DE3208506A1 - METHOD FOR PRODUCING 6- (D (-) - (ALPHA) - (4-C (ARROW DOWN)) (ARROW DOWN) (ARROW DOWN) - (ARROW DOWN) (ARROW DOWN) 4 (ARROW DOWN)) - ALKYL -2,3-DIOXO-1- PIPERAZINOCARBONYLAMINO) -PHENYLACETAMIDO) - PENICILLANIC ACIDS - Google Patents

Description

1A-3829
28,538

AMERICAN CYANAMID COMPANY Wayne, N.J., USA

Process for the preparation of 6- [D (-) - a- (4-C ₁ _ _i f.) - Alkyl-2,3-dioxo-1 -piperazinocarbonylamino.) -Phenylacetaraido j-

■ penicillanic acids

The invention relates to new, improved processes for the preparation of 6-subst.-penicillanic acids. In particular The invention relates to an improved process for the preparation of 6- [D (-) - <x- (4-alkyl-2,3-dioxo - 1-piperazinocarbonylamino) phenylacetamido ] penicillanic acids of the formula (I)

OHHOH

CH ₃ (D

CO ₂ H

where R is a C ^ _ · alkyl group. These connections are useful as antibiotics for the treatment of pneumonia, peritonitis and infections of the Blood system.

US Pat. No. 4,112,090 describes a process for the preparation of δ-substituted penicillanic acids of the formula (i). Reacting a 4- (C ₁ __ _Zf) alkyl-2,3-dioxo-1-piperazinocarbonylchlorids of the formula II

R-N N-C-Cl (II)

o ^s o ·

where R is a C _1- ^ -alkyl group, with the 6- [D (-) · cc-Amino-plienyIacetamido] -penicillanic acid trihydrate of the formula III

3H ₂ O (TII)

The anhydrous form of the compound (III) is hereinafter referred to as "ampicillin". In Example 23 of this publication, a suspension of the compound (III) in a mixture of 10 parts by weight of water and 4.5 parts by weight of ethyl acetate per part by weight of the compound (III) is cooled to 2 ° C. and treated with 2 molar equiv. potassium carbonate and mixed at 2 to 3 ⁰ C for several minutes then treated with 1 · MoI-a (IUiV .. a Verbindung'der formula (II) to give I? is methyl, namely 2 to 3 ⁰ C in the course of 10 min, followed by a further reaction at the same temperature for 15 min. The reaction mixture is freed from insoluble constituents and the

Mother liquor is mixed with an additional amount of 18 parts by weight of ethyl acetate / 1 part by weight of compound (III) which was originally used. The resulting mixture is then with 1 mol equiv. 2N HCl acidified at 20 to 22 ^° C. in the course of 5 min and then ^{stirred at 20 to 22 °} C. for a further 5 h. The precipitated crystals are separated off, washed successively with water and isopropanol and then dried, a dihydrate of 6- [D (-) - oc- (4-methyl-2,3-dioxo-1-piperazinocarbonylamino) - phenylacetamido] penicillanic acid with a yield of 75.4%. A monohydrate of 6 ~ [D (-) - oc- (4-ethyl-2, 5-dioxo-1-piperaazinocarbonylamino) phenylacetamido] -penic.illic acid is obtained in a similar manner in a yield of 84.8% the compound of the formula. (II) where R is ethyl.

There is a need for an improved process that results in increased yield. The present invention provides a process in which a final yield of about 93% is achieved.

According to the invention an improved method /, for the preparation of 6- [D (-) - a- (4-C ₁ _ _Zt alkyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamido "J-penicillanG-äure of formula (I) created, wherein a 4-C., .- alkyl-2., 3-dioxo-1-piperazinocarbonyl halide to a solution or suspension of ampicillin in a mixture of ethyl acetate and • water is added, in the presence of a Base. A reaction mixture is formed, which is stirred until the reaction is complete. The reaction mixture is then acidified and a crystalline product is separated off. The following improvement measures are taken:

(1) Addition of about 1 to 1.5 moles of a 4-C ₁ ^ "alkyl-2,3-dioxo-1-piperazinocarbonyl halide to a stirred suspension of about 1 mole of ampicillin and an appropriate amount of a suitable base in a solvent mixture which consists of about 9 to 12 parts by weight of water and about 0.5 to 8 parts by weight of ethyl acetate per part by weight of ampicillin, for at least 30 minutes at about 10 to 25 ° C, the pH held at about 6 to 8.3;

(2) further stirring of the reaction mixture at about 10 to 25 ° C for at least 15 min after the addition of the 4-C _l _ ^ - alkyl ~ 2,3-dioxo-1-piperazinocarbonylhalogenids in step (1);

(3) adding 0.05 to 0.2 parts by weight of activated charcoal and filter aid per part by weight of the ampicillin used in stage (1) and stirring the resulting mixture at 10 to 25 ^° C. for at least 10 minutes;

(4) Clarify the resulting mixture and wash it out the insoluble constituents with about 0.6 to 2.5 parts by weight of water / part by weight of that used in stage (1) Ampicillins;

(5) Combination of the mother liquor and the washing liquid of step (4) with about 2 to 12.5 parts by weight EthyXacetate / part by weight of ampicillin of step (1) on condition that the total amount of ethyl acetate in the Steps (1) and (5) about 10 to 13 parts by weight / part by weight Ampicillin, and heating the resulting mixture to about 15 to 25 ° C;

(6) acidifying the mixture obtained in step (5) to a pH of about 2.0 to 2.5 at about 15 to 25 ° C;

(7) Stir the acidified mixture for at least 1 hour at about 15 to 25 ° C before separating the resulting, crystalline product; and

(8) optionally converting the product to a pharmaceutically acceptable salt.

The process according to the invention leads to a yield of the end product of formula (I) of about

When carrying out the process according to the invention stirred a suspension of ampicillin in a mixture of water and ethyl acetate. The suspension contains about 9 to 12 and preferably about 10 to 11 parts by weight of water and about 0.5 to 8 and preferably about 4 to 6 parts by weight Ethyl acetate per part by weight of ampicillin. The ampicillin is defined as the anhydrous form of the compound (III).

An appropriate amount of a suitable base is added to this mixture. To ensure high yields the amount of base must be sufficient to bring the pH of the initial mixture to about 6 to 8.3 and preferably about 6 to 3 to 8 to bring and around the pH range during the subsequent addition of 4-C ^ _ ^ - alkyl-2,3-dioxo-1-piperazinocarbonyl halide maintain. The preferred method of adding the base is the initial Mixture with about 2.4 to 3.0 and preferably about 2.5 to 2.7 mol equiv. the base, such as sodium or potassium bicarbonate, to be added per mole of ampicillin. If these conditions are met, the following ' Addition of the carbonyl halide no change in pH. Alternatively, you can use a base such as potassium or sodium hydroxide or potassium or sodium carbonate, to bring the pH of the initial mixture to about 6 to 8.3 and preferably about 6.5 to 8. However, it must be borne in mind that the pH value is monitored afterwards and the pH range during the subsequent addition of the carbonyl halide is maintained. "The

pH must and must be monitored by direct measurement an appropriate acid or base is added or the pH value must be kept in the correct range, by adding an appropriate one to the initial reaction system Amount of a non-interfering buffer system clogs. The nature of such a buffer system can vary from easily determined by one of ordinary skill in the art.

The initial mixture is adjusted to a temperature of about 10 to -3 ° and preferably about 12 to 18 ° C. About 1 to 1.5 and preferably about 1.05 to 1.15 mol equiv. 4-C ₁ ^ alkyl-2,3-dioxc ~ 1 -piperazinocarbonylhalogenid the formula.

0
R-NN-CX · (IV)

0 0

where R is a C ^^ - alkyl group and X is fluorine, chlorine, bromine or iodine. The compound of the formula (IV) is added to the aforementioned mixture over a period of at least 30 minutes, and preferably over 40 to 60 minutes, while the reaction mixture is kept at the above temperature, namely at a pH of about 6 to 8.3, and preferably about 6.5 to 8. In a preferred process, the compound of Formula (IV) is 4-C _1- ^ alkyl-2,3-dioxo-1-piperazinocarbonyl chloride; 4-Ethyl-2,3-dioxo-i-piperazinocarbonyl chloride is particularly preferred.

The resulting mixture is kept at the same for at least 15 minutes Temperature and stirred at the same pH, preferably about '' 0 to 30 min, after the addition of the Compound of formula (IV). The reaction mixture is then about 0.05 to 0.2, and preferably about 0.08 to

1 part by weight activated carbon / weight Part of the originally ■ put ampicillins treated. The activated carbon can be, for example, activated carbon of the type RB Activated Carbon (Pittsburgh Coke, and Chemical Co.) and treated with about 0.05 to 0.2 and preferably about 0.1 to 0.15 parts by weight of a filter aid such as ITyflo ^ Super-Cel (Johns-Manvilie Gales Corp.) per 1 part by weight of the initially used ampicillins. The mixture obtained is then kept at the same temperature during stirred for at least 10 minutes and preferably for about 15 to 20 minutes.

The insolubles are then separated from the reaction mixture in a conventional manner. The preferred one The method of separation is filtration. The filter cake is about 0.6 to 2.5 and preferably about 1.0 to 1.2 parts by weight of water / part by weight of the original used ampicillins washed. The washing liquid is then mixed with the mother liquor of the filtration process combined and about 2 to 12.5 and preferably about 6 to 7 parts by weight of ethyl acetate / part by weight of the originally used Ampicillins are added. The condition is met that the total amount of ethyl acetate including the ethyl acetate in the original reaction mixture about TO to 13 and preferably about 11 Ms 1?. Parts by weight / part by weight of the originally used Ampicillins is.

The resulting mixture is heated to about 15 to 25 ° and preferably about 18 to 22 ⁰ C at this temperature to a pH of about 2.0 to 2.5 and preferably about 2.2 to 2.5 with. diluted mineral acid how ? am 5N hydrochloric acid or sulfuric acid, "acidified.

- he -

The acidified reaction mixture is then stirred at the same temperature for at least 1 hour and preferably for about 2 to 3 hours, and the crystals obtained are in a known manner, e.g. by filtration or centrifugation. The crystals are then washed with water and dried. The orwUn-schtc product is obtained in the form of the free acid in a yield of about 9k to 96.6. This free acid can be hydrated to various degrees.

The choice of ethyl acetate as solvent is critical and also the relative concentration of ethyl acetate during the crystallization step. Control of pH during the reaction and crystallization stages is also critical. Changes in the stated ranges of these factors will either result in a decrease the final yield or a poorer crystal structure and possibly even an amorphous mass without any crystal structure. In such a case, isolation and purification of the final product is time consuming and expensive.

The free acid obtained in this way can be converted into a. pharmaceutically acceptable salt are converted by known methods. Pharmaceutically acceptable O salts are ".B. Alkali metal salts, alkaline earth metal salts, Ammonium salts, salts of N-methylglucamine, etc .. That Sodium salt is preferred. It is preferably obtained by treating the compound of formula (I) with a equivalent amount of sodium bicarbonate in water.

All temperature data relate to the Celsius syatom. Percentages relate to weight and moles relate to g-mol. The term "equivalent" refers to the amount of a reagent which,

^{::: ..:} .... 3208 5th floor al

expressed in moles, equal to the amount expressed in moles of the preceding or the subsequent reactant in the respective preparation or in the respective example is. The molar data relate to the final weight or volume.

In the following, a preferred embodiment of the invention Procedure are explained. This includes the following levels:

(1) about 1.05 to 1.15 mole of the 4-C ₁ _ ₄ ~ alkyl-2,3-dioxo-1-piperazinocarbonylhalogenids of formula (IV) are added to a suspension containing 2.5 to 2.7 MoI-. Equiv. contains an appropriate base in a solvent mixture. The solvent mixture consists of about 10 to 11 parts by weight of water and about 4 to 6 parts by weight of ethyl acetate per part by weight of ampicillin. The addition takes place over the course of about 40 to 60 minutes at about 12 to 18 ° C., the pH being maintained at about 6.5 to 8;

(2) the reaction mixture is continued for about 20 to 30 minutes at about 12 to 18 ⁰ C;

(3) The reaction mixture is treated with about 0.08 to 0.1 parts by weight of activated carbon and about 0.1 to 0.1 ^r j parts by weight of a filter aid per part by weight of ampicillin originally used. The resulting mixture is stirred at about 12 to 10 ° C. for about 15 to 20 min /;

(4) After clearing, the insoluble components become with about 1.0 to 1.2 parts by weight of water / part by weight Ampicillin washed; ·

(5) the mother liquor and the washing liquid are combined and mixed with about 6 to 7 parts by weight of ethyl acetate / part by weight of the ampicillin originally used. The resulting mixture is heated to about 10 to 22 ° C heated, provided that the total amount of ethyl acetate, which in steps (1) and (5) is used, about 11 to 12 parts by weight, based on.

the ampicillin originally used is ;.

(6) the reaction ^{equipment is acidified at about 18 to 22 0} C to a pH of about 2.2 to 2.3;

(7) the acidified reaction mixture becomes about

Stirred for 2 to 3 h at about 18 to 22 ° C before the crystalline, separates free acid; and

. (8) the free acid is optionally dissolved in water at a concentration of about 13.125% (weight of anhydrous free acid / volume of the water). Now you gradually give about 1 mole equiv. Add alkali metal bicarbonate. The reaction mixture is

Stirred 3 to 4 h at 6 + 4 ° C until the pH value at least 6.5 has dropped. Only then does the alkali metal salt become of the product of the formula (I) separated. '

The invention is explained in more detail below with the aid of examples explained. All partial data relate, if, nothing else is stated on the weight.

example 1

Preparation of 6- [D (- ^ - oc- (4-AtIIyI ^, 3-dioxo-i-piperazino carbonylamino) -phenylacetamido1-penicillanic acid monohydrate

A slurry of 27.00 grams of ampicillin trihydrate (equivalent to 22.86 grams (0.0654 moles) of anhydrous ampicillin), 14.50 grams (0.1726 moles) of sodium bicarbonate, 238 grams of Was-Mr unil 119 / ■; Allyl acetate is stirred at 15 ° C. and 2 ° C. and 14.73 g (0.0720 mol) of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride are added to such an extent that the pH remains above 6 and the temperature rises 15 + 2 ° C is maintained. After the addition has ended, the reaction mixture is stirred for 20 min at 15 + 2 ° C. and 2.1 g of activated carbon (type RB Activated Carbon; Pittsburgh Coke and Chemical Company) and 3.0 g of filter aid (Hyflo ' ^R ^ Super-Cel; Johns-Manville Sales Corp.) are added. The mixture is stirred for a further 10 min and the solids are filtered off and

A ¹ S

washed with 26 g of water. The filtrate and the washing liquid are combined and mixed with 142.5 g of ethyl acetate. The temperature of the mixture obtained is adjusted to 20 to 22 ° C. and the pH is adjusted to 2.3 by adding ΓΝ hydrochloric acid. The acidic mixture is stirred for 2.5 hours at 20 to 22 ° C. and the crystalline precipitate is isolated by filtration, washed with 1.50 g of water and dried. 55, h ') g (95.58 μs of theory) of the desired product are obtained.

Example 2

Preparation of the sodium salt of 6- [D (-) '- a- (4-ethyl-2,3-dioxo-1-piperazincarbonylaminoO-phenylacetamido] -penicil lanic acid ■

13.5 g of the product from Example 1 (0.025 mol, equivalent to 13.125 g of the anhydrous, free acid) are dissolved in 100 ml of water and the solution is stirred at 6 + 4 ° C with 2.06 g sodium bicarbonate in 10 increments of 0.206 g each (0.025 mol of sodium bicarbonate, equivalent to 15.685% (w / w) of the anhydrous, free 3 acid). The reaction proceeds, now in the course of 3 to 4 hours, until the pH drops to at least 6.5. The reaction mixture is sterilized by cold filtration, filled into aseptic ampoules and lyophilized. White or pale yellow crystals are obtained. • ■ Sodium salt of 6- [D (-) - oc- (4-ethyl-2, 3-dioxo-i-pipernzinocnrbonylamino) -phenylacetainido J-pen i ο i 1 lansäiire.

Claims (1)

Claims 1. Process for the preparation of a 6- [D (-) - <x- (4-C, ^ j. -Alkyl-2,3-dioxo-1 -piperazinocarbonylamino) -phenylacetamido] -penicillanic acid, in which a 4- C _1- ^ -AlKyI-2,3-dioxo-1-piperazinocarbonyl halide is added to a solution or suspension of ampicillin in a mixture of ethyl acetate and water, in the presence of a base to form a reaction mixture which is stirred until the reaction is complete whereupon the reaction mixture is acidified and the crystalline product is isolated, characterized by the following stages: (a) Adding about 1 to 1.5 moles of 4-C ₁ __ ^ - alkyl-2,3-dioxo-1-piperazinocarbonyl halide to a stirred suspension of about 1 mole of ampicillin and an appropriate amount of a suitable base in one Solvent mixture, consisting of about 9 to 12 parts by weight of water and about 0.5 to 8 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of at least 30 min at about 10 to 25 ⁰ C while maintaining a pH in the range of about 6 to 8.3; (b) Stir the reaction mixture with about 10 hl. ··. 25 ° C for at least 15 minutes after the end of the 'addition doo 4-C. ι-Alkyl - ?, 3-dioxo-1-piperazlnocarbonylhalogen Ida in Stage (a); · (c) adding to the Reaktionsmischung- each with about 0.05 to 0.2 parts by weight of activated carbon and filter aid per part by weight of ampicillin and stirring used in stage (a) of the formed mixture at about 10 to 25 ⁰ C "during at least 10 min; (d) Clarifying the resulting mixture and washing the insoluble components with about 0.6 to 2.5 parts by weight 32Ü85ÜG len water / part by weight of the ampicillin used in stage (a); (e) Combination of the mother liquor and the washing liquid obtained in stage (d) with about 2 to 12.5 parts by weight / part by weight of the ampicillin used in step (a), with the proviso that the total amount of ethyl acetate of steps (a) and (e) about 10 to 13 parts by weight / part by weight of the ampicillin, followed by heating the resulting mixture to about 15-25 ° C; (f) acidifying the mixture obtained in step (e) to about pH 2.0 to 2.5 at about 15 to 25 ° C; and (g) stirring the acidified mixture for at least 1 h at about 15 to 25 ^° C. before separating off the crystalline, free acid formed; and (h) optionally converting the free acid to a pharmaceutically acceptable salt. 2. Improved method according to claim 1, characterized through the following stages: (a) Addition of about 1.05 to 1.15 mol of 4-C _1- ^ -Alky1-2,3-dioxo-1-piperazinocarbony halide to a suspension of 2.5 to 2.7 mol equivalents. a base in a solvent mixture consisting of about 10 to 11 parts by weight of water and about 4 to 6 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of about. 40 to 60 minutes at about 12 to 18 ° C while maintaining a pH of about 6.5 to 8; (B) further stirring of the reaction mixture while. rend about 20 to 30 minutes at about 12 to 18 ° C; (c) Handling of the reaction mixture with about 0.03 to 0.1 parts by weight of activated carbon and about 0.1 to 0.15 parts by weight of filter aid per part by weight of the amicillin used in step (a) and stirring the mixture obtained wiilirond el.wn Λ ^Γ > up to 20 min at about 12 to 1R ° C; 3205506 (d) Washing the insoluble constituents with about 1.0 to 1.2 parts by weight of water / part by weight of des in ntufe (a) ampicillins used; . (e) Association of the mother liquor and the washing liquid having about 6 to 7 parts by weight Äthylacebit / Oew. part ampicillin step (a) and heating the mixture to about 18 to 22 ⁰ C, under the condition where the dai3 The total amount of ethyl acetate of steps (a) and (e) is about 11 to 12 parts by weight / part by weight of ampicillin; (f) acidifying the reaction mixture at about 18 to 22 ° C to a pH of about 2.2 to 2.3; (g) stirring des.angesäuerten reaction mixture at about 18 to 22 ⁰ C for about 2 to 3 hours, separating the crystalline free acid, washing with water and drying; and (h) optionally dissolving the free acid in water to a concentration of about 131.25 g anhydrous free acid / liter of water, followed by a gradual addition of about 1 mole equiv. Alkali metal bicarbonate, after which the mixture is stirred for about 3 to 4 h at about 6 + 4- ⁰ C until the pH drops to at least 6.5 * before the alkali metal salt of the product of the formula (I) is separated off. 3. The method according to any one of claims 1 or .2, characterized in that the 4-C. λ-alkyl- «?, 3-dioxo-ipiperazinocarbonyl halide is a 4-C ^ _ ^ - alkyl-2,3-dloxo-1-piperazinocarbonal chloride. · ' 4. The method according to any one of claims 1 or 2, characterized in that the 4-C ₁ _ _i ^ -alkyl -?., 3-dioxo-1-piperazinocarbonyl halide is a 4-ethyl-2,3-dioxo ~ 1-piperazinocarbonyl chloride is. -V- ü. Method according to one of Claims 1 or 2, characterized characterized in that the product is converted to the sodium salt. 6. ·. Product obtained according to one of claims 1 until 5.