MXPA00001989A - Procedure for the preparation of dioxopenicillanic acid derivatives - Google Patents

Abstract

Procedure for the preparation of dioxopenicillanic acid derivatives and its salts pharmaceutically acceptable with general formula I, where, R is hydrogen, alkyl group containing 1 to 5 Carbon atoms or a residue of type -CH2R', where R'is hydrogen, halogen or a p-toluensulfonyl group. These are prepared by treatment of the compounds of general formula II, where R is as previously defined and X may be hydrogen or bromine, with a metallic reagent constituted by a mixture or alloy of copper and/or cobalt and/or manganese with iron and/or nickel in an aqueous/organic medium. These compounds are useful as inhibitors of beta-lactamase.

Description

PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF D1OXOPENIC1LÁNICO ACID - DESCRIPTIVE MEMORY The present invention consists of a process for the preparation of denvates of 1,1-dioxopenicuic acid and its pharmaceutically acceptable salts of general formula I l o (i) 1 • -) where R is hydrogen, lower alkyl or a residue of the type -C1I2R ' where R 'is hydrogen, halogen or a p-toluenesulfonyl group; the term "lower alkyl" refers to branched or non-branched alkyl radicals, give 5 carbon atoms.

The products object of this invention constitute one of the most important groups of semisynthetic inhibitors of beta-lactamases, as described by A. R. Español en? Ntimicrob. Ag. Chemother., J4, 414 (1978).

Many clinical studies have been carried out combining these types of products with penicillic antibiotics. in particular with Ampicillin. This very interesting line is the work of Campoli-Richards and Brodget published in Drugs 11, 577-609 (1987), in which the authors review the synergistic effect of Ampicillin with Sulbactam. 1 - . 1-The results obtained in these studies and in many subsequent studies have led to the application of the combination of penicillanic antibiotics with Sulbactam (I, R-Hydrogen) or similar products as standard therapy. With this the correct dosage of antibiotic is achieved: inhibitor in the right proportion and place.

The positive activity of this type of inhibitors has been evidenced by the development of another type of active principles in which the inhibitory inhibitory combination is established by a chemical bond of the type of methanediol ester, saponifiable "in vivo", such is the case of Sultamicillin.

In this way, an identical transport is achieved for the syringe and the antibiotic and, therefore, maximum efficiency in its action.

Numerous methods of preparation of the products object of the present invention have been described. Among them, procedures involving the direct oxidation of pcnicilic acid obtained by direct deamination of 6-aminophenic acid can be cited. The method described in the Belgian patent BE 867859, in which the oxidation is carried out with alkaline perganganies, deserves special mention. b Other processes involve the dehalogepation of previously dioxidized 6-halo and 6,6-dihalopenicillanic acids by reaction with hydrogen in the presence of a palladium on carbon catalyst, such is the case of the method claimed in DE 3008257. The preparation of products Starting halogenates are carried out via diazotation of 6-aminopenicillanic acid.

Variants of the latter method have also been described. Thus, those methods in which the final halogenation is carried out by treatment of the starting products with metals of the Cd type, in ES 8609339, Mg in EP 138282 or Zn in EP 092286 deniio of a neutral or weakly medium, can be cited. acid.

An example of particular interest is that described in patents EP 139048 and EP 138282, in which the treatment of the halogenated derivative with Mg cn hydrochloric acid leads to dehalogenation with an acceptable yield. In this case, the starting product is obtained by diazotization and subsequent dehalogenation of the dioxidized 6-aminopenicillanic acid.

A similar method is the dehalogenation process collected in the Spanish patent ES 8901442, where the process is carried out using iron powder in an aqueous-organic medium.

Another system has been described for the preparation of dioxopenicillanic acids, which consists in the electrolytic reduction of the corresponding mono- and di-laginated derivatives, as described in JP 61063683.

As detailed below, the process claimed herein consists in the preparation of the compounds of general formula I, by the action of the compounds of formula II with a mixture or alloy of metals of reducing nature. gave) where R was previously defined and X can be hydrogen or bromine The use of a mixture or alloy of two or more metals of the type used in the present invention, has allowed to considerably improve the purification process and to soften the conditions of 'action, in contrast to the procedures previously described in the literature.

The following table shows the comparative results obtained in the tests using a single metal, Fc, against mixtures or alloys of two or more metals such as Iron, Nickel, Cobalt, Copper and Manganese. All the tests have been carried out. under similar conditions, using a mixture of an organic solvent, ethyl acetate or acetonitrile, with a skinned solution at a pH between 3 5 and 4 5.

Table 1. Tests for dehydrogenase synthesis of 6,6-piibromic acid - 1,! -dioxopenicillaniC? (II, R-- Br) The pure metal Fe has been selected as the base of compatibility, because, according to the available literature, the best results have been obtained with it. ñ The detailed analysis of the obtained results, reveals the following conclusions In the alloys of Iron with other metals, excluding the Nickel, the yield of the reaction rises when increasing the proportion of these on a base of Iron 0 However, there is a maximum point from which, an increase in the proportion of these metals causes a sharp decrease in the reaction yield for a given time.

The results obtained with Nickel mixtures and / or alloys with others 1 b metals confirm a behavior similar to that of Iron.

The tests that were carried out show that the dcshulogenation occurs more effectively with a mixture or alloy of Iron or Nickel with Cobalt than with Cobtc or Manganese. However, the best results were obtained with? 0 Iron or Nickel mixtures or alloys used simultaneously with other metals and with each other It should be noted, with respect to the combination of metals, that the physical mixtures and alloys of an approximately equal composition behaved same way without significant variations in the yield or purity of the final product On a practical level, it has also been shown that the use of this mixture or alloy of different metals, by increasing the yield, generates less secondary products, thus providing a much simpler purification process Under certain conditions, the mere elimination of the aqueous phase and filtration makes it possible to obtain, after evaporating the solvent, a final product of high purity.

Also, the almost total absence of impurities in the products thus obtained has facilitated the preparation of alkali salts of 1, 1-dioxo-enicillanic acid (compound I, R = T I) in the form of highly crystalline products The resulting products show a high purity and an extraordinary stability, showing no signs of degradation after long periods of time subjected to rigorous conditions The greater crislainity of the salts also involves considerable improvements in their properties, facilitating their subsequent formulation. Thus, they present less hygroscopicity, greater powder fluidity, and greater ease in mixing with other products, making them particularly useful for the preparation of injectables Therefore, the procedure reveals an important advance with regard to what has been described, now suffices in the bibliography.

Thus, in the face of the instrumental complications required in complex processes such as catalytic hydrogenation, the advantages of working with metals, such as low cost and simple reaction conditions, are presented.

In addition, compared to the methods described in the available literature in which metals are used, this invention provides a significant increase in yields without increasing costs, and with obvious advantages in terms of reaction times and product purification procedures. final. This is sufficiently demonstrated with the results shown in Table I.

The process consists basically in the preparation of compounds of the formula genet 1 and their salts, by treatment of the compounds of general formula II with a mixture or alloy of metals of a reducing nature.

The metallic reagent is a mixture or alloy of Cobi e and / or Cobalt and / or Manganese with Iron and / or Nickel. The composition of this mixture or cubic alloy a wide range When mixtures and / or alloys of Iron are used with other metals with the exception of Nickel, the best results are obtained if the percentage of Iron is greater than 50%. In these cases the percentage of at least one of the other metals must be within the range of 0.05% to 40%. 0 When Nickel mixtures and / or alloys are used with other metals with the exception of Iron, the best results are obtained if the percentage of Nickel is greater than 50%. In such cases the percentage of at least one of the other metals must be in the range of 0.05% to 40%.

In the case of alloys and mixtures that simultaneously contain the two metals, Iron and Nickel, the best results are obtained when the percentages of the two are similar, and together exceed 80%. In these cases, the percentage of at least one of the other metals must be in the range from 0 05% to 20%.

The composition of the dehalogenating reagent that produced the best results, includes the following values, for Iron 75 to 90%, for Cobalt 10 to 15% and for Copper 5 to 10% With a similar composition, but replacing Iron for Nickel, sc Did they obtain slightly lower yields? The reaction medium is constituted by a mixture of water and a polar organic solvent such as ethyl ether, ethyl acetate, acetonitrile, methyl acetate or the like. The best results were obtained with ethyl acetate Although the temperature does not have a significant influence on the development of the reaction, the tests were carried out at temperatures ranging from 10 to 30 ° C. Temperatures higher than these, did not lead to better results. On the contrary, the pH was an important parameter. The reaction led to good results with a pH between 2 and 6. The best results were obtained by controlling the pH value between 3.5 and 5.

B After the completion of the reaction, isolation and purification were, in most cases, relatively simple, given the almost total absence of by-products or degradation. In these cases, the preparation of the final compounds was carried out according to the usual methods.

The following examples are described below, which, together with the results collected in Table t, help to show the scope of the invention.

Example 1 b 1,1-Dioxopenicillanic acid On a mixture of: 40 g of 6,6-dibromo-1,1-dioxopephenylalanic acid 220 ml of ethyl acetate or 80 ml of water is added a solution of; 10 g of sodium acetate together with 30 ml of glacial acetic acid 20 ml of water The mixture is stirred for ten minutes at room temperature and a homogeneous mixture of; 15 g of Iron LO g of Cobalt 0 2.0 g of Copper in the form of very fine powder.

The constant temperature is maintained and the stirring lasts 2.5 hours and then it is filtered.

The organic layer is decanted and washed with: 200 ml of brine, and 100 ml of water. It is dried over sodium sulfate, filtered and evaporated to obtain: 22. 0 g of the title product as a slightly creamy white solid (Rt.92%).

Spectroscopic data l fKB) max. 2650-3350, 1780, 1740 cm-1, 111 NMR (DMSO) 1.40 (s), 1.50 (s), 3.60 (dd), 4.10 (s) 5.10 (d) ppm Kjcmplo 2 The dehalogenation of 6-bromo-l, l-dioxopenicillanic acid according to the procedure of Example 1 leads essentially to the same results Example 3 1. 1-Methyl dioxopcnicilanate On a solution of: 20.2 g of methyl 6,6-dibromo-l, l-dioxopenicilanate 100 ml of acetonitrile 50 ml of water: previously cooled to 10 ° C, a solution of: I I 10 g of monosodium phosphate 10 ml of phosphoric acid 50 ml of water S keeping the temperature below 15 * C.

The mixture is stirred for 10 minutes and a mixture of 10 g of Iron 10 g of Nickel or 3.0 g of Oxide-free Copper in powder form is added.

Stirring is continued at room temperature between 1 and 15 ° C for 4 hours and the mixture is filtered, evaporating the organic solvent in vacuo. 150 ml of dichloromethane are added and the organic layer is decanted and washed with 120 ml of brine, and 50 ml of water (). It is dried over sodium sulphate and evaporated. The residue is dissolved in the minimum possible amount of ethyl acetate and, stirring vigorously, petroleum ether is added dropwise until turbidity.

The stirring is maintained overnight and the solid obtained is filtered and dried under vacuum to obtain: . 8 g of the title product as a solid colored clary cream (Rto.88%) 0 Ducks of es ectrpSC¿P'CQg IR (KBr) max. 1800, 1740, 1320 cm-1, 1 H NMR (DMSO) 1.40 (s), 1.50 (s), 3.25 (s), 3 60 (m), 3.70 (s), 4.35 (s) 5.20 (s) ppm Example 4 1. 1-Chloromethyl Dioxopenicilanate On a solution of: 16.0 g. of 6,6-dibromo-1,1-chloromethyl dichloropenicillanate and] 60 ml of ethyl acetate / water (1.1) is added an alloy of 15 g of Cobalt 1 1 g of Manganese powder 10 g of Iron powder The mixture is stirred at room temperature for 30 minutes and 15 ml of glacial acetic acid are added. It is stirred for two hours and filtered The organic layer is decanted and washed with 50 ml of water Dry, filter, and the solvent is evaporated to dryness. The residue is macerated overnight with n-pentane and then filtered and dried under vacuum to obtain 8. 3 g of the title compound as a white solid (Rto.81.5%) Spectra or? 2 data.

IR (KDr) max 1800, 1750, 650 cm -1, Example 5 1.1-Dioxopenicillanic acid b To a mixture of 40 g of 6,6-dibromo-1,1-dioxopepicilipic acid 200 ml of acetonitrile 70 ml of water is added a solution of 0-10 ml of glacial acetic acid 50 ml of water The mixture was stirred for ten minutes at room temperature and a homogeneous mixture of. 1 5 9.0 g Nickel 1 0 g Copper powder • The temperature is maintained and the mixture is stirred for 2 5 hours A? or continue to filter Sc decanted the organic layer and washed with: 300 ml of dichlorometap? 200 ml of brine, and 25 100 ml of water The organic layer is decanted, dried over sodium sulfate, filtered and the solvent is evaporated under vacuum to obtain . 0 g of the title compound as a solid a light white 30 cream (Rto 84%) cspectroscopic data IR (KBr) max 2650-3350, 1780, I 740 cm- I > lll NMR (DMSO) 1.40 (s), 1.50 (s), 3 60 (dd), 4 30 (s) 5 10 (d) cl ppm Example 6 The dehalogenation of 6,6-dibromo-1, 1-dioxopic acid and acid 6-bromo-l, 1-dioxopenicillanic acid, according to the procedure of Example 5 using an alloy of the same metals and composition in place of the mixture of Example 5, leads essentially to the same results.

Example 7 L-Dioxopenicil Amino Acid A mixture of 20 g of 6-bromo-1, 1-cyclopentane dioxide 150 ml of methyl acetate 50 ml of water is added, a solution of 5 ml of phosphoric acid 50 ml of water is added. mix of. 7 g of Iron 3 0 g of Manganese cn powder form.

The mixture is stirred for 2.5 hours and filtered. The organic layer is decanted and washed with 150 ml of brine, and 100 ml of dry Sc water over sodium sulfate, filtered and evaporated to obtain. 12. 2 g of the title compound as a solid (Rio.80%).

Example 8 1. 1-DioxopepicilanatÓ of methyl On a dissolution of. 10.8 g of methyl 6,6-dibromo-l, 1-dioxopcnicilanate 200 ml of ethyl acetate 20 ml of water previously cooled to 5 ° C, a solution of ml of 10% acetic acid in sol. watery while keeping the temperature below 15o C The mixture is stirred for 10 minutes and an alloy with a metallic content of 0.9 g of Nickel or 5 g of Cobalt or 5 g of Manganese in powder form is added.

Maintaining the temperature between 10 a 15 ° C, stir for 4 hours and the mixture is filtered. The organic solvent is evaporated in vacuo. 1 ml of dichloromethane is added and the organic layer is decanted and washed with: 120 ml of brine, and 50 ml of water. It is dried over sodium sulphate and evaporated. The residue is dissolved in the smallest possible amount of ethyl acetate and, with vigorous stirring, petroleum ether is added dropwise to rough turbidity. The stirring is maintained overnight and the solid is filtered and dried under vacuum to obtain: . 54 g of the title compound as a solid (Rto.84.5%) 10 fifteen twenty

Claims (8)

1. CLAIMS: L- Process for the preparation of derivatives of 1,1-dioxopenicillanic acid and its pharmaceutically acceptable salts of the general formula 5 I 10 (i) where R is hydrogen, alkyl of 1 to 5 carbon atoms or a radical of formula -CH2R '1 5 where R' cs hydrogen, halogen or p-toluenesulfonyl, which consists of the removal of the compounds of general formula I: 20 (II) where R is defined anti- chronically and X is ludrogen or bromine, with a metallic reagent consisting of a mixture or alloy of Copper and / or Cobalt and / or Manganese with Iron and / or Nickel in an aqueous-organic medium.
2. The method according to claim 1 wherein the dehalogenating reagent is composed of a mixture or alloy of Cobalt and / or Copper with Nickel, where the proportion of Cobalt in the mixture or alloy would be between 0 05% and 40% but preferably between 10 and 15%, and Copper between 0 05% and, 40% preferably between 5 and 10%
3. 3. - Process according to claim 1 wherein the dehalogenating reagent is composed of a mixture or alloy of Cobalt and / or Cobte with Iron where the proportion of Cobalt in the mixture or alloy would be between 0 05% and 40%, preferably between 10 and 15 Copper% and Cl between 0.05% and 40% preferably between 5 and 10%
4. 4. - Process according to claim 1 wherein the reagent is constituted by a mixture or nickel, iron and cobalt alloy where the proportion of nickel is 30%, the proportion of iron is 65% and cl 5% i shelf is cobalt
5. 5. - Process according to claim 1 wherein the pH value is maintained between 2 and 6, preferably between 3 and 5 6 -.
6. 6 - Process according to claim 1 wherein X is bromine and R cs a hydrogen atom. 7 -.
7. 7 - Process according to claim 1 wherein X cs Bromine and R is methyl
8. 8. - Process according to claim 1 wherein X is Bromine and R is a radical -CH2R ', where R' is a Chlorine atom. z? ¡¡, s.; - '. . -t? a .. -. : - .. b S U M E N Process for the preparation of dioxopeuicilonic acid derivatives. Process for the preparation of dioxopenicillanic acid derivatives and their pharmaceutically acceptable salts of general formula I, wherein R is hydrogen, branched alkyl or not of 1 to 5 carbon atoms or residue of the -CH2R 'type, where R * is hydrogen , halogen or p-toluenesulfonyl group These are obtained by reaction of the compounds of general formula II wherein, R is defined above and X can take the hydrogen or bromine values, with a metallic reagent consisting of a mixture or copper and / or cobalt alloy and / or manganese with iron and / or nickel in an aqueous-organic medium. They are useful as beta-lactamase inhibitors (J) I heard)