CA2417353C - Single-step process for preparing 7,16-deoxy-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle (11.2.1)hexadeca-1(2)-en-8-one, and obtaining a new form of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin a - Google Patents

Single-step process for preparing 7,16-deoxy-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle (11.2.1)hexadeca-1(2)-en-8-one, and obtaining a new form of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin a Download PDF

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CA2417353C
CA2417353C CA002417353A CA2417353A CA2417353C CA 2417353 C CA2417353 C CA 2417353C CA 002417353 A CA002417353 A CA 002417353A CA 2417353 A CA2417353 A CA 2417353A CA 2417353 C CA2417353 C CA 2417353C
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aza
methyl
homoerythromycin
deoxo
ethyl
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CA2417353A1 (en
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Juan Antonio De La Torre Garcia
Fidencio Franco Andrade
Jose Manuel Francisco Lara Ochoa
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Instituto de Investigacion en Quimica Aplicada SC
Laboratorios Silanes SA de CV
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Instituto de Investigacion en Quimica Aplicada SC
Laboratorios Silanes SA de CV
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08Hetero rings containing eight or more ring members, e.g. erythromycins
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D267/00Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals

Abstract

The invention relates to an improved method for preparing 7,16-deoxy-2-aza-10-O-cladinosil-12-O-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[11.2.1]hexa-deca-1(2)-en-8-ona from erythromycin A, wherein said compound is obtained from erythromycin A with high yields and under soft and adequate production conditions in a single-step process. Transformation of erythromycin A into an intermediate compound called 6,9-iminoether, which is obtained in a single step, is carried out by forming "in situ"
mesitylenesulfonyloxime from erythromycin, which undergoes Beckmann's transposition in the presence of a base in aqueous acetone thus giving rise to the iminoether with the aid of the hydroxyl in position 6 of the macrolide ring. Said intermediate compound is transformed into the antibiotic called 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, which is obtained by appropriate precipitation in hexane. A novel form with an anhydrous crystalline structure and physical properties differing from those of forms known to date is thus obtained.

Description

SINGLE-STEP PROCESS FOR PREPARING 7, 16-DEOXY-2-AZA-10-O-CLADINOSIL-12-O-DESOSAMINIL-4, 5-DIHYDROXI-6-ETHYL-3, 5, 9, 11, 13, 15-HEXAMETHYLBICYCLE (11.2.1) HEXADECA-1(2)-EN-1-ONE, AND
OBTAINING A NEW FORM OF 9-DEOXO-9a-METHYL-9a-AZA-9a-HOMOERYTHROMYCIN A

1:IELD OF THE INVENTION
This invention consists of forming an intermediate product called 6,9 iminoether in a single step from erythromycin, which is transformed into a new and useful form of azithromycin, which is recovered by means of precipitation in hexane.

i5 BACKGROUND OF THE INVENTION

The antibiotic [2R-(2R*, 3S*, 4R*, 5R*, 8R*, I0R*, I IR*, 12S*, 13S*, 14R')]-13-[(2, 6-Dideoxy-3-C-methyl-3-O-methyi-a.-L-ribo-hexopyranosyl) oxy]-2-ethyl-3, 4, 10-trihydroxy-3, 5, 6, 8, 10, 12, 14-heptamethyl-l1-[[3, 4, 6-trideoxy-3-(dimethylamino)-P-D-xylo-hexopyranosyl]oxy]=1-oxa-6-azacyclopentadecan-l5-one, or IUPAC name 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, and generic name azithromycin is a broad-spectrum bactericide derived from erythromycin A. It differs structurally from erythromycin A due to the insertion of a methylated nitrogen moiety in position 9a in the lactone ring to create a 15-member macrolide. The structural modification significantly improves the aatibiotic's effectiveness against defective cell wall bacteria such as Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia pneumoniae, etc. or the complex Mycobacteria avium, and achieves higher concentrations in the organism.
Azithromycin was discovered by Kobrehel et al. and first patented in Yugoslavia under number P592/81, and subsequently in Belgium under number 892357, under the name N-methyl-ll-aza-l0-deoxy-l0-dihydroerythromycin A. The reaction sequence reported in the literature used to transform erythromycin A (1) into azithromycin (5) includes 4 principal steps, illustrated in Figure 1, which are described in general terms below.

a) Formation of oxime (2) The oxime is formed from erythromycin A (1) by means of reaction with hydroxylamine hydrochloride in methanol.

b) Beclcmann's rearrangement of the oxime (2) The intramolecular participation of the neighboring 6-hydroxy group is observed when Beckmann's rearrangement is carried out at 0 C with p-toluenesulfonyl chloride in aqueous acetone, producing the 6,9-iminoether (3). This iminoether (3) and the process used to obtain it have been described in worldwide patent 26,758, and European patent 0,137,132. In U.S. patent 4,328,334, this iminoether is enoneously assigned to the structure of a lactam obtained using Beckmann's rearrangement from the oxime of erythromycin A(1).

c) Reduction of the iminoether (3) Reduction of the iminoether (3) to the secondary amine (4) with sodium borohydride in methanol (J. Chem. Soc. Perkin Trans. 1, 1986, 1881; J. Org, Chem. 1997, 62, 7479-7481) or by catalytic hydrogenation in the presence of platinum dioxide and acetic acid as solvents (Tetrahedron Lett. 1994, 35, 3025).

d) Reductive methylation of the secondary amine (4) to obtain azithromycin (5) This process is described in U.S. patent 4,517,359, and in J. Chem. Res. 1988, 132.
It consists basically of the Escheweiler-Clarke reaction and uses formaldehyde in acetic acid or formaldehyde, and formic acid in carbon tetrachloride or chloroform for methylation (Figure 1). The main difficulty with these reactions, as they are described, is the formation of certain impurities such as formamide, derived from the amine 9-deoxy-9a-aza-9a-homoerythromycin A.

Recently, an alternative method was described in which the iminoether (3) can be reduced and the product obtained subsequently submitted to reductive methylation in the presence of formaldehyde with a noble metal as catalyst, without the need to isolate the intermediary (Figure 1). Under these conditions, we obtain azithromycin with high purity and good yield in a single step from the iminoether (3) (European patent 0,879,823 Al).

Studies to elucidate the structure of azithromycin have brought to light two crystalline forms corresponding to the monohydrate and dihydrated forms (W089/00576, and J. Chem. -Res. 1988, 132). W089/00576 attributes to the azithromycin patented by Kobrehel et ai. (Yugoslav patent P592/81, Belgian patent 892357 and U.S.
patent 4,517,359) to correspond with the amorphous form.

This invention is intended to offer an altemative to known methods, in order to form the intermediary 6,9-iminoether in a single step from erythromycin to obtain 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, which is an evident improvement on existing preparation methods.

A further purpose of this invention is to prepare a novel form of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with physical characteristics different from those detected thus far.
DESCRIPTION OF THE INVENTION

All the methods reported to date for preparing azithromycin (5) involve the formation of the oxime (2) from erythromycin A (Figure 1) by treating the erythromycin in methanol with hydroxylamine hydrochloride and a base at reflux temperature for at least 10 hours.
This oxime is isolated, purified and subsequently subjected to Beckmann's rearrangement to obtain the intermediary (3) (Figure 1) in aqueous acetone in the presence of p-toluenesulfonylchloride and base for 2 hours at 5 C and 2 hours more at room temperature. The innovative aspect of this invention is that the iminoether (3) is prepared in a single step (Figure 2) from erythromycin A(1), which is operatively and economically more feasible than the aforementioned methods:The reaction described in this invention consists of treating an erythromycin A (1) solution in acetone with 0-mesitylenesulfonylhydroxylamine (MSH), to form the mesitylenesulfonyloxime "in situ" from erythromycin A, which, on being treated with an aqueous base (sodium bicarbonate) at 0 C, undergoes a Beckmann's rearrangement, giving rise to the intermediary 6-9-iminoether (3) (Figure 2). Reaction conditions are soft, with short times and the reactive used in this transformation (MSH) is easily prepared as described in Tetrahedron lett. No. 40, p. 4133-4135 (1972). Also, the method described in this invention is scalable for industrial production. After preparing the intermediary (3) (Figure 2), it is possible to obtain azithromycin (S) by means of catalytic reduction followed by reductive methylation using common techniques described in the literature (see for example M. Hudlicky, Reductions in Organic Chemistry 2d ed., ACS
monograph 188, 1996 or S.H. Pine and B.L. Sanchez, J. Org. Chem. 36, 829-832 (1971).
The procedure for producing the intermediate compound Q), called 7,16 deoxy-2-aza-10-O-cladinosyl-1-2-O-disosarninyl-4, 5-dihydroxy-6-ethyl-3, 5,9,11,13,15-hexamethylbicyclo[l1,2,1) hexadeca-1(2)-en-8-one is described below, using the following example:

A solution of erythromycin A (6.0 g, 0.082 mol) in 30 ml of acetone, in an N2 5 atmosphere was cooled to 0 C, and 1.62g (1.05 eq) of O-(mesitylenesulfonyl) hydroxylamine (MSH) was added. Agitation was continued at 0 C for 5 minutes and the temperature was allowed to rise to room temperature, continuing agitation for one hour more. Thereafter the reaction mixture was again cooled to 0 C, and a solution of 2.75 g (0.032 mol) of sodium bicarbonate in 30 ml of water was added drop by drop, maintaining the internal temperature between 0 and 5 C; the addition time was minutes, and having finished adding the aforementioned solution the temperature was allowed to rise to room temperature and the mixture was agitated for additional 2 hours.
Finally, the acetone was evaporated under low pressure and the aqueous residue was adjusted to a pH of 5.5 with HCI 2N. This phase was extracted twice with CH2CI2 (20 ml). Extraction was repeated at pH of 6.0 (2 x 20 ml) and finally at pH 8.0 (3 x 20 ml).
The pH 8.0 extracts were dried with potassium carbonate and evaporated to dryness, obtaining 4.48 grams (75%) of compound (3). The iminoether (3) obtained was reduced by catalytic hydrogenation iri Raney nickel W6 which contains 10% to 11 %
aluminum, under pressure of 85 bars. The cyclic amine obtained was isolated and dissolved in methylene chloride to be subjected to reductive methylation using formic acid at 88%, formaldehyde at 33% and sodium formiate (S. H. Pine and B. L. Sanchez, J. Org.
Chem.
36, 829-832 (1971)). The reaction takes place at 80 C and lasts 24 hours. At the end of the reaction, pH is adjusted to 8 with NaOH and the organic phase is separated. The aqueous layer is extracted several times with methylene chloride, the extracts are combined with the organic layer, the mixture is dried with a drying agent such as sodium sulfate, the methylene chloride is evaporated and the solid obtained is rinsed with water and oven dried. The solid is dissolved in hexane and, under appropriate reflux conditions, precipitates a white crystalline solid which, by means of 13C
nuclear magnetic resonance and mass spectrometry, is identified as the compound 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A. Chemical shifts characterizing the f3C(CDCI3) spectrum are as follows: 178.9 ppm, 149.9 ppm, 102.8 ppm, 94.3 ppm, 83.18 ppm (the spectrum is shown in Figure 3). The molecular weight determined by mass spectrometry is 748, and the fragmentation pattern is consistent with that of a 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A molecule (the mass spectrum is shown in Figure 4).

The melting point of the crystal, determined by the Fisher Jones method, is 188 C to 189 C. Using Scanning Differential Thermal Analysis, it is obtained an endotherm at 187.70 C The corresponding graph is shown in Figure 5. Calculating specific rotation gives a value of - 0.36 (1% in CHC13). These parameters are clearly different from the values found for other forms of azithromycin patented to date. Thus, we find that the azithromycin reported by Kobrehel et al. (Yugoslav patent 592/81, Belgian patent 892357) U.S. patent 4,517,359, Mexican patent 9100364) has a melting point from 113 C to 115 C and its specific rotation is -37.0 (1% in CHCI3). The azithromycin patented by Bright (U.S. patent 4474768 ) has a melting point of 142 C (in recrystalized form), and the dihydrated crystalline azithromycin has a melting point of 125 C and a specific rotation of -4 1.4 (1% in CHCI3) (W089/00576, and Mexican patent 176627).

The new crystal's infrared spectrum shows four medium intensity signals in the cm"' to 3700 crri'region, located at approximately 3600 crri ", 3553 cm-1, 3375 cm'1, and 3075 cm". On the contrary, it does not display the intense signal reported for the dihydrated form (W089/00576) located at 3488 cm' , or those located at 2089 cm" and 1644 cm". In contrast, the new crystal's spectrum shows two signals around 2365 cni'. The infrared spectrum of the crystal obtained is shown in Figure 6.
Calculating the amount of w&ter present in the new crystal using Karl Fishei's method gives us a value of 0.65%. Using thermogravimetric analysis we obtain a weight loss equal to 0.6% by heating to 200 C at a rate of 30 C per minute. Figure 7 shows the graph obtained using this method. These results indicate that the water present in the sample corresponds to moisture absorbed from the atmosphere but not hydration water (defined as water molecules that form part of the crystalline network), as the theoretical minimum corresponding to a hydration water molecule will be 2.35% of its total weight.
This conclusion that the detected water correspond only to moisture is corroborated by the elemental analysis of the sample, obtaining the ratio: C 60.59%, H 10.06%, N
3.65%, 0 25.77%, which coincides with condensate formula C38H72N2012.

Based on the physical characteristics identified for the new crystal, we conclude that the new physical form is clearly different in its physical properties from the types of azithromycin patented to date. In order to confirm this conclusion, the structure was elucidated by single crystal X-ray diffraction, finding that it coincides with the an]:iydrous crystalline form, with a tetragonal crystal system and the space group P42212. These and other crystallographic data from the diffraction analysis are compared with data reported for the dihydrated crystalline form in Table 1(J. Chem. Res. 152-(1998)). Figure 8 shows the molecular structure of the anhydrous crystalline azithromycin, and Figure 9 illustrates the corresponding molecular packing.

TABLE 1.- CRYSTALLOGRAPHIC DATA FOR THE ANHYDROUS
CRYSTALLINE FORM AND COMPARISON WITH DATA REPORTED FOR THE
DIHYDRATED CRYSTALLINE FORM OF AZITHROMYCIN.

ANHYDROUS DIHYDRATED
CRYSTAL SYSTEM TETRAGONAL ORTHORHOMBIC

CELL CONSTANTS A= 14.452 A a= 17.860 A
B= 14.452A b= 16.889A
C = 41.645 A c = 14.752 A
Volume 8698 A 3 4449:8 A 3 Calculated density 1.144 g/cm3 1.177 g/cm3 X (Cu-K(x) 1.5418 A 1.5418 A
Number of reflections 3412 3846 R 0.0546 0.077 According to existing definitions (e.g. J.P. Glisker, Crystal Structure Analysis for Chemists and Biologists, VCH publishers, 1994, page 657, and H.G. Brittain, Physical Characteristics of Pharmaceutical Solids, Marcel Dekker, Inc., 1995, page.
108) the hydrated physical forms of azithromycin reported in U.S. patent 4474768 and W089/00576 are pseudo-polymorphous forms of the anhydrous crystalline form obtained here, while the physical form reported by Kobrehel et al. (Yugoslav patent 592/81, Belgian patent 892357 U.S. patent 4,517,359, Mexican patent 9100364), according to W089/00576 corresponds to the amorphous form.

In addition to its novel features, the physical form obtained has physical characteristics that make it useful in preparing pharmaceutical preparations, with significant advantages over the forms existing to date. Thus, W089/00576 indicates that the forms reported by Kobrehel et al. (Yugoslav patent 592/81, Belgian patent 892357, U.S. patent 4,517,359, Mexican patent 9100364) and by Bright (U.S. patent 4474768) are highly hygroscopes, which significantly complicates the production of pharmaceutical preparations. In contrast, the anhydrous crystalline form obtained here, when exposed to room conditions, at an relative humidity average of 45%, for ten days, increases its moisture content by only 0.55%, while a reference sample of dihydrated azithromycin increased its moisture content by 1% in the same time. These data are indicative of anhydrous crystalline azithromycin's stability when exposed to moisture, which makes it useful in producing pharmaceutical preparations and represents a significant advantage over the more hygroscope forms.
In order to test the performance of anhydrous crystalline azithromycin in producing pharmaceutical preparations, 500 mg azithromycin tablets were made with total weight of one gram. The dissolution profile of these tablets was determined, and compared with the dissolution profile of tablets made with the same preparation using dihydrated azithromycin. The used solvents, and the procedure followed, were similar to those indicated for capsules in U.S. Pharmacopoeia 2000, page 186. The dissolution values obtained for the tablets made with anhydrous crystalline azithromycin were significantly ', L=.; ;
higher than those obtained for the dihydrated form. This property gives the anhydrous crystalline form reported herein significant practical advantages over the dihydrated forms, given that increased solubility of the pharmaceutical preparation generally implies greater bioavailabilty of the drug and in consequence increases its therapeutic effectiveness.

The two characteristics described above for the anhydrous crystalline form, of its low hygroscope quality, and the fact that their pharmaceutical preparations have adequate /
dissolution, offering even higher solubility than the equivalent preparation using the dihydrated form, give the new crystalline form reported herein significant practical advantages over the forms of azithromycin reported to date.

9a In one aspect, the invention provides a single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicyclo [11.2.1]
hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, comprising mixing erythromycin A in acetone with mesitylenesulfonylhydroxylamine, and treating the resulting mixture with aqueous sodium bicarbonate to obtain the intermediate compound, which is the 6,9-iminoether.

In alternative embodiments, the invention provides a single-step process for preparing 7,16-deoxy-2-aza- 10-O-cladinosyl-l2-O-desosaminyl4,5-dihydroxy-6-ethyl-3, 5, 9,11,13,15-hexamethylbicycle[11.2.1] hexadeca-1(2)-en-8- one, an intermediate compound in the production of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A as described herein, characterized by the fact that the solution of erythromycin in 30 ml of acetone under an inert atmosphere is cooled to 0 C and 1.62g (1.05 equivalents) of O-(mesitylenesulfonyl)hydroxylamine (MSH) is added; the mixture is agitated at 0 C in 5 minute intervals after which the temperature is raised continuing to agitate it for another hour.

In alternative embodiments, the invention provides a single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[11.2.1] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl- 9a-aza-9a-homoerythromycin A as described herein, characterized by the fact that the mixture obtained is again cooled to 0 C, adding a sodium bicarbonate solution in a concentration of 0.032 mol in 30 ml of water drop by drop over a 30 minute interval; the temperature is maintained for an interval ranging from 0 to 5 C, the temperature is increased and the mixture is agitated for additional two hours.

In alternative embodiments, the invention provides a single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[ 11.2.1 ] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl- 9a-aza-9a-homoerythromycin A as described herein, characterized by the fact that to arrive at the intermediate product, called iminoether, the following procedure is used:
the acetone is evaporated under low pressure and the residue is adjusted to pH
5.5 with HC12N, this phase is extracted with CH2ClZ, extraction is repeated at pH 6.0 and pH
8.0; the extracts from each pH are combined, and dried with K2C03, evaporating to dryness; at pH 8.0 the iminoether 9b (3) is isolated from the intermediate compound, and finally transformed into 9-deoxo-9amethyl-9a-aza-9a-homoerythromycin A.

In alternative embodiments, the invention provides a single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[11.2.1] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A as described herein by appropriate crystallization in hexane.

In another aspect, the invention provides a compound having the anhydrous crystalline form of [2R-(2R*, 3S*, 4R*, 5R*, 8R*, lOR*, 11R*, 12S*, 13S*, 14R*)]-13-[(2, 6-dideoxy-3-C-methyl-3-O-methyl-a-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)-[3-D-xylohexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one (or IUPAC name 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A) wherein the compound has the following physical properties:

a) main chemical shifts determined by Nuclear Magnetic Resonance of C 13 are:
178.9 ppm, 149.9 ppm, 102.8 ppm, 94.3 ppm, 83.18 ppm;

b) the melting point is 188 C to 189 C;

c) the scanning differential thermal analysis endotherm is at 187.7 C;
d) specific rotation - 0.36 (1 % in CHC13);

e) infrared spectroscopy main signals are: 3650 cm', 3600 cxn'', 3553 crri', cm', 3075 cm', 2950 cm', 2945 cm', 1750 crri';

f) X ray diffraction shows a tetragonal crystal system, space group P42212, with cell constants a = 14.452 A , b = 14.452 A , c = 41.645 A and volume 8698 A03 In another aspect, the invention provides a pharmaceutical composition comprising a compound as described herein in combination with a pharmaceutically acceptable carrier.

Claims (7)

1. Single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicyclo [11.2.1] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, comprising mixing erythromycin A in acetone with mesitylenesulfonylhydroxylamine, and treating the resulting mixture with aqueous sodium bicarbonate to obtain the intermediate compound, which is the 6,9-iminoether.
2. Single-step process for preparing 7,16-deoxy-2-aza- 10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[11.2.1] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A in accordance with claim 1, characterized by the fact that the solution of erythromycin in 30 ml of acetone under an inert atmosphere is cooled to 0°C
and 1.62g (1.05 equivalents) of O-(mesitylenesulfonyl)hydroxylamine (MSH) is added;
the mixture is agitated at 0°C in 5 minute intervals after which the temperature is raised continuing to agitate it for another hour.
3. Single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[11.2.1] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl- 9a-aza-9a-homoerythromycin A in accordance with claim 1, characterized by the fact that the mixture obtained is again cooled to 0°C, adding a sodium bicarbonate solution in a concentration of 0.032 mol in 30 ml of water drop by drop over a 30 minute interval; the temperature is maintained for an interval ranging from 0 to 5°C, the temperature is increased and the mixture is agitated for additional two hours.
4. Single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[11.2.1] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl- 9a-aza-9a-homoerythromycin A in accordance with claim 3, characterized by the fact that to arrive at the intermediate product, called iminoether, the following procedure is used: the acetone is evaporated under low pressure and the residue is adjusted to pH 5.5 with HCl 2N, this phase is extracted with CH2Cl2, extraction is repeated at pH 6.0 and pH 8.0; the extracts from each pH are combined, and dried with K2CO3, evaporating to dryness; at pH 8.0 the iminoether (3) is isolated from the intermediate compound, and finally transformed into 9-deoxo-9amethyl-9a-aza-9a-homoerythromycin A.
5. Single-step process for preparing 7,16-deoxy-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethylbicycle[11.2.1] hexadeca-1(2)-en-8-one, an intermediate compound in the production of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A in accordance with claims 1 through 4 by appropriate crystallization in hexane.
6. A compound having the anhydrous crystalline form of [2R-(2R*, 3S*, 4R*, 5R*, 8R*, 10R*, 11R*, 12S*, 13S*, 14R*)]-13-[(2, 6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3, 5,6,8, 10,12, 14-heptamethyl-[[3,4,6-trideoxy-3-(dimethylamino)-[3-D-xylohexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan- 15-one (or IUPAC name 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A) wherein the compound has the following physical properties:

a) main chemical shifts determined by Nuclear Magnetic Resonance of C13 are:
178.9 ppm, 149.9 ppm, 102.8 ppm, 94.3 ppm, 83.18 ppm;

b) the melting point is 188°C to 189°C;

c) the scanning differential thermal analysis endotherm is at 187.7°C;
d) specific rotation - 0.36 (1 % in CHCl3);

e) infrared spectroscopy main signals are: 3650 cm-1, 3600 cm-1, 3553 cm-1, cm-1, 3075 cm-1, 2950 cm-1, 2945 cm-1, 1750 cm-1;

f) X ray diffraction shows a tetragonal crystal system, space group P4 2 2 1 2, with cell constants a = 14.452 A0, b = 14.452 A0, c = 41.645 A0 and volume 8698 A03.
7. A pharmaceutical composition comprising a compound defined by claim 6 in combination with a pharmaceutically acceptable carrier.
CA002417353A 2000-07-25 2000-07-25 Single-step process for preparing 7,16-deoxy-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle (11.2.1)hexadeca-1(2)-en-8-one, and obtaining a new form of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin a Expired - Fee Related CA2417353C (en)

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Families Citing this family (9)

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Publication number Priority date Publication date Assignee Title
HRP20020231A2 (en) * 2002-03-18 2003-12-31 Pliva D D ISOSTRUCTURAL PSEUDOPOLYMORPHS OF 9-DEOXO-9a-AZA-9a-METHYL-9a-HOMOERYTHROMYCIN A
GEP20084399B (en) * 2001-05-22 2008-06-10 Pfizer Prod Inc Crystal forms of azithromycin
US6861413B2 (en) 2001-05-22 2005-03-01 Pfizer Inc. Stable non-dihydrate azithromycin oral suspensions
HRP20020614A2 (en) 2002-07-22 2004-06-30 PLIVA-ISTRAŽIVAČKI INSTITUT d.o.o. Rhombic pseudopolymorph of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin a
US20060116336A1 (en) * 2004-03-17 2006-06-01 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US7468428B2 (en) * 2004-03-17 2008-12-23 App Pharmaceuticals, Llc Lyophilized azithromycin formulation
WO2007080507A2 (en) * 2006-01-12 2007-07-19 Wockhardt Ltd Processes for the preparation of azithromycin
EP2405909A1 (en) 2009-03-13 2012-01-18 Da Volterra Compositions and methods for elimination of gram-negative bacteria
CN103087125B (en) * 2013-02-06 2015-12-02 浙江国邦药业有限公司 Prepare the processing method that Azythromycin is treated different things alike

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1100504A (en) 1967-08-16 1968-01-24 Pliva Pharm & Chem Works Erythromycin oxime and 9-amino-3-o-cladinosyl-5-o-desosaminyl-6,11,12-trihydroxy-2,4,6,8,10,12-hexamethylpentadecane-13-olide
SI7910768A8 (en) 1979-04-02 1996-06-30 Pliva Pharm & Chem Works Process for pripering 11-aza-4-0-cladinosyl-6-0-desosaminyl-15-ethyl- 7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl- oxacyclopentadecane-2-one and their derivatives
YU43006B (en) 1981-03-06 1989-02-28 Pliva Pharm & Chem Works Process for preparing n-methyl-11-aza-10-deoxo-10-dihydro erythromycin and derivatives thereof
US4474768A (en) 1982-07-19 1984-10-02 Pfizer Inc. N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor
WO1989000576A1 (en) 1987-07-09 1989-01-26 Pfizer Inc. Azithromycin dihydrate
WO1989002271A1 (en) 1987-09-10 1989-03-23 Pfizer Azithromycin and derivatives as antiprotozoal agents
JP2696608B2 (en) * 1993-05-19 1998-01-14 ファイザー・インク. Azithromycin intermediate
US5605889A (en) * 1994-04-29 1997-02-25 Pfizer Inc. Method of administering azithromycin
ES2122905B1 (en) * 1996-07-11 1999-11-16 Astur Pharma Sa SYNTHESIS OF 11,12-HYDROGENOORTOBORATE 9-DESOXO-9A-AZA-11,12-DESOXI-9A-METHYL-9A-HOMOERYTHROMYCIN A. A PROCEDURE FOR THE PREPARATION OF 9-DESOXO-9A-AZA-9A-METHYL-9A -HOMOERYTHROMYCIN TO DIHYDRATE (AZYTHROMYCIN DIHYDRATE).
PT102006B (en) 1997-05-19 2000-06-30 Hovione Sociedade Quimica S A NEW AZITROMYCIN PREPARATION PROCESS
TW546302B (en) 1998-05-08 2003-08-11 Biochemie Sa Improvements in macrolide production
CA2245398C (en) 1998-08-21 2002-01-29 Apotex Inc. Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof
GB9824580D0 (en) * 1998-11-10 1999-01-06 Biochemie Sa Organic compounds
ES2267549T3 (en) 1999-06-29 2007-03-16 Sandoz Ag PROCEDURE FOR THE PRODUCTION OF AZITHROMYCIN.
AU2001214115A1 (en) 2000-08-01 2002-02-13 Habil F. Khorakiwala Process for the preparation of anhydrous azithromycin
JP2004506664A (en) 2000-08-23 2004-03-04 ウォックハート・リミテッド Method for producing anhydrous azithromycin

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