CS202505B2 - Process for preparing hydrochloride of phthaldiestere of 6-/d/-/-alpha-aminophenylacetamido/penicilanic acid - Google Patents

Description

The present invention relates to a process for the preparation of 6- [d] - (- (- aminophenylacetamido) penicillanic acid phthalide ester hydrochloride).

6- [d-N-X-aminophenylacetaraido] penicillanic acid phthalide ester of formula (I)

Which is hereinafter referred to as talampicillin ', a useful ester of 6- [d] -. Beta.-aminophenylacetamido-penicillanic acid, hereinafter referred to as ampicillin ”; this ester, when administered orally in human and veterinary medicine, is well absorbed by the body, providing a higher level of the active substance in the blood as compared to maternal ampieilin. <

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Talampicillin and its addition salts, in particular its hydrochloride, are described and claimed in English Patent 1,364,672.

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According to the English patent, talampicillin is prepared by a process comprising reacting a 6-aminopenicillanic acid phthalide ester or a silyl derivative thereof with a reactive acylation derivative of the D-isoraer of a compound of formula II

ÍV '

CH-COOH (11) wherein X is an amino group, a protected amino group, or a group that can be converted to an amino group, optionally eliminating the silyl group, and converting the group convertible to an amine group under neutral or acidic conditions to an amino group when X is not an amino group.

According to an alternative method also described in the aforementioned English patent, talampicillin can also be prepared by reacting a compound of formula IIIa.

COOA (111), wherein X is as defined above and A is, for example, sodium or potassium, with a compound of formula IV

(IV), in which B represents, for example, chlorine or bromine, and in the case where X is not an amino group, this group is also converted under neutral or acidic conditions to an amino group.

Examples of protected amine groups or groups convertible into amine groups include all the groups that are commonly used in penicillin chemistry for this purpose. Particular mention may be made of an optionally substituted benzoyloxycarbonylamino group, an azide group or an enamine group.

Specific examples describe the preparation of talampicillin according to the above methods. In one such example, talampicillin hydrochloride is prepared in a total yield of 68% by the reaction of 6- [D- N -methoxycarbonyl-2-propenyl] - α-aminophenylacethanidone of the lanthanum potassium or ampicillin potassium, in which the X-amino group is protected in the enamine form, 8 with 3-bromophthalide and subsequent hydrolysis of the product thus obtained with an aqueous solution of hydrochloric acid at pU. 2.5.

Japanese Patent 77/43839 discloses another process for the preparation of talampicillin by reacting ampicillin with berfzaldehyde, then treating X- (benzilideneamino) benzylpenicillin with 3-halophthalide and the Sehiff base of formula V thus obtained. /IN/

is hydrolyzed under acidic conditions.

According to a preferred embodiment of the aforementioned Japanese patent, talampicillin hydrochloride is obtained in a yield of 62.7% by converting trihydrated ampicillin into its potassium salt, reacting said potassium salt with benzaldehyde, then with 3-bromophthalide and finally hydrolyzing the Schiff base dissolved in acetonitrile by treatment with aqueous hydrochloric acid.

English patent 1,081,093 describes a series of Schiff bases ampicillin, wherein said Schiff base ^of the general Formula VX

(VI), wherein R is a hydrogen atom, a linear or branched alkyl radical having 1 to 12 carbon atoms, or an optionally substituted aryl or aralkyl group.

A preferred compound of U.S. Pat. No. 1,081,093 is a product of formula VI wherein R is hydrogen, i.e. 6-.alpha.,. Beta.-.alpha.-methylenaminophenyl] penicillanic acid, hereinafter referred to as metampicillin. properties, and since ampicillin has the advantage that it provides a higher gallbladder level of antibiotic when administered parenterally.

It has now been found that talampicillin hydrochloride can be obtained in a yield of 80 to 85 Z from ampicillin in a simple and rapid manner, comprising a) converting ampicillin to an alkali metal salt and then reacting with methicillin phthalide ester with formaldehyde followed by 3'-halophthalide hydrolysis of the metampicillin phthalide ester thus obtained in a biphasic organic-aqueous solvent under acidic conditions.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 6 - ((R) -aminophenylacetamido) phthalide ester hydrochloride of the formula

which comprises reacting ampicillin with formaldehyde in an alkaline medium in an organic solvent, treating the reaction mixture with 3-halophthalide, then pouring the mixture into water and finally hydrolyzing the metampicillin phthalide ester obtained in a two-phase organic phase an aqueous solvent in the presence of hydrochloric acid. - <.

In the process according to the invention, an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate is preferably used as the alkaline environment-forming agent in the reaction of ampicillin with formaldehyde.

Ampicillin is preferably used in anhydrous form. It is also possible to use ampicillin in the form of its sodium salt, the reaction being carried out in the absence of an alkaline agent.

Preferably, a polar aprotic solvent is used in the reaction of ampicillin with formaldehyde and 3-halophthalide as the organic roxulant.

3-Bromophthalide is preferably used as 3-halophthalide. Also, a mixture of acetone or ethyl acetate and an aqueous solution of hydrochloric acid may also be used as the two-phase organic-aqueous solvent in the presence of hydrochloric acid.

In view of the known processes for the preparation of talampicillin hydrochlorides, the process of the invention is more advantageous in that it provides talampicillin hydrochloride of high quality and in excellent yield.

The process according to the invention is carried out by adding 3-halophthalide to the reaction mixture containing freshly prepared alkali metal salt of metampieiline from ampicillin and formaldehyde in an alkaline medium. The reaction mixture was sweeps for 2-3 hours at 10 to 30 ° C, preferably at 15 to 20 ° P Najs .mu.l ^was poured into water, and the precipitated phthalide is dissolved in an organic solvent, preferably acetone or ethyl acetate, and then aqueous hydrochloric acid solution is added. After stirring for 30 to 60 minutes, hydrolysis is complete and talampicillin hydrochloride is isolated by conventional procedures. ''

In a preferred embodiment of the process according to the invention, ampicillin is reacted in bexhydrated or trihydrated form with aqueous non-alcoholic formaldehyde and an alkali metal hydroxide, carbonate or bicarbonate. The reaction is carried out in an aprotic solvent such as dimethylformamide, dimethylacetamide and dimethylsulfoxide at a temperature of -15 to -30 ° C.

° C, preferably at 0 to 5 ° C, for 1 and 3 hours.

The reaction mixture containing the alkali metal salt of metampieiline is then mixed with 3-halophthalide and stirred for 2 to 5 hours at 10 to 30 ° C. The crude metampieiline phthalide ester is isolated by pouring the reaction mixture on ice or ice water and filtering off the isolated phthalide ester is dissolved in a suitable organic solvent, water is added to the solution, and the phthalide is hydrolyzed by the addition of monooral hydrochloric acid.

The resulting talampicillin hydrochloride is then isolated according to a known method, e.g. by precipitation from the organic solution by addition of diethyl ether or methyl tert-butyl ether.

Of course, when an alkali metal salt of ampicillin is available, the conversion of the product to its salt may be omitted, since the above-mentioned ampicillin salt may be used as the starting material. ...

The surprising and exclusive behavior of formdehyde and metampicillin phthalide ester. of the process according to the invention as. The intermediate in the preparation of talampicillin hydrochloride according to the invention was confirmed by ampicillin reacting with acetaldehyde instead of formaldehyde using the compound of the above formula VI, wherein R is methyl. Using the reaction conditions of the invention, an unidentified orange product was obtained in low yield upon completion of the reaction.

In order to illustrate the invention in more detail, several examples are set forth below.

He did

To a suspension of anhydrous ampicillin (34.94 g) in dimethylformamide (250 ml) was added aqueous 40% formaldehyde (5%) at 5 ° C, followed by anhydrous potassium carbonate (7.2 g). The mixture is stirred at a temperature between 0 and 5 ° C for 90 minutes and 21.3 g of 3-bromophthalide are added. After stirring at 10 to 13 ° C for 4 hours, the reaction mixture is poured into 1000 g of cold water with stirring. ’

The precipitate formed is filtered off, washed with water and dissolved in 25 ml of ethyl acetate. To the organic solution is then added 100 ml of 1N hydrochloric acid and 230 ml of water, and the resulting mixture is stirred for 45 minutes.

The aqueous phase is washed with 50 ml of diethyl ether, 200 ml of methylene chloride are added, followed by 125 g of sodium chloride, and the mixture is stirred for 5 to 10 minutes. The methylene chloride solution was separated and the aqueous phase was extracted with a further 50 ml of methylene chloride and the combined organic solutions were dried over anhydrous sodium sulfate. The volume of the solution is then reduced to 150 ml by evaporation of the solvent under reduced pressure at an external temperature of 30 to 40 ° C and the resulting volume of the solution is poured into 300 ml of diethyl ether with stirring. '

The precipitate formed is filtered off, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure to give 42.7 g (82.5% of theory) of talampicillin hydrochloride corresponding to an authentic sample. ”

Infrared (KSr): 1780, 1690, 1295, 1150, 985, 760 and 700 cm ^-1 .

In the same way, a suspension of 34.94 g of anhydrous ampicillin in 250 ml of dimethylformamide was treated by adding 8.25 ml of a 40% aqueous formaldehyde solution and then a solution of 48 g of sodium hydroxide in 10 water; the mixture is stirred at 0-5 ° C for one hour.

To this mixture is then added 3-bromophthalide (21.3 g) and proceeded as above to give 35 g (67.5% of the theoretical yield) of talampicillin hydrochloride.

Example 2

The procedure is as in Example 1, except that 7.2 g of potassium carbonate is replaced by 11 g of potassium bicarbonate; after. Stirring for 3 hours to convert the ampicillin to the salt yields 36.4 g (70% of theory) of talampicillin hydrochloride in pure form.

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Example .3

To a suspension of 87.35 g of anhydrous ampicillin in 500 ml of diethylformaldehyde was added 45 ml of a 20X ethanolic formaldehyde solution at 5 ° C, followed by 18 g of anhydrous potassium carbonate. The mixture was stirred at 0-5 ° C for 90 minutes, then 53.25 g of 3-bromophthalide was added.

The reaction mixture was stirred for 4 hours at a temperature of 10-13 ° C and then poured into 2000 g of cold water with stirring. The precipitate formed is filtered off, washed with water and dissolved in 500 ml of ethyl acetate. 250 ml ^of 1N hydrochloric acid and 450 ml of water are added to the solution thus obtained, and the mixture is stirred for 45 minutes.

The aqueous phase is washed with 125 ml of diethyl ether, 400 ml of methylene chloride are added, followed by 312.5 g of sodium chloride, and the mixture is stirred for about 10 minutes. The methylene chloride solution is then separated and the aqueous phase is re-extracted with 100 ml of methylene chloride and the combined organic solutions are dried over anhydrous sodium sulfate. The volume of the solution is reduced to 300 ml by evaporation of the solvent under reduced pressure at an external temperature of 30 to 40 ° C and the resulting volume of the solution is then poured into 600 ml of diethyl ether with stirring. The precipitate is washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure. g (79% of theoretical yield) of pure talampicillin hydrochloride identical to the product obtained in Example 1.

Example 1 a. D 4

To a solution of 37.1 g of sodiumampicillin in 250 ml of dimethylformamide was added 8.25 ml of a 40% aqueous formaldehyde solution at 5 ° C. The reaction mixture was then stirred at 0-5 ° C for 1 hour and then 3-bromophthalide (21.3 g) was added. Then proceed as in Example 1 to obtain 36.4 g./70% of the theoretical yield / talampicillin hydrochloride in the pure state.

Reaction of ampicillin with acetaldehyde, potassium carbonate and 3-bromophthalide and subsequent acid hydrolysis according to Example 1.

To a suspension of anhydrous ampicillin (34.94 g) in dimethylformamide (250 ml) was added acetaldehyde (4.8 g) at 5 DEG C. followed by anhydrous potassium carbonate (7.2 g). The mixture thus obtained is stirred for 90 minutes at a temperature between 0 and 5 ° C and 21.3 g of 3-bromophthalide are added to the resulting mixture.

The resulting mixture was stirred for 4 hours at 10-13 ° C, and the resulting red-orange product was poured into 1000 g of cold water with stirring. The precipitate was filtered off, washed with water and then dissolved in 250 ml of ethyl acetate.

100 ml of 1N hydrochloric acid and 230 ml of water are added to the organic solution and the mixture is stirred for 45 minutes. The aqueous phase is washed with 50 ml of diethyl ether, 200 ml of methylene chloride are added, followed by 125 g of sodium chloride, and the mixture is stirred for 5 to 10 minutes. The methylene chloride solution is separated, the aqueous phase is washed again with 50 ml of methylene chloride and the total organic solution is dried over anhydrous sodium sulfate.

The volume of the solution is then reduced to 150 ml by evaporation of the solvent under reduced pressure at an external temperature of 30 to 40 ° C and the resulting volume of the solution is poured into 300 ml of diethyl ether with stirring. The precipitate formed is filtered off, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure. Yield: 20.7 g (40% of theory) of a strong orange-colored product containing numerous impurities.

Claims (7)

1. A process for the preparation of 6- [d] - [-, d-aminophenylacetamido] nicilanic acid hydrochloride, characterized in that it is reacted with ampicillin with formaldehyde in an alkaline medium and in an organic solvent, followed by treatment with the reaction mixture. with halophthalide, the mixture is poured into water and the metampicillin phthalide ester thus obtained is then hydrolyzed in a two-phase organic-aqueous solvent in the presence of hydrochloric acid. 2. A process according to claim 1, wherein the alkali-forming alkali is an alkali metal hydroxide, carbonate or bicarbonate. 3. The process of claim 1 wherein the ampicillin is used in anhydrous form. 4. The process of claim 1, wherein ampicillin is used in the form of a sodium salt, wherein the reaction is carried out in the absence of an alkaline agent. 5. A process as claimed in any one of claims 1 to 4, wherein a polar aprotic solvent is used as the organic solvent in the reaction of ampicillin with formaldehyde and 3-halophthalide. 6. A process according to claim 1, wherein 3-halophthalide is 3-bromophthalide. 7. A process as claimed in claim 1, wherein a mixture of acetone or ethyl acetate and an aqueous solution of hydrochloric acid is used as the two-phase organic-aqueous solvent in the presence of hydrochloric acid.