The way to get azithromycin and methods of making intermediates

 

(57) Abstract:

Describes how to obtain azithromycin (I). Eritromicin (II) maximilianeum the action of hydroxylamine hydrochloric acid in the presence of sodium carbonate in ethanol - water (20-40% water) at an initial ratio erythromycin/solvent, g/ml, 1:1.4 to 1:1.7 and a temperature of 50-80oWith the product maximiliane - oxime erythromycin (III) is recovered from the reaction mixture by extraction of chlorinated hydrocarbons at pH 9-11 and subjected to the Beckmann rearrangement the action of the acid chloride arylsulfonic acid in the two-phase solvent system water/chlorinated hydrocarbons, formed iminoethyl erythromycin (IV) is recovered from aqueous solution by crystallization at pH 9-11 and the temperature of 605oC, with subsequent restoration of aminoether IV in aqueous medium at room temperature by the action of complex metal borohydride, taken at 0-0,2 molar excess, the product recovery - atherothrombosis (V) in the form of borate complex mineral or organic acid, preferably oxicology, at pH of 2.5, was identified in the chloroform formaldehyde in the presence of formic acid, the product of methylation are re-extraction of water at pH 4.5-5.5, n is the temperature of 50-80oS, followed by recrystallization from a mixture of acetone - water or ethanol - water, taken in the ratio from 2:1 to 1:2. Describes how to obtain the intermediate compounds. The technical result is to simplify the process and increase the yield of the target product. 3 S. p. f-crystals.

The invention relates to an improved method for producing a semi-synthetic macrolide antibiotic derivative of erythromycin A, and in particular to a method for producing N-methyl-11-Aza-10-desoxo-10-dihydroartemisinin-azithromycin (I), which has a broad spectrum of antimicrobial activity.

Known methods for producing azithromycin N-methylation of 11-Aza-10-deoxy-10-dihydroartemisinin (hereinafter atherothrombosis). Describes two methods of N-methylation of etherically (V, scheme 1). First, by pre-oxidation of etherically hydrogen peroxide with the formation of N-oxide, followed by alkylation idestam the stands in the presence of acceptor iodine hydrogen and catalyst recovery received alkyl derived over Pd/C or above Ni-Raney (U.S. patent N 4474468, class C 07 H 17/08, 1984 [1] . And second, the effect on atherothrombosis formaldehyde in the presence of formic acid in the environment chlorinophenothane of the target product are reextraction the reaction mass with water at pH 5.0, then the product is again extracted with a 4-fold volume of chloroform at pH 7.5, the extract was dried and evaporated to dryness. The output of azithromycin allocated thus, is 83,0% ([2], example 1).

The second method is closest to the present invention and is its prototype.

Source atherothrombosis (V) according to known methods, derived from erythromycin (II) according to the following scheme (scheme 1):

- maximilianii erythromycin (II) receipt of erythromycin oxime (III);

- the conversion of the oxime III in iminoethyl erythromycin (IV) by Beckmann rearrangement;

- restore aminoether IV to etherically (V).

Maximilianii erythromycin, according to all known methods are conducted in the medium of anhydrous methanol by the action of hydroxylamine, which is used either as a free base, partially neutralized acid (European patent N 0342990, class C 07 H 17/086, 1989 [3]), or in the form of hydrochloride in the presence of an acceptor of hydrogen chloride; erythromycin reacts with hydroxylamine hydrochloric acid in the presence of barium carbonate in absolute methanol at boiling point (patent England N 1100504, class C 07 H 21/00, 1968, [4]); the original ratio erythromycin/methanol attribuut in vacuo to 1/3 of the volume, when cooled concentrate crystallizes the oxime of erythromycin, the output of the oxime III are 48.3% ([4], example 1) prototype on p. 2 of the claims.

The Beckmann rearrangement of the oxime of erythromycin (III) by the described methods is performed by the action of acid chlorides arylsulfonic acid in a mixture of acetone-water (J. Chem. Soc. Perkin. Traus, 1986, c. 1881-90 [6], U.S. patent N 4328334, class C 07 H 17/08, 1982 [7]. According to the patent of the USSR N 1447288, class C 07 H 17/08, 1983 [5] oxime III is subjected to the Beckmann rearrangement effect 2-4 molar excess of n-toluensulfonate, p-iodobenzaldehyde or p-acetamidobenzenesulfonyl in the presence of 2 to 8 molar excess of sodium bicarbonate or triethylamine at a temperature of 0-5oC in a mixture of acetone-water. For example 2 [5] for separation of the reaction product IV acetone evaporated in vacuo, the aqueous residue pH-gradient is extracted with chloroform, the extract obtained at pH 8.0, dried and evaporated to dryness. The output thus obtained of aminoether IV (74.3%.

Restoring aminoether IV by known methods carried out by catalytic hydrogenation under hydrogen pressure of 65-70 ATI in glacial acetic acid as solvent, using as catalyst noble metals or their about the 1982 [7]), electrochemically in the cell with a synthetic aperture by a mercury cathode, a lead anode in the presence of iodotope tetrabutylammonium using as Catolica acetic acid as anolyte aqueous solution of sodium acetate, the output of etherically by this method is of 81.5% (patent USSR N 1530096, class C 07 H 17/08, 1990 [8]); chemical recovery complex metal hydrides, such as sodium borohydride in absolute methanol at a temperature of about 4oC [7]. According to example 4 of [7] to restore aminoether IV use 20-fold molar excess of sodium borohydride, to highlight product recovery - etherically (V), the reaction mass after bubbling CO2filtered, the filtrate is evaporated to dryness, the residue dissolved in chloroform, add water, spend a pH-gradient extraction, the extract was dried, evaporated to dryness, the solid residue is extracted with ether, the extract evaporated to dryness. The output thus obtained of etherically is of 60.5%.

The aim of the invention is to simplify the process (technology simplification, reduction of energy consumption, improvement of fire and ecological security) and increase the yield of the target about maximilianeum hydroxylamine hydrochloric acid in the presence of sodium carbonate in ethanol-water (20-40% water), if the original ratio erythromycin/solvent 1:(1,4-1,7) at a temperature of 50-80oC, to highlight product maximiliane use the extraction method, for which the reaction mass is extracted with a chlorinated hydrocarbon at a pH of 9-11. The output of the oxime of erythromycin is 75-80%.

The above implementation of this stage can significantly increase the concentration of the reacting substances, which is essential, because the reaction maximiliane erythromycin is always accompanied by a process of dehydration erythromycin education anhydroerythromycin; this adverse reaction is monomolecular and, therefore, its speed does not depend on concentration, whereas the target speed of the reaction increases in proportion to the concentration of the reacting substances. Thus increasing the concentration of reactant decreases the content of an impurity of anhydroerythromycin in the reaction mass, and increase in the yield of the oxime of erythromycin. In addition, it eliminates the use of methanol is toxic and flammable solvent and the need for evaporation of the reaction mass at the end of the reaction, which can significantly reduce the energy consumption of the process. Use extrac is) an excess of hydroxylamine, whereas by a known method [4] excess hydroxylamine largely decomposed by prolonged boiling of the reaction mass, and partly cocrystallized with oxime III after concentration of the reaction mixture and cooling the concentrate, which contaminates the reaction product.

For Beckmann rearrangement under the action of the acid chloride arylsulfonic acid using a two-phase solvent system: chlorinated hydrocarbons - water. This allows for the termination of the reaction is easy to separate impurities and precipitate iminoethyl erythromycin from aqueous solution in crystalline form. Upon termination of the reaction by separating the aqueous phase separated all inorganic impurities during the subsequent Stripping of aminoether in water at pH 4.5 to 5.5 in chloroform remain all the impurities of organic nature. From water reextract after establishing pH 9-11 at the temperature (605)oC crystallizes net iminoethyl IV. The use of two-phase solvent system eliminates the need for evaporation of the acetone from the reaction mass after the reaction, and manual extraction of impurities. Product highlight of the DS-low-tech instead of parki "dry". The output of aminoet and metals in the solvent is water, the reaction is carried out at ambient temperature (16-20)oC, the reducing agent is used in amounts of from 1.0 to 1.2 mol per mole of aminoether. We found that under the action of borohydrides metals or during preview processing of aminoether IV boric acid to form water-soluble borate complexes of aminoether, enabling the conduct of reduction reaction in aqueous solution at pH 9-11, what is the optimal area when working with complex borohydride metals. Therefore, for a complete recovery aminoether IV in these conditions quite equimolar amount of the reducing agent. When this reaction product recovery is a borate complex of etherically, which is used for azithromycin by methylation and subsequent hydrolysis of the borate complex, or borate complex of etherically hydrolyzing before methylation. And in that and in other case borate complex hydrolyzing treatment of dilute mineral or organic acid at a pH of 2.5, usually within 5-15 minutes at a temperature of 18-20oC. is Preferably used for the hydrolysis of oxyacids, because their presence prevents the flow of reverse reaction is theraromachine is 85-88%, considering iminoethyl IV.

Azithromycin (I) receive from etherically (V) or borate complex by methylation in chloroform by the action of formaldehyde and formic acid, the product of the methylation extravert water at pH 4,5-5,5, if necessary, conduct the hydrolysis of the borate complex of azithromycin mineral or organic acid at a pH of 2.5, the desired product precipitated from the aqueous solution at a pH of 9-11 and the temperature of 50-80oC (output of azithromycin is 76-78%, considering iminoethyl erythromycin) and purified by recrystallization from a mixture of acetone-water or ethanol-water in the ratio (2:1) to (1:2). Use for cleaning azithromycin mixture of acetone-water or ethanol-water in a wide range of ratios allows you to adjust the quality of the product: when using more water mixtures increases the yield of the target product, but partially decrystallized impurities, while reducing the amount of water in the crystallization mixture reduces the yield of the target product, but ensures the preparation of high purity. The output stage of recrystallization is 70-94%.

Thus the proposed method of obtaining azithromycin is as follows:

the ethanol-water (20-40% water) at an initial ratio erythromycin/solvent 1:(1,4-1,7) (weight/volume) and temperature (50-80%)oC, the reaction product - oxime erythromycin (III) is recovered from the reaction mixture by extraction with a chlorinated hydrocarbon at a pH of 9-11. The oxime III is subjected to the Beckmann rearrangement the action of the acid chloride arylsulfonic acid in two-phase solvent mixtures: water-chlorinated hydrocarbons, obtained iminoethyl erythromycin (IV) is recovered from aqueous solution by crystallization at pH 9-11 and temperature (605)oC. Iminoethyl IV restore the action of complex metal borohydride, taken at 0-0,2 molar excess, in the aquatic environment, received borate complex of etherically emit extraction with chloroform and, in the form of a borate compound or after hydrolysis of the complex action of a mineral or organic acid, preferably a hydroxy acid, at a pH of 2.5, was identified in the chloroform formaldehyde in the presence of formic acid, the product of the methylation extravert water at a pH of 3.5 to 5.5, if necessary, conduct the hydrolysis of the borate complex, and azithromycin allocate deposition from aqueous solution at pH 9-11 and temperature (50-30)oC. Azithromycin purified by recrystallization from a mixture of acetone-water or ethanol-water in a ratio of (2:1) to (1:2).

This method allows you to get azithromycin romycin.

Another aim of the invention is to increase the output and simplify the process of obtaining erythromycin oxime (III).

The closest analogue is the prototype of the proposed method is the method of obtaining the oxime of erythromycin in the patent [4].

This goal is achieved by the fact that when maximilianii erythromycin (II) hydroxylamine hydrochloric acid in the presence of sodium carbonate as solvent a mixture of ethanol-water (20-40% water), which allows you to create high reactant concentrations (initial value erythromycin/solvent is 1:1.4 to 1:1.7 weight/volume), the reaction is carried out at a temperature (50-80)oC, the process maximiliane ends 2-0,3 h, erythromycin oxime (III) was isolated by extraction of chlorinated hydrocarbons such as methylene chloride or chloroform. The output of the oxime III is 75-80%.

The third objective of the invention is to increase the yield of etherically (V), we obtain the restoration of aminoether erythromycin (IV) complex metal borohydride.

The closest analogue is the prototype of the proposed method is a method for etherically [7], example 4.

This goal is achieved by h is taken at 0-0,2 molar excess at ambient temperature, product recovery - borate complex of etherically subjected to hydrolysis by the action of a mineral or organic acid, preferably a hydroxy acid, at a pH of 2.5, atherothrombosis (V) was isolated by extraction with chloroform at pH 9-11. The output of etherically is 85-88%.

The method can be illustrated by the following examples.

Example 1. Receiving erythromycin oxime (III).

Erythromycin (200 g) was dissolved in 210 ml of ethanol under heating to 60oC. To the resulting solution add a solution of erythromycin, containing 36,0 g sodium carbonate and 90.0 g of hydroxylamine hydrochloric acid in 90 ml of water, with a temperature of 60oC. Receive a water-alcohol solution (30% water) with the initial value erythromycin/solvent 1: 1.5 g/ml, the Reaction mass is stirred at a temperature of 60oC for 1 h, then transferred into an extractor containing 1.5 liters of water and 1.5 chloroform. With stirring, add 20% sodium hydroxide solution to establish a pH value of the aqueous phase in the range of 9-11. The layers are separated, the chloroform extract washed with 300 ml of water. Get 2,15 l of a chloroform solution containing 66,0 mg/ml of erythromycin oxime (polarimetric). Output 77.3 per cent.

Crystalline oxime e is -10)oC for 16 hours Get 134,0 g of colorless crystals with so pl. 157-159oC, which corresponds to the data of the literature (Tetrahedren Letters, 1970, c. 157-160 [9]). The output was 72.8%.

Example 2. Getting aminoether erythromycin (IV).

In a glass reactor load of a chloroform solution of erythromycin oxime (example 1), add a solution of 54.0 g of sodium bicarbonate in 2 l of water. The mixture is cooled to (52)oC and with stirring from a dropping funnel a solution of p-toluensulfonate in chloroform (64,0 g p-TLC) in 250 ml of chloroform). Adding reagent continued for 1 h, the Reaction mass is maintained with stirring and the temperature (7-10)oC for another 2 h, and then the layers separated. To a chloroform layer add 1.5 liters of water and diluted hydrochloric acid to establish a pH value of the aqueous phase in the range of 4.5 to 5.5. The mass is stirred for 30 minutes while controlling the pH value of the aqueous phase, which must remain within the specified limits. Then the layers separated. Water extarct poured with stirring 120 ml conc. ammonia, while the pH is set in the range of 9-11. Crystallization mass is heated with stirring to (605)oC and kept at this temperature for 15 minutes, still stirring. The precipitate of aminoether IV from the ECA. Get 115,0 g of white crystalline powder, so pl. 129-130oC []2D0minus 55o(in chloroform). The output of aminoether and 82.2%, considering the oxime III, 63.5%, counting on erythromycin (II).

Example 3. Getting etherically (V).

In a glass reactor placed in 100.0 g of aminoether erythromycin (example 2) and 1.2 l of water. To the suspension was added with stirring from a dropping funnel 20% sulfuric acid to dissolve aminoether (pH of 5.6 and 6.4). To the solution, continuing the stirring, poured a solution of 13.8 g of potassium borohydride in 100 ml of water. The reaction mass leave at room temperature for 16-18 h to complete the reaction of recovery. The reaction mass is a colourless solution with a pH of from 9.0 to 11.0. Upon completion of the reaction the solution was added to 1.3 liters of chloroform, stirred for 30 min, the layers separated. To a chloroform layer (Solution A) containing borate complex of etherically add 1.0 l of water and 20% solution of sulfuric acid to establish a pH value of the aqueous phase (2,50,1). The reaction mass is maintained at this pH for 15 min at temperature (18-20)oC, then add 130 ml of 20% sodium hydroxide solution, the mixture is stirred for 30 min, then the layers separated. When are square-1.22 l of a chloroform solution of etherically, with a basic substance concentration of 65 mg/ml (polarimetric) - Solution B. the Extract evaporated to dryness, get of 87.3 g of an amorphous powder. The content of etherically 90,0% []2D0minus 34,7o(1% in chloroform). Output 88,0%, considering iminoethyl IV.

Example 4. Receiving azithromycin.

A) A Solution (example 3) containing borate complex of etherically, placed in a flask equipped with a reflux condenser, add to 18.0 ml of formaldehyde (40%) and 9.7 ml of formic acid (99%). The reaction mass is heated to boiling and boiled for 6 hours Then the mass is cooled, if necessary add a 20% solution of sulfuric acid to establish a pH value of the aqueous phase in the range of 4.5 to 5.5. The layers separated, the aqueous layer add citric acid (19.5 g) to pH (2,50,1), the solution stirred for 15 min, then add 1.4 l of chloroform and 20% sodium hydroxide solution to establish a pH value of the aqueous phase in the range of 9-11. The layers are separated. To a chloroform layer is poured 1.4 l of water and 20% solution of sulfuric acid to a pH of 4.5 to 5.5. The mixture is stirred for 30 minutes while controlling the pH of the aqueous phase. The layers separated, the aqueous layer was placed in a crystallizer, added 1.5 liters of water and 82,0 ml conc. of ammonia. At this pH, the crystallization mass installed is mperature 15 min and filtered. The precipitate is washed on the filter with 300 ml of water with a temperature of about 70oC and dried to constant weight. Receive and 75.5 g of white crystalline powder, the mass fraction of azithromycin 86,0% (microbiological method). Output 74,8%, considering iminoethyl erythromycin (IV).

B. Solution B (example 3) containing atherothrombosis, transferred into a flask, equipped with reflux condenser, add the 9.7 ml of formic acid and of 18.0 ml of formalin (40%). The reaction mass is heated to boiling and boiled for 6 hours Then the mass is cooled, add 1.4 l of water and 20% solution of sulfuric acid to establish a pH value of the aqueous phase of 4.5 to 5.5. The mixture is stirred for 30 minutes while controlling the pH of the aqueous phase, which should be between 4.5 to 5.5. The layers are separated. The aqueous layer was placed in the mold and add 1.5 liters of water and 82 ml conc. of ammonia. At this pH, the crystallization mass is set in the range of 9-11. Crystallization of azithromycin conduct, as described in p. A. Get 76,2, the Output 75,3%, considering iminoethyl erythromycin.

Example 5. Recrystallization of azithromycin.

To the 75.5 g of azithromycin, obtained according to example 4, add 225 ml of acetone and the suspension is stirred until complete dissolution of azithromycin. Received rest is drawn into the mould and with stirring, add water up to the beginning of crystallization. Crystallization mass is stirred for 1 h, then from a dropping funnel, water is added so that the total quantity of water added was 150 ml, and the ratio of acetone to water in the crystallization mass 2:1. The mass is stirred for further two hours at room temperature to complete the crystallization, then filtered. The precipitate is washed on the filter with a mixture of acetone-water (2:1). The product is dried to constant weight, get to 66.8 g of a white hygroscopic crystalline substance, with a mass fraction of the basic substance 94,0% and a water content of 4.8%. The output of azithromycin is 37,5%, counting on erythromycin.

Specific rotation: minus 41o< / BR>
Specific impurities: less than 0.5%

Sulphate ash: trace amounts

the pH of aqueous suspension: 8,6

The acetone: 0,10%

The diffraction pattern of the product corresponds to the standard sample of azithromycin.

1. The method of obtaining azithromycin (I), characterized in that, to simplify the process and increase the yield of the target product, erythromycin A (II) maximilianeum the action of hydroxylamine hydrochloric acid in the presence of sodium carbonate in ethanol - water (20-40% water) at an initial ratio erythromycin/solvent, g/ml, 1: 1,4 - extraction of chlorinated hydrocarbons at pH 9-11 and subjected to the Beckmann rearrangement the action of the acid chloride arylsulfonic acid in the two-phase solvent system - water/chlorinated hydrocarbons, formed iminoethyl erythromycin (IV) is recovered from aqueous solution by crystallization at pH 9-11 and the temperature of 605oC, with subsequent restoration of aminoether IV in aqueous medium at room temperature by the action of complex metal borohydride, taken at 0-0,2 molar excess, the product recovery - atherothrombosis (V) in the form of a borate compound or after hydrolysis of complex mineral or organic acid, preferably oxicology, at pH of 2.5, was identified in the chloroform formaldehyde in the presence of formic acid, the product of methylation are re-extraction of water at pH 4.5 - 5.5, if necessary, conduct the hydrolysis of the borate complex, the desired product precipitated from aqueous solution at pH 9-11 and the temperature of 50-80oC, followed by recrystallization from a mixture of acetone - water or ethanol - water, taken in the ratio from 2:1 to 1:2.

2. The way to get erythromycin oxime (III) of erythromycin A (II) the action of hydroxylamine hydrochloric acid in the presence of sodium carbonate, characterized in that, with a view to increasing output and simplify the process, the reaction is carried out in aqueous-alcoholic medium with a water content of 20 to 40%, at a temperature of 50-80oC and is authorized hydrocarbon.

3. The method of producing etherically (V) recovery of aminoether erythromycin (IV) the action of a complex metal borohydride, wherein, to increase the yield of the target product, the recovery is carried out in aqueous medium, using a reducing agent in 0-0,2 molar excess, the reaction product - borate complex of etherically subjected to hydrolysis by the action of a mineral or organic acid, preferably a hydroxy acid, at pH 2.5, the target product is separated from the hydrolysate by extraction with chloroform at pH 9 - 11.

 

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