The way to get ampicillin
(57) Abstract:The inventive ice-cold suspension of a water-acetone solution of salt 6 - aminopenicillanic acid is subjected to acylation cooled to (-10) - (-30)oWith an acetone solution of the mixed anhydride of N-substituted D- (-)-alpha - aminophenylacetic acid and ether harpalinae acid. The resulting N - substituted ampicillin subjected to hydrolysis with subsequent isolation of the target product. 1 C.p. f-crystals. The invention relates to chemical-pharmaceutical industry, namely the improvement of technology for semi-synthetic penicillin ampicillin (aminobenzylpenicillin) formula:
Known methods for producing ampicillin by acylation of 6-aminopenicillanic acid (6-AIC) phenylglycine derivative, activated at the carboxyl group (galogenangidridy or mixed anhydride) in aqueous organic solution upon cooling [1, 2, 3]
The closest in technical essence and the achieved economic effect to the proposed method of obtaining ampicillin are methods of acylation of 6-APK mixed anhydride of N-substituted dicarbonyl derivative phenylglycine [agent at a temperature of from -10 to -45aboutC.The disadvantages of these methods are.Low yield of ampicillin not exceeding 80% of the 6-APK. In the described conditions, the process of acylation is accompanied by heating of the reaction mass and local overheating, particularly strong in the production environment. With increasing temperature reduces the efficiency of the protection of the amino group phenylglycine balance, increases the number of free amino groups, which come in a competing reaction of acylation, reducing the degree of transformation of 6-AIC ampicillin; the presence in the finished product oligomeric forms ampicillinampicillin substances; high energy consumption for cooling the source of solutions to operating temperature.The aim of the invention is to increase the yield and quality of ampicillin and reduce energy consumption.This goal is achieved due to the fact that in ice-cold suspension of a water-acetone solution of salt 6-APK within a certain time prilisaetsa acetone solution derived phenylglycine, activated at the carboxyl group. To do this, get a water-acetone solution of salt 6-APK with the same ratio of acetone:water to the freezing temperature of the solution was at 5-20aboutC above tempor salt 6-AIC to the temperature for 3-10aboutWith lower temperature at the start freezing, forming ice-water-acetone solution of salt 6-APK, due to the accumulation of the ice phase in suspension its temperature remains almost constant, does not decrease the temperature difference between the refrigerant-suspension, no decrease in the heat transfer coefficient, as compared with the prototypes, leads to the reduction of energy consumption. Known methods get the acetone solution derived phenylglycine, activated by carboxyl group, cool it to a temperature of from -10 to -30about(Depending on the temperature of refrigerant), and within 2-4 min, poured into ice-cold suspension of water-acetabula solution of 6-APK. The change in the ratio of acetone:water in the ice slurry leads to rapid melting of the ice phase, so the acylation process in which heat is produced, occurs simultaneously with the melting of ice, in which heat is absorbed. The proposed scheme for the synthesis eliminates warm-up and local overheating of the reaction mixture at the stage of acylation and, in particular, to obtain the reaction mass to a temperature below the temperature of refrigerant, which leads to increased yield and quality of ampicillin.
to pH 8,2-8,4, to the resulting solution pour 80 ml of acetone, cooled to a temperature from -22 to -24aboutC. During the cooling process at a temperature of -17aboutWith the solution begins to freeze and the further cooling of the ice slurry thickens.26,25 g of potassium salt of N-(1-methyl-2-ethoxycarbonylphenyl) D(-) -aminophenylarsonic acid suspended in 239 ml of acetone, cooled to a temperature of from -25 to -28aboutWith, to flow to a mixture of 6.6 ml (100% basis) methylcarbamate and 3.4 ml of a 1% solution in acetone N. N-dimethylbenzylamine, stir for 45 min, keeping the temperature from -25 to -28aboutWith, then pour the mixture over 2-4 min in ice-cold suspension of a solution of ammonium salt of 6-APK. The temperature of the reaction mass is reduced by 4-6aboutC. Stir the mixture for 20 min, then warmed to -10aboutAnd pour a 10% solution of hydrochloric acid to a pH of 2.5-3.2, pour 400 ml of methylene chloride, acidified mixture of 10% hydrochloric acid to pH 1.5 to 2.0, to separate the upper water layer solution of the hydrochloride ampicillin, podselect 10% sodium hydroxide solution to pH 4.5 to 5.0, which results in a precipitate ampicillin three-hydrate, stirred suspension of 5-10 h at 0-5aboutWith, then offline of three-hydrate 26,3 g, the output from the original 6-APK 85%
Distinctive features of the proposed method are the following:
at the stage of acylation acetone solution derived phenylglycine, activated by carboxyl group, prilisaetsa to suspension of ice-water-acetone solution of salt 6-AIC;
ice-cold suspension of a water-acetone solution of salt 6-APK get freezing, why in the preparation of salt solution 6-agricultural use is the ratio of acetone: water to the temperature at which freezing was 5-20aboutWith higher temperature of refrigerant. 1. The WAY to GET AMPICILLIN by acylation of salt 6-aminopenicillanic acid cooled to minus 10 to minus 30oWith an acetone solution of the mixed anhydride of N-substituted D(-)-- aminophenylarsonic acid and ether harpalinae acid and subsequent hydrolysis of the resulting N-substituted ampicillin and selection of the target product, wherein atilirovanie subjected to ice-cold suspension of a water-acetone solution of salt 6-aminopenicillanic acid.2. The method according to p. 1, characterized in that ice-cold suspension of a water-acetone solution of salt 6-the biotechnological acid get n the La freezing 5 20oWith higher than the temperature of the refrigerant used for cooling of reagents before acylation, with its subsequent freezing.
SUBSTANCE: invention relates to a method of producing a sodium salt of 6-[3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbamino]-penicillanic acid (flucloxacillin). The method is realised by simultaneously feeding into an aqueous solution of a sodium salt 6-aminopenicillanic acid, acetone solution of acid chloride of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid and aqueous solution of sodium hydroxide while keeping pH of the medium at 6.5-9.0. The formed sodium salt of flucloxacillin is extracted after preliminary removal of acetone and is carried out by feeding a saturated solution of sodium chloride or acetate into the reaction mass.
EFFECT: improved method of producing a sodium salt of 6-[3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbamino]-penicillanic acid.
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.
EFFECT: valuable medicinal properties of medicinal substances and compositions.
7 cl, 8 tbl, 32 ex