MXPA00006130A - Process for purifying a solution of an ampicillin pro-drug ester - Google Patents

Abstract

A process for purifying a solution of an ampicillin pro-drug, e.g. bacampicillin, or an acid addition salt thereof, which comprises a step wherein a crude solution thereof is subjected to an evaporation which is controlled by the evaporation rate of the organic solvent such that a continous operation is accomplished for the crystallization of the desired purified pro-drug ester, or salt thereof. Said crystallization is preferably preceded by an aqueous phase extraction and/or an organic phase extraction, both preferably also being performed continuously.

Description

PROCEDURE FOR PURIFYING A SOLUTION OF AN ESTER OF AN AMPICILLIN P R O M E N T FIELD OF THE INVENTION The present invention relates to a new and improved process for purifying a solution of an ester of a ampicillin prodrug from contaminants that originate from the manufacture of the same. The new procedure is of special value in connection with the elimination of the basic components used to neutralize the acidic components that are present in the synthesis of the ester of the average ammonium ester at the same time. which is referenced.

Background of the invention One of the commercially available ampicillin esters of p r o m e d i c a m e n t is the b a c a m a c i n e, or one of the same, as the hydrochloride of b a c a m a c i a n a n c e. The final stage in the manufacture of the same can be represented, in general, by the following reaction scheme: REF.120826 I.PCI5 DMA (N.N-dimethyl-aniline 2. MeOH 3.H, O DM anil Accordingly, ester II of penicillin G is reacted with phosphorus pentachloride at low temperature, followed by an alcohol, e.g. , methanol and water; and the 6-aminoethoxy acid 6-aminoethoxycarbonyl ester (6-APA), formed in this form (Illa), is then reacted with the hydrochloride of phenylglycine chloride (form IV). under conditions such that the bacamillil hydrochloride of the formula la. These conditions involve the presence of DMA (N, N-dimethylaline) or other bases, to be added to the hydrochloric acid that is released in the reaction. If the base is not efficiently removed in the insulation of the hydrochloric acid, it will contaminate the fine product to be used in a pharmaceutical preparation. In addition, because it has been shown that AMD involves potential health risks, it is necessary to eliminate the contaminant at the highest possible level. Despite the availability of various purification techniques that may seem efficient when used alone in other connections, it has not been possible, however, in prior practice, to develop a procedure that satisfies the requirements. In addition to being inadequate as regards the purity of the final product, these techniques have also involved some inactivation of the esters. A method for improving the purification operation is described in Swedish Patent No. 7810122-7, which describes a method for removing DMA from some ampicillin amphoteric esters by means of a step where a specific cation exchanger is used. The present invention is based on a simple and very efficient alternative for the operation of the ion exchange resin, which has been shown to result in better yields as well as a higher purity of the desired final product, despite the fact that the new process claimed involves a crystallization operation, against which there was some prejudice in the prior art.

GENERAL DESCRIPTION OF THE INVENTION The present invention is based on the discovery that it is possible to carry out, on a commercial scale and in a simple and efficient manner, a continuous operation of crystallization on a crude organic solution of the type mentioned above, of a prodrug ester of ampicillin. This is certainly unexpected since the organic phase which is taken for the crystallization operation is unstable, which means that the crystallization operation would be expected to result in an inoperative and / or inferior process. However, according to the present invention, it has been found that it is possible to subject the raw organic solution to an evaporation resulting in a continuous crystallization of the desired product, viz. by proper control of the evaporation rate of the organic solvent to achieve continuous crystallization. By this means the desired final product is obtained with very good yields and in a highly purified state. further, the product obtained by the purification process, according to the invention, is of a very homogeneous quality, which is also easy to centrifuge and is not inactivated by the crystallization operation. More specifically, a first aspect of the invention relates to a process for purifying a solution of the ampicillin amphoteric ester of the formula I: where R O CH2-0 - CO - C (CH3) 3 or acid addition salts thereof; of the contaminants originated from the manufacture thereof, especially to eliminate the base used when incorporating the group R in the ester of the formula I, as when it is of the corresponding ester where R is phenylacetyl (PhCH2CO), comprising a stage where a crude solution of the ester of the ampicillin prodrug, of the formula I, or an acid addition salt thereof, in an organic solvent for that purpose, is subjected to an evaporation which is controlled by the evaporation rate of the organic solvent in such a way that it is possible to establish a continuous operation for the crystallization of the purified, desired prodrug ester, or the salt thereof. In other words, the process is applicable, in general, the purification of the bacamillin talampicillin and pivampicillin, or the acid addition salts thereof, for example, the hydrochloride salts thereof. According to an especially preferred embodiment of the invention, the process is adapted to the purification of bacampicillin, or an acid addition salt thereof, preferably the hydrochloride salt. The ester of the ampicillin prodrug which is to be purified by the claimed process is manufactured, in general, from penicillin G, or a salt thereof, especially the potassium salt, which is reacted with an R-X reagent , where R1 is as defined in connection with formula (I), and X is halogen, with the formation of an ester of penicillin G, the ester group is R1, as defined above. This ester is reacted with phosphorus pentachloride, at low temperature, followed by an alcohol, for example, methanol, and water; and then with a reagent RY, where R is as defined in connection with formula (I), and Y is halogen, under conditions such that the phenylacetyl group is replaced by the R group. In this reaction, a base is used organic, such as N, N-dimethylaniline, as mentioned at the beginning of the present description, and the organic base is, therefore, one of the main impurities that must be eliminated from the ester of the ampicillin prodrug which will subsequently be used for medical purposes. However, by more preferable methods of the process, substantially all of the contaminants that originate from the entire manufacturing process can be eliminated or at least substantially eliminated. Details of the complete manufacturing process and contaminants in connection therewith can be found in the technical literature in this field, and the manufacturing process is previously known per se and is not part of the present invention. As referred to above, the invention is mainly based on the idea of carrying out a continuous crystallization operation, of which several advantages are achieved. This continuous crystallization can be operated by an adequate control of the evaporation rate of the organic solvent. In this context, it is not possible to define the control in specific exact figures, but now that the inventive idea has been described, the adequate control conditions could easily be established by anyone trained in the technique in each specific case. Preferably, however, the evaporation rate could be defined, in general, in such a way that the crystallization is carried out continuously at a rate of evaporation corresponding to 0.1 to 0.6 times the volume added continuously of the solution that is added. will purify, per hour. More preferably, the evaporation rate corresponds to 0.3 to 0.5 times, even more preferably, approximately 0.4 times the volume mentioned, per hour. The continuous crystallization operation is preferably carried out under vacuum, i.e., at less than atmospheric pressure, mainly because the temperatures involved in it will be sufficiently low to not decompose the desired product, or deteriorate it in any way. In general, the temperatures used in the continuous crystallization operation are at a level where the decomposition or deterioration of the desired product is prevented. As is well known, they also depend on the pressure used in the operation. However, a preferred temperature range is, in general, from 25 ° C to 75 ° C, more preferably from 25 ° C to 50 ° C. Due to cost and investment reasons, as well as reasons of the quality of the product, a particularly preferred temperature range, in particular when the operation is performed under vacuum, is, however, a range of low temperature as low as 25 ° C to 35 ° C, especially around 30 ° C. The main purpose of the continuous crystallization operation is, as mentioned above, to subtract or substantially im- port the base to which reference was made, e.g. , DMA, but, because the procedure for the manufacture of the initial solution of the crude ester involves the use of several different reagents, also many other contaminants must be immersed in order to obtain an ester of Promedicamento de am picil ina of high quality. Furthermore, the outstanding results of the crystallization operation, or of the total process as described in detail below, are achieved by these additional operations, since they also involve, in general, the elimination of larger amounts of DMA, or other bases, before carrying out the crystallization reaction. According to a preferred embodiment of the claimed procedure, this involves a stage before continuous crystallization where other contaminants, more specifically polar pollutants, are removed from the solution to be purified, subjecting it to an extraction with a phase watery A particularly preferred embodiment in this aspect is represented by a case where the aqueous phase extraction step is carried out continuously. Through continuous extraction of this type, it has been found that it is possible to reduce the level of polar contaminants to an extremely low value, compared to a case where an extraction is performed in a batch mode. Furthermore, in such a process, only one batch extraction is possible since the different phases can not be separated a second or third time, but only once. In this regard, an extremely efficient extraction is achieved, according to the invention, if the continuous extraction step is performed in a countercurrent flow column, where a screen column is especially preferred. The ratio of the volumetric flow of the organic solution to be purified, with respect to the aqueous extraction phase, is preferably in the range from 2: 1 to 1: 2, more preferably, about 1: 1. The extraction in this mode is extremely high if water containing an inorganic acid salt is used, to establish the adequate density difference as well as a sufficiently fast separation of the phases involved. Although many metal salts may be used, in this aspect, an alkali metal salt, preferably an alkali metal halide, is preferably used. A chloride salt, such as sodium chloride, is especially used. An efficient extraction is achieved by means of an aqueous medium containing from 5% to 30%, preferably from 5% to 20%, more preferably from 8% to 18% (w / w) of the salt. The pH to be used in the aqueous phase extraction step is suitably controlled, in the range of 2 to 5, preferably 3 to 4, more preferably 3.4 to 3.7.

According to another preferred embodiment of the method according to the invention, the continuous crystallization operation is preceded by a step where the organic contaminants are also removed, viz. , by extraction with an organic phase. The organic solvent used in the organic phase extraction step is any solvent that has the ability to remove the desired organic contaminants, but is preferably selected from butyl acetate, methyl isobutyl ketone and ethyl acetate, where especially preferred is ethyl acetate. butyl. As it should be understood from the foregoing, the most interesting aspect of the claimed procedure is represented by an operation where extraction in aqueous phase, as well as extraction in organic phase, are both used before the crystallization operation; All these steps are carried out, preferably, continuously. In this connection, an advantageous embodiment of the invention means that extraction in aqueous phase precedes extraction in organic phase. In addition, the different steps of the total process are preferably arranged in such a way that the aqueous phase which leaves the extraction operation in organic phase, enriched with the desired product, is subjected to the step of extraction with the addition of salt (as described above). - out), where the desired product to be subsequently crystallized is transferred from the aqueous phase to a new organic phase. This new organic phase, enriched in the desired product, is then passed to the continuous crystallization stage. It is important that the organic phase is formed in the correct manner in order to achieve the most successful result of the subsequent crystallization operation. Accordingly, the organic solution containing the product to be crystallized in the continuous crystallization operation is s u p e r a t u r a d a a and the crystallization starts at an initial stage. By means of the new technique, according to the present invention, the salt addition extraction ("salting-out") does not result in any problems in phase separation or any substantial loss of the final desired product in the aqueous phase, as was the case in connection with the techniques of the prior art. In addition, the separation step with addition of salt, facilitates the subsequent crystallization operation and makes the aforementioned operation much more efficient.

The salt addition extraction step, mentioned above, is also preferably performed in a continuous manner. The term "salting-out" extraction step originates from the fact that this step is preferably carried out in the presence of a salt, eg, an inorganic salt, makes the salt of the ester of the prodrug desired is transferred from the aqueous phase to the new organic phase. The purpose of the salt is to change the distribution coefficient between the two phases and the use of any other "phase transfer" agent in place of the salt, to improve the transfer is also within the scope of the invention. However, a preferable salt in this aspect is a metal salt of an inorganic acid, especially in the form of an aqueous solution thereof. Many metal salts are useful, but an alkali metal, e.g., salt of sodium is preferred. A halide salt is especially preferred, such as a chloride salt, e.g., sodium chloride. In addition, it has been found that it is especially preferable to use a saturated aqueous solution of the salt to which reference is made. The organic solvent to be used for this extraction step by salt addition is selected in general while taking into account the ability to dissolve the desired product, as well as crystallize the product in the subsequent crystallization operation. However, it is preferably selected from butyl acetate, methyl isobutyl ketone, dichloromethane and ethyl acetate, where butyl acetate is especially preferred. An advantageous embodiment of the invention, in this aspect, is represented by the case where the volumetric flow relation of the ester solution of the prodrug: so l uci o n: organic solvent, is in the range of 1.0-1.5 : 1.5-2.0: 1, especially 1.3: 1.6: 1. Yet another advantageous embodiment of the claimed process encompasses an evaporation step between the aqueous phase extraction stage and the organic phase extraction stage, to evaporate the organic solvent from the organic phase that contains the product, which leaves the extraction in aqueous phase, where the organic solvent is then replaced by another organic solvent, which is going to be used in the extraction in organic phase, for the extractions of the organic contaminants contained in it .

This evaporation stage allows an adequate control of the organic contaminants that are going to be eliminated. That is, through the proper selection of the replacement solvent, the efficiency in the elimination of contamination can be adapted to the specific procedure used. Preferred organic replacement solvents are those solvents mentioned above, in connection with organic phase extraction. According to another aspect of the invention, there is provided a new process for purifying a solution of an ester of a prodrug of amylillin, of the formula I, or the acid addition salts thereof, of the contaminants that are made reference above, wherein the new process comprises a step wherein a crude solution of the ester or salt is subjected to an extraction with an aqueous phase to remove polar contaminants from the same, where the extraction is effected in a continuous operation. That is, without taking into account whether any of the other steps referred to above is performed, or not, this represents a new and advantageous technique in this field, which, per se, is not obvious and provides unexpected results, among other things, for the reasons stated above. In general, the continuous extraction is effected in a countercurrent flow column, preferably; a sieve column, and preferably also with an aqueous medium containing an inorganic acid salt, the details concerning these salts are the same as those described above. As to other preferred embodiments of this aspect of the invention, reference is made to the preferred embodiments presented above, in connection with the aqueous phase extraction step. Therefore, these modalities do not need to be repeated here. In this second aspect of the invention, the extraction in aqueous phase can also be followed by an extraction in organic phase and / or evaporation step and / or extraction step by addition of salt and / or continuous crystallization operation, as defined above, all preferred embodiments of the two steps mentioned above are the same as the preferred embodiments described above.

As can also be deduced from the above, an advantageous application of the claimed procedures is related to the case where the initial crude solution has been manufactured by the incorporation of the group R in the formula I, in the ester 6-APA, of the formula III : wherein R1 is as defined above, in the presence of a base, especially N, N-dimethylaniline; R is preferably incorporated by means of a phenylglycine halide, especially the chloride, or the hydrochloride thereof, as a reagent.

According to an interesting embodiment of the invention, the ester of the pyrimidine of the amylillin to be purified is bacampicillin, or an acid addition salt thereof, preferably the hydrochloride thereof. The final purified product, as obtained from the continuous crystallization operation, is finally subjected to conventional recovery operations, such as centrifugation, drying, etc., which do not need to be described in greater detail here.

Figure The procedure, according to the invention, will be exemplified additionally by means of the document 1 and the examples mentioned below, where these illustrations are of a non-limiting nature. The figure shows a schematic diagram of a modality of the new procedure, according to the invention. This fl ow diagram shows a procedure where a curd solution of the ester of the ampicillin prodrug to be purified, designated, in general, as A, is passed through a first extraction operation 1, which it is carried out as an extraction in aqueous phase. More specifically, the contaminants are extracted from the raw solution A by means of an aqueous phase, 2, which is discarded as the aqueous phase 3. The organic phase 4, which leaves the first extraction operation 1, is passed , then, au evaporation stage 5, from which the organic solvent is extracted via line 6 and residue 7 is made rau na extraction in organic phase 8. To this extraction in organic phase 8, a new solvent is added organic, as well as water, via lines 9 and 10, respectively. The organic contaminants are then discarded in the organic phase 11, while the aqueous phase 12, from the extraction mentioned above, is passed to an extraction by addition of salt, 13, which is carried out in the presence of an organic solvent, as well as an aqueous, saturated saline solution, which is added via lines 14 and 15, respectively. The aqueous phase 16, from the extraction by addition of salt, is discarded while the organic phase 17, of it, is passed to a crystallization operation, 18. From step 18, an organic solvent, 19, is obtained, and the desired crystallized product, which can then be recovered in any conventional manner. In the modality shown, all the stages are carried out continuously, as previously described.

EXAMPLE 1 Synthesis and purification of the hydrochloride of bacamillin-1'-ethoxycarbonyloxyethyl 6- (D-a-amophenylacetamido) penicillanate. N, N-dimethylaniline (36.3 g, 0.30 mol) was added to a stirred solution of 1'-ethoxycarboni I oxyethi 6- (phenyl I acetamido) penici Ito (54 g, 0.12 mol) in dichloromethane no (420 mL) at a temperature of -45 ° C. While the temperature of -45 ° C was maintained, phosphorus pentachloride (29.7 g, 0.142 mol) was added in portions in 5 equal portions, at intervals of 6 m inutes. 45 m inutes after the last addition, methanol (49.7 g, 1.55 mol) was added, drop by drop, to the mixture, for 45 minutes, at a rate such that the temperature did not exceed -24 ° C. After stirring a period of 30 minutes, water (26.8 g, 1.49 mol) was added over 15 minutes, and the temperature was adjusted to -45 ° C and adhered to, N-dimethylanimine (64.7 g, 0.535 mol) followed by hydrochloride of Da-phenylglycine chloride (25.6 g, 0.124 mol). The mixture was diluted with 70 μL of dichloromethane and 7g of hydrochloric acid were added, and the obtained solution was extracted in an extraction column with countercurrent flow with diluted saline as the aqueous phase. The dichloromethane phase was evaporated and the residue was partitioned between butyl acetate (255 mL) and water (580 mL), after adjusting the pH with sodium bicarbonate until pH = 3. The aqueous phase was washed with butyl acetate (100 mL) and the combined organic phases were extracted with water (120 mL). The combined aqueous phases were mixed continuously with a saturated solution of sodium chloride (760 μL) and butyl acetate (480 mL) and then continuously separated. The organic phase was evaporated continuously during the operation of removing the salt, under vacuum, in a bath at a temperature of 40-45 ° C, after which the product began to crystallize. After about 4 hours at room temperature, the product was filtered and washed with 190 mL of butyl acetate and 190 mL of ethyl acetate. The wet substance was dried at a temperature of 50-60 ° C and white to yellowish crystals were obtained (47g, 78% yield, based on the ester of penicillin G). The contamination with N, N-dimethylaniline was < 10 ppm, according to the CG analysis.

Example 2 Synthesis and purification of 1'-ethoxycarbonyloxyethyl hydrochloride (D-a-amidophenylacetamido) penici lanato. N, N-dimethoxyan (31 g, 0.256 mol) was added to a stirred solution of 1'-ethoxycarbonyloxyethyl 6 - (phenylacetamide) penicillin (54 g, 0.12 mol), in dichloromethane ( 440 m L) at -35 ° C. While the temperature was maintained at -35 ° C, phosphorus pentachloride (2 '7.6 g, 0.132 mol) was added in 5 equal portions, at intervals of 6 m inutes. 6 minutes after the last addition, methanol (24 g, 0.75 mol) was added dropwise to the mixture at a rate such that the temperature did not exceed -20 ° C. Then ag ua (21.6 g, 1.2 mol) was added for 10 minutes, and the temperature was adjusted to -35 ° C and N, - dimethylanimide (62.2 g, 0.514 mol) was added followed by chloride hydrochloride. of Da-phenylglycine (27.2 g, 0.132 mol). The mixture was stirred for 1 hour, and the temperature was increased to -23 ° C during this period. The mixture was then poured into a sodium bicarbonate solution (8.2 g) in 360 ml of water. After a stirring period of a few minutes, the aqueous phase was separated and extracted with 200 mL of dichloromethane. The organic phases were combined, and the dissolved substances were removed from the solvent and the residue was divided between methyl isobutyl ketone (240 mL) and water (600 mL). The aqueous phase was washed with butyl acetate (100 mL) and the combined organic phases were extracted with water (60 mL). The combined aqueous phases were stirred for a few minutes with sodium chloride (130 g) and butyl acetate (320 mL). After the separation, the aqueous layer was extracted once more with butyl acetate (160 mL). The organic phases were dried by diatomaceous earth (4 g) and about 1/3 of the solvent was evaporated in vacuo, at a bath temperature of 40-45 ° C, the product began to crystallize. After 10-15 hours at room temperature, the product was filtered, washed with 2x250 mL of ethyl acetate and dried in vacuo at 50 ° C. White to yellowish crystals were obtained (36 g, yield of 53.7%, based on the ester of penicillin G). The N, N-dimethylaniline contamination was 1100 ppm (GC analysis). The comparative example described above represents the non-continuous technique described in SE Patent No. 7810122-7, to which reference is made in the initial part of the description. Although this Swedish patent describes the use of an ion exchange resin to further purify the product, a comparison again here clearly demonstrates the great advantages that are achieved with the new process according to the present invention. In addition, none of the methods of the ion exchange resin described in the Swedish Patent gives a degree of purity at the level that is obtained by the present invention. Without taking this into account, however, the new procedure also indicates a non-obvious alternative and much more advantageous than the ion exchange resin from a technological perspective of the process, in addition to which the new procedure gives a very homogeneous, high-performance product. quality. It is stated that, in relation to. on this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (30)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property. 1. A process for purifying a solution of an ester of ammonium pyrimidine, of the formula I: where R
1. • CH2-0- CO-C (CH3) 3 or acid addition salts of the same; of the contaminants originated from the manufacture of the same, especially to eliminate the base used when incorporating the group R in the ester of the formula (I), as when it is of the corresponding ester where R is phenyl I acetyl or; wherein the process is characterized in that it comprises a step where a crude solution of the ester of the amylillin prodrug, of the formula (I), or an acid addition salt thereof, in an organic solvent for that purpose, is submitted to an evaporation which is controlled by the rate of evaporation of the organic solvent in such a way that a continuous operation for the crystallization of the desired purified prodrug ester or the salt thereof is achieved.
2. 2. The process, according to claim 1, characterized in that the continuous crystallization is carried out at an evaporation rate corresponding to 0.1 to 0.6, preferably 0.3 to 0.5, more preferably approximately 0.4, times the volume of the added solution, per hour.
3. 3. The process according to any of claims 1 and 2, characterized in that the continuous crystallization is carried out at a lower than atmospheric pressure.
4. 4. The method according to any of the preceding claims, characterized in that the continuous crystallization is carried out at a temperature in the range of 25 to 75 ° C, preferably 25 to 50 ° C, more preferably 25 to 35 ° C, more preferably about 30 ° C.
5. 5. The process, according to any of the preceding claims, characterized in that the continuous crystallization step is preceded by a step where the solution to be purified, of the ester of the formula (I), or an acid addition salt thereof. , it is subjected to a stage where the polar contaminants are eliminated from it by means of an extraction with an aqueous phase.
6. 6. The method according to claim 5, characterized in that the stage of extraction in aqueous phase is carried out continuously.
7. 7. The method according to claim 6, characterized in that the step of continuous extraction is carried out in a column of countercurrent flow, preferably a column of sieve.
8. 8. The process according to claim 7, characterized in that the volumetric flow ratio of the organic solution to be purified to the phase of the aqueous extraction used is within the range of 2: 1 to 1: 2, preferably around eleven.
9. 9. The process according to any of claims 5 to 8, characterized in that the medium used in the extraction in aqueous phase comprises water having an inorganic acid salt, preferably an alkali metal salt, more preferably a chloride salt, as the sodium chloride.
10. 10. The method according to claim 9, characterized in that the medium contains 5-30%, preferably 5-20%, more preferably 8-18% (w / w), of the salt.
11. 11. The process according to any of claims 5 to 10, characterized in that the pH used in the aqueous phase extraction step is controlled within the range of 2-5, preferably 3-4, more preferably 3.4-3-7.
12. 12. The process, according to any of the preceding claims, characterized in that the continuous crystallization step is preceded by a step where the solution to be purified, of the ester of the formula (I), or an acid addition salt thereof. , it is subjected to a stage where the organic contaminants are eliminated from it by means of an extraction with an organic phase.
13. 13. The method according to claim 12, characterized in that the step of extraction in organic phase is carried out continuously.
14. 14. The process, according to any of claims 12 and 13, characterized in that the organic solvent used in the extraction step in organic phase is selected from butyl acetate, methyl isobutyl ketone and ethyl acetate, or mixtures thereof, preferably acetate of butilo.
15. 15. The process, according to any of claims 5-11 and 12-14, characterized in that the extraction in aqueous phase precedes the extraction in organic phase.
16. 16. The method according to claim 15, characterized in that an evaporation step is incorporated between the extraction stage in the aqueous phase and the extraction stage in organic phase to evaporate the organic solvent from the organic phase containing the product, leaving the extraction in aqueous phase, where the organic solvent is then replaced by another organic solvent that is going to be used in the extraction in organic phase, for the extraction of the organic contaminants that are in it.
17. 17. The process, according to any of claims 12-16, characterized in that the aqueous phase leaving the extraction stage in organic phase, is subjected to a step of extraction by addition of salt (salting-out), where the ester of the The product to be crystallized is transferred from the aqueous phase to a new organic phase to be crystallized in a continuous crystallization operation, wherein the step of extraction by addition of salt is preferably carried out continuously.
18. 18. The process according to claim 17, characterized in that the step of extraction by addition of salt is carried out in the presence of an aqueous solution of an inorganic acid salt, preferably an alkali metal salt, more preferably a chloride salt, as Sodium chloride, especially a saturated aqueous solution of this salt.
19. 19. The process according to any of claims 17 and 18, characterized in that the organic solvent used in the step of extraction by addition of salt, is selected from butyl acetate, methyl isobutyl ketone, dichloromethane and ethyl acetate, or mixtures of them, preferably butyl acetate.
20. 20. The method, according to any of claims 17-19, characterized in that the volumetric flow ratio of the ester solution of the prodrug: so I uci or nsa I n: organic solvent is within the range of 1.0- 1.5: 1: 5-2.0: 1, especially 1.3: 1.6: 1.
21. 21. A procedure for pu rifying a solution of an ampicillin ester of p r o m e n t i n g of formula I: where R CH2-0- CO-C (CH3 > 3 or acid addition salts of the same; of the contaminants originated from the manufacture of the same, especially to eliminate the base used when incorporating the group R in the ester of the formula (I), as when it is of the corresponding ester where R is phenyl I aceti I or; wherein the process is characterized in that it comprises a step wherein a crude solution of the ester of the ampicillin prodrug, of the formula (I), or an acid addition salt thereof, in an organic solvent for that purpose, is subjected to an extraction with an aqueous phase for removing polar contaminants therefrom, where the extraction is effected continuously in a countercurrent flow column, preferably a screen column, and with an aqueous medium containing an inorganic acid salt, preferably a salt of alkali metal, more preferably a chloride salt, such as sodium chloride.
22. 22. The process, according to the rei indication 21, characterized in that the volumetric flow ratio of organic solution to be purified to aqueous extraction phase used is within the range from 2: 1 to 1: 2, preferably around 1 : 1.
23. 23. The method according to any of claims 21-22, characterized in that the means contains 5-30%, preferably 5-20%, more preferably 8-18% (w / w), of the salt.
24. 24. The process according to any of claims 21-23, characterized in that the pH used in the aqueous phase extraction step is controlled within the range of 2-5, preferably 3-4, more preferably 3.4-3.7. .
25. 25. The method, according to any of claims 21-24, characterized in that it is segregated by a step where the organic contaminants are eliminated by means of an extraction with an organic phase, as defined in any of the claims. 12- 14.
26. 26. The process according to claim 25, characterized in that an evaporation step, as defined in claim 16, is incorporated between the extraction stage in aqueous phase and the extraction step in organic phase.
27. 27. The process, according to any of claims 25-26, characterized in that the step of extraction in organic phase is followed by a step of extraction by addition of salt, as defined in any of claims 17-20 .
28. 28. The process according to any of claims 21-27, characterized in that it is followed by a continuous crystallization operation as defined in any of claims 1-4.
29. 29. The process according to any of the preceding claims, characterized in that the raw initial solution of the ester of the formula (I), or the acid addition salt thereof, has been manufactured incorporating the group R, in the Formula (I), in the 6-APA ester, of the formula (III): where R1 is as defined in claim 1, in the presence of a base, preferably N, N-dimethylaniline; R is preferably incorporated by means of the chlorine of the ion, or the hydrochloride thereof, as a reagent.
30. 30. The process according to any one of the preceding claims, characterized in that the amphotiline ester of the formula (I) is the bacampicillin or an acid addition salt thereof, preferably the hydrochloride thereof. EKXEDM ™ MD FOR RFIFING LN ^ JSOICICN EE IN ESEER EE IN Pf AND ICAMENID EE ANPICI INA SUMMARY OF THE INVENTION A procedure for purification < 5e a gnhrnrncfe r-promedicamento of ampicillin, eg, bacampicilina, or an acid addition salt thereof, where the process comprises a stage where a crude solution thereof is subjected to evaporation, which is controlled by the rate of evaporation of the solvent organic, in such a way that a continuous operation is achieved for the crystallization of the ester of the desired purified prodrug, or salt thereof. The crystallization is preceded, preferably, by an extraction in aqueous phase and / or extraction in organic phase, where the two are preferably carried out continuously.