ES2197790B1 - INTERMEDIATE COMPOSITE OF UTILITY IN THE SYNTHESIS OF MACROLIDOS. - Google Patents

Abstract

Intermediate compound useful in the synthesis of macrolides. Specifically, the invention relates to the compound 9-dexo-o-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A in the form of a hydrate and its use as intermediate in the production of azithromycin. The invention also describes a process for the production of said intermediate compound, which comprises isolating said compound from an aqueous solvent system by adding a base and adjusting the pH.

Description

Intermediate compound useful in synthesis of macrolides.

The present invention relates to the synthesis of antibacterial macrolides, such as erythromycins, for example erythromycin type A, such as roxithromycin, Diritromycin, clarithromycin, azithromycin and compounds Similar.

Azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A) is a well known antibacterial agent described, for example, in The Merck Index, 12th edition (1996), page 157 (946). A Compound useful in the preparation of azithromycin is the compound of the following formula I

one

that is, 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A. This compound can be prepared by known methods comprising (i) the in situ preparation of a compound of formula I from an O-arylsulfonyloxime of erythromycin A, for example, by a Beckmann transposition, and (ü) the isolation of a compound of formula I whose operation involves a large number of extractions using chlorinated solvents.

It has now been surprisingly found that a compound of formula I can be isolated by means of a method much simpler and this with important sales, for example, of utility on an industrial scale, such as avoiding the stages of extraction and, for example, avoiding the use of solvents halogenated

Thus, according to one aspect, the invention provides a compound of formula I in the form of a stable hydrate, for example, with a water content of 4 to 10%, for example, from 8 to 10%.

According to another aspect, the present invention provides a process for the production of a compound of formula I in the form of a stable hydrate, for example, with a water content of 4 to 10%, for example, 8 to 10%, whose method comprises isolating a compound of formula I in the form of a stable hydrate, for example, with a water content of 4 to 10%, for example, from 8 to 10%, from a solvent system aqueous by adding a base and adjusting the pH, for example, the preparation of a compound of formula I in the form of a hydrate stable, for example, with a water content of 4 to 10%, for example of 8 to 10%, from erythromycin A oxime by means of a Beckmann transposition.

The process according to the present invention is can be carried out as follows: a derivative of Erythromycin A oxime, susceptible to a Beckmann transposition, for example, by reacting an erythromycin A oxime with a arenesulfonyl halide, optionally in the presence of a base. He term "erythromycin A oxime" includes erythromycin A oxime in form of a free base and erythromycin A oxime in the form of a salt. Erythromycin A oxime in the form of a salt includes an erythromycin Oxime in the form of an acid addition salt, for example, with the dimethylamino group at the 3 'position of the sugar residue of the position 5 of the ring system, for example, with organic acids or inorganic, for example, a salt with an organic acid such as a formate or acetate, or with an inorganic acid, such as a hydrochloride or thiocyanate.

The term "arenesulfonyl halide" It includes a compound of formula:

R-C 6 H 4 -SO 2 X

where R is hydrogen, alkyl, halogen or acylamino and X is halogen, preferably a halide of p-toluenesulfonyl, for example, p-toluenesulfonyl. The basis of stage (ii) includes, for example, a suitable basis to act as a acid neutralizer, including organic bases, such as inorganic amines and bases such as a hydroxide, carbonate or alkali metal bicarbonate, for example, sodium, potassium; of metal alkaline earth, for example, calcium, magnesium; and ammonium, preferably sodium bicarbonate. Unless indicated Otherwise, any group containing carbon can contain up to 22 carbon atoms; for example, alkyl includes alkyl C 1-22, for example, alkyl alkyl C 1-8, such as lower alkyl, for example, C 1-6 alkyl, for example alkyl C_ {1-4}. Acyl includes acyl C 1-12, for example, acyl C 1-6, in particular acyl C_ {1-4}.

The reaction between an erythromycin A oxime and an arenosulfonyl halide can be preferably carried out under conditions such as conventional ones for a Beckmann transposition, including the in situ preparation of an erythromycin A O-arylsulfonyl oxime in aqueous medium, where a transposition can occur intermediate to provide a compound of formula I. The term "aqueous medium" includes a mixture of water with one or more water miscible solvents, such as alcohols, for example, methanol, ethanol or isopropanol; lower ketones such as acetone; and amides such as dimethylformamide and dimethylacetamide, preferably a mixture of water and acetone. One or more equivalents of a arenesulfonyl chloride can be used per equivalent of erythromycin A oxime, for example, preferably 1 to 2 and more preferably 1 to 1.5 equivalents. Suitable reaction conditions for the preparation of a compound of formula I according to the present invention may include, for example:

-

a range of temperatures ranging from around -15ºC to the temperature of reflux of the solvent system used, such as from -10 ° C to 50 ° C, by example, from -5 ° C to 30 ° C.

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a pressure suitable, for example, atmospheric pressure, or a pressure above or below atmospheric pressure; Y

-

a dilution suitable, for example, a dilution range between 1 and 1,000 g of the starting compound of erythromycin A oxime per liter of aqueous medium. The water-solvent ratio or Organic solvents in the aqueous medium used is not critical; for example, you can use a ratio that ranges between 50 and 0.02 parts (by volume) of water per part of organic solvent (by volume), such as between 5 and 0.2, for example, 1.5 and 0.67 parts of water by organic solvent (by volume).

The compound of formula I obtained can be isolate from an aqueous solvent system by adding a base and pH adjustment, for example, at an appropriate value.

The expression "aqueous solvent system" it includes, for example, the same aqueous medium, for example, in same ranges of organic solvent solvent ratio, used for Beckmann transposition, or more dilute medium, preferably, more water can be added to the aqueous medium used for the reaction from Beckmann, for example, the relationship water-solvent or organic solvents can be on the order of 50 to 0.67, such as 5 to 0.67, for example, you can use more than one part of water per part of organic solvent. The pH of the aqueous solvent system can be adjusted to a pH suitable, for example, by adding a base. Adequate basis they include, for example, an inorganic base such as, for example, a hydroxide, carbonate, alkali metal bicarbonate, for example, sodium, potassium; alkaline earth metal, for example, calcium, magnesium; and ammonium; and an organic base such as ammonia and a amine, such as an alkylamine. The base may preferably be a hydroxide, for example, sodium or ammonium, preferably in aqueous solution. The term "adequate pH" includes a range of pH wherein the compound of formula I is present in the solution or suspension in the form of the free base. An adequate pH includes, for Example, a pH of about 8.5 to 12, such as 9 to 11, per example, from 10 to 11.5. The compound of formula I can be isolated from conventional manner, for example, by centrifugation or filtration, and dried, for example, to provide a compound of formula I in the form of a stable hydrate, for example, with a water content of 8 to 10%. The yields can be very high, even greater than 85%, for example, even greater than 90%. He analysis of the product obtained according to the present invention can be also very high, even greater than 95%, even greater than 97%, On an anhydrous basis. The compound of formula I in the form of a hydrate according to the present invention can be dried to provide a water content below 2%, for example, by drying at temperatures greater than 70 ° C.

According to a preferred method herein invention, erythromycin A oxime, in the form of a free base or in form of a salt, it can be suspended or dissolved in a mixture of water and acetone, in the presence of a base such as bicarbonate sodium Chloride can be added p-toluenesulfonyl and the mixture can be left then under stirring at room temperature approximately, for example, until Beckmann's transposition of the compound. The aqueous medium can be diluted by adding more water and the pH can be adjusted, for example, to a value of 10 to 11.5 approximately. The compound of formula I in the form of a hydrate It can be precipitated and can be isolated by filtration.

The isolated compound of formula I according to the The present invention may have a water content of about 4 to 10%, for example, about 8 to 10%, such as around 8.5 to 9.5%, for example, from 8.8 to 9.2%. Calorimetry by differential scanning of a compound of formula I in the form of a hydrate can reveal at a heating rate of 10ºC / minute, at an endotherm between 50 and 105ºC (loss of water) and a decomposition peak that starts at 250 ° C with a maximum of 270ºC approximately. The thermal gravimetric analysis at a heating rate of 5 ° C / minute can reveal a 8.92% weight loss between room temperature and 95 ° C. The stoichiometric amount of water is 8.97% and the compound of formula I can be found, for example, in the form of a tetrahydrate

The compound of formula I in the form of a hydrate stable, for example, with a water content of 4 to 10%, for example, from 8 to 10%, it can be crystalline. In Table 1 and form more detailed in Table 2 X-ray diffractograms are offered in powder of a compound of formula I in the form of a stable hydrate for example, with a water content of 4 to 10%, for example, of 8 to 10%

TABLE 1

gives) I / I_ {0} 8.53 100 7.94 33.4 7.23 40.2 5.95 42.4 5.32 50.1 5.19 69.5 5.10 50.1 4.49 32.5 3.96 37.0

TABLE 2

gives) I / I_ {0} 9.84 22.9 9.70 28.0 8.53 100 8.36 23.1 7.94 33.4 7.23 40.2 7.13 22.6 5.95 42.4 5.32 50.1 5.19 69.5 5.10 50.1 4.49 32.5

TABLE 2 (continued)

gives) I / I_ {0} 4.29 25.1 3.96 37.0 3.90 20.5

In Tables 1 and 2, "d" represents the interplanar separation; "I / I_ {0}" represents the intensity relative; and A represents Angstrom.

According to another aspect, the present invention provides a compound of formula I in the form of a hydrate stable, for example, with a water content of 4 to 10%, for for example, from 8 to 10%, in crystalline form, for example, with a X-ray diffractogram as indicated in Table 1.

The process according to the present invention is Economical and ecological and can be used on an industrial scale. The advantages of the process of the present invention can include:

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you can remove the use of halogenated solvents;

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yields they can be greater than 85%, for example, even greater than 90%;

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the analysis, about an anhydrous base, of the compound of formula I thus obtained is greater 95%, for example, greater than 97%.

The compound of formula I in the form of a hydrate stable, for example, with a water content of 8 to 10%, can be useful in the production of azithromycin.

According to another aspect, the present invention provides a procedure for the production of erythromycins, for example, azithromycin, for example, in the form of a solvate, which understands:

(i)

reduce a compound of formula I in the form of a serce hydrate, for example, in the presence of hydrogen and a catalyst or a metal hydride, for example, sodium borohydride, to form 9-deoxo-9a-aza-9a-homoerythromycin TO;

(ii)

methylate 9-deoxo-9a-aza-9a-homoerythromycin A obtained in stage (i) in position 9a-aza to form 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin TO; Y

(iii)

isolate Erythromycins, for example, in the form of a solvate.

Production and isolation can be perform, for example, as is conventional but using a compound of formula I in the form of a stable hydrate as a material of departure.

According to another aspect, the present invention provides the use of the compound of formula I in the form of a hydrate stable, for example, with a water content of 4 to 10%, for for example, from 8 to 10%, in the production of erythromycins, for example, azithromycin

The use of a compound of formula I in the form of a stable hydrate as a starting material for the production of erythromycin, for example, azithromycin or azithromycin in the form of A solvate, according to the present invention, may have the following advantages:

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the material of departure can be stable;

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the material of heading can be pure, for example, can have a greater analysis 97% with respect to an anhydrous base;

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the material of heading may not contain halogenated solvents;

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the material of Item can be produced on an industrial scale.

The following example may illustrate the invention. without limiting its scope. All temperatures are offered in degrees Celsius and are uncorrected. Preferably, it you can use liquid chromatography, for example, HPLC to analyze Erythromycin A oxime used as a starting material and the compound of formula I thus obtained.

Example

To a suspension of 6.27 g of erythromycin A oxime (analysis: 95.5%) in 25 ml of acetone at approximately 5 ° C, a solution of 1.68 g of sodium bicarbonate in 30 ml of Water. To the obtained mixture is added, drop by drop, a solution of 1.90 g of p-toluenesulfonyl chloride in 8 ml of acetone, keeping the temperature at approximately 5 ° C. The reaction mixture is allowed to stir at approximately 5 ° C for another hour or so and for another hour at room temperature The reaction mixture is dilute with 50 ml of water and the pH is adjusted to 10-11 by the addition of 20% w / w aqueous sodium hydroxide. In this way precipitates 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A, the crystals are filtered off and washed with water. He solid obtained is dried at 60 ° C. 6.05 g (92% of the theory) of 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A in the form of a stable hydrate. Water content: 9%. Analysis with respect to an anhydrous base: 97.2%.

IR (KBr): 3489, 3447, 3290, 1717, 1697, 1456, 1383, 1197, l 165, 1126, 1112, 1095, 1017, 959 cm -1; DSC (heating rate of 10 ° C / minute); endotherm between 50 and 105 ° C (loss of water); decomposition point that begins to 250 ° C with a maximum of approximately 270 ° C; gravimetric analysis Thermal (heating rate of 5ºC / minute): 8.92% loss of weight between room temperature and 95 ° C. The amount Stoichiometric water hydrate is 8.97%. The kind of X-ray powder diffraction is as described in Tables 1 and 2.

Claims (7)

1. A compound of formula 2 in the form of a stable hydrate having a water content from 4 to 10% 2. A compound according to claim 1, characterized in that it has an X-ray powder diffraction model according to Table 1:  TABLE 1 gives) I / I_ {0} 8.53 100 7.94 33.4 7.23 40.2 5.95 42.4 5.32 50.1 5.19 69.5 5.10 50.1 4.49 32.5 3.96 37.0 3. A compound according to any of the claims 1 or 2 in crystalline form. 4. A compound according to any one of claims 1 to 3, characterized in that it has a water content of 8 to 10%.

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5. Process for the production of a compound of formula I according to any one of claims 1 to 3, characterized in that it comprises isolating a compound of formula I from an aqueous solvent system by adding a base and adjusting the pH. 6. Use of a compound according to any of the claims 1 to 4 in the production of erythromycins. 7. Use of a compound according to any of the claims 1 to 4 in the production of azithromycin.