FR2502623A1 - PROCESS FOR THE PREPARATION OF 6- (D (-) - ALPHA- (4-ALCOYL (EN C1 TO C4) -2,3-DIOXO-1-PIPERAZINOCARBONYLAMINO) PHENYLACETAMIDO) -PENICILLANIC ACIDS - Google Patents

Abstract

The object of the invention is an improved process for the preparation of penicillan acids substituted in position 6, in particular 6-D (-) - ALPHA- (4-ALCOYL (C1 to C4) -2,3-DIOXO- acids. 1-PIPERAZINO-CARBONYLAMINO) PHENYLACETAMIDOPENICILLANIQUES, AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS.

Description

The present invention relates to a new pro-

  yielded improved preparation of penicillanic acids

  substituted in position 6. More particularly, the invention

  tion relates to an improved process for the preparation of 6- / D () - alpha- (4-alkyl-2,3-dioxo-1-piperazino-carboxylamino) phenylacetamido7 penicillanic acids of formula

0 <HHOH

R-N N-C-N-C-C-N H ()

OH3 O o'N0 02H \ H

  in which R represents a C1 to C4 alkyl group.

  These compounds can be used in particular as antibiotics for the treatment of pneumonia, peritonitis and

  infections of the circulatory system.

  In the U.S. patent 4,112,090, Saikawa et al.

  describe a process for the preparation of penicillanic acids

  ques substituted in position 6 corresponding to formula (I) consisting in reacting a 4-alkyl chloride (C1 to C4) -2,3-dioxo-1piperazinocarbonyl of formula (II): o0 RN NC-Cl - (II ) in which R represents a C1 to C4 alkyl group,

  on acid 6- / D (-) - alpha-amino-phenylacetamido7penicilla-

  pic trihydrate, corresponding to formula (III):

H O.H H H.

He I SHCH

H2N --- C-N C NH3 3H20

t O.J. / CH3 3H20 Io "N02H

N H O :-( III)

  The anhydrous form of (III) is hereinafter called "ampi-

  cilline ". In example 23 of the aforementioned patent, a suspension

  of (III) in a mixture of 10 parts of water and 4.5 parts

  parts by weight of ethyl acetate per part by weight of compound (III) is cooled to 2 ° C., mixed with 2 molar equivalents of potassium carbonate at a temperature

  from 2 to 3 C for several minutes, mixed with 1 pro-

  molar portion of a compound of formula (II) in which R = methyl, at a temperature of 2 to 3 C for a period of 10 minutes, after which it is allowed to react

  this temperature for 15 minutes. The reaction mixture-

  nel is clarified in order to remove a few substances

  insoluble and the mother liquor is mixed with a supplement

  ment of 18 parts by weight of ethyl acetate per part by weight of compound (III) initially charged. The resulting mixture is then acidified using a molar equivalent of 2N HCl at a temperature of 20 to 22 C, for a period of 5 minutes, and is then stirred at a temperature of 20 to 22 C for 5 hours. The precipitating crystals are collected, washed successively with water and isopropanol, and dried, thus providing a

  6- / D acid dihydrate - (-) - alpha- (4-methyl-2,3-dioxo-1-

  piperazinocarbonylimino) phenylacetamido / penicillanic with a yield of 75.4%. In a similar example, we

  obtains a 6- / D acid monohydrate - (-) - alpha- (4-ethyl-

  2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido_ / peni-

  cillanic with a yield of 84.8%, using the

  compound of formula (II) in which R = ethyl.

  It is necessary to have a perfecti-

  which significantly increases the yield obtained.

  The present invention provides such a method, with a

final yield of about 95%.

  The subject of the present invention is a perfected process

  tioned with. preparation of a 6- / D (-) - alpha- (4-alkyl) acid

  (in C1 to C4) -2,3-dioxo-1-piperazinocarbonylamino) phenyl-

  acetamido7 penicillanic of formula (I), according to which

  a 4-alkyl halide (C1 to C4) -2,3-dioxo-1-pipéra-

  zinocarbonyl is added to a solution or suspension of ampicillin in a mixture of ethyl acetate and water

  in the presence of a base in order to obtain a reaction mixture

  nel, the resulting mixture is stirred until the reaction is complete, the reaction mixture is acidified and a crystalline product is collected therefrom, said process being characterized in that: (1) about 1 to 1.5 molar proportion

  of a 4-alkyl halide (C1 to C4) -2,3-dioxo-1-pipé

  razinocarbonyl to a stirred suspension of about a pro-

  molar portion of ampicillin and an appropriate amount

  a suitable base in a mixture of solvents

  killed by about 9 to 12 parts by weight of water and envi-

  0.5 to 8 parts by weight of ethyl acetate per part by weight of ampicillin, over a period of at least 30 minutes, at a temperature of approximately 10 to 25 ° C., while maintaining a pH of about 6 to 8, 3; (2) the reaction mixture is then stirred at a temperature of about 10 to 25 C for at least 15 minutes

  after the addition of the 4-alkyl halide (C1 to C4) -

  2,3-dioxo-1-piperazinocarbonyl in step (1); (3) adding the reaction mixture of approximately 0.05 to 0.2 parts by weight each of an activated carbon and a filtration agent per part by weight of ampicillin charged in stage (1), and stir the resulting mixture at a temperature of about 10 to 25 C for a period of at least 10 minutes; (4) the resulting mixture is clarified, and the insoluble substances are washed with the aid of approximately 0.6 to 2.5 parts by weight of water per part by weight of ampicillin charged in stage (1); (5) the mother liquor and the washing liquor obtained in stage (4) are combined with from approximately 2 to 12.5 parts by weight of ethyl acetate per part by weight of ampicillin charged in stage (1 ), provided that the total quantity

  of ethyl acetate used in stages (1) and (5) represented

  about 10 to 13 parts by weight per part by weight.

  said ampicillin, and the resulting mixture is brought to a temperature of about 15 to 25 C; (6) the mixture obtained in stage (5) is acidified, at a temperature of approximately 15 to 25 ° C., until a pH of approximately 2.0 to 2.5 is obtained; (7) the acidified mixture is stirred for at least one

  hour at a temperature of about 15 to 25 C, before re-

  picking the resulting crystalline product; and (8) optionally converting the product to a salt

pharmaceutically acceptable.

  The process according to the present invention results in

  state a yield of about 95% in the product of formula (I).

  During the implementation of the process according to the invention

  tion, a stirred suspension of ampicillin is prepared in a mixture of water and ethyl acetate in proportions

  making it possible to obtain approximately 9 to 12, preferably

  about 10 to 11 parts by weight of water and about 0.5 to 8, preferably about 4 to 6 parts by weight of acetate

  ethyl per part by weight of ampicillin. Ampicillin-

  is defined as the anhydrous form of the compound (III).

  This mixture is added by an appropriate amount

  from an appropriate base. In order to ensure that

  dements high achievable with the present invention, the amount of base must be sufficient to bring the pH

  of the initial mixture to a value of about 6 to 8.3, from pre--

  ference of about 6.5 to 8, and to keep the pH within these limits during the subsequent addition of the halide

  of 4-alkyl (C1 to C4) -2,3-dioxo-1-piperazinocarbonyl.

  The preferable mode of addition of the base is to charge the initial mixture with from about 2.4 to 3.0, preferably from about 2.5 to 2.7 molecular equivalents of a base such as sodium bicarbonate or potassium per mole

  charged ampicillin. When using this operating mode

  rake, the subsequent addition of the carbonyl halide

  does not cause a change in pH. You can also use

  serve as a base such as, for example, sodium or potassium hydroxide or potassium or sodium carbonate to bring the pH of the initial mixture to a value of about 6

  to 8.3, preferably about 6.5 to 8, but then

  Take care to monitor the pH and keep it within these limits during the subsequent addition of the carbonyl halide. The pH can be monitored by direct inspection and addition of an appropriate acid or base, or the pH can be kept within the appropriate limits by adding the initial reaction system to a buffer system not involved in the reaction, a buffer system easily determined by specialists in

the technique.

  The initial mixture is brought to a temperature of about

  from 10 to 250C, preferably from about 12 to 180C, and is added from about 1 to 1.5, preferably from about 1.05 to 1.15 molecular proportion of a halide of

  4-alkyl (C1 to C4) -2,3-dioxo-1-piperazinocarbonyl re-

according to the formula: o

R-N N-C -X (IV)

  in which R represents a C1 to C4 alkyl group, and X represents a fluoro, chloro, bromo or iodo radical. The compound of formula (IV) is added to the mixture over a period of at least 30 minutes, preferably approximately 40 to minutes, while maintaining the reaction mixture at the

  above temperature and at a pH of about 6 to 8.3, pre-

  ference of about 6.5 to 8. According to the preferred embodiment, the compound of formula (IV) is a 4-alkyl chloride (C1 to C4) -2,3-dioxo1-piperazinocarbonyl; 4-ethyl-2,3-dioxo-1piperazinocarbonyl chloride being

particularly preferable.

  The resulting mixture is stirred under the above temperature and pH conditions for at least 15 minutes, and preferably for about 20 to 30 minutes after the addition of the compound of formula (IV). Then the reaction mixture is treated with about 0.05 to 0.2 and preferably about 0.08 to 0.1 part by weight of an activated carbon such as, for example, activated carbon. or "Type RB Activated Carbon" (Pittsburgh Coke and Chemical Co.), and about 0.05 to 0.2 and, preferably,

  from about 0.1 to 0.15 parts by weight of a wire aid

  tration as, for example, Hyflo Super-Cel (Johns-Manville

  Sales Corp.), per part by weight of initial ampicillin-

  loaded. The resulting mixture is then stirred at

  said temperature for at least 10 minutes, and pre-

  ference for about 15 to 20 minutes.

  The insoluble substances are then separated from the reaction mixture, according to standard operating procedures.

  known to those skilled in the art. The mode of separation

  preferable ration is filtration. We wash the cake

  filter using about 0.6 to 2.5, preferably approx.

  1.0 to 1.2 parts by weight of water per part by weight of ampicillin initially charged. Then we bring together the

  washing liquor with mother liquor resulting from the filtration

  tion and about 2 to 12.5 is added, preferably about

  about 6 to 7 parts by weight of ethyl acetate per part by weight of ampicillin initially charged, subject to

  than the total amount of ethyl acetate used, including

  taken ethyl acetate from the initial reaction mixture

  tial is about 10 to 13 and preferably about

  about 11 to 12 parts by weight per part by weight of amp

initially charged cillin.

  The resulting mixture is brought to an ambient temperature

  about 15 to 25 C, preferably about 18 to 22 C, and it is acidified at this temperature until a pH of about 2.0 to 2.5 is obtained, preferably about 2, 2 to 2.3, using a dilute mineral acid, for example acid

  hydrochloric or sulfuric from 2 to 5N.

  The acidified reaction mixture is then stirred,

  this temperature, for at least one hour, preferably

  this for a period of approximately 2 to 3 hours, and the resulting crystals are collected by means well known to those skilled in the art, for example by

  filtration or centrifugation. After which we wash the cris

  rate with water and dried, thereby obtaining the desired product, in the form of free acid, with a yield of about 94 to 96%. This free acid can be hydrated to

varying degrees.

  The choice of ethyl acetate as a solvent is important.

  critical lift, as does the relative concentration of ethyl acetate during the crystallization stage. Monitoring pH during the reaction and crystallization stages is also of critical importance. The variation of the limits indicated for these factors has the effect either of reducing the final yield, or of achieving a structure of crystallization of inferior quality which can even result in obtaining a mass

  without any crystal structure, which means that the iso-

  and the purification of the final product takes time.

time and are expensive.

  The free acid obtained above can be converted into

  a pharmaceutically acceptable salt, by procedures

  roofs well known to those skilled in the art. Examples of pharmaceutically acceptable salts that may be mentioned are the alkali metal, alkaline earth metal, ammonium, N-methylglucamine, etc. salts. The sodium salt is preferable and is preferably obtained by treatment of the compound of formula (I) obtained by the above process with an equivalent amount of sodium bicarbonate in

some water.

  Unless otherwise stated, all temperatures and

  temperature ranges are expressed in Centigrade degrees.

  By percentage (%) we mean the weighted percentage

  ral and by mole (s) we mean gram-molecules.

  By "equivalent" is meant a quantity of reagent equal, in moles, to the moles of the preceding or following reagent

  indicated in the preparation or example concerned in ter-

  mes de moles having a well defined weight or volume.

  According to the preferred embodiment of the present invention:

  (1) about 1.05 to 1.15 molar proportions are added

  re 4-alkyl halide (C1 to C4) -2,3-dioxo-1-

  piperazinocarbonyl of formula (IV) to a suspension

  holding from 2.5 to 2.7 molar equivalents of a suitable base in a mixture of solvents consisting of from about 11 parts by weight of water and from about 4 to 6 parts

  by weight of ethyl acetate per part by weight of ampicill-

  line, in a period of about 40 to 60 minutes, at a temperature of about 12 to 18 C, while maintaining the pH at a value of about 6.5 to 8;

  (2) then the reaction mixture is stirred at a temperature

  rature of about 12 to 18 C for a period of approxi-

ron. 20 to 30 minutes;

  (3) the reaction mixture is treated with about

  ron 0.08 to 0.1. part by weight of an activated carbon and

  about 0.1 to 0.15 parts by weight of a filter aid

  tion per part by weight of ampicillin initially loaded

  and the resulting mixture is stirred at a temperature of about

  ron 12 to 18 C, for a period of about 15 to 20 minutes;

  (4) after clarification, the insoluble substances are washed

  soluble using about 1.0 to 1.2 parts by weight of water

  per part by weight of ampicillin; -

  (5) the mother liquor and the washing liquor are combined with approximately 6 to 7 parts by weight of ethyl acetate per part by weight of ampicillin initially charged, and the resulting mixture is brought to a temperature d '' around 18 to 22 C, provided that the total amount of acetate

  ethyl used in stages (1) and (5) represents about

  11 to 12 parts by weight per part by weight of ampicill-

line initially loaded;

  (6) the reaction mixture is acidified, at a temperature

  ture of around 18 to 22 C, until a pH of approx.

  ron 2.2 to 2.3; (7) the acidified reaction mixture is stirred at a temperature of about 18 to 22 ° C., for a period of approximately 2 to 3 hours, before collecting the free crystalline acid; and (8) optionally dissolving the free acid in water, in a concentration of approximately 13.125% (weight of anhydrous free acid / volume of water), and approximately one molar equivalent of alkali metal bicarbonate; the reaction mixture is stirred for 3 to 4 hours at a temperature of 6 +4 until the pH drops to at least 6.5, before collecting the alkali metal salt of the product of formula ( I). The following nonlimiting examples are given by way of illustration of the invention. Unless otherwise stated,

  all parts are expressed by weight.

Example 1

  Preparation of acid 6- / D (-) - alpha- (4-ethyl-2,3-dioxo-1-

  piperazinocarbonylamino) phenylacetamido7 penicillanic monohydrate

  To a stirred suspension of 27.00 g of tri-ampicillin

  hydrated (equivalent to 22.86 g (0.0654 mole) of ampicillin

  true anhydrous), 14.50 g (0.1726 mole) of bicarbonate

  sodium, 238 g of water, and 119 g of ethyl acetate, all at 15 + 2 C, 14.73 g (0.0720 mole) of 4-ethyl-2,3-dioxo chloride are added -1 piperazinocarbonyl, at a speed

  allowing to maintain a pH higher than 6 and a temperature

  rature of 15 + 2 C. Once the addition is complete, the reaction mixture is stirred at a temperature of 15 + 2 C for minutes, and 2.1 g of activated carbon are added (Type RB Activated Carbon; Pittsburgh Coke and Chemical Company), and

  30. 3.0 g of a filter aid (Hyfloe Super-Cel; Johns-

  Manville Sales Corp.). The mixture is stirred for a further few minutes, the solids are separated by filtration and washed with 26 g of water. The filtrate and the washing liquor are combined and mixed with 142.5 g

  ethyl acetate. The temperature of the mixed mixture is brought up

  resulting in a value of 20 to 22 C and the pH is brought to 2.3 by addition of 2N hydrochloric acid. The acidified mixture is stirred at 20-22 ° C. for 2.5 hours and the crystalline precipitate is isolated by filtration, washed with 120 g of water and dried, thus obtaining 33.49 g

  (95.58% of theory) of the product sought.

Example 2

  Preparation of the sodium salt of 6- / D (-) - alpha- (4-

  ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido / -

  penicillanic 13.5 g of the product of Example 1 (0.025 mole, equivalent to 13.125 g of anhydrous free acid) are dissolved in ml of water and, while stirring the solution,

  6 + 4 C, 2.06 g of sodium bicarbonate (0.025 mole, equi-

  equal to 15.685 w / w of anhydrous free acid) in 10 increments of 0, 206 g each. The reaction is allowed to continue until the pH drops to at least 6.5, a period of 3 to 4 hours. The reaction mixture is sterilized by cold filtration, it is introduced into aseptic flasks and it is lyophilized, thus obtaining white or pale yellow crystals of the sodium salt of

  6- / D (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazinocar-) acid

  bonylamino) phenylacetamido / penicillanic.

Claims (6)

  1. Process for the preparation of a 6- / D (-) - alpha- acid   - (4-alkyl (C1 to C4) -2,3-dioxo-1-piperazinocarbonyl-   amino) phenylacetamido7penicillanic according to which a 4-alkyl halide (C1 to C4) -2,3-dioxo- is added   1-piperazinocarbonyl to an ampoule solution or suspension   cillin in a mixture of ethyl acetate and water in the presence of a base in order to obtain a reaction mixture,   the resulting mixture is stirred until the reaction is complete   tion, the reaction mixture is acidified, and a crystalline product is collected therefrom; characterized in that: (a) about 1 to 1.5 molar proportions of   4-alkyl halide (C1 to C4) -2,3-dioxo-1-piperazi-.   nocarbonyl to a stirred suspension of about a proportion   molar ampicillin and an appropriate amount of a suitable base in a mixture of solvents consisting of about 9 to 12 parts by weight of water and about 0.5 to 8 parts by weight of acetate ethyl per part by weight of ampicillin, in a period of at least 30 minutes, at a temperature of approximately 10 to 25 C, while maintaining the pH at a value of approximately 6 to 8.3 ; (b) the reaction mixture is then stirred at a temperature of approximately 10 to 25 ° C. during. at least 15 minutes after the end of the addition of the 4-alkyl halide (C1 to C4) -2,3-dioxo-1-piperazinocarbonyl. in stage (a); (c) adding to the reaction mixture approximately 0.05 to   0.2 parts by weight each of an activated carbon and an adjuvant of.   filtration by part by weight of ampicillin loaded with   stage (a), and the resulting mixture is stirred at a temperature   about 10 to. 25 C for at least 10 minutes; (d) the resulting mixture is clarified, and the insoluble substances are washed with the aid of about 0.6 to 2.5 parts by weight of water per part by weight of ampicillin charged in stage (a); (e) the mother liquor and the washing liquor obtained in stage (d) are combined with from approximately 2 to 12.5 parts by weight of ethyl acetate per part by weight of ampicillin charged in stage (a ), provided that the total amount of ethyl acetate used in stages (a) and (e) is about 10 to 13 parts by weight per part by weight of the ampicillin, and the resulting mixture is brought to a temperature of about 15 to 25 C; (f) oh acidifies the mixture obtained in stage (e), at a temperature of approximately 15 to 25 ° C., until a pH of approximately 2.0 to 2.5 is obtained; and (g) the acidified mixture is stirred for at least one hour at a temperature of about 15 to 25 ° C before collecting the resulting free crystalline acid; and (h) optionally converting the free acid to a pharmaceutically acceptable salt.   2. Method according to claim 1, characterized in that: (a) about 1.05 to 1.15 molar proportions are added   a 4-alkyl halide (C1 to C4) -2,3-dioxo-1-pipéra-   zinocarbonyl suspension containing 2.5 to 2.7 equivalents   basic molar valents in a mixture of solvents   made up 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 a temperature of about 12 to 18 C, while maintaining the pH at a value of about 6.5 to 8;   (b) the reaction mixture is then stirred at a temperature   temperature from 12 to 18 C approximately for approximately 20 to 30 minutes;   (c) treating the reaction mixture with about   ron 0.08 to 0.1 part by weight of an activated carbon and   vironri 0.1 to 0.15 part by weight of a filter aid   per part by weight of ampicillin loaded in stage (a),   and the resulting mixture is stirred at a temperature of about   ron 12 to 18 C for about 15 to 20 minutes;   (d) the insoluble substances are washed with the aid of   1.0 to 1.2 parts by weight of water per part by weight of ampicillin charged in stage (a); (e) the mother liquor and the washing liquor are combined with about 6 to 7 parts by weight of ethyl acetate per part by weight of ampicillin charged in stage (a), and the resulting mixture is brought at a temperature of about 18 to 22 C, provided that the total amount of ethyl acetate used in stages (a) and (e) is about 11 to 12 parts by weight per part by weight of the ampicillin;   (f) the reaction mixture is acidified to a temperature   ture of around 18 to 22 C, until a pH of approx.   ron 2.2 to 2.3; (g) the acidified reaction mixture is stirred at a temperature of about 18 to 22 C for about 2 to 3 hours before collecting the free crystalline acid, washing it with water and drying it; and (h) optionally dissolving the free acid in water, at a concentration of approximately 131.25 g of anhydrous free acid per liter of water which is gradually added with approximately one molar equivalent of bicarbonate alkali metal; the reaction mixture is stirred for about 3 to 4 hours at a temperature of about 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. Method according to claim 1 or 2, characterized   in that the 4-alkyl halide (C1 to C4) -2,3-dioxo-1-   piperazinocarbonyl is a 4-alkyl chloride (C1 to C4) -   -2,3-dioxo-1-pipérazinocarbonyle. 4. Method according to claim 1 or 2, characterized   in that the 4-alkyl halide (C1 to C4) -2,3-dioxo-   1-piperazinocarbonyl is 4-ethyl-2,3-dioxo- chloride 1-piperazinocarbonyl.   5. Method according to claim 1 or 2, character-   dried in that the product is converted to the sodium salt.   6. Product obtained by a process according to any one   than previous claims.