AP768A

AP768A - Method for preparing streptogramines.

Info

Publication number: AP768A
Application number: APAP/P/1997/001121A
Authority: AP
Inventors: Jean-Claude Barriere; Luc Grondard; Patrick Lefevre; Stephane Mutti
Original assignee: Rhone Poulenc Rorer Sa
Priority date: 1995-04-18
Filing date: 1996-04-16
Publication date: 1999-09-29
Also published as: DK0821697T3; NZ307236A; JP3856342B2; FR2733236A1; EA000350B1; NO974747L; JP2007031434A; SK140497A3; NO974747D0; AR002291A1; TW334437B; EG20782A; HUP9802942A2; AP9701121A0; DE69609499D1; GR3033873T3; CN1181758A; IN185120B; IL117968A; AU708419B2

Abstract

A method for preparing streptogramines of general formula (I), wherein Ri is methyl or ethyl, R2 is H and X and Y togemei form an oxo radical or Ri is ethyl. R2 and X are H and Y is Hor OH, or else R1 is ethyl. R2 is OH and X and Y together form an oxo radical, by demethylating a synergistin derivative of general formula (II). wherein RI. R2. X and Y are as defined abovc, by means of a treatment with a periodate in an acetic medium, follow by a treatment in an aqueous medium.

Description

PROCESS FOR

THE PREPARATION OF STREPTOGRAMINS

The present invention relates to a novel process for the preparation of streptogramins of general formula:

in which:

either the radical R_x Represents a methyl or ethyl group, the radical R₂ Represents a hydrogen atom and X and Y together ftrm an oxo radical, i , or R_x represents an ethyl radical, R₂ and X 10 represent a hydrogen atom and Y represents a hydrogen atoRa or a hydroxyl radical, or R_x represents an ethyl radical, R₂ represents a hydroxyl radical and X and Y together form an oxo radical, from a synergistih derivative of general formula:

AP. ΰ ΟΊ6 8

in which the radicals R_x, R₂, X and Y are as defined above .

Streptogramins are a known class of compounds comprising components of group B [to which the products of general formula (I) belong] which, when combined with components of group A, bring about a synergism of the antimicrobial action.

The product of general formula (I) for which R_x is ethyl and R₂ is hydrogen is known under the name of pristinamycin IB. The product of general formula (I) for which R_x is methyl and R₂ is hydrogen is known under the name of vernamycin Βδ. The product of general formula (II) for which R_x is ethyl and R₂ is hydrogen is known under the name of pristinamycin IA. The product of general formula (II) for which R_x is methyl and R₂ is hydrogen is known under the name of pristinamycin IC or vernamycin Βγ. The product of general formula (II) for which R_x is ethyl and R₂ is hydroxyl is known under the name of pristinamycin ID.

General methods of demethylation were already

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AP.00768 known, for examplje such as the methods described in Tet. Lett., 18, 1567 (1977); J. Org. Chem., 49, 2795 (1984); J. C. S. jchem. Comm. , 905 (1989), Tet. Lett., 33, 6991 (1992); (however, these methods could not be adapted to fragilie products such as streptogramins, either because thje reaction did not take place or because the operating conditions were degrading towards these products. Yet other mtethods involved toxic reactants which wiere not totally removable from the final product, this being unacceptable from the pharmaceutical pojint of view.

It has jiow been found, and this forms the subject of the priesent invehtion, that the streptogramins of! general formula (I) could be obtained by demethylation Of the corresponding derivative of general formula (ll) by treatment with a periodate in acetic medium followed by a treatment in aqueous acidic medium or by a treatment with an agent capable of consuming the fortoaldehyde in situ.

The periodate used is advantageously tetran-butylammonium periodate or an alkaline periodate (sodium periodate!) . The reaction is carried out in a solvent such as as chlorinated solvent (for example dichloromethane, Chloroform, dichloroethane or trichloroethane) ,j an ester (for example ethyl acetate) , a nitrile (for example acetonitrile) or in tetrahydrofuran, !N-methylpyrrolidone or optionally a mixture of these isolvents, in the presence or absence

AP/P/ 9 7/01 121

AP . Ο Ο 7 6 8 of ethylene glycol. The reaction takes place at a temperature of between 2 0 and 40°C.

The subsequent treatment is a hydrolysis, in aqueous medium, which releases formaldehyde. It is possible to perform the process by treatment of the product obtained in a homogeneous aqueous medium to which is added a strong acid, or directly in an acidic or non-acidic two-phase medium; in particular, the process may be performed in a dichloromethane/water mixture. In this case, preferably, the pH of the aqueous medium will he weakly acidic; it is understood that the acidity of the medium will be provided, indiscriminately, by addition of a strong or weak acid.

The acids used may be« chosen in particular from trifluoroacetic acid, sulphuric acid, hydrochloric acid, methanesulphonic acid, p-toluenesulphonic acid or formic acid. The treatment in acidic medium is carried out at a temperature of between 0 and 40°C.

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

The products of general formula (I) thus obtained may be purified, where appropriate, by the

AP/P/ 9 7/01121

AP.00768 usual methods sucl} as crystallization, precipitation,

I flash chromatography or HPLC.

The products of general formula (I) in which

R₃ represents an ejthyl radical, R₂ and X represent a 5 hydrogen atom and )Y represents a hydrogen atom or a hydroxyl radical ajre novel products of the streptogramin family.

The examjples which follow, given without any limitation being implied, illustrate the process according to the invention.

Example 1

540 g of) crude pristinamycin I [pristinamycin !

I_A 72.2 % (433 g),jpristinamycin I_B 4.2 % (25 g), pristinamycin I_c 2).67 % (16 g) , pristinamycin I_D 3.17 % (19 g) ] are placed) in solution in a mixture of 1460 cm³ of dichloromethane), 500 cm³ Of acetic acid and 40 cm³ of ethylene glycol, ijn a three-hecked flask. 97.5 g of tetra-n-butylammonjium perioddte are added, while maintaining the tejmperature at 30°C. After stirring for

3 hours at 30°C, tjhe reaction is stopped by addition, i

with stirring, of )2000 cm³ of demineralized water. The aqueous phase is sjeparated out by settling and the organic phase is hashed again with 2000 cm³ of demineralized watejr. The aqueous phase is separated out by settling and the organic phase is concentrated to a volutae of 800 cm³.) 1000 cm³ of methyl ethyl ketone are added to the concentrate and the mixture is concentrated undef· reduced pressure (1.5 kPa) to a

AP/P/ 9 7/01121

AP. ο ο 7 6 8 volume of 1300 cm³. Methyl ethyl ketone is added up to a total volume of 2400 cm³ and the mixture is cooled to 0°C. The precipitated solid is filtered off, washed with 3 times 250 cm³ of methyl ethyl ketone and then dried at 40°C under reduced pressure (1.5 kPa). 441 g of a white solid are thus obtained, which product is dissolved in 8800 cm³ of 0.25 N hydrochloric acid and stirred for 1 hour and then extracted with 3500 cm³ of dichloromethane, adjusting the pH of the aqueous phase to 4 with 30 % sodium hydroxide. The organic phase is separated out by settling, washed with 3500 cm³ of water and then concentrated to dryness under reduced pressure (50 kPa at 30°C) to a volume of about 1100 cm³. 2200 cm³ of ethanol are added to this solution and the evaporation under reduced pressure is continued down to 1800 cm³ . 3500 cm³ of ethanol are then added.

The crystals obtained are filtered off at 10°C, filtered off and then rinsed with 3 times 330 cm³ of cold ethanol, then dried at 40°C under reduced pressure (1.5 kPa). 360 g of pristinamycin I_B are thus obtained in the form of white, 80.7 % pure crystals, i.e. containing 290.4 g of pristinamycin I_B .

Moreover, 1.1 % of vernamycin Βδ was obtained, equivalent to a conversion yield of 41.2 %, and 2 % of pristinamycin of general formula (I) in which is ethyl and R₂ is hydroxyl, equivalent to a conversion yield of 63 % (HPLC assay).

AP/P/97/0 1 1 2 1

AP. Ο Ο 7 6 β

Example 2 g of jpristinamycin I [pristinamycin I_A

76.5 % (15.3 g) , piristinamycin I_B 7 % (1.4 g) ] are placed in solution), in a three-necked flask, in a mixture of 2 8 cm³ tof 1,2-dichloroethane, 70 cm³ of acetic acid and 2 cm³ of ethylene glycol. 4.9 g of sodium periodate ajre added, while maintaining the temperature at 25°C. After stirring for 6 hours, the reaction is stoppejd by addition, with stirring, of

100 cm³ of deminerialized water. The aqueous phase is separated out by Settling arid the organic phase is washed again with(50 cm³ of demineralized water. The aqueous phase is Separated dut by settling and the organic phase is Concentrated to dryness under reduced pressure. The sol4d is takeri up in 400 cm³ of methyl isobutyl ketone arid the product is extracted with twice 32 0 cm³ and then β|θ cm³ of 0.2 N sulphuric acid. The aqueous phases arC combined and then extracted with 400 cm³ of dichloComethane. The organic phase is separated out by Settling, concentrated to dryness under reduced pressure (30 kPa) at 30°C and then dried under reduced pressure (150 Pa) at 40°C to give 12.5 g of a white solid Containing 72 % (9 g) of pristinamycin I_B and 5.6 % (0.7!g) of pristinamycin I_A. Conversion yield: 84.9 %. j Example 3

540 g ojf crude pristinamycin I (pristinamycin I_A 433 g, pristinamycin I_B 25 g, pristinamycin I_c 16 g,

AP/P/ 9 7/01 121

AP. Ο Ο 7 6 8 pristinamycin I_D 19 g) are placed in solution, in a three-necked flask, in a mixture of 1460 cd? of dichioromethane, 50 0 cnJ of acetic acid and 40 cirJ of ethylene glycol. 97.5 g of tetra-n-butylammonium periodate are added, while maintaining the temperature at 30°C. After stirring for 3 hours at 30°C, the reaction is stopped by addition, with stirring, of 2000 cm³ of demineralized water containing 34.7 g of hydroxylamine hydrochloride. The aqueous phase is settled and then separated out. The organic phase is washed with 2000 cm³ of water. After settling and separation, the organic phase is concentrated to a syrup. 2500 cm³ of ethyl acetate are poured onto this concentrate and the solution is then concentrated to a final volume of 1300 cm³. The suspension is filtered at 5°C. The crystals are washed with 3 times 400 cm³ of fresh ethyl acetate and dried at 40 °C under 1500 Pa of residual pressure. 331 g of a white product giving a pristinamycin IB assay of 91 % are thus obtained.

Example 4

180 g of crude pristinamycin I (containing

111.1 g of pristinamycin IA and 35.6 g of pri rH namyri n IB) are placed in solution, in a three-necked flask, in a mixture of 444 cm³ of dichioromethane, 128 cm³ of acetic acid and 10 cm³ of ethylene glycol. 25.9 g of tetra-n-butylammonium periodate are added. After stirring for 4 hours at 32 °C, the reaction is stopped by addition, with stirring, of 1100 cm³ of tap water.

21

CD £

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AP .00768

The two phases ajfe settled and separated. The organic phase is washed c.gain 4 times in succession with, on each occasion, 1400 cm³ of tap water. The pH of these four washes is readjusted downwards with 5 ml of normal hydrochloric acid to facilitate the settlings. These four washes, settlings and separations are carried out at 35°C. The organic phase is concentrated by a factor of about two. 60(j cm³ of ethyl acetate are gradually ι

poured onto this iconcentrate, the crystallization being 10 initiated after a[bout one-third has been added. After the addition, supplying with ethyl acetate is continued with concomitant (distillation, so as to keep a constant volume in the fla^sk, i.e. about 60 0 cm³. After distillation to constant volume of about 800 cm³, the 15 suspension is coaled to 0°C and filtered. The filter cake is washed with twice 125 cm³ of ethyl acetate at

0°C and dried unc.er reduced pressure (1.5 kPa) at 40°C j

to constant weight. 120 g of a light beige product containing 110 g of pristinamycin IB are obtained.

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Claims

Having now particularly described and ascertained tny/oursaid invention and in what manner the same is to be performed l/we declare that what l/we claim m — _{A prooe}es for the preparation of streptogramins of general formulas in which:

either the radical R_x represents a methyl or ethyl group, the radical R₂ represents a hydrogen atom and X and Y together form an oxo radical, or R_a represents an ethyl radical, R_a and X represent a hydrogen atom and Y represents a hydrogen atom or a hydroxyl radical, or R_x represents an ethyl radical, R_a represents a hydroxyl radical and X and Y together form an oxo radical, by demethylation of a synergistin derivative of general

AP/P/ 9 7/01 121 formula:

AP.00768 in which the radicals R_1Z R₂, X and Y are as defined above, by treatment with a periodate in acetic medium followed by a treatment in aqueous medium.
2. Process according to claim 1,

5 characterized in that the periodate is chosen from tetra-n-butylammo)nium “periodate or an alkaline periodate.
3. Process according to claim 2, characterized in [that the alkaline periodate is sodium

10 periodate. '
4. Process according to claim 1, characterized in that the subsequent treatment is a hydrolysis, in aqueous medium, either in a homogeneous medium to which 4^s added a strong acid, or in an acidic 15 or non-acidic twp-phase medium.
5. Process according to claim 1, that an agent capable of consuming the formaldehyde in £itu is added, this agent being chosen from hydroxylamine, a bisulphite or hydrogen peroxide,

20 during the subsequent treatment.

characterized in

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AP . 0 0 7 6 8
6. A streptogramin derivative, characterized in that it corresponds to the general formula:

in which R_x represents an ethyl radical, R₂ and X 5 represent a hydrogen atom and Y represents a hydrogen atom or a hydroxyl radical.