NZ199869A

NZ199869A - Preparation of 6-(d(-)-alpha-(4-c1-4-alkyl-2,3-dioxo-1-piperazinocarbonylamino)-phenyl-acetamido)-penicillanic acids

Info

Publication number: NZ199869A
Application number: NZ199869A
Authority: NZ
Inventors: D C Boop; K F Bernady
Original assignee: American Cyanamid Co
Priority date: 1981-03-30
Filing date: 1982-03-01
Publication date: 1985-07-31
Also published as: IE52907B1; SE452767B; GR76054B; DK161079C; FR2502623B1; PL235508A1; GB2095661A; ES8306376A1; ATA93082A; SE8201998L; DE3208506C2; ES509424A0; CH654309A5; BE892586A; AU7996482A; AT381706B; PH19765A; CA1200239A; DK161079B; GB2095661B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 99869 1 99869 fittests): r9J......... Complete Specification Filed: Class: ..£e7£ft?.7 Publication Date: ..... 5.1JUL19A5,. P.O. Journal No: - hs cs NEW ZEALAND PATENTS ACT, 1953 No.: Date: R- "fv COMPLETE SPECIFICATION PROCESS FOR PREPARING 6-[D- (-)-ALPHA-(4-C1-C4-ALKYL-2,3-DIOXO-l-PIPERAZINOCARBONYL-AMINO)-PHENYLACETAMIDO]PENICILLANIC ACIDS }C/We, AMERICAN CYANAMID COMPANY, a corporation organized and existing under the laws of the State of Maine, United States of America, and having its executive offices at Wayne, New Jersey, United States of America, hereby declare the invention for which K/ we pray that a patent may be granted to mx/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by jLa) - la - 199869 IMPROVED PROCESS FOR PREPARING 6-[D(-)-alpha-(4-Ci-C&-ALKYL-2,3-DIOXO-1-PIPERA2IN0CARB0NYLAMIN0)PHENYL-ACETAMIDO]PENICILLANIC ACIDS BACKGROUND OF THE INVENTION Field of Invention The present invention relates to a novel improved process for the preparation of 6-substituted penicillanic acids. More particularly, it relates to an improved process for the preparation of 6-[D(-)-alpha-(4-alkyl-2,3-dioxo-1-piperazinocarboxy1amino)phenylacetamido]penicillanic acids of Formula (I) 0 H H 0 H II I I i! I R-N N-C-N-C-C-N- /W 0 0 ch3 ^ch3 0 -N -CO2H H (I) wherein R represents C1-C4 alkyl. These compounds are useful as antibiotics for the treatment of pneumonia, peritonitis, and blood system infections. Description of Prior Art Saikawa e£ al^. disclose in U.S. Patent 4,112,090 a process for preparing 6-substituted penicillanic acids of formula (I) by reacting a 4-C1-C4 alkyl-2,3-dioxo-l-piperazinocarbonyl chloride of Formula II 1998 6$ - 2 - wherein R is C1-C4 alkyl, with 6 —[D(-)-alpha-amino-phen-ylacetamido]penicillanic acid trihydrate, represented by Formula (III). 10 15 20 25 30 H H -N. H ^CH3 0 ' 3H20 \ ■G02H H (III) The anhydrous form of (III) is hereafter referred to as ampicillin. In Example 23 of this reference, a suspension of (III) in a mixture of 10 parts water and 4.5 parts by weight of ethyl acetate per part by weight of compound III is cooled to 2°C, admixed with 2 molar equivalents of potassium carbonate at 2-3°C for several minutes, admixed with 1 molar proportion of a compound of formula (II).wherein R is methyl^at 2-3°C over a period of 10 minutes, and further reacted at said temperature for 15 minutes. The reaction mixture is clarified to remove some insolubles and the mother liquor is mixed with an additional 18 parts by weight of ethyl acetate per part by weight of compound III originally charged. The resulting mixture is then acidified with 1 molar equivalent of 2N HC1 at 20-22°C over a period of 5 minutes, and stirred at 20-22°C for 5 hours. The crystals which precipitate are collected, washed successively with water and isopropanol, and dried to obtain a dihydrate of 6-[D(-)-alpha-(4-methyl-2,3-dioxo-1-piperazinocarbonylimino)phen-ylacetamidojpenicillanic acid in a yield of 75.4%. In a similar example, a monohydrate of 6-[D(-)-alpha-(4-ethyl--2,3-dioxo-1-piperazinocarbony1amino)phenylacetamido]penicillanic acid is obtained in a yield of 84.8% with the compound of Formula (II) wherein R = ethyl. There is a need for an improved process which significantly increases the yield obtained. The present invention provides such a process, with a final yield of about 95%. - 3 - 199863 SUMMARY OF THE INVENTION The present invention provides an improvement in a process for preparing a 6-[D(-)-alpha-(4-C^-C^ alkyl--2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido] penicillanic acid of Formula (I) wherein a 4-C^-C^ alkyl-2,3-dioxo-l-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, the resulting mixture is agitated until the reaction is completed, the reaction mixture is acidified, and a crystalline product is recovered therefrom; said improvement corrprising: (1) adding substantially 1-1.5 molar proportions of a 4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarboryl halide to an agitated suspension of about one molar proportion of ampicillin and an appropriate amount of a suitable base in a solvent mixture consisting of substantially 9-12 parts by weight of water and substantially 0.5-8 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of at least 30 minutes, at substantially 10°-25°C, while maintaining a pH of substantially 6-8.3; (2) further agitating the reaction mixture at substantially 10°-25°Cfor at least 15 minutes upon completing the addition of the 4-C.^-C^ alkyl-2,3-dioxo-l-piperazino-carbonyl halide in step (1); (3) adding to the reaction mixture substantially 0.05-0.2 part by weight each of an activated carbon and a filter-aid per part by weight of ampicillin charged in step (1), and agitating the resulting mixture at substantially 10°-25°Cfor at least 10 minutes; (4) clarifying the resulting mixture, and washing the insoluble materials with substantially 0.6-2.5 parts by weight of water per part by weight of ampicillin charged in step (1); (5) combining the mother liquor and wash liquor obtained in step (4) with substantially 2-12.5 parts by weight ethY1 acetate per part by weight of ampicillin charged in G§.£\ep (1) , with the proviso that the total amount of ethyl 'V.'l - 4 - 199869 acetate used in steps (1) and (5) is substantially 10-13 parts by weight per part by weight of said ampicillin, and warming the resulting mixture to substantially 15°-25°C. (6) acidifying the mixture obtained in step (5) to substantially 15°-25°C to a pH of substantially 2.0-2.5; (7) agitating the acidified mixture for at least one hour at substantially 15°-25°C, before collecting the resulting crystalline product; and (8) optionally converting the product to a pharmaceutically acceptable salt. The process of the present invention results in about a 95% yield of the product of Formula (I) . DETAILED DESCRIPTION OF THE INVENTION In carrying out the process of this invention, a stirred suspension of ampicillin in a mixture of water and ethyl acetate is prepared in amounts to provide substantially 9-12, preferably substantially 10-11, parts by weight of water and substantially 0.5-8, preferably substantially 4-6, parts by weight of ethyl acetate per part by weight of ampicillin. Ampicillin is defined as the anhydrous form of Compound III. To this mixture is added an appropriate amount of a suitable base. In order to insure the high yields of the present invention, the amount of base must be sufficient to bring the pH of the initial mixture to substantially 6-8.3, preferably substantially 6.5-8, and to maintain the pH range during the subsequent addition of the 4-C^-C^ alkyl-2,3-dioxo-1-piperazinocarbonyl halide. The preferred method of adding base is to charge the initial mixture with substantially 2.4-3.0, preferably substantially 2.5-2.7, molecular equivalents of a base such as sodium or potassium bicarbonate per mole of ampicillin charged. With this method the subsequent addition of the carbonyl halide will not induce a pH change. Alterna- - 1 tively, a base such as, e.g., potassium or sodium hydroxide or potassium or sodium carbonate may be used to bring the pH of "teethe initial mixture to substantially 6-8.3, preferably substantially 6.5-8, but care must be taken thereafter to monitor i; the pH and to maintain this pH range during the subsequent addi- 199863 - 5 - tion of the carbonyl halide. The pH may be monitored by direct inspection and addition of appropriate acid or base or the pH may be maintained at the proper range by the addition to the initial reaction system of an appropriate non-interfering buffer system, which buffer system is readily determined by those skilled in the art. The initial mixture is adjusted to a temperature of substantially 10-25°C, preferably substantially 12-18°C, to which is added substantially 1-1.5, preferably substantially 1.05-1.15, molecular proportions of a 4-C^-C^alkyl--2,3-dioxo-l-piperazinocarbonyl halide of the formula: 0 wherein R is C^-C^ alkyl and X is fluoro, chloro, bromo, or iodo. The compound of Formula IV is added to the mixture over a period of at least 30 minutes, preferably over substantially 40-60 minutes, while maintaining the reaction mixture at the above-stated temperature and a pH of substantially 6-8.3, preferably sybstantially 6.5-8. In the preferred process the compound of Formula IV is 4-C^-C^ alkyl-2,3-dioxo-l-piper-: azinocarbonyl chloride; 4-ethyl-2,3-dioxo-l-piperazinocarbonyl chloride is particularly preferred. The resulting mixture is stirred at said temperature and pH for at least 15 minutes; and preferably for substantially 20-30 minutes, after completion of the addition of the compound of Formula IV. The reaction mixture is then treated with substantially 0.05-0.2, preferably substantially 0.08-0.1, part by weight of an activated carbon such as, e.g., activated charcoal or Type RB Activated Carbon (Pittsburgh Coke and Chemical Co.), and substantially 0.0 5-0.2, preferably substantially 0.1-0.15, part by weight of a filter aid such as, e.g., Hyflo® Super-Cel (Johns-Manville Sales Corp.), per part by.weight of ampicillin originally charged. The resulting / mixture is then stirred at said temperature for at least 10 - 6 - 199863 minutes, and preferably for substantially 15-20 minutes. The insolubles are then separated from the reaction mixture by conventional methods well known to those skilled in the art. The preferred method of separation is filtration. The filter cake is washed with substantially 0.6-2.5, preferably substantially 1.0-1.2, parts by weight of water per weight of ampicillin originally charged. The wash liquor is then combined with the mother liquor obtained from the filtration process and substantially 2-12.5, preferably substantially 6-7, parts by weight of ethyl acetate per part by weight of ampicillin originally charged is added thereto, with the proviso that the total amount of ethyl acetate used, including the ethyl acetate in the original reaction mixture, is substantially 10-13, preferably substantially 11-12, parts by weight per part by weight of ampicillin originally charged. The resulting mixture is warmed to substantially 15-25°C, preferably to substantially 18-22°C, and acidified at said temperature to a pH of substantially 2.0-2.5, preferably substantially 2.2-2.3, with dilute mineral acid, e.g. 2-5 N hydrochloric or sulfuric acid. The acidified reaction mixture is then stirred at said temperature for at least one hour, preferably for substantially 2-3 hours, and the resulting crystals are collected by means well known to those skilled in the art, such as, e.g. , by filtration or centrifugation. The crystals are then washed with water and dried to obtain the desired free acid product in a yield of about 94-96%. This free acid may be hydrated in varying degrees. The choice of ethyl acetate as a solvent is critical, as is the relative concentration of ethyl acetate during the crystallization step. Control of the pH during the reaction and crystallization stages is also critical. Variation of the stated ranges of these factors will either decrease the ultimate yield or result in an inferior crystallization structure, ossibly even resulting in an amorphous mass with no crystalline si^ucture at all, which makes isolation and purification of ■' o r m 7 199869 the final product time-consuming and expensive. The free acid obtained above may be converted to a pharmaceutically acceptable salt by procedures well known to those skilled in the art. Pharmaceutically acceptable salts include, e.g., alkali metal, alkaline earth metal, ammonium, N-methylglucamine, etc. The sodium salt is preferred and is preferably obtained by treatment of the compound of Formula (I) obtained by the above process with an equivalant amount of sodium bicarbonate in water. stated to the contrary, all temperatures and temperature ranges refer to the centigrade system. The term percent or (%) refers to the weight percent and the terms mole and moles refer to gram moles. The term equivalent refers to a quantity of reagent equal in moles to the moles of the preceding or succeeding reactant cited in that particular preparation or example in terms of moles of finite weight or volume. DESCRIPTION OF THE PREFERRED.EMBODIMENT The present invention also provides for a preferred improved process, wherein (1) substantially 1.05-1.15 molar proportions of the 4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarbonyl halide of Formula IV is added to a suspension containing 2.5-2.7 molar equivalents of an appropriate base in a solvent mixture consisting of substantially 10-11 parts by weight of water and substantially 4-6 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of substantially 40-60 minutes at substantially 12-18°C, while'maintaining a pH of substantially 6.5-8; (2) the reaction mixture is further agitated at substantially 12°-18°C for substantially 20-30 minutes; (3) the reaction mixture is treated with substantially 0.08-0.1 part by weight of an activated carbon and substantially 0.1-0.15 part by weight of a filter-aid per part by weight of ampicillin originally charged and the ^resulting mixture is agitated at substantially 12°-18°C for substantially 15-20 minutes; As used hereinabove and below unless expressly S5 A - 8 - (4) after clarification, the insoluble materials are washed with substantially 1.0-1.2 parts by weight of water per part by weight of ampicillin; (5) the mother liquor and wash liquor are combined with substantially 6-7 parts by weight of ethyl acetate per part by weight of ampicillin originally charged, and the resulting mixture is warmed to substantially 18°-22°C, with the proviso that the total amount of ethyl acetate used in steps (1) and (5) is substantially 11-12 parts by weight of ampicillin originally charged; (6) the reaction mixture is acidified at substantially 18°-22°C to a pH of substantially 2.2-2.3; (7) the acidified reaction mixture is agitated at substantially 18°-22°C for substantially 2-3 hours, before collecting the crystalline 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 water), to which is gradually added about one molar equivalent of alkali metal bicarbonate; the reaction mixture is stirred for 3-4 hours at 6°±4° until the pH drops to at least 6.5, before collecting the alkali metal salt of the product of Formula (I). A further understanding of the invention can be had from the following non-limiting examples. All parts are by weight unless otherwise indicated. Example 1 Preparation of 6-[D(-)-alpha-(4-Ethyl-2,3-dioxo-l-piperazino-carbonylamino)phenylacetamido]penicillanic Acid Monohydrate To an agitated slurry of 27.00 grams of ampicillin trihydrate (equivalent to 22.86 grams (0.0654 mole) of real anhydrous ampicillin), 14.50 grams (0.1726 mole) of sodium bicarbonate, 238 grams of water, and 119 grams of ethyl acetate, all at 15±2°C, is added 14.73 grams (0.0720 mole) of 4-ethyl-2,3-dioxo-l-piperazinocarbonyl chloride at a rate to maintain a pH greater than 6 and a temperature of 15 ± 2°C. Upon completion of the addition, the reaction mixture is agitated at 15 ± 2°C for 20 minutes, and 2.1 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 1 9 98 6 - 9 - grams of activated carbon (Type RB Activated Carbon; Pittsburgh Coke and Chemical Company), and 3.0 grams of a filter--aid (Hyflo® Super-Cel; Johns-Manville Sales Corp.) are added thereto. The^mixture is stirred for an additional 10 5 minutes, and the solids are removed by filtration and wwashed with 26 grams of water. The filtrate and wash liquor are combined and then mixed with 142.5 grams of ethyl acetate. The temperature of the resulting mixture is adjusted to 20-22°C, and the pH is adjusted to 2.3 by the 10 addition of 2N hydrochloric acid thereto. The acidified mixture is agitated at 20-22°C for 2.5 hours and the crystalline precipitate is isolated by filtration, washed with 120 grams of water, and dried to obtain 33.49 grams (95.58% of theoretical) of the desired product; 15 Example 2 Preparation of 6-[D(-)-alpha-(4-Ethyl-2,3-dioxo-l-pipera-zinocarbonylamino) phenyl acetamidojpenicillanic Acid, Sodium Salt 13.5 g. of the product of Example 1 (0.025 moles, 20 equivalent to 13.125 g. of the anhydrous free acid) is dissolved in 100 milliliters of water, and to the stirred solution at 6°+4°C is added 2.06 grams of sodium bicarbonate (0.025 moles, equivalent to 15.685% w/w of the anhydrous free acid) in 10 increments of 0.206 grams each. The reac-25 tion is allowed to proceed until the pH drops to at least 6.5, a period of 3-4 hours. The reaction mixture is sterilized by cold filtration, filled into asceptic vials and lyophilized to produce white or pale yellow crystals of 6 — [D( — )-alpha-(4-ethyl-2,3-dioxo-1-piperazinocarbony1amino) 30 phenylacetamido]penicillanic acid, sodium salt. - 10 - 199863 WHAT WE CLAIM IS:

1. In a process for preparing a 6-[D(-)-alpha--(4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarbonylamino)-phenyl-acetamido]penicillanic acid wherein a 4-C^-C^ alkyl-2,3--dioxo-l-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, the resulting mixture is agitated until the reaction is completed, the reaction mixture is acidified, and a crystalline product is recovered therefrom; the improvement which comprises: (a) adding substantially 1-1.5 molar proportions of the 4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarbonyl halide to an agitated suspension of about one molar proportion of ampicillin and an appropriate amount of a suitable base in a solvent mixture consisting of substantially 9-12 parts by weight of water and substantially 0.5-8 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of at least 30 minutes at substantially 10-25°C while maintaining a pH of substantially 6-8.3; (b) further agitating the reaction mixture at substantially 10°-25°C for at least 15 minutes upon completing the addition of the 4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarbonyl halide in step (a); (c) adding to the reaction mixture substantially 0.05-0.2 part by weight each of an activated carbon and a filter-aid per part by weight of ampicillin charged in step (a) , and agitating the resulting mixture at substantially 10°-25°C for at least 10 minutes; (d) clarifying the resulting mixture, and washing the insoluble materials with substantially 0.6-2.5 parts by weight of water per part by weight of ampicillin charged in Step (a); (e) combining the mother liquor and wash liquor obtained in step (d) with substantially 2-12.5 parts by weight of ethyl acetate per part by weight of ampicillin charged in step (a), with the proviso that the total amount of ethyl acetate used in steps (a) and (e) is substantially 10-13 . n . 199869 parts by weight per part by weight of said ampicillin, and warming the resultinq mixture to substantially 15°-25°C; (f) acidifying the mixture obtained in step (e) at substantially 15°-25°C to a pH of substantially 2.0-2.5; and (g) agitating the acidified mixture for at least one hour at substantially 15°-25°C before collecting the resulting crystalline free acid; and (h) optionally converting the free acid to a pharmaceutically acceptable salt.

2. The improved process of Claim 1 wherein (a) substantially 1.05-1.15 molar proportions of 4-C.^-C^ alkyl-2,3-dioxo-l-piperazinocarbonyl halide is added to the suspension containing 2.5-2.7 molar equivalents of base in a solvent mixture consisting of substantially 10-11 parts by weight of water and substantially 4-6 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of substantially 40-60 minutes at substantially 12-18°C while maintaining a pH of substantially 6.5-8; (b) the reaction mixture is further agitated at substantially 12°-18°C for substantially 20-30 minutes; (c) the reaction mixture is treated with substantially 0.08-0.1 part by weight of an activated carbon and substantially 0.1-0.15 part by weight of a filter-aid per part by weight of ampicillin charged in Step (a), and the resulting mixture is agitated at substantially 12°-18°C for substantially 15-20 minutes; (d) the insoluble materials are washed with substantially 1.0-1.2 parts by weight of water per part by weight of ampicillin charged in Step (a) ; (e) the mother liquor and wash liquor are combined with substantially 6-7 parts by weight of ethyl acetate per part by weight of ampicillin charged in Step (a), and the resulting mixture is warmed to substantially 18°-22°C, with the proviso that the total amount of ethyl acetate used in steps (a) and (e) is substantially 11-12 parts-; by weight per part by weight of said ampicillin; (f) the reaction mixture is acidified at | 11 apr;SS5S,, V- J> 199869 - 12 - substantially 18°-22°C to a pH of substantially 2.2-2.3; (q) the acidified reaction mixture is agitated at substantially 18°-22°C for substantially 2-3 hours, before the crystalline free acid is collected, washed with water, and dried; and (h) the free acid is optionally dissolved in water at a concentration of about 131.25 g. anhydrous free acid per liter of water to which is gradually added about one molar eauivalent of alkali metal bicarbonate; the reaction mixture is stirred for substantially 3-4 hours at substantially 6°±4°C until the pH drops to at least 6.5, before collecting the alkali metal salt of the product of Formula (I).

3. The process of Claim 1 or 2, wherein the 4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarbonyl halide is 4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarbonyl chloride.

4. The process of Claim 1 or 2, wherein the 4-C^-C^ alkyl-2,3-dioxo-l-piperazinocarbonyl halide is 4-ethyl-2,3-dioxo-l-piperazinocarbonyl chloride.

5. The process of Claim 1 or 2, wherein the product is converted to the sodium salt.

6. The product of the process of Claim 1, 2, 3, 4 , or 5. DATED THIS DAY OF IB*";A . J. PARK & SON;psr 4-;AGENT 0 FOR THE APPLICANTS* </div>