JPS628434B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved process for the preparation of the antibiotic talampicillin, whose chemical structure corresponds to 6-[D(-)-α-aminophenyl acetamide]penicillanic acid phthalide ester. Such compounds are described in GB 1364672, which discloses various methods for obtaining them. The method described in Example 2,
That is, method 1 of the above patent - by which the best yield is obtained, but not more than 68% -
6-[D(-)methoxycarbonylpropene-2
-yl)-α-aminophenyl acetamide] The potassium salt of penicillanic acid is reacted with 3-bromophthalide to obtain the phthalide ester of said acid. Such methods have a number of drawbacks, including: That is, since the potassium salt of the acid cited above is insoluble and merely suspended in a large volume of acetone/ethyl acetate mixed solvent, a large volume of these solvents is entrained and contained, and as a result, an appropriate volume of A reaction vessel is required. moreover,
Due to the heterogeneity of the reaction mixture, the reaction itself proceeds very slowly. In fact, the reaction time required for this first stage of the synthesis is approximately 24 hours. British Patent No. 1364672 - This patent relates in effect to a protected ampicillin suspension;
Considering the very slow solubility of ampicillin in the usual solvents described in 2003, which does not concern solutions of ampicillin in solvents, the increase in the concentration of ampicillin is clearly slow.

Moreover, according to the above method, the phthalide ester so produced, which is soluble in the used solvent, can be dissolved only after suitable vacuum evaporation of such solvent and filtration of the recovered solid product. It can be separated and subsequently hydrolyzed in aqueous acetone with hydrochloric acid. Such methods, which are well known to those skilled in the art, are clearly very complex and time-consuming. Furthermore, GB 1364672 describes the use of protected ampicillin, which is subsequently esterified with 3-bromophthalide.
Little has been described about the preparation of protected ampicillin. All of the methods described in the above patents for the preparation of protected ampicillin are difficult and expensive, and the yields obtained are almost always low.

For example, Example 2, i.e. Method 2 of the UK patent already cited, or the same applicant's Irish patent no.
According to Examples 5 and 6 of No. 27777, protected ampicillin was prepared by reacting the protected phenylglycine with a salt of 6-amino-penicillanic acid in dilute solution and at a temperature below 0°C. A salt is obtained, but the purity of what is obtained is very low (purity can vary from 59% to 75%). A similar method is also used in the
Chemische Berichte) 98, 789 (1965).

The inherent drawbacks of such methods are clearly the rather long reaction times and large volumes of solvent required.

The object of the present invention is to realize a process in which very pure talampicillin is obtained by shortening the reaction time and by operating with concentrated solutions using a significantly reduced volume of solvent. .

According to our improved method, free ampicillin amino groups are reacted with methyl or ethyl acetoacetate in dimethylformamide or dimethylacetamide at temperatures between 50°C and 70°C to give the corresponding enamines. A concentrated solution of enamine is
Treatment with 3-bromophthalide in the presence of the hydrogen bromide acceptor results in increased yields to the related enamino ester, the enamino group of which is finally removed in the same solution by addition of dilute hydrochloric acid. It is then hydrolyzed. Either alkaline carbonate or bicarbonate can be used as the hydrogen bromide acceptor.

It has never occurred to anyone skilled in the art to dissolve ampicillin, either in anhydrous or trihydrate form, in dimethylformamide or dimethylacetamide. This is because these solvents react with ampicillin to form solid adduct compounds, which are practically useless for the next reaction step due to their low solubility. We have now surprisingly found that by adding ampicillin to dimethylformamide or dimethylacetamide to which methyl or ethyl acetoacetate has been previously added at a temperature higher than 50°C, no insoluble adduct is formed; It has thus been found that protected ampicillin is obtained and, more importantly, it is obtained in the form of a concentrated solution.

Also, according to known methods, the reaction of ampicillin with methyl or ethyl acetoacetate or acetylacetone should be carried out in aqueous alcoholic solution in the presence of a strongly alkaline hydrate at a temperature higher than 50 °C. It is also important to emphasize that That is, the reaction conditions described above actually involve a certain and almost complete decomposition of ampicillin itself. In fact, no method for the direct protection of ampicillin in its enamine form has ever been made public.

Our claimed process, contrary to the above-mentioned process, produces the desired enamine to be obtained directly from ampicillin in a short time and in the form of a concentrated solution.

Compared to known methods, our method for producing talampicillin offers many improvements over previous improvements. Due to the relatively small volume of spent solvent and therefore the high concentration of reagents, the reaction proceeds in a short time (approximately 2 hours). Shortening of the reaction time is also ensured by the homogeneity of the reaction mixture and by the use of dimethylformamide or dimethylacetamide, which increases the rate of the nucleophilic reaction, as is known.

Furthermore, since a water-miscible solvent is used, the final hydrolysis step can be easily carried out by adding the appropriate mineral acid directly to the reaction mixture.

The yield of pure talampicillin obtained is higher than 80% of theory and therefore higher than the best yields described in the patents cited above.

The following examples are illustrative of the invention and are not intended to limit the scope of the invention.

Example 1 A mixture of dimethylformamide (300 ml) and ethyl acetoacetate (63.5 ml) is warmed to 60° C. with stirring.

Add anhydrous ampicillin (86.6 g) and stir for 64 hours.
Continue at ~65 °C until a completely clear solution is obtained. The reaction mixture is then cooled to 5° C. and stirred for a further 5 minutes after addition of potassium carbonate (20.5 g).

60.6 g of 3-bromophthalide are then added, the temperature raised to 14° C. and stirring continued for a further 60 minutes.

Then the temperature of the reaction mixture was increased with stirring for 30 min.
Raise to 18℃. After cooling to 0°C, add dilute hydrochloric acid to approx.
Add dropwise over 60 minutes to adjust pH to 2.5.

The reaction mixture is then diluted with water (1750ml) and extracted with toluene (290ml). Subsequently, the toluene layer is washed with dilute hydrochloric acid. The combined aqueous phases were washed twice with toluene (2 x 290 ml) and
After evaporation, sodium carbonate (46.0 g) is added with stirring until the pH is adjusted to 6.5-7.5.

The talampicillin base precipitates in the form of a white solid and is filtered off and washed with water. The still wet solid is then suspended in hydrochloric acid (500 ml) and the PH is maintained at 2.5 by adding more hydrochloric acid with stirring until a clear solution is obtained.

Add 300g of sodium chloride and stir at 0℃ for 10 minutes.
Continue for a minute.

The precipitated white solid was extracted with methylene dichloride,
The organic layer is dried over anhydrous sodium sulfate, filtered and poured dropwise into twice the volume of toluene with stirring under reduced pressure at 25° C. (external bath). The white precipitate obtained is filtered and dried under reduced pressure at room temperature and then at 40°C. 95-96 g of pure talampicillin hydrochloride are obtained.

TLC (Thin Layer Chromatography): Single Spot Example 2 Proceed in the same manner as Example 1 - but using 100 g of ampicillin trihydrate and 230 ml of dimethylformamide, which are cheaper than anhydrous ampicillin (Example 1) (in which 300 ml of such solvent was used), pure talampicillin hydrochloride is obtained in comparable yield and purity.

Example 3 A solution of methyl acetoacetate (17.2 ml) in dimethylformamide (100 ml) is stirred at 65°C and ampicillin (28.9 g) is added. at 65℃
After stirring for 15 minutes, the resulting solution was cooled to 5°C and
Add potassium carbonate (6.8g) and 3-bromophthalide (20.2g).

The mixture is stirred at 16-17°C for 90 minutes, then brought to 0°C and adjusted to pH 2.5 by addition of dilute hydrochloric acid.

The solution is diluted with cold water (600 ml) and then washed several times with toluene. Talampicillin base can be adjusted to PH by adding potassium bicarbonate.
7.0, precipitation and then using the same procedure as in Example 1, pure talampicillin hydrochloride (32 g) is obtained.

Purity: 95.7% Example 4 Dimethylacetamide (100ml) and ethyl acetoacetate (21ml) are mixed at 63°C. Add ampicillin trihydrate (33.3 g) and dissolve at 65° C. for 5 minutes. The solution was stirred at 65°C for 30 minutes, the temperature was lowered to 10°C, and potassium carbonate (6.8g) and 3-
Bromophthalide (30.3g) was added and the temperature was increased to 90% at 18°C.
Let it react for a minute. The reaction mixture is cooled to 5°C and adjusted to pH 2.5 by adding dilute hydrochloric acid.

Next, by carrying out the same operation as in Example 1, 30.5 g of pure talampicillin hydrochloride with [α] _D (1% methanol) = +160° is obtained.

Claims (1)

[Claims] 1. Ampicillin is reacted with methyl acetoacetate or ethyl acetoacetate in dimethylformamide or dimethylacetamide at a temperature of 50°C to 70°C to produce a concentrated solution of the corresponding enamine, which is then bromated. tal, characterized in that it is treated with 3-bromophthalide in the presence of a hydrogen acid acceptor to obtain the related enamine ester, and the enamine group is finally hydrolyzed by adding dilute hydrochloric acid in the same solution. Ampicillin manufacturing method. 2. Process according to claim 1, characterized in that the hydrogen bromide acceptor is selected from the group consisting of alkaline carbonates and bicarbonates.