MXPA97007749A - Procedure for preparation of estreptogrami - Google Patents

Abstract

The present invention relates to a process for the preparation of streptogramins of general formula (I): in which either R 1 is methyl or ethyl, R 2 is H and X and Y together form an oxo radical, whether R 1 is ethyl, R 2 and X represents H and Y is H or OH, either R1 is ethyl R2 is OH, and X and Y together form an oxo radical, by demethylation of a synergistine derivative of the general formula

Description

PROCEDURE FOR PREPARATION OF STREPTOGRAMS The present invention relates to a new process for the preparation of streptogramins of the general formula: In which: either the radical R1 represents a methyl or ethyl group, the radical R2 represents a hydrogen atom and X and Y together form an oxo radical, either Rl represents an ethyl radical, R2 and X represent a hydrogen atom and Y represents a hydrogen atom or a hydroxy radical, either Rl represents an ethyl radical R2 represents a hydroxy radical and X and Y together form an oxo radical From a synergistic derivative of the general formula REP: 25565 wherein the radicals R1, R2, X and Y are defined above.

Streptogramins are a class of known compounds comprising components of group B [to which belong the products of general formula (I)] which, associated with components of group A, cause a synergy of the antimicrobial action.

The product of general formula (I) by which R2 is ethyl and R2 is hydrogen is known under the name of pristinamycin IB. The product of general formula (I) by which Rl is methyl and R 2 is hydrogen is known under the name of vernamycin Bd. The product of general formula (II) whereby R 2 is ethyl and R 2 is hydrogen is known under the name of pristinamycin IA. The product of the general formula (II) by which R1 is methyl and R2 is hydrogen is known under the name of pristinamycin IC or vernamycin B ?. The product of general formula (II) by which Rl is ethyl and R2 is hydroxy is known under the name of pristinamycin ID.

General demethylation methods were already known as for example the methods described in Tet. Let. , 18, 1567 (1997); J. Org. Chem., 49, 2795 (1984); J. C. S. Chem. Comm. , 905 (1989), Tet. Lett., 33, 6991 (1992), however these methods were not adapted to fragile products such as streptogramins, either because the reaction did not intervene, or because the operating conditions were degrading with respect to those products. Others still involved toxic reagents and not totally removable from the final product, which is unacceptable from the pharmaceutical point of view.

It has now been found, and this is the object of the present invention, that streptogramins of general formula (I) could be obtained by demethylation of the corresponding derivative of general formula (II) by treatment by a periodate in acetic medium followed by a treatment in aqueous acid medium or of a treatment by an agent capable of consuming formaldehyde in situ.

The periodate used is advantageously the periodate of tetra N-butyl ammonium or an akaline period (sodium periodate). the reaction is carried out in a tel solvent which is a chlorinated solvent (dichloromethane, chloroform, diclorethane, trichlorothane, for example), an ester (ethyl acetate for example) or in tetrahydrofuran, N-methyl pyrrolidone or possibly a mixture of these solvents in the presence or absence of ethylene glycol. The reaction is carried out at a temperature between 20 and 40 ° C.

The subsequent treatment is a hydrolysis in aqueous medium releasing formaldehyde. It is possible to operate by treatment of the obtained product, in homogeneous aqueous medium added with a strong acid or, directly in acidic or biphasic medium; It can also be operated in a dichloromethane / water mixture. In this case preferably the pH of the aqueous medium will be slightly acidic; understanding that the acidity of the medium will be indifferently by the addition of a strong or light acid.

The acids used can also be chosen from trifluoroacetic acid, sulfuric acid, hydrochloric acid, methane sulphonic acid, p-toluene sulphonic acid or formic acid. The treatment in acid medium is carried out at a temperature comprised between 0 and 40 ° C.

When the subsequent treatment is carried out, it is also possible to add an agent capable of consuming formaldehyde in situ, this agent is advantageously chosen from hydroxylamino, a bisulfite (sodium bisulfite, for example) or hydrogen peroxide in an aqueous medium. The operation is preferably carried out in two-phase medium at a temperature comprised between 0 and 40 ° C at a pH comprised between 1 and 7.

The products of general formula (I) thus obtained can be purified, if necessary, by the usual methods such as crystallization, precipitation, flash chromatography or CLHP.

The products of the general formula (I) in which R 1 represents an ethyl radical, R 2 and X represent a hydrogen atom and Y represents a hydrogen atom or a hydroxy radical are new products of the streptogramin family.

The following examples, given by non-limiting titles, illustrate the process according to the invention.

Example 1. Tricin Pristinamycin I 540 g [pristinamycin IA 72.2% (433 g), pristinamycin IB 4.2% (25 g), pristinamycin 2.67% (16 g), pristinamycin is placed in a tricol. ID 3.17% (19 g)] in solution in a mixture of 1460 cm 3 of dichloromethane, 500 cm 3 of acetic acid and 40 cm 3 of ethylene glycol. 97.5 g of tetra-N-butyl ammonium periodate is added maintaining the temperature at 30 ° C. After 3 hours of stirring at 30 ° C, the reaction is stopped by addition, under stirring, of 2000 cm 3 of demineralized water. The aqueous phase is decanted and the organic phase is washed again with 2000 cm.sup.3 of demineralized water. The aqueous phase is decanted and the organic phase is concentrated to a volume of 800 cm 3. 1000 cm 3 of methyl ethyl ketone is added to the concentrate and the mixture is concentrated under reduced pressure (1.5 kPa) to a volume of 1300 cm 3. The methyl ethyl ketone is added to a total volume of 2400 cm 3 and the mixture is cooled to 0 ° C. The precipitated solid is filtered, washed 3 times with 250 cm3 of methyl ethyl ketone and then dried at 40 ° C under reduced pressure (1.5 kPa). This gives 441 g of a white solid which is put into solution in 8800 cm3 of 0.25 N hydrochloric acid and stirred for one hour, then extracted by 3500 cm3 of dichloromethane, adjusting the pH of the aqueous phase to 4 with 30% sodium hydroxide solution. . The organic phase is decanted, washed by 3500 cm3 of water then concentrated in dry under reduced pressure (50 kPOa at 30 ° C) to a volume of around 1100 cm3. To this solution is added 2,200 cm 3 of ethanol and evaporation is continued under reduced pressure to 1800 cm 3. 3500 cm 3 of ethanol is then added. The obtained crystals are filtered at 10 ° C, filtered, then rinsed 3 times with 330 cm 3 of cold ethanol, then dried at 40 ° C under reduced pressure (1.5 kPa). Thus, 360 g of pristinamycin IB is obtained in the form of white crystals, pure at 80.7%, or containing 290.4 g of pristinamycin IB.

On the other hand 1.1% of vernamycin Bd was obtained, a transformation yield of 41.1% and 2% of pristinamycin of general formula (I) in which R1 is ethyl and R2 is hydroxy or a transformation yield of 63% (CLHP dosage).

Example 2. 20 g of pristinamycin I [pristinamycin IA 76.5% (15.3g), pristinamycin IB 7% (1.4g)] in solution in a mixture of 28 cm3 of dichloro-1 is placed in a tricol. , 2 ethane, 70 cm3 of acetic acid and 2 cm3 of ethylene glycol. 4.9 g of sodium periodate are added maintaining the temperature at 25 ° C. After stirring for 6 hours, the reaction is stopped by adding, under stirring, 100 cm 3 of demineralized water. The aqueous phase is decanted and the organic phase is washed again with 50 cm.sup.3 of demineralized water. The aqueous phase is decanted and the organic phase is dry concentrated under reduced pressure. The solid is replaced by 400 cm3 of methyl insobutyl ketone and the product extracted twice with 320 cm3 then with 80 cm3 of 0.2 N sulfuric acid. The aqueous phases are combined and then extracted by 400 cm3 of dichloromethanol. The organic phase is decanted, concentrated in dry under reduced pressure (30kPa) at 30 ° C then dried under reduced pressure (150 Pa) at 40 ° C to give 12.5 g of a white solid containing 71% (9 g) of pristinamycin IB 5.6% (0.7 g) of pristinamycin IA. Conversion yield 84.9%.

EXAMPLE 3. Tricine pristinamycin I (pristinamycin IA 433 g, pristinamycin IB 25 g, pristinamycin IC 16 g is placed in a tricol, 540 g of crude pristinamycin I, pristinamycin ID 19 g) in solution in a mixture of 1460 cm 3 of dichloromethanol, 500 cm 3 of acetic acid and 40 cm 3 of ethylene glycol. 97.5 g of periodate a of tetra N-butyl ammonium is added maintaining the temperature at 30 ° C. After 3 hours of stirring at 30 ° C, the reaction is stopped by addition with stirring of 2000 cm 3 of demineralized water containing 34,7 hydroxylamino hydrochloride. The aqueous phase is decanted then separated. The organic phase is washed by 2000 cm 3 of water. After decanting and separating, the organic phase is concentrated until it is like honey. 2500 cm3 of ethyl acetate are poured onto this concentrate, then it is concentrated to a final volume of 1300 cm3. The suspension is filtered at 5 ° C. The crystals are washed 3 times with 400 cm3 of fresh ethyl acetate and dried at 40 ° C under 1500 Pa residual pressure. In this way, 331 g of white product are obtained, titrating 91% in pristinamiciria IB.

Example 4. 180 g of crude pristinamycin I (containing 111.1 g of pristinamycin IA and 35.6 of pristinamycin IB) is placed in a tricol in a mixture of 444 cm3 of dichloromethane, 128 cm3 of acetic acid and of 10 cm3 of ethylene glycol. 25.9 g of tetra-N-butyl ammonium periodate are added. After stirring for 4 hours at 32 ° C, the reaction is stopped by the addition, under stirring, of 1100 cm3 of city water. The two phases are decanted and separated. The organic phase is washed again 4 times followed by, each time, 1400 cm3 of city water. The pH of these four washes is readjusted downwards by 5 ml of normal hydrochloric acid by means of easy decanting. These 4 washes, decantations and separations are carried out at 35 ° C. The organic phase is concentrated of a factor 2 more or less. 600 cm.sup.3 of ethyl acetate are progressively poured onto this concentrate, initiating the crystallization after about one-third more. After the addition, the ethyl acetate feed is followed by distillation in parallel so that a constant volume remains in the flask, or about 600 cm3. After distillation at constant volume of about 800 cm3, the suspension is cooled to 0 ° C and filtered. The cake is washed twice with 125 cm3 of ethyl acetate at 0 ° C and dried under reduced pressure (1.5 kPa) at 40 ° C until constant weight. 120 g of a light beige product containing 110 g of pristinamycin IB are obtained.

Claims (6)

CLAIMS.

1 - . 1 - a procedure of preparation of streptogramins of general formula: in which: either the radical R1 represents a methyl or ethyl group, the radical R2 represents a hydrogen atom and X and Y together form an oxo radical, - either Rl represents an ethyl radical, R2 and X represent a hydrogen atom and Y represents a hydrogen atom or a hydroxy radical, either Rl represents an ethyl radical R2 represents a hydroxy radical and X and Y together form an oxo or demethylation radical of a synergistin derivative of general formula: wherein the radicals R1, R2, X and Y are defined as above indicated by treatment by a periodate in acetic medium followed by treatment in an aqueous medium.

2 - . 2 - Process according to claim 1, characterized in that the periodate is chosen between the periodate of tetra N-butyl ammonium or an alkaline periodate.

3 - . 3 - Method according to claim 2, characterized in that the alkaline periodate is sodium periodate.

4 - . 4 - Method according to claim 1, characterized in that the subsequent treatment is a hydrolysis in aqueous medium, either in homogeneous medium added a strong acid, either in acidic biphasic medium or not.

5 - . 5 - Process according to claim 1, characterized in that an agent capable of consuming the formaldehyde or in situ, chosen between hydroxylamine, a bisulfite or hydrogen peroxide, is added in the course of subsequent treatment.

6 -. 6 - A streptogramin derivative characterized in that it responds to the general formula: wherein R 1 represents an ethyl radical, R 2 and X represent a hydrogen atom and Y represents a hydrogen atom or a hydroxy radical. SUMMARY OF THE INVENTION Method of streptogramin preparation and general formula. wherein R 1 is methyl or ethyl, R 2 is H and X and Y together form an oxo radical, either R 1 is ethyl, R 2 and X represent H and Y is H or OH, either R 1 is ethyl R 2 is OH , and X and Y together form an oxo radical, by demethylation of a synergistine derivative of general formula. wherein R 1, R 2, X and Y are defined as indicated above, by treatment for a perdiodate in acetic medium followed by treatment in an aqueous medium.