SU474991A3 - Method for producing crystalline alkali metal salt of carboxybenzylpenicillin - Google Patents

Description

e) The organic extract is dried, preferably with anhydrous sodium sulfate (other drying agents can be used, for example, anhydrous calcium sulfate) or filtering through a cloth, centrifuging, etc. In this case, the water content should be 3-20%, preferably 7-15. g) Next, the dried extract is treated with an appropriate amount of alkali, or alkali metal salts such as alkoxides, or salts of organic acids containing up to 18 carbon atoms, which would dissolve in organic solvents or water present in the extract. These are sodium or potassium salt 2-ethylxanthates due to their availability and adequate solubility in solvents. Mono-or alkali salts are obtained, depending on the ratio of the components taken. Salts or alkalis are introduced into the reaction in the form of solutions. The solvents used are acetone, methyl isopropyl ketone, n-butapol, etc., in which these salts dissolve, and at least 0.05%. h) The resulting crystalline salt is isolated by filtration and washed or repeated pressing with an organic solvent such as n-butanol, acetone, methyl isopropyl ketone, then the product is present at a temperature of 40-65 ° C by blowing nitrogen or air or in a vacuum. For greater stability of the obtained compound, the presence of hydration water is necessary. This must be taken into account when drying. The whole process is desirable to conduct at 5-25 ° C. The application of stages c, d, and d is optional. It depends on the shape of the product used and its purity. Example 1. Preparation of crystalline disodium-cc-carboxybenzylpeipzilin from crude amorphous a-carboxybenzylpeneillin. 250 g of dry disodium-a-carboxybenzylpenicillin (ioluchen by irimer FOR, patent No. 1.004.670, United Kingdom) is dissolved in 2.5 L, 600 ml of methylisobutyl ketone is added and the mixture is cooled to 5 ° C. After that, the pH is maintained at 2, 2, adding about 650 ml of 2 and under stirring. hydrochloric acid for 20 min. After mixing, methyl isobutyl ketone is released. The aqueous acid is then extracted twice with about 600 ml of methyl isobutyl ketone. The extracts are mixed, 1250 ml of water are added and the mixture is cooled to 8 ° C. The pH is maintained at 7 with a saturated aqueous solution of sodium bicarbonate (1600 ml), but the aqueous phase is separated. 650 ml of n-butanol is added to it, and then cooled to 5-8 ° C and with an RP of 3 supported by 850 ml of 2N. hydrochloric acid, the mixture is thoroughly mixed, the n-butanol phase is separated and the aqueous phase is extracted twice with 400 and 250 ml of n-butanol. The n-butanol extracts are combined, dried with 600 g of anhydrous sodium sulphate and filtered through a filter paper and then through a microporous filter. 2.1 equivalents of sodium 2-ethylhexanate in 960 ml of acetone are then added to the filter over 1.5 hours. Acetone is additionally added to maintain the easily stirred suspension (total volume 2300 ml). Mixing was continued for another 1 hour at room temperature and after the addition of sodium 2-ethylhexanate, the product was isolated by filtration. The filtered product is stirred with acetone at room temperature for 15 minutes, then filtered and the stirring step is repeated. The crystalline disodium salt is dried overnight in a stream of nitrogen. Further drying is carried out by heating the product to 65 ° C until complete drying. The yield of the product is 178.5 g (717 ° from the theory). When using 1.05 equivalents of 2-ethylhexaiate iatry in the above sequence, instead of 2.1 equivalents, a crystalline monosodium salt is obtained. Example 2. Obtaining dipatrium-a-carboxybeisylpenicillia from a-carbox asbestosylpenicillin. A sample of crude 7.5 g of a-carboxybeisylpenicillin is dissolved in 76 ml of water by adding a 10% solution of the crude acid, and cooled to 10 ° C. The reagent-base is maintained at 2.2 by adding 2N. sulfuric acid. The solution is extracted three times with 20 ml of methyl isobutyl ketone and the combined extracts are dried with anhydrous calcium sulfate. The dried extract is filtered, cooled to 8 ° C and treated with 18 ml of an acetoic solution of sodium 2-ethylhexanate, containing 1.20 ml of sodium salt. Acetone is added for efficient mixing. After 1 hour at 8-10 ° C, the crystalline and sodium salt is isolated by filtration, washed with acetone and dried at 40 ° C. Applying this technique using anhydrous magnesium and sodium sulphates, centrifuging, filtering through a cloth filter or azeotropic drying instead of anhydrous calcium sulfate also allows the preparation of a crystalline sodium salt. Example 3. Obtaining crystalline a-carboxybenzylpenicillin from ether a-carboxybenzylamine. A. Monophenyl ester feiylmaloi acid. 421 g of phosphorus oxychloride and 576 g of phenol are added to 1000 g of phenylmalonic acid in a three-neck flask with a capacity of 12 liters. The contents of the flask are well mixed and then agitated on a steam bath for 4-5 hours under nitrogen atmosphere. The temperature of the mixture is above 87 ° C. A clear mixture is formed within 15 minutes, and hydrogen chloride is released within 4 hours. 13.8 L of benzene was introduced into the reaction mixture and the mixture was distilled for 15 minutes. Hot benzene solution

decanted from the swelling of phosphoric acid and phenol, poured onto a mixture of ice and water. The pH of the aqueous phase is adjusted to 6.5 with a nominal 8 n. sodium hydroxide and finally pH 7.8 by the addition of 10% sodium carbonate solution. The mixture is stirred well, the aqueous extract is collected, the benzene layer and the small volume of water are poured, which is then combined with the first aqueous extract and adjusted to pH 2.2 with concentrated hydrochloric acid in the combined aqueous extract solution. The resulting heavy precipitate is extracted with chloroform. The total volume of 5 liters. The extract is washed with water once, dried (anhydrous sodium sulphate) and evaporated to give a solid suspension, which crystallizes upon trituration with hexane. The product is filtered off, washed with a small volume of 5% chloroform in hexane and air dried. The product yield 430 g (33% of theory), so pl. 103-110 ° C.

B. Phenylmalonylchloride monophenyl

ether.

92.5 g of thionyl chloride are introduced into a solution of propylmalonic acid in methylene chloride (1000 ml) and the solution is carefully distilled over 4 hours. Then 50 ml of toluene are added, the mixture is evaporated under reduced pressure and the desired product is obtained - an amber liquid in the form of a syrup.

B. Sol c-carbofioxybenzylpenicillium and N-ethylpiperidium.

In a solution of 86.4 g of 6-aminopenicillanic acid in 850 ml of water, the pH is adjusted to 6.7, by adding 8 n. sodium hydroxide, after which it is cooled to 10 ° C. Then, one portion of phenylmaloyl chloride of myophenyl ether is added and the mixture is stirred vigorously for 40 min at pH 6.5-7, which is maintained with 2N. sodium hydroxide. The cooling bath is removed 10 minutes after the end of the addition of the acid ACI chloride. The reaction mixture is adjusted to RP.

2.12 AD hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate extracts were shaken with a 10% potassium bicarbonate solution, the aqueous solution (pp 7.8) was separated and washed once with a small volume of ethyl acetate, which was discarded.

Fresh ethyl acetate is added to the aqueous solution, followed by a sufficient amount of potassium chloride to separate the salt from the aqueous phase. The aqueous layer is discarded and salt is added to the solution. Nenicillinate potassium salt readily dissolves in fresh water, and the ethyl acetate layer is discarded. The aqueous solution containing the desired product is acidified to pH.

2.22 n. hydrochloric acid, extracted with ethyl acetate, the extract is dried with Na2SO4, evaporated and 117 g of crude acarboxybenzylpenicillin phenyl ether are obtained.

This substance is redissolved in 100 ml of ethyl acetate and 35.3 ml of Netineridine is added. The amnna salt, which crystallizes, is collected by filtration.

and have air. The yield of the product is 97 g (12.7%), so pl. 145-147 ° C.

G. Hydrolysis of the salt of a-carbophenoxybenzylpenicillin and N-ethylpiperidine.

61.8 g of boric acid and 74.56 g of chloride

Potassium is dissolved in water and its volume is adjusted to 2 liters. Then, this amount of 0.5 N is introduced. sodium hydroxide to pH of the solution was equal to 9. Salt a-carbophenoxybenzylpenicillinphenyl solution

and N-ethylpiperidine is dissolved in this buffer solution and the mixture is stirred at room temperature (25 ° C) for 2.5 hours. The hydrolysis is carried out until the reaction mixture becomes more acidic until it stops.

reaction. The mixture has a pH of 8.5. In the last 15 minutes of reaction, the mixture becomes turbid due to the release of phenol from the weakly basic solution. D. Isolation of crystalline disodium salt.

The reaction mixture is cooled to O-10 ° C and 100 ml of methyl isobutyl ketone are added after 250 ml of 2N is injected. hydrochloric acid to pH 2.2. The mixture was allowed to stand, the methyl isobutyl ketone extract was collected and the aqueous solution was extracted with twice the large volumes of methyl isobutyl ketone (300 ml each). 200 ml of water are added to the combined extracts, the mixture is cooled to -10 ° C and

A solution of sodium bicarbonate (8 g in 20 ml of P20) is added dropwise over 5 minutes. A small volume of saturated sodium bicarbonate is carefully added to the mixture with RP 5.8 until the pH is 7. The aqueous extract of the α-carboxybeisylpenicillin sodium salt is collected and methylisobutyl ketone is extracted twice with 150 ml of water. 10 ml of n-butapol are added to the combined aqueous extracts, the mixture is stirred and cooled to O-10 ° C. Then the required amount of 2 n is added. hydrochloric acid to obtain a pH of 3, after which the mixture is settled and the layer is collected. The acidified aqueous solution is extracted twice with 75 ml.

butanol, combined solutions of buta yola (250 ml), dried over 300 g anhydrous; Sodium sulfate 1 hour n is filtered into a three-neck flask with a capacity of 1 ml with a mechanical stirrer and an additional funnel

(169 ml) of an acetone solution of sodium 2-ethylhexaiate containing 207.5 mg of salt / ml is added dropwise to the flask over a period of 20-30 minutes. When approximately half of the solution is added, the mixture is released as

Disodium salt crystals.

Next, the mixture is stirred for 30 minutes, after addition of sodium ethylhexanate to Heii, another 225 ml of acetone is added and the mixture is not mixed up for 15 minutes. Crystal Dinatra 1 about

salt is collected by filtration on a glass

funnel under a dry nitrogen atmosphere and the filtered residue is washed with 500 ml of acetone.

The residue is stirred with 100 ml of fresh acetone for 30 minutes at room temperature, filtered as described above, and dried on a filter in a stream of dry nitrogen for 16 hours. The product is a white crystalline powder, slightly microscopic, easily soluble in water.

The product yield of 25.6 g (60%), so pl. 198 - 210 ° C.

The repetition of the described procedure, but using n-butanol solution of sodium 2-ethylhexanate instead of the acetone solution, gives sushi, similar results.

Example 4. The aqueous hydrolyzed mixture obtained by the method of Example 3, D was adjusted to pH 7 with 2 n. hydrochloric acid, and then extracted three times but 200 ml of n-butanole. The n-butanol extract is discarded, 100 ml of c-butanol is added to the aqueous phase, the mixture is stirred, cooled to 5-10 ° C and at a temperature of 2N. hydrochloric acid is maintained at a pH of 2.2. The n-butaiol phase is settled, separated, collected, and the aqueous layer is extracted twice with 75 ml of each two times with f-butane. The combined n-butanol extracts are dried over anhydrous sodium sulphate, filtered and treated at 10 ° C with sodium 2-ethylhexanate (169 ml of an acetone solution containing 207.5 ml of sodium salt per 1 ml) for 30 minutes. The mixture is stirred

1/2 hour, 250 ml of acetone are added and stirring is carried out for another 1.5 min. To 1ccallic 1 disodium salt is collected and dried with a stream of nitrogen.

Example 5. The process of Example 3 is repeated, D, but using 1 equivalent of sodium 2-ethylhexanate instead of 2.1 equivalent. A crystalline monosodium salt is obtained. In the same way, crystalline mono- and di-potassium salts are obtained using 1 and 2.2 equivalents of potassium 2-ethylhexanate instead of sodium 2-ethylhexanoate.

Example 6. The procedure of Example 1 is repeated, but in the initial stage of acidification, the pH is maintained at 3.3. Get essentially the same results.

Subject invention

Claims (2)

1. A method for the preparation of the crystal salt of the alkali metal salt of a-carboxybenzylpenicillin, characterized in that the a-carboxybenzylpenicillin aqueous solution having a pH of 2-3.5 is extracted with a solvent such as n-butapol or methyl isobutyl ketone, the extract obtained is dried to a content of water is 3-20 wt.%, and then treated with an alkali metal 2-ethylhexanate such as sodium, potassium, followed by isolation of products in a known manner. 2. A method according to claim 1, characterized in that the process is conducted at 5 to 25 ° C.