation of phenoxymethylpenicillin (patent of Russia 17264796, CL 07 D 499/16; patent Czechoslovakia 124845, patent Czechoslovakia 127853).The method of selection of K-salt of the prototype (Production of antibiotics, edited by S. M. Novasina. - M. Medicine, 1970, c. 221-224) is as follows: to the native solution dentists add butyl acetate and at pH from 2.9 to 3.2 conduct the first butylacetate extraction, then spend soda reextraction at pH from 6.8 to 7.2 (activity soda reextract ranges from 30 000 to 50 000 UNITS/ml), then the second butylacetate extraction at pH from 2.9 to 3.2, from the received butylacetate extract are freezing moisture and precipitated potassium salt of phenoxymethylpenicillin the potassium acetate solution with a density of 1.26 to 1.28 g/cm3at the rate of 0.5 liters per billion UNITS of dentists in butylacetate extract, followed by vacuum evaporation of a suspension of the potassium salt, after which it is filtered, the precipitate of the potassium salt washed with butanol and dried.The disadvantages of this method:
1. A multi-stage process, the use of large amounts of organic solvents, the use of various types of raw materials.2. Potassium salt and phenoxymethylpenicillin contain admixtures phenoxyalkanoic kislotami, used in the synthesis of semi-synthetic drugs.3. Potassium salt of phenoxymethylpenicillin does not meet the requirements of leading foreign pharmacopoeias indicators "content phenoxyalkanoic acid", "content parahydrogen", "specific rotation", the values of which are regulated for the potassium salt used to get it finished dosage forms.These drawbacks are eliminated in the present method of selection of the potassium salt of phenoxymethylpenicillin.The aim of the present invention is to enhance yield and quality of the potassium salt of phenoxymethylpenicillin, reducing raw material and energy costs and reducing production costs. This objective is achieved in that soda reextract lead deposition technical phenoxymethylpenicillin, which is dissolved in an organic solvent, and the obtained concentrate is precipitated potassium salt of phenoxymethylpenicillin.Distinctive features of the proposed method:
1. For deposition of technical acid is used soda reextract with activity from 60 000 to 80 000 IU/ml2. The intermediate product is t is t acidified water until colorless wash water.3. Technical acid dissolved in the organic solvent from the obtained concentrate dentists precipitated potassium salt (which in this way is the target product) solution of potassium acetate based from 0.3 to 0.35 liters per billion UNITS dentists contained in concentrate. Specified amount of a potassium acetate solution allows to obtain a potassium salt in accordance with the requirements of the foreign pharmacopoeias indicators "specific rotation" and "activity".The proposed technology allows you to:
1. To significantly improve the yield of the finished product due to:
1.1. exceptions to technological scheme of stages of the second butylacetate extraction, freezing of moisture from the second butylacetate extract and vacuum evaporation of a suspension of potassium salt;
1.2. use for deposition of technical acid soda reextract with activity up to 80 000 IU/ml2. To obtain the potassium salt in accordance with the requirements of the leading foreign pharmacopoeias in all respects.The proposed method experimental operations in the shop, the output of the potassium salt from the native solution amounted to 80.3 per cent (according to the method of the prototype - 70%), i.e. the increase in the output of SOS is P CLASS="ptx2">The economic effect from implementation of this invention will be about 15 million rubles per year.The following examples illustrate the invention:
Example 1.1. First butylacetate extraction (BAE).To 10 l of a native solution with activity 9100 IU/ml, the content of dentists (FMP) 91 million UNITS poured 5 liters of butyl acetate (BAM), the mixture is acidified with a solution of sulfuric acid with memorial plaques 10% to a pH of 2.9, stirred for 15 min, and then separated the layers. Get 4.8 l BAE activity of 18,200 IU/ml, the content of the SEF 87,36 million UNITS. The output stage 96%.2. Soda reextracted (SRA).To the resulting BAE poured 1.2 l of sodium bicarbonate solution, get 1, 224 l soda reextract with activity 68 500 U/ml, pH of 6.9, the content of the SEF 83,86 million UNITS. The output stage 96%.3. The deposition of technical acid.To soda to reextract add the sulfuric acid solution with memorial plaques 10% to a pH of 1.55, R. M. stirred for 1 hour, then the precipitate is filtered off, washed with acidified water and dried. Get 53,1 g technical FMP acid with an activity of 1500 U/mg, the content of the SEF 79,66 million UNITS. The output stage of the deposition 95,0%.3. Dissolution is centrata (leaching) with an activity of 100 000 IU/ml, the content of the SEF 78.1 million IU/ml. Output at the stage of dissolution of 98%.5. The precipitation of the potassium salt EFM.From the obtained acetone concentrate precipitated potassium salt by adding 0.3 ml of 1 million UNITS, it and 23.4 ml of a potassium acetate solution with a density of 1.26 g/cm3. R. M. stirred for 30 minutes, the precipitate filtered off, washed with butanol and dried. Get 50,14 g of the potassium salt with activity 1480 U/ mg, the content of the SEF 74,2 million UNITS. The output stage of the deposition - 95,01%. The output from the native solution of 81.5% (output by way of a prototype - 70%), the increase amounted to 16.4 Rel.%.The quality of the potassium salt by main indicators:
Specific rotation, deg. - 225
Content FOC, % - Missing
Content parahydrogen, % - 3,5
Activity, U/mg - 1480
Example 2.Native solution:
10 l 11200 IU/ml =112 million UNITS.BAE:
4,85 l 21940 IU/ml =106,4 million UNITS.The output stage BAE 95%.Soda reextracted:
1.3 l 79200 IU/ml =102,16 million UNITS.The output stage SRE 96%.The deposition of technical acid:
and 62.6 g 1550 U/mg =97,03 million UNITS.The output stage of deposition of 95%.Dissolution technical acid:
0,627 l 150 000 IU/ml =94,1 ASS="ptx2">The output stage of deposition of 95%.The output from the content in native SEF solution 79,83%, increase output against output by way of the prototype was 14,04 Rel.%. The quality of the potassium salt by main indicators:
Specific rotation, deg. - 230
Content FOC, % - traces
Content parahydrogen, % - 2,5
Activity, U/mg - P 1. Method of extraction of the potassium salt of phenoxymethylpenicillin, including the first butylacetate extraction and soda reextraction, characterized in that soda reextract besieged phenoxymethylpenicillin at pH 1.5 to 1.7, followed by separation of the crystalline phenoxymethylpenicillin, which is dissolved in an organic solvent, and the obtained concentrated solution precipitated potassium salt of phenoxymethylpenicillin using potassium acetate solution at the rate of 0.3 to 0.35 l to 1 billion UNITS of dentists contained in the concentrated solution.2. The method according to p. 1, characterized in that the activity of soda reextract is from 60000 to 80000 IU/ml3. The method according to p. 1, wherein the organic solvent is preferable to use acetone in about this
FIELD: chemical-pharmaceutical industry and technology, pharmacy.
SUBSTANCE: invention describes a method for isolating oxacillin sodium salt from aqueous or aqueous-organic solution that involves its extraction into organic solvent by addition of mineral acid sodium salt followed by crystallization of oxacillin sodium salt from organic extract. Invention provides the increasing yield and quality of prepared crystalline oxacillin sodium salt.
EFFECT: improved isolating method.
FIELD: organic chemistry, chemical technology, antibiotics.
SUBSTANCE: invention relates to an improved method for synthesis of benzyl-penicillin diethylaminoethyl ester hydroiodide. Method involves interaction of benzyl-penicillin alkaline salt with N-(2-chloroethyl)-diethylamine in acetonitrile or N,N-dimethylformamide medium in the presence of hydroiodic acid alkaline metal salt followed by distilling off acetonitrile or N,N-dimethylformamide under vacuum and crystallization of benzyl-penicillin diethylaminoethyl ester hydroiodide in acetone medium. The crystallization process of benzyl-penicillin diethylaminoethyl ester hydroiodide is carried out in the presence of phosphoric acid alkaline metal salts wherein a mixture of potassium dihydrogen phosphate and sodium hydrogen phosphate as phosphoric acid alkaline metal salts are used in the amount 0.5-1.0% of benzyl-penicillin alkaline salt mass charged to the esterification process reaction mass. Method provides enhancing stability of aqueous suspension prepared with using product synthesized on the basis of invention claimed.
EFFECT: improved method of synthesis.
2 cl, 2 ex