MXPA04010587A - Novel manufacturing method of [2r -(2r*, 3s*, 4r*, 5r*, 8r*, 10r*, 11r*, 12s*, 13s*, 14r*)]-13 -[(2, 6- dideoxy 3-c-methyl -3 -o-methyl -(-l-ribo -hexopyranosyl) oxy]-2-ethyl-3, 4, 10- trihydroxy -3, 5, 6, 8, 10, 12, 14-heptamethyl -11-[[3, 4, 6-trid - Google Patents

Abstract

Provided herein is a novel manufacturing process of the anhydrous crystalline form of the [2R -(2R*, 3S*, 4R*, 5R*, 8R*, 10R*, 11R*, 12S*, 13S*, 14R*)]-13 -[(2, 6-Dideoxy -3-C-methyI -3 -O-methyl - (-L-ribo -hexopyranosyl)oxy] -2-ethyl-3, 4, 10- trihydroxy -3, 5, 6, 8, 10, 12, 14-heptamethyl -11-[[3, 4, 6-trideoxy -3-(dimethylamino) -('-D-xyl -5-hexopyranosyl] oxy]-1-oxa-6 -aza cyclopentadecan -15-one compound, which is also known as IUPAC 9- deoxo-9a -aza-9a -methyl-9a- homoerythromycin A obtained from the 9- deoxo-9a -aza-9a- homoerythromycin amine, which is also known as 11-aza-10-deoxo-10duhydroerythromicin.

Description

[2R- (2R *, 3S *, 4R *, 5R *, 8R *, 10R *, 11R *, 12S *, 13S *, 14R *)] - 13 - [(2,6-DIDEOXY-3-C- METHYL-3-0-METHYL-aL-RIBO-HEXOPYRANOSIL) OXYJ-2-ETHYL-3], 4, 10-TRIHYDROXY-3,5,6,8, 10,12,14-HEPTAMETIL-ll - [[3 , 4,6-TRIDEOXY-3- (DIMETHYLAMINE) -PD-XYLO- 5 HEXOPYRANOSYL] OXI] -l-0XA-6- AZACICLOPENTADEGAN-15 - ??? A NEW MANUFACTURING PROCESS FIELD OF THE INVENTION A new process for the manufacture of the new compound [2R- (2R *, 3S *, 4R *, 5R *, 8R *. 10R *, 11 R *, 12S *, 13S *, 14R *)] - 13 - [( 2,6-D-Deoxy-3-C-methyl-3-0-methyl- -Lr / 5-hexopyranosyl) oxy] -2-ethyl-3] 4,10-trihydroxy-3,5,6 , 8,10,12,14-heptamethyl-11 - [[3, 4,6-trideoxy-3- (dimethylamino) -pDx / 7o-hexopyranosyl] oxy] -1-oxa-6 azacyclopentadecan-15-one, whose Physical properties make it useful for the manufacture of stable pharmaceutical preparations against bacterial infections, and that corresponds with the anhydrous crystalline form + BACKGROUND OF THE INVENTION In the patent PCT / MXOO / 00030 the new compound is reported [2R- (2R \ 3S *, 4R *, 5R *, 8R *, 10R *, 1 1 R *. 12S *. 13S *, 14R *)] - 13 - [(2,6-Dideoxy-3-C-methyl-3-O-methyl-aL-róo-hexopyranosyl) oxy] -2-ethyl-3], 4, 10-trihydroxy-3,5,6, 8,10,12,14-heptamethyl-H -p, 4,6-trideoxy-3- (dimethylamino) - -Dx / 7o-hexopyranosyl] oxy] -1 -oxa-6-azacyclopentadecan-15-one or with name IUPAC 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A and generic name Azithromycin, which by different physicochemical methods was elucidated corresponding to the anhydrous crystalline form, with a tetragonal crystalline system, with spatial group P422Í2, cell constants a = 14.452 A °, b = 14.452 A °, c = 41.645 A ° and volume 8698 A03. This compound was synthesized from Erythromycin A and was identified by Nuclear Magnetic Resonance and Mass Spectrometry.

Azithromycin differs structurally from Erythromycin A by inserting a methylated nitrogen group at position 9a into the lactone ring, to create a 15-member macrolide. The structural modification 5 significantly improves the effectiveness of the antibiotic especially against gram-negative bacteria and reaches higher concentrations in the organism than its precursor. Azithromycin acts by inhibiting the ^ Synthesis ~ 'proteins * in = bacteria ^ Chlamidia trachomatis, Chlamidia pneumoniae, the Mycobacterium complex 10 avium, etc.

A method of obtaining Azithromycin was patented by Slobodan Dokic and Gabriela Kobrehel in Yugoslavia under number P 592/81. With this method the amorphous form of the solid Azithromycin was obtained, which presents the The disadvantage of being very hygroscopic and therefore not suitable for the preparation of stable pharmaceutical preparations. Subsequently, Gene M. Bright in U.S. Patent 4,474,768 reports a new crystalline form of azithromycin corresponding to the monohydrated form, which still has the characteristic of being hygroscopic and therefore is not useful for 20 the preparation of stable pharmaceutical preparations. Therefore, D.J.M. Alien and K.M. Nepveux report in patent PCT / US87 / 01612 a new crystalline form of Azithromycin corresponding to the dihydrate form, which is not hygroscopic and therefore suitable for the preparation of stable pharmaceutical preparations. In this last patent, 25 to obtain the dihydrated form, we start from the amorphous form reported by Dokic and Kobrehel or from the monohydrate, reported by Bright, which are recrystallized in an adequate liquid medium to obtain the dihydrated form. In the US patent application US 2003/0162730 30 15 new crystalline compounds are reported, which are grouped into two families of space groups. Family I groups the crystalline forms F, G, H, J, M, N, O! > \ i and P corresponding to the monoclinic space group P2i and with cell dimensions a = 16.3 A °, b = 16.2 A ° and c = 18.4 A ° and angle 109.2 °. Family II groups the crystalline forms C, D, E and R and corresponds to the Oorombic space group P2- | 2-i2i with cell dimensions a = 8.9 A °, b = 12.3 A °, c = 45.8 5 A °. In addition, the crystalline forms L, K which are metastable forms of the dihydrate detected at high temperature and the Q form whose spatial group is different from the two families are reported. However, all these '^' ^ Compounds'are'hydrates.or solvates, for which I agree with the existing definitions are pseudopolymorphs of the anhydrous crystalline compound invented in 10 patent PCT / MX00 / 00030.

The purpose of the present invention is to provide a new process for the manufacture of the new solid form of the compound 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, valuable for the preparation of stable pharmaceutical preparations obtained by a process different from that previously reported in patent PCT / MX00 / 00030 and that is described below.

DESCRIPTION OF THE INVENTION 20 To obtain the new anhydrous crystalline form of the compound [2R- (2R *, 3S *, 4R *, 5R *, 8R *, 10R *, 11 R *. 12S *. 13S *. 14R *)] - 13 - [(2,6-Dideoxy-3-C-methyl-3-O-methyl-aL-n'bo-hexopyranosyl) oxy] -2-ethyl-3], 4, 10-trihydroxy -3,5,6,8,10,12,14-heptamethyl-1 1 - [[3,4- trideoxy-3- (dimethylamino) -pDx / 7o-hexopyranosyl] oxy] -1-oxa-6 -zazacyclopentadecan-15-one is reductively methylated 9-deoxo-9a-aza-9a-homoerythromycin also called 11-aza-10-deoxo-10 dihydroerythromycin or known by the common names azaerythromycin or azithromycin amine, through the following process. This precursor is dissolved in acetone and methylated using formaldehyde in 37% aqueous solution and 88% formic acid. The reaction occurs rapidly by heating 30 and with magnificent yields of around 96%, obtaining a purity of 97%. The methylated product is isolated by precipitation in water. The solid crystalline form is filtered off in a centrifuge and dissolved in hot Hexane. This solution is refluxed using a Dean Stark trap, during which time it is dehydrated and after which the "Azithromycin Crystalline Anhydrous" starts to precipitate. The precipitate is filtered and dried in vacuo at 40 ° C until free of organic solvent and obtain an anhydrous crystalline solid.

- ^, ^. ^ ^ ÷ * ^ EI = crystal-obtained-identified 13C, proton, and by mass spectrometry as the compound 9-deoxo- 10 9a-aza-9a-methyl-9a-homoerythromycin A. Chemical shifts characteristic of the 13C spectrum (CDC) were located at: 178.54 ppm, 102.89 ppm, 94.82 ppm, 83.68 ppm, 77 ppm, 49.36 ppm, 45.04 ppm, 40.32 ppm (the spectrum is presented in Figure 1). The molecular weight, determined by Mass Spectrometry / FAB +, was 748 being the pattern of 15 fragmentation congruent with that of the molecule 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (the corresponding mass spectrum is shown in Figure 2).

The melting point of the crystal obtained, as determined by the Fisher Jones method, is 188 ° C to 189 ° C. By Thermal Differential Scanning an endotherm is obtained at 187.7 ° C. The corresponding graph is shown in Figure 3. The determination of the specific rotation gives a value of. { to} = - 38.0 (1% in CHCI3). These parameters obtained are clearly different from the values found for other 25 previously patented forms of Azithromycin. Thus it is that the Azithromycin reported by Dokic and Kobrehel (Yugoslav patent 592/81, Belgian patent 892357, US patent 4,517,359, Mexican patent 9100364) has a melting point of 113 ° C to 115 ° C and its specific rotation is de - 37.0 (1% in CHCI3). Azithromycin patented by Bright (US patent 4,474,768), has a melting point of 142 ° C (the recrystallized form) and crystallized azithromycin dihydrate has a melting point of 125 ° C and a specific rotation of -41.4 ( 1% in CHCI3) (patent PCT / US87 / 01612 and Mexican patent 176627).

The infrared spectrum of the new crystal has six signals of medium intensity in the region of 2900 cm'1 to 3700 cm "1 located at approximately 3595 cm'1, 3553 cm" 1, 3375 cm "1, 3075 cm'1 and two around of 2965 cm'1 Unlike the spectrum reported for the dihydrate form, it does not show the 'intense' signal at 3488.cmj.ini.las located at.2089 cm "_1, v_ 1664 cm'1 (patent PCT / US87 / 01612). On the other hand, the spectrum of the new crystal, shows an aallrreeddeeddoorr signal of 11726 cm'1. The infrared spectrum of the crystal obtained is shown in Figure 4.

The water determination of the new crystal by the Karl Fisher method gives a value of 0.65%. By thermogravimetric analysis, by heating up to 200 ° C at a speed of 30 ° C / minute, a weight loss equal to 0.6% is observed. In Figure 5 the graph obtained by this method is shown. These results indicate that the water present in the sample corresponds to humidity absorbed from the environment, but not with water of hydration (defined as water molecules that are part of the crystal lattice), since the theoretical minimum corresponding to a water molecule of hydration would be 2.35% of the total weight. This conclusion, that the weight increase is only of humidity, is corroborated with the elemental analysis performed on this sample, obtaining the relation: C 60.59%, H 10:06%, N 3.65%, OR 25.77%, corresponding to the condensed formula C38H72 2012.

Based on the physical characteristics determined for the new crystal, it is concluded that the new physical form is clearly different in its physical properties from the previously patented forms of Azithromycin. In order to confirm this conclusion, we proceeded to elucidate the structure by single-crystal X-ray diffraction, obtaining that the compound corresponds to the anhydrous crystalline form, with tetragonal crystalline system and a space group P422i2. These and other crystalline data of the diffraction analysis performed are compared in Table 1 with the data reported for the crystalline dihydrate form (J. Chem. Res. 152-153 (1988)). The molecular structure of anhydrous crystalline Azltromycin is shown in Figure 6 and the corresponding crystal lattice is illustrated in Figure 7.

TABLE 1.- CRYSTAL DATA OF THE CRYSTAL FORM ANHYDRA OF DIHYDRATED ANHYDRA TETRAGONAL ORTHRONOMIC CRYSTAL SYSTEM SPACE GROUP P422i2 P2i2i2i CELL CONSTANTS a = 14.452 A ° a = 17.86 A ° b = 14.452 A ° b = 16.889 A ° c = 41.645 A ° c = 14.752 A ° Volume 8698 A03 4449.8 A03 Calculated Density 1.144 g / cm3 1.177 g / cm3? (Cu-Ka) 1.5418 A ° 1.5418 A ° Number of Reflections 3412 3846 R 0.0546 · 0.077 According to the existing definitions (see for example JP Glisker, Crystal Structure Analysis for Chemists and Biologists, VCH publishers, 1994, page 657 and HG Brittain, Physical Characteristics of Pharmaceutical Solids, Marcel Dekker, Inc., 1995, page 108 ), the hydrated physical forms of Azithromycin, reported in US Patent 4474768 and in PCT / US87 / 016 2, are pseudopolymorphic forms of the anhydrous crystalline form obtained herein, while the physical form reported by Kobrehel and and collaborators (Yugoslav patent 592/81, Belgian patent 892357, US patent 4,517,359, Mexican patent 9100364), according to patent PCT / US87 / 01612, corresponds to the amorphous form.

The physical form obtained here in addition to being novel has physical characteristics that make it useful and valuable for the preparation of pharmaceutical formulations, with important advantages over the up to now forms. In the patent PCT / US87 / 0612 it is indicated that the forms reported by Kobrehel et al. (Patent yokes) ava ~ 5927817 Belgian patent 892357, US patent 4,517,359, Mexican patent 9100364) and by Brigth (US patent 4474768) are highly hygroscopic, which seriously hinders the preparation of pharmaceutical preparations. In contrast, the anhydrous crystalline form obtained here, when exposed to the environment at a relative humidity of 45%, for ten days, increases its moisture content only by 0.55%; while a reference sample of Azithromycin dihydrate, during the same time Japso, increases its humidity by 1%. These data indicate the high stability of crystalline Azithromycin anhydrous against moisture, which makes it useful and valuable for the preparation of pharmaceutical preparations and advantageous compared to the other more hygroscopic forms.

In order to test the behavior of anhydrous crystalline azithromycin in the preparation of pharmaceutical preparations, 500 milligrams of Azithromycin tablets, with a total weight of one gram, were formulated and made. These tablets were determined their dissolution profile, which is Consequently, the properties described above for the anhydrous crystalline form, of being less hygroscopic, of being more stable and more soluble in water than the other existing forms and of having their pharmaceutical preparations have an adequate dissolution, make the new crystalline form reported here has an advantageous utility against the forms of Azithromycin until now existing. For example, its greater solubility in c - .. ^^ average »polafrhace.que ^ of utility higher than those of the dihydrated form, since a greater The solubility of the pharmaceutical preparation generally implies a greater bioavailability of the drug and therefore greater therapeutic efficacy, which can be achieved with the appropriate pharmaceutical preparation. 4 The production method used to obtain the compound [2R- (2R *, 15 3S *. 4R *, 5R *, 8R *, 10R *. 11 R *, 12S *, 13S *, 14R *)] - 13- [ (2, 6-Dιdeoxy-3-C-methyl-3-0-methylol-rιg-o-hexopyranosyl) oxy] -2-ethyl-3], 4, 10-trihydroxy- 3,5,6,8,10,12,14-heptamethyl-11 - [[3, 4,6-trideoxy-3- (dimethylamino) - -Dx / Vo-hexopyranosyl] oxy] -1- oxa- Anhydrous crystalline 6-azacyclopentadecan-15-one can be illustrated by the following example: Example It starts from 25 kilograms of the amine 9-deoxo-9a-aza-9a-homoerythromycin also called 11-aza-10-deoxo-10 dihydroerythromycin or known by the common names azaerithromycin or azithromycin amine. 25 This precursor is dissolved in 250 liters of acetone and 6 liters of formaldehyde and formic acid are added. The mixture is heated to reflux and the progress of the reaction is monitored by chromatography. In order to eliminate small suspended solids in the reaction medium, the solution is filtered in line and discharged into another reactor of sufficient volume. The solution is concentrated and alkalized with a sodium hydroxide solution until pH 10. The compound is precipitated with water and the precipitate is separated by centrifugation. The compound obtained is dissolved in Hexane and refluxed for four hours, using a Dean Stark trap, until complete dehydration of the solution is achieved. Once crystals suspended in the organic solvent are obtained, the solution is concentrated and then the crystals are filtered, for example with a Sparklet filter. The anhydrous crystalline azithromycin obtained is placed in a vacuum oven at 40 ° C. Once you have the product completely dry, free of the organic solvent, proceed to its

Claims (1)

1. CLAIMS 1. A compound [2R- (2R *, 3S *, 4R *, 5R *, 8R *, 10R *, 11R *, 12S *, 13S *, 14R *)] - 13 - [(2,6-Dideoxy-3 -C-methyl-3-0-methyl-aLr / o-hexopyranosyl) oxy] -2-ethyl-3, 4, 10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11 - [[3, 4, 6-trideoxyl-3- (dimethyllamine) -pDx / o-hexopyranosyl] oxy] -1-oxa-6-azacyclopentadecan-15-one or with the same name of IUPAC 9-deoxo- ^ 9a aza-9a- "methyl-9a-homoentromicinatA; which has anhydrous crystalline form. According to clause 1 the compound has the following properties: a) The main chemical deviations determined by Nuclear Magnetic Resonance of 13C are located at 178.9 ppm, 102.8 ppm, 94.3 ppm, 83.18 ppm, 77 ppm, 49.36 ppm, 45.04 ppm, 40.32 ppm b) The melting point is 188 ° C to 189 ° C c) The endotherm of the differential thermal analysis is at 187.7 ° C. d) The specific rotation is. { to} =: -35 ° (c = 1% in CHCI3). e) Infrared spectroscopy signals are located ¡ azaerythromycin or azithromycin amine. This precursor is dissolved in acetone and methylated using formaldehyde in 37% aqueous solution and 88% formic acid. The reaction occurs by heating rapidly and with magnificent yields of around 96%, obtaining a purity of 97%. Subsequently the product obtained is refluxed in Hexane and dehydrated, using a Dean Stark trap. The solution is concentrated by distillation of Hexane and the precipitate is separated off by evaporation under a reduced pressure. 4. According to clauses 1 and 2, a process for the preparation of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A in its anhydrous crystalline form from its salts or its derivatives, after the regeneration of the base form and consisting of the recrystallization of the regenerated, isolated or in situ form of the regeneration medium of the base form, in a suitable non-polar organic solvent such as Hexane, at reflux, using a Dean Stark trap. 5. According to clauses 1, 2, 3, 4, 5, 6, pharmaceutical compositions such as tablets, suspension, injectables, powder for reconstitution, etc. using as active substance the compound 9-deoxy-9a-aza-9a-m "ethyl-9a-homoerythromycin A. 6. According to clauses 1, 2, 3, 4, 5, 6, 7, the use of the pharmaceutical preparation acts as an effective medicine in sexually transmitted diseases, respiratory diseases and infections of the skin and soft tissues. " 7. According to clauses 1, 2, 3, 4, 5, 6, 7, the use of the pharmaceutical preparation acts as an effective medication in otitis media. 8. According to clauses 1, 2, 3, 4, 5, 6, 7, the use of the pharmaceutical preparation acts as a broad spectrum antibacterial drug. 10 15 ¡20 ·