MXPA97005190A

MXPA97005190A - Synthesis of 11,12-hydrogenoborate of 9-desoxy-9a-aza-11,12-desoxy-9a-methyl-9a-homoeritromycin a. a procedure for the preparation of 9-desoxy-9a-aza-9a-methyl-9a -homoeritromycin a dihydrate (azitromycin dihydra

Info

Publication number: MXPA97005190A
Application number: MXPA/A/1997/005190A
Authority: MX
Inventors: Santos Bayod Jasanada Miguel; Ramon Fernandez Gonzalez Jose
Original assignee: Asturpharma Sa
Priority date: 1996-07-11
Filing date: 1997-07-09
Publication date: 1998-01-01

Abstract

The present invention relates to the preparation of azithromycin dihydrate from 11,12-hydrogeno-orthoborate of 9-deoxo-9a-aza-11,12-deoxy-9a-methyl-9a-homoerythromycin A, obtained in a stepwise process from 9-deoxo-6-dexosi-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A is a procedure that takes place under mild conditions and with good performance.

Description

Synthesis of 11,12-hydrogenoortorate of 9-deoxo-9a-aza-ll, 12-deoxy-9a-methyl-9a-homoerythromycin A. A procedure for the preparation of 9-deoxo-9a-aza-9a-methyl-9a -homoerythromycin A dihydrate (Azithromycin dihydrate).

BACKGROUND Azithromycin is the generic name USAN of the product 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (4), a compound derived from erythromycin A, which constitutes the first example of a new class of antibiotics (azalides ) and which is an effective therapeutic agent in the treatment of sexually transmitted diseases, respiratory tract infections and skin infections (HA Kirst, GD Sides, Antimicrob Agents Chemother, 1989, 33, 1419-1422).

In the Figure 1 the bibliographic antecedents referring to the synthesis of this macrolide are represented. Azithromycin has been described for the first time by S. Djokic and G. Kobrehel in Pat. Bel. No. 892,357 and its related US Pat. No. 4,517,359, by the reductive alkylation of 9-deoxo-9a-aza-9a-homoerythromycin A (3), by treatment of said amine with a mixture of formic acid and aqueous formaldehyde at chloroform reflux, following the experimental conditions Classics of the Eschweiler-Clarke reaction.

The synthesis of 9-deoxo-9a-aza-9a-homoerythromycin A (3), is described by S. Djokic and G. Kobrehel in US Pat. No. 4,328,334, and J. Chem. Soc. Perkin Trans 1, 1986, 1881. In these publications, this product is named 10-dihydro-10-deoxo-11-azaerythromycin A, and is obtained by a sequence of synthesis that schematically consists of: • Obtaining the oxime of erythromycin A (1) by reaction of erythromycin A with hydroxylamine hydrochloride.

Obtaining the iminoether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A (2) by transposing the oxime of erythromycin A (1) . This iminoether and its obtaining procedure is also described in Pat. WO 94/26758 and in Eur. Pat. 0.137.132. In US Pat No. 4,328,324 this iminoether is mistakenly assigned to the structure of lactam obtained by a transposition of Beckman from the oxime of erythromycin. Obtaining 9-deoxo-9a-aza-9a-homoerythromycin A (3) by imino ether reduction (2) by sodium borohydride in methanol, or by catalytic hydrogenation in the presence of platinum dioxide and with acetic acid as solvent.

In the aforementioned literature the reduction of the iminoether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A (2), can be carried out following two different methods: a) Reduction with sodium borohydride in methanol at 0 ° C. This method has a series of drawbacks: methanol destroys the reducing agent, and some of the operations that include the isolation of the reaction product (azaerythromycin) affects its quality. In the aforementioned literature it is described how, in the presence of aqueous acidic media, azaerythromycin (3) is partially hydrolyzed to give desosaminilazaerythromycin (6) (S. Djokic et al in J. Chem. Soc. Perkin Trans I, 1986, 1881). b) Catalytic hydrogenation with platinum dioxide at high pressures (70 atm). The disadvantages of this method, from its point of view of industrial application are obvious: the high working pressures and the handling of platinum dioxide The Eschweiler-Clarke reaction used in US Pat. No. 4,517,359, and in J. Chem.

Res., 1988, 132; and idem miniprint., 1988, 1239, to obtain azithromycin (4) has as main drawback the formation of some reaction impurities as is the case of the formamide derived from the amine 9-deoxo-9a-aza-9a-homoerythromycin TO .

The structural elucidation studies of azithromycin (4) (S. Djokic and G. Kobrehel J. Chem. Res., 1988, 132, and idem miniprint., 1988, 1239) have revealed their existence in two crystalline forms: hygroscopic monohydrate (4) and non-hygroscopic crystalline dihydrate (5). The latter form being preferred for its manipulation with the aim of preparing formulations for therapeutic use, as described in Eur. Pat. No. 0298,650 DESCRIPTION OF THE INVENTION The object of the present invention is shown in Figure 2, which consists of obtaining in four steps 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, azithromycin dihydrate (5), from the imino-ether 9 -deoxy-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A (2). The procedure described here involves the preparation of two new products that are used as synthesis intermediates of azithromycin: 11,12-hydrogenoortorate of 9-deoxo-9a-aza-, ll, 12-deoxy-9a-homoerythromycin A (8) , and 11,12-hydrogenoortorate of 9-deoxo-9a-aza-l, 12-deoxy-9a-methyl-9a-homoerythromycin A (9). It is also object of the present invention, the conversion of the hygroscopic form of azithromycin (4) in its non-hygroscopic dihydrate form (5), by agitation of the hygroscopic form in a mixture of acetone-water with seeding of crystals of the dihydrate form.

The design of the new process of synthesis of azithromycin object of the present invention starts from the careful comparison of the obtained product and the set of impurities present in different batches of azithromycin obtained at laboratory scale by means of the repetition of the experimental conditions described by the discoverers of the product (S. Djokic et al) in J. Chem. Soc. Perkin Trans I, 1986, 1881, J. Chem. Res., 1988, 132; and idem miniprint., 1988, 1239.

The different batches studied differ in the way of obtaining the mentioned azaerythromycin from the iminoether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoeritrornicina A (2): either by reduction with sodium borohydride, either by catalytic hydrogenation.

These studies have allowed us to make the following original observations: The reduction of the imino ether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A (2) by catalytic hydrogenation is possible in the presence of platinum on activated carbon as a catalyst. The method described in the present invention for the reduction of 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A (2) consists of its catalytic hydrogenation at low pressure (between 3 and 10 atm) in the presence of platinum on activated carbon as a catalyst, and with the use as solvents of acidic aqueous systems: methanol / water / acid. hydrochloric or 2 N aqueous acetic acid. The reduction times are moderate (12-16 hours), and the experimental work of isolation of 9-deoxo-9a-aza-9a-homoerythromycin A (3) is simple and does not affect its stability: simple filtration of the catalyst, and subsequent extraction in alkaline medium, concentration and precipitation. In the study of the contaminants present in 9-deoxo-9a-aza-9a-homoerythromycin A (3) (azaerythromycin) obtained by reduction with sodium borohydride, the presence of a contaminant not described in the literature has been observed: 11, 12-Hydrobortoborate of 9-deoxo-9a-aza-, ll, 12-deoxy-9a-homoerythromycin A (8). In the study of the contaminants present in 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (azithromycin) (4), prepared from the azaerythromycin obtained via reduction with sodium borohydride, the presence of a contaminant not described in the literature: 11,12-hydrogenoortorate of 9-deoxo-9a-aza-11,12-deoxy-9a-methyl-9a-homoerythromycin A (9).

The formation of these 11,12-hydrogenortortorates should not be surprising, as it is known, the formation of this functional group is one of the classical methods of protection of vicinal diols ("Protective Groups in Organic Synthesis", TW Greene, Wyley & Sons, 2nd, p 115, 141, and 173; RJ Ferier, Adv. Carbohydr, Chem. Biochem., 35, 31-80, 1978) The presence of boron in compounds (8) and (9) was revealed by 11B-NMR and mass spectroscopy. For its structural elucidation, special NMR techniques have been used, such as heteronuclear two-dimensional correlations: HMAC and HMBC. It can be affirmed that the OH groups that occupy positions 11 and 12 of the macrolide are bound to the boron atom, as can be deduced from the disappearances that have these carbon atoms: * Solvent: CDC13 * Ta = 293 oK * v of 1H = 400 MHz; v of 13C = 100.61 MHz The synthesis process of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (azithromycin) (4) object of the present invention consists of using the 11,12-hydrogenortoborates (8) and (9) as intermediates of synthesis, adequately modifying the reaction conditions so that they are the intermediate products obtained. The substantial advantage of this synthesis method is that when carrying out the hydrolysis of 11,12-hydrogenoortorate of 9-deoxo-9a-aza-l, 12-deoxy-9a-methyl-9a-homoerythromycin A (9), in the conditions described in the experimental part, both the presence of desosaminilazaeritromicina (6) and desosaminilazitromicina (7) (products of acid degradation), as well as the presence of the 11,12-hidrogenoortoboratos themselves (8) and (9), all of them are minimized contaminants of synthesis of azithromycin (4). The concentration of 11,12-hydrogenoortorate of 9-deoxo-9a-aza-l, 12-deoxy-9a-methyl-9a-homoerythromycin A (9) as a contaminant is a determining factor in the conversion of hygroscopic azithromycin (4) in azithromycin dihydrate (5).

In this way, the product that is the object of this invention is obtained by a process consisting of the following stages: • The first step is the reduction of the iminoether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-aza-homoerythromycin A (2) with sodium borohydride in methanol between -10 and 0 oC .

The experimental work of the process is carried out in an aqueous medium but with the absence of mineral acid, which leads to the obtaining of 11,12-hydrogenoortorate of 9-deoxo-9a-aza-l, 12-deoxy-9a-homoerythromycin A ( 8) • The second step is the reductive alkylation of 9,12-hydrogenortoborate of 9-deoxo-9a-aza-l, 12-deoxy-9a-homoerythromycin A (8) with formaldehyde and formic acid at reflux of an organic solvent (preferably chloroform or acetonitrile). In this manner, 11,12-hydrogenortoborate of 9-deoxo-9a-aza-1, 12-deoxy-9a-methyl-9a-homoerythromycin A (9) is obtained. • The third step is hydrolysis in organic medium (preferably acetonitrile) and presence of dilute mineral acid (preferably sulfuric acid) of 11,12- 9-deoxo-9a-aza-l l, 12-deoxy-9a-methyl hydrogenoborate -9a- homoerythromycin A (9) to obtain azithromycin in its hygroscopic form (4). • The fourth step is the recrystallization of hygroscopic azithromycin from a mixture of acetone and water to obtain 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate (azithromycin dihydrate) (5).

Azithromycin dihydrate is easily distinguishable from hygroscopic azithromycin by the following differential tests: a) The dihydrate form maintains its percentage content in water constant at values (4.5-5%) very close to the theoretical value (4.6%) . b) The thermogravimetric analysis (TGA) of azithromycin dihydrate indicates a total weight loss between 4.5 and 5% at 200 oC, with a graph without inflections in the whole process. c) Differential calorimetry analysis (DSC) of azithromycin dihydrate shows the presence of a single endotherm that can vary between 126 and 135 oC, with an energy absorbed in the process ranging between 27 and 34 cal / g. d) The infrared spectra in KBr of both crystalline forms show clear differences: EXPERIMENTAL PART • Preparation of 9-deoxo-9a-aza-9a-homoerythromycin A. Dissolve 2 g of the iminoether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-aza-homoerythromycin A in a solution of 4.8 ml of acetic acid in 40 ml of H20, and 2 g of Platinum on 5% active carbon (with a H20 content of 60%) are added, and hydrogenation is initiated at a pressure of 75 psi . After 12 hours of reaction the catalyst is filtered and the liquid phase is discharged onto 100 ml of methylene chloride and 100 ml of H20, the aqueous phase is brought to pH = 9 and the organic phase is decanted. The aqueous phase is extracted with 2 x 50 ml of methylene chloride, the organic phases are combined, dried with anhydrous sodium sulfate and evaporated to give 1.55 g of 9-deoxo-9a-aza-9a-homoerythromycin A.

IR (KBr) vmax = 3500, 2980, 2960, 1740, 1470, 1380, 1180, 970 crn-1 1 H-NMR (CDC13) d = 2.3 (NMe2), 3.35 (OMe), ppm (partial) , 3 C-NMR (CDCl 3) 6 = 178.9 (C = O), 72.63 (C12), 71, 94 (Cp) 57.3 (C9), 56.9 (C, 0 (partial)), 49.4 (OMe), 40.2 (NMe2) ppm HPLC: corresponds according to USP XXIII TLC rf = 0.54 (petroleum ether: ethyl acetate: 75:25:10 diethylamine; developer: ethanol / vanillin (sulfuric acid) Preparation of 9,12-Hydroortoborate of 9-deoxo-9a-aza-11.12-deoxy-9a-homoerythromycin A. 89 g of 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro- are dissolved. 9a-aza-homoerythromycin A in 450 ml of methanol and cooled between -5 and -10 oC. Maintaining the temperature between the mentioned values, 16 portions of 2.2 g of sodium borohydride are added each. The stirring and temperature conditions are maintained for an additional 2 h and the reaction mass is allowed to reach 20 ° C. After 20 h the methanol is evaporated to dryness. The residue is dissolved in 500 ml of methylene chloride and 750 ml of water, stirring for 30 min. The organic phase is separated and the aqueous phase is extracted with 250 ml of methylene chloride. The organic phases are combined, filtered over celite, dried over anhydrous sodium sulfate and concentrated to dryness to give 85 g of 11,12-hydrogenortoborate of 9-deoxo-9a-aza-l 1.12-deoxy-9a-homoerythromycin A IR (KBr) vmax = 3500, 2980, 2960, 1730, 1470, 1390, 1170, 1090, 1060 c '1 1 H-NMR (CDC13) d = 2.21 (NMe2), 3.27 (OMe) ppm. (partial) 13 C-NMR (CDCl 3) d = 180.0 (C = O), 79.63 (C "), 76.46 (C, 2) 58.7 (Cio), 57, 1 (partial) (C9), 49.4 (OMe), 40.2 (NMe2) ppm nB-NMR (CDCl3) d = 9.9 ppm? Yl = 200 Hz TLC rf = 0.28 (petroleum ether: acetate of ethyl: diethylamine 75:25: 10; developer: ethanol / vanillin (sulfuric acid) Preparation of 9,12-hydrogeonoortorate of 9-deoxo-9a-aza-11,12-deoxy-9a-methyl-9a-homoerythromycin A. 50 g of 11,12-hydrogenortoborate of 9-deoxo-9a-azale are dissolved. 11.12-deoxy-9a-homoerythromycin A in 500 ml of chloroform and a mixture of 5.5 ml of formic acid and 11.75 ml of 35-40% aqueous formaldehyde is added. The reaction mass is refluxed for 14 h, and subsequently cooled to 15-20 ° C. 500 ml of water are added and it is brought to pH = 4 by the addition of 20% sulfuric acid. It is stirred for 15 min and the organic phase which is discarded is separated. To the acidic aqueous phase, 350 ml of methylene chloride are added, and 48% soda is added until pH = 9 of the aqueous phase. The mixture is stirred for 15 min and the lower organic phase is separated. The alkaline aqueous phase is extracted with 2 x 100 ml of methylene chloride. The organic phases are combined and filtered over celite, dried over anhydrous sodium sulfate and evaporated to dryness. The residue obtained is washed twice with 250 ml of ethyl ether, obtaining a dry residue of 29 g of 1,12-hydrogeonoortoborate of 9-deoxo-9a-aza-l, 12-deoxy-9a-methyl-9a- homoerythromycin A IR (KBr) Vma? = 3500, 1730, 1470, 1390, 1090, 1070 cm'1 1H-NMR (CDC13) d = 2.00 (Nme2), 2.30 (NMe), 3.37 (OMe) ppm (partial), 3 C-NMR (CDCl 3) d-179.9 (CO), 79.40 (Cu), 77.09 (C12), 68.84 (C9), 64.08 (partial) (Cio), 49.36 (OMe), 40, 18 (NMe2), 34.39 (NMe) ppm nB-NMR (CDCI3) d = 10.1 ppm? Vl = 180 Hz m / e M + = 775.5 TLC rf = 0.38 (petroleum ether: ethyl acetate: diethyl ina 75:25: 10; developer: ethanol / vanillin (sulfuric acid) Hydrolysis of 11,12-hydrogenortoborate of 9-deoxo-9a-aza-l l, 12-deoxy-9a-methyl-9a-homoerythromycin A. Synthesis of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (Azithromycin) 22 g of l, 12-hydrogeonoortoborate of 9-deoxo-9a-aza-l, 12-deoxy-9a-methyl-9a-homoerythromycin A are dissolved in 250 ml of acetonitrile and 125 ml of water are added. 20% sulfuric acid is added until pH = 2 and the stirring is maintained for 30 min. The acid solution is discharged onto a mixture of 350 ml of methylene chloride and 350 ml of water, added with 48% soda immediately until the pH of the aqueous phase is 9. It is stirred for 15 minutes and the lower organic phase is separated . The alkaline aqueous phase is extracted with 2 x 100 ml of methylene chloride. The methylene chloride is combined, filtered over celite and evaporated to dryness. The residue is dissolved in 50 ml of ethanol and 60 ml of water are added over 30 min. Allow to precipitate for 2 h, filter and dry under vacuum and 40 oC to give 15 g of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (Azithromycin) IR (KBr) vmax = 3500, 3000 , 2970, 1740, 1470, 1380, 1280, 1060 cm "1 1 H-NMR (CDC) d = 2.31 (Nme 2), 2.34 (NMe), 3.38 (OMe) ppm (partial) 13 C-NMR (CDCb) d = 178.9 (CO), 73.08 (C? 2), 72.32 (Cu), 69.88 (C9), 62.43 (partial) (C, 0), 49.37 (OMe), 40.23 (NMe2), 35.92 (NMe) ppm m / e M + = 749.5 HPLC corresponds to USP XXIII TLC rf = 0.62 ( petroleum ether: ethyl acetate: diethylamine 75:25: 10; developer: ethanol / vanillin (sulfuric acid) Preparation of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate. 51 g of hygroscopic azithromycin are dissolved in 130 ml of acetone and the solution is filtered. For 30 min. 100 ml of water are added and stirred at room temperature for 24 hours. The precipitated solid is filtered and dried under vacuum and 40 ° C to give 45 g of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A dihydrate. From the point of view of their spectroscopic data, the hygroscopic and dihydrate forms only differ in some bands of their infrared spectrum.

IR (KBr) vmax = 3600, 3520, 3000, 2970, 1740, 1470, 1380, 1340, 1285, 1270, 1080, 1060 cm'1 Conversion of hygroscopic azithromycin into azithromycin dihydrate. A mixture of 35 ml of acetone and 27 ml of water is prepared, and 14 g of azithromycin dihydrate are added. 3.5 g of azithromycin dihydrate are added and the suspension is stirred at room temperature for 24 h. It is filtered and dried under vacuum and 40 ° C to give 13.6 g of azithromycin dihydrate.

Claims

CLAIMS.

1. The product: 11,12-hydrogenortoborate of 9-deoxo-9a-aza-l l, 12-deoxy-9a-methyl-9a-homoerythromycin A.

2. A process for the preparation of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (Azithromycin) in its dihydrate form characterized by recrystallization of the hygroscopic form of azithromycin in an acetone-water mixture.

3. A process for the preparation of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (Azithromycin) in its dihydrate form characterized by the agitation of crystals of the hygroscopic form of azithromycin in a mixture of acetone-water with addition initial crystals of the dihydrata form of azithromycin.

4. A procedure for the preparation of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (Azithromycin) characterized by the hydrolysis of 11,12-hydrogenortoborate of 9-deoxo-9a-aza-l, 12-deoxy -9a-methyl-9a-homoerythromycin A in an organic solvent (preferably acetonitrile or methanol) by the action of a dilute mineral acid (preferably sulfuric acid) at room temperature in a pH range comprised between 2 and 4.

5. A process for the preparation of 9,12-hydrogenortoborate of 9-deoxo-9a-aza-l, 12-deso? I-9a-methyl-9a-homoerythromycin A characterized by the reaction of 11,12-hydrogenortoate of 9 -desoxo-9a-aza-l, 1,2-deoxa ^ a-homoeritrornicina A with formic acid and aqueous rmaldehyde under reflux of an organic solvent (preferably acetonitrile and chloroform).

6. A process for obtaining 11,12-hydrogenortoborate of 9-deoxo-9a-aza-11.12-deoxy-9a-homoerythromycin A characterized by the reduction of 9-deoxo-6-deoxy-6,9-epoxy-9,9a -dihydro-9a-azahomoerythromycin A with sodium borohydride in methanol as solvent, at low temperature (preferably between -10 and 0 or C); with subsequent hydrolysis in the absence of mineral acid medium.

7. A process for the preparation of 9-deoxo-9a-aza-9a-homoerythromycin A characterized by the catalytic hydrogenation at low pressure (between 3 and 10 atm) of 9-deoxo-6-deoxy-6,9-epoxy- 9,9a-dihydro-9a-azahomoerythromycin A using as platinum catalyst on carbon, and as solvent a mixture of alcohol (methyl or ethyl) and aqueous acid (preferably acetic acid).