HU203763B - Process for producing azitromycin-dihydrate - Google Patents

Abstract

Crystalline azithromycin dihydrate cpd. is navel. Prepn. of crystalline azithromyin dihydrate comprises crystallisation from a mixt. of THF and hence in the presence of at least 2 mol. equivs. of K2O.

Description

The present invention relates to a process for the preparation of azithromycin, i

For the preparation of a non-hygroscopic dihydrate of 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A.

Azithromycin, a generic name of U.S.A.N, is a broad-spectrum antibacterial compound that bills erythromycin A. Azithromycin was independently discovered by Bright (U.S. Pat. No. 4,474,768) and Kobrehel (U.S. Pat. No. 4,517,359). In these patents, azithromycin is referred to as "N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A". The more systematic name used in this specification is derived from the "IUPAC Nomenclature of Organic Chemistry, 1979 edition" (Pergamon Press, 1979, pages 68-70, 459 and 500-503), taking into account ring expansion and substitution.

Azithromycin has so far been crystallized from aqueous ethanol (e.g., Example 3 of U.S. Patent No. 4,474,768) to give the product as a water-aspirated monohydrate (detailed description of process 1 below). Due to its hygroscopic nature, it is very difficult to produce and store this monohydrate product so that its water content is constant and reproducible. It is particularly difficult to handle the product during formulation, as electrostatic problems (eg casting speed, explosive dusting) require working at high relative humidity and the monohydrate absorbs different amounts of water, depending on how long it is exposed to the given humidity and how accurately its relative humidity is set (1. for the procedure detailed below). These difficulties are solved by the present invention, since the dihydrate thus prepared is essentially non-water-absorbing at the relative humidity used for the formulation of azithromycin.

The present invention relates to a process for the preparation of azithromycin as a crystalline non-hygroscopic dihydrate comprising crystallization in a mixture of at least two molar equivalents of water in tetrahydrofuran and an aliphatic C 5-7 hydrocarbon.

Azithromycin is derived from erythromycin A, the derivatization centers leaving the asymmetric centers intact, so that all asymmetric centers (represented by an asterisk) are stereochemically identical to the corresponding asymmetric center of erythromycin A. The systematic name of the compound derived from erythromycin A is 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A. Azithromycin, including its dihydrate, has broad-spectrum antibacterial activity and can therefore be used to treat bacterial infections in mammals and humans that are sensitive to azithromycin.

The term "aliphatic hydrocarbon having from 5 to 7 carbon atoms" refers to low boiling point hydrocarbon solvents, most often boiling point solvent mixtures such as "pentane", "hexane", "hexanes", and the like. but may use homogeneous solvents such as n-hexane, cyclohexane or methylcyclohexane

The process of the present invention is readily accomplished by dissolving azithromycin (Bright or Kobrehel) (1 above) in amorphous or monohydrate form (which may contain more than one molar equivalent of water as a water suction) in tetrahydrofuran. Since the initial step is indifferent to the temperature at which it is carried out, it is usually carried out at room temperature to avoid the cost of heating or cooling. The volume of tetrahydrofuran is kept close to the minimum required, which is 2 liters of solvent per kilogram of material. lab, device costs. Insoluble impurities are removed by birth as usual. If necessary, decolorize the solution with charcoal. The highly concentrated solution may, if necessary, be diluted with C 5-7 hydrocarbons prior to filtration to facilitate handling.

If the water content of the starting material is greater than one molar equivalent, for example, it is close to two molar equivalents, it is preferable to dry the solution, for example, by briefly drying the solution, e.g. magnesium sulfate. This is especially the case if hydrocarbon is added to the solution prior to filtration. To obtain the crystalline dihydrate, water is added to the resulting clear solution in an amount such that the total water content is at least two molar equivalents, and generally does not exceed 3-4 molar equivalents. The water content of the system is easily determined by standard Kari Fischer titration. After the addition of water, the hydrocarbon solvent or other hydrocarbon solvents are added to the system if they have already been diluted with the hydrocarbon solvent prior to filtration to initiate crystallization of the desired dihydrate. This step of the process can be carried out at ambient temperature (17-30 ° C) but it is preferable to use a slightly higher temperature (e.g. 3040 ° C) to accelerate crystallization. The volume of hydrocarbon used is usually at least four times the volume of the tetrahydrofuran solution. Higher amounts of hydrocarbons can be used, but are generally unnecessary because they increase the cost of the process. Once crystallization is complete, the product is recovered by filtration, usually after granulation at ambient temperature (e.g., 3 to 24 hours). The product is dried under reduced pressure from the solvent (at a temperature of 20 to 0 ° C, preferably at ambient temperature). During drying, check the amount of volatile solvent and water to avoid loss of water. Tetrahydrofuran and hydrocarbon content are generally less than 0.25% and water content (0.3%) is theoretical (4.6%).

Azithromycin dihydrate is formulated and administered according to U.S. Patent No. 4,474,769 (Bright), to treat bacterial infections.

The following examples illustrate the preparation of the non-hygroscopic azithromycin dihydrate and the hygroscopic azithromycin monohydrate. The examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

HU 203 763 Β

Example 1

The water-suction azithromycin monohydrate is prepared essentially by the Kobrehel methylation process (US Patent 4,517,359) and the Bright crystallization process (US Patent 4,474,768). 100 g (0.218 mol) of 9-deoxo-9a-aza-9a-homoerythromycin A (formerly 11-aza-10-deoxo-10-dihydroerythromycin A) are dissolved in 400 ml of chloroform with stirring. 10.4 ml of 98% formic acid (0.436 mol) and 16.4 ml of 37% formaldehyde (0.349 mol) are added. The above reagents were added to the solution over a period of 4-5 minutes and the reaction mixture was refluxed for 20 hours. The solution was cooled to room temperature, diluted with 400 mL of water and adjusted to pH 105 with 50% sodium hydroxide. The aqueous phase was separated and extracted with chloroform (2 x 100 mL). The organic phases were combined, concentrated under reduced pressure to a volume of 350 ml, diluted with ethanol (2 x 450 ml) and concentrated to 350 ml, and then diluted with water (1000 ml) over 1 hour. Wait 15 minutes from the onset of precipitation. Appearance of precipitation is approx. After adding 250 ml of water. The product was recovered by filtration and dried at 50 ° C for 24 hours to give 85 mg.

Mp .: 136 'C. Differential thermal analysis (heating rate of 20 'C / min) shows endotherm at 142' C; thermal gravity analysis (heating rate 30 ° C / min) at 100 ° C resulted in a weight loss of 2.6% and at 150 ° C 45%. Water content 3.92%, ethanol content 1.09%.

Elemental analysis based on the formula C38H72N2O12 (corrected for ethanol and water):

Calculated for C 58.46 H 9.78 N 3.74 alkoxy 4.67% Found C 58.40 H 9.29 N 3.50 alkoxy 552%

The monohydrate sample containing 3.2% water was kept in an 18% relative humidity space for 14 days. The sample loses water during the first 24 hours, reaching a theoretical water content of 2.35% of the monohydrate. During the next 14 days, the water content remains essentially constant at 2.26% on the 14th day.

If the same monohydrate is maintained at 33% relative humidity, the water content of the sample increases rapidly to 5.6% and remains at this value for at least three days. At 75% and 100% relative humidity, the water content is similarly rising, but now the water content is at least 3 days higher

6.6 and 7.2% respectively.

Example 2

Two methods for preparing the non-hygroscopic azithromycin dihydrate are described below:

Method A - Weigh 100 g of the hygroscopic monohydrate prepared in Example 1 (water content 3.1%), 220 ml of tetrahydrofuran and 5 g of diatomaceous earth into a 500 ml Erlenmeyer flask. After stirring for 30 minutes, the mixture is filtered and the filtrate is washed with 20 ml of tetrahydrofuran. Combine the filtrate and wash, transfer to a 3 L round bottom flask and add 2.0 mL of water with vigorous stirring. After 5 minutes, 1800 ml of hexane was added to the solution with vigorous stirring over 5 minutes. After 18 hours, the crystalline material was precipitated, and the desired product was collected by filtration, washed with hexane (1 x 10 mL), dried under reduced pressure to a water content of 4.6 ± 0.2% (according to Kari Fischer) to yield 89.5 g.

Method B - 197.6 g of the hygroscopic monohydrate prepared as described in Example 1 and 430 ml of tetrahydrofuran are charged to a reactor and the mixture is stirred until a milky-white liquid is obtained. 10 g of activated carbon and 10 g of diatomaceous earth were added, stirred for 15 minutes, diluted with 800 ml of hexane, filtered through a pad of diatomaceous earth and washed with 250 ml of hexane. The filtrate and wash were combined, diluted with 2500 mL of hexane and heated to 34 ° C. 24.7 ml of water are added with stirring and allowed to cool to room temperature. The crystalline product is allowed to precipitate for 5 hours and the desired product is collected and dried as described in Method A to give 177.8 g of product.

The dihydrate has a sharp melting point at 126 ° C (heating rate lOVmin). Differential scanning calorimetry (heating rate 20'C / min) shows endotherm at 127'C, product gravimetric analysis (heating rate 30'C / min) shows a weight loss of 100% at 100'C, 150 At 4.3 ° C.

IR (KBr) 3953, 3553,3488,2968,2930,2888,

2872,2827,2089,1722,1664,1468,

1426,1380,1359,1344,1326,1318,

1282,1270,1252,1187,1167,1157,

1123,1107,1081,1050,1004,993,

997,955,930,902,986,879,864,833,

803,794,775,756,729,694,671,

661,637,598,571,526,

495,459,399, 374.321 and 207 ^cm-1;

[[alpha]] < ^{2 * * * < 6 >} -41.4 [deg.] (Cl chloroform).

Analysis by C H72N2Oi2 _3g * 2H2 O: Calculated C 58.14 H 3.95 9.77 N 357 _OCH3

H2O 459% measured C 58.02 H 9.66 N 356 OCH ₃ 4.11 H ₂ O 4.19% neutralization equivalent (05 N hydrochloric acid in acetonitrile / water,

1: 1); calcd. 374.5; found 393.4.

The dihydrate samples, which were slightly overdried,

Up to 4.1% water (less than theoretical), water was rapidly taken up in 33%, 75% and 100% relative humidities, reaching a theoretical water content of 4.6% for the dihydrate state, At 100% relative humidity, the water content increased further to 5.2% and remained essentially at this level for 3 days.

Keeping a sample of the same dihydrate in 18% relative humidity, it gradually loses water. On the fourth day the water content was 2.5% and on the 12th day 1.1%.

Claims (2)

CLAIMS 1. A process for the preparation of crystalline azithromycin dihydrate, wherein the azithromycin is crystallized from a mixture of tetrahydrofuran and 5 to 7 Sr aliphatic hydrocarbons in the presence of at least two molar equivalents of water. 2. The process of claim 1 wherein the hydrocarbon is hexane.