Method for synthesis of fluconazole monohydrate, method for synthesis of crystalline modification ii of fluconazole (variants) and method for synthesis of crystalline modification i of fluconazole

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes a method for synthesis of fluconazole monohydrate of the formula (I): . Method involves hydrolysis of silyl ester derivative of the formula (II): wherein R² means hydrogen atom, (C₁-C₁₀)-alkyl or phenyl group; R³ and R⁴ mean independently of one another (C₁-C₁₀)-alkyl or phenyl group at pH value below 3 or above 8 in an aqueous solution followed by cooling the prepared reaction mixture and isolation of the precipitated fluconazole monohydrate. Also, invention describes methods for synthesis of crystalline modification II of fluconazole of the formula (I). These methods involve dissolving anhydrous fluconazole or its monohydrate in (C₁-C₄)-alcohol of the linear or branched chain at the boiling point and cooling this solution at the rate 5-15°C/h, or fluconazole monohydrate is dried at 30-70°C. Except for, invention describes a method for synthesis of crystalline modification I of fluconazole of the formula (I) wherein fluconazole monohydrate is dried at 80°C. This invention provides preparing pure or easily purifying fluconazole in crystalline modifications allowing easy preparing the suitable medicinal formulations from them.

EFFECT: improved synthesis method.

16 cl, 1 tbl, 7 dwg, 8 ex

The present invention relates to a method of synthesis monohydrate and crystalline modifications of fluconazole formula I

Hereinafter, the terms "crystalline modification" and "polymorphs" have the same meaning and are used interchangeably.

Patent of great Britain No. 2078719 And describes a very effective antifungal compounds that have also a significant effect of regulating the growth of plants. The above compounds illustrated by formula (A)

where the value R is alkyl, cycloalkyl, aryl or kalkilya group or their derivatives containing one or two halogen atom, or substituted alkoxy, phenyl, phenoxy or trifluoromethyl aryl and benzyl group, a Y¹and Y²independently represent a group-N= or-CH=.

According to the United Kingdom patent No. 2099818 And the compound 2-(2,4-differenl)-1,3-bis(1,2,4-triazole-1-yl)-propan-2-ol, belonging to the above group (hereinafter referred to fluconazole)may also be used as a fungicide in humans. Fluconazole is the other active ingredient of diflucan, which is a very effective antifungal medicine for men on the market.

According to the United Kingdom patent No. 2078719 And derived propan-2-ol is ormula (A) synthesized by interaction of the Grignard reagent of the formula R-Mg-halogen, where the value R is as defined above, with dichloroacetone. Thus formed is derived 1,3-dichloropropan-2-ol of the formula (VI)

subjected to interaction with excess salt of imidazole or triazole, for example the sodium salt, in a proton or aprotic medium (for example, in dimethylformamide). This reaction can be made with epoxy-derivatives, which are formed in situ from the above dihalogen connection in the presence of a base when you remove hydrogen chloride. The desired compound can also be synthesized with the cooperation of the appropriate 1,3-bisimilarity or 1,3-bis(1,2,4-triazole-1-yl)-acetone with a Grignard reagent of the formula R-Mg-halogen. In accordance with another by the synthesis of the compounds of formula (VII), where the values of R and Y¹such as defined above,

turn in the compounds of formula (IV)containing substituent R instead of R¹using dimethyl-oxazolone matilida,

and obtained is subjected to interaction with the sodium salt of imidazole or triazole by analogy with the above method. Raw materials receive in accordance with known methods.

In the method of synthesis of the active substance is fluconazole described in UK patent No. 2099818 And using the Xia compounds of formulas (VI) and (IV), which contain substituent R instead of R¹as raw materials, but as reagents instead cresolate sodium use basis and triazole.

A common feature of the methods of both patents is that the selection of the reaction products is carried out by extraction after diluting the reaction mixture with water, followed by purification using column chromatography, or distillation under vacuum, or by other methods. The yield of the obtained product is 30-50%.

According to the patent Spain no ES 549020 A1, 1 mol of 1,3-dichloroacetone subjected to interaction with 2 moles of 1,2,4-triazole, and then obtained with low yield 1,3-bis(1,2,4-triazole-1-yl)-propan-2-he is subjected to interaction with 2,4-differentialalgebraic getting fluconazole. The yield is about 45% in the calculation of the Grignard reagent.

A common feature of the methods described in the patents of Spain No. ES 549021 A1, ES 549022 A1 and ES 549684 A1, is that one or both of the triazole group of fluconazole is introduced into the molecule using (1,2,4-triazole-1-yl)-methylaniline. In accordance with the descriptions of the outputs of approximately 45-55%. It is known that the Grignard reagents containing triazole groups are unstable or sometimes inactive, so they give reactions with low outputs. When playing the methods described in these patents, o the d was always below 10%.

In the patent Spain no ES 2026416 described the best way than in the above patents. In accordance with 1-(1,2,4-triazole-1-yl)-2-(2,4-differenl)-3-halogen-propan-2-ol is subjected to interaction with 4-amino-1,2,4-triazole, and the resulting 1-(1,2,4-triazole-1-yl)-2-(2,4-differenl)-3-(4-amino-1,2,4-triazole-1-yl)-propan-2-ol diasterous and thus formed Sol, page hydrolyzing removal of the amino group. The above outputs are 78% for the first stage and 85% for the second stage. This method has several disadvantages from the industrial point of view. The first is that the derived C-halogen-propan-2-ol used as starting material synthesized from epoxy-derivative of formula (IV) by boiling under reflux in an aggressive environment halogenated. Another disadvantage is the fact that used as the reagent 4-amino-1,2,4-triazole can be purchased only as a product of fine organic synthesis. The reaction of diazotization and hydrolysis of diazonium salts on an industrial scale are a very dangerous process. Finally, the total output of the multistage method is only 42-43%.

In issue of the Journal of Ph. Sciences (Vol. 84, No. 12) in December 1995, the crystalline forms I and II of fluconazole, as well as data from x-ray powder diffraction and Raman scattering for different cristalli the definition of the modifications described without method of their synthesis.

In the patent GB 2270521 described the synthesis of the monohydrate of the anhydrous fluconazole fluconazole. In accordance with the data of powder x-ray diffraction anhydrous fluconazole, used as starting material is identical to the crystalline modification II. In the description of this patent, reference is made to the patent US 4404219 in relation to the synthesis of this crystalline modification, but there is no indication of crystalline modifications.

The task of this invention is economical synthesis of clean or easy to clean the final product of fluconazole without the use of reagents that are difficult when applied on an industrial scale, and the allocation of educated fluconazole in its desired crystalline modification I or II, and the task is to make possible the transformation of these various crystal modifications of each other.

Thus, in the present invention, a method of synthesis of the monohydrate of fluconazole formula (I)

characterized in that

carry out the hydrolysis derived salelologa ether of the formula (II)

where a value of R²represents hydrogen or C₁-C₁₀alkyl or phenyl group, R³and R⁴independently of one another represent C₁-C₁₀and kilou or phenyl group, when pH or below 3 or above 8, in aqueous solution,

then cool the reaction mixture containing fluconazole formula (I), and allocate the besieged monohydrate of fluconazole.

Preferably the hydrolysis is derived salelologa ether of the formula (II), where the values of R², R³and R⁴such as defined above, is carried out in aqueous methanol solution in the presence of sodium hydroxide.

Preferably the hydrolysis is derived salelologa ether of the formula (II), where the values of R², R³and R⁴such as defined above, is carried out in aqueous sodium hydroxide solution.

Preferably as the source material used is derived salelologa ether of the formula (II), where R², R³and R⁴represent a methyl group.

In addition, in the present invention, a method of synthesis of the crystalline modification II of fluconazole formula I

characterized in that

anhydrous fluconazole or its monohydrate dissolved in₁-C₄-alcohol with a straight or branched chain at boiling point and cooling the solution with a speed of 5-15°/hour with obtaining the crystalline modification II of fluconazole.

Preferably the monohydrate of fluconazole used for synthesis of the crystalline modification II of fluconaz the La, obtained by hydrolysis silyl-fluconazole as defined above.

Preferably a solution of anhydrous fluconazole or its monohydrate in isopropanol obtained at the boiling point, cooled at a rate of 10°C/hour.

Preferably a solution of anhydrous fluconazole or its monohydrate in ethanol, obtained at the boiling point, cooled at a rate of 10°C/hour.

Preferably a solution of anhydrous fluconazole or its monohydrate in sec-butanol obtained at the boiling point, cooled at a rate of 10°C/hour.

More preferably, the above solution is cooled to 0°C.

In addition, in the present invention, a method of synthesis of the crystalline modification II of fluconazole formula (I)

characterized in that

monohydrate fluconazole dried at 30-70°obtaining crystalline modification II of fluconazole.

Preferably the monohydrate of fluconazole dried in the presence of seed crystals of the crystalline modification II.

More preferably the specified drying is carried out under stirring in vacuum at 40°C for 2 hours and then at 70°C for 4 hours.

In addition, in the present invention, a method of synthesis of the crystalline modification I of fluconazole formula (I)

characterized in that

monohydrate fluconazole dried at 80°obtaining crystalline modification I of fluconazole.

Preferably the monohydrate of fluconazole dried in the presence of seed crystals of the crystalline modification I.

More preferably the specified drying is carried out under stirring in vacuum at 80°C for 4 hours, up until the mixture becomes constant.

The basis of this invention is the discovery that Silovye esters of the formula (II), which represent the desired compounds of U.S. patent No. 5707976,

where a value of R²represents hydrogen or C₁-C₁₀alkyl or phenyl group, R³and R⁴independently from each other represent a₁-C₁₀alkyl or phenyl groups, in an aqueous acidic or basic conditions can be quantitatively hydrolyzed to fluconazole formula (I). The compounds of formula (II) can be obtained in accordance with U.S. patent No. 5707976, for example, from the appropriately substituted epoxy-derivatives of the formula (IV) using the appropriately substituted cylindrical formula (V), where the values of R², R³and R⁴such as described above, in the presence of a strong base as a catalyst.

Because the obtained silyl-fluconazole derivatives are very non-polar due to the presence of trialkylsilyl group, they can be easily separated from impurities and can be economically synthesized in a very pure form.

In accordance with the present invention monohydrate fluconazole formula (I) are synthesized by carrying out the hydrolysis derived salelologa ether of the formula (II) in aqueous solution at pH or lower, preferably 3 or greater than 8.

Hydrolysis is a fast process. For example, trimethylsilyloxy ether fluconazole fully hydrolyzed at pH above 10 in a 10% aqueous solution of dimethylformamide at room temperature for 10 minutes. In similar conditions, but at pH below 2 hydrolysis fully exposed for 0.5-1 hours

The hydrolysis can be performed in a neutral conditions in a homogeneous phase in the presence of water at elevated temperature, preferably at the temperature of reflux distilled. Quick and effective industrial hydrolysis is preferably carried out either at pH less than 3 or at pH greater than 8. This hydrolysis is very soft, undesired by-products are not formed even in trace quantities, therefore, the hydrolysis properly cleared derivatives cyrilovich esters of the formula (II) can be synthesized very clean fluconazole and he can is to be isolated from the reaction mixture in the form of a monohydrate.

The hydrolysis is preferably carried out in a homogeneous phase, in a mixture of a proton or a dipolar aprotic solvent, miscible with water, and water at pH above. Fluconazole formed in this reaction is preferably emit by diluting the reaction mixture with water and cooling. As a result of cooling the formed fluconazole crystallizes from the reaction mixture in the form of very pure monohydrate and may be selected, for example, by filtration.

Monohydrate is stable at room temperature; it becomes anhydrous fluconazole, the so-called anhedral, between 40 and 90°With a rate depending on the conditions of dehydration.

Polymorphic modifications have different crystal structure, crystallographic constants (distance and energy of the crystal lattice and, consequently, have different dissolution rate. Different polymorphic modifications can be differentiated from each other by their spectra Raman scattering. Figure 1 and 2 shows the Raman spectrum of crystalline modification I and II between fluconazole 3500,0 and 200,0 cm^-1, while in figure 3 and 4 shows the area between 3300,0 and 2800,0 cm^-1where can be found the characteristic differences for crystalline modifications I and II of fluconazole.

In Ter the FDI prerequisite reproduced permanent effect of solid pharmaceutical dosage forms (for example, oral dosage forms) is that the dissolution of the active ingredient should be constant in the case of various parties. For this reason, it is advisable to always use the same crystalline modification of those active ingredients that have several crystalline modifications, such as fluconazole.

When the preparation conditions of formation of the crystalline modification I and II were studied in detail to meet the morphological requirements of fluconazole.

It has been unexpectedly discovered that if a solution of anhydrous fluconazole or monohydrate fluconazole obtained by dissolving them in a₁-C₄-alcohol with a straight or branched chain at boiling point, slowly cooled, preferably with a speed of 5-15°C/h, then precipitated and dried crystals are identical to the crystalline modification II of fluconazole.

The crystalline modification I and II can be obtained by drying the monohydrate of fluconazole at different temperatures. In this case, the use of appropriate seed crystals contributes to the formation of the desired modification.

If monohydrate fluconazole dried after persecution crystals of the crystalline modification II slowly, preferably in a vacuum, at a temperature between 30 and 70°then the Yes is formed of the crystalline modification II. If the drying is carried out rapidly at 80°then of the monohydrate of fluconazole is formed crystalline modification I.

The alcohols used for crystallization may constitute alcohols with branched-chain, preferably isopropanol or sec-butanol, or alcohols with straight-chain, preferably ethanol. The water content of the₁-C₄-alcohols with straight or branched chain used during crystallization, can even reach 5%. Thus, the quality of purity is sufficient in the case of 96%ethanol. The best results are obtained when using isopropanol.

Table 1 shows the data of x-ray powder diffraction (RPD) of the crystalline modifications I and II of fluconazole, as measured on the samples of Examples 2 and 5. (X-ray powder diffractometer Philips PW 1840; CuKα radiation, 30 kV and 30 mA; goniometer speed of 0.05 °2θ/s; sensitivity: 2·10³imp/s; FT: 5 C.; slit width of 0.05 mm).

Figure 5 and 6 shows the picture of the x-ray powder diffraction (RPD) of the samples of Examples 2 and 5. Picture of x-ray powder diffraction pattern of Example 3 is the same as the sample of Example 2; picture x-ray powder diffraction of the samples of Examples 6, 7 and 8 are the same as the sample of Example 5.

The method and the finding is illustrated by the following non-limiting Examples.

Example 1

The monohydrate of 2-(2,4-differenl)-1,3-bis(1,2,4-triazole-1-yl)-propan-2-ol

A mixture of 7.50 g (0.02 mol) of 2-(2,4-differenl)-1,3-bis(1,2,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 25 ml of methanol, 2 ml of water and 1.0 ml conc. hydrochloric acid was stirred at 30°C for 1 hour. The reaction mixture was concentrated to a volume of 10 ml and after adding 50 ml of water the pH of the hot solution was brought to 8 with 10% aqueous sodium hydroxide solution. After cooling, the precipitated crystals were filtered and dried at 40°until then, until the mixture became constant, with the release of the 6.06 g (93.5 per cent) of the connection specified in the header. So pl. 139-140°C.

Example 2

The synthesis of the crystalline modification I of fluconazole

A mixture of 7.5 g (0.02 mol) of 2-(2,4-differenl)-1,3-bis(1,2,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 40 ml of methanol, 3 ml of water and 0.1 g of sodium hydroxide was stirred at room temperature for 1 hour. After adding 300 ml of water the solution was concentrated to a volume of 50 ml by vacuum distillation. The resulting suspension was cooled to 0°and filtered. The mass of the obtained product was 6,12 g, water content of 11.5%. After drying at 80°received 5.35 g of the compound indicated in the title. Output: 87,4%. So pl. 139-141°C.

Example 3

The synthesis of the crystalline modification I of fluconazole

A mixture of 7.5 g (0.02 mol) of 2-(2,4-differenl)-1,3-bis(1,,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 40 ml of methanol, 3 ml of water and 0.1 g of sodium hydroxide was stirred at room temperature for 1 hour. After adding 300 ml of water the solution was concentrated to a volume of 50 ml by vacuum distillation. The resulting suspension was cooled to 0°and filtered. Got 6,12 g of the product, the water content was 11.5 percent. It was placed in a flask of 100 ml and was added 0.1 g of seed crystals of the crystalline modification I of fluconazole. The compound was dried in a rotary evaporator at 80°C for 3-4 hours, until then, until the mixture became constant. Received of 5.45 g of compound indicated in the title. Output: 87,4%. So pl. 139-141°C.

Example 4

Synthesis monohydrate fluconazole

The mixture 7,58 g (0.02 mol) of 2-(2,4-differenl)-1,3-bis(1,2,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 0.04 g of sodium hydroxide and 70 ml of water was stirred at 80°C for 10 minutes. Then added 0.5 g of coal and the hot solution was filtered. The filtrate was cooled to 0°C. Precipitated crystals were filtered and dried at 40°until then, until the mixture became constant, with the release 5,98 g (92.1 per cent) of the connection specified in the header. The water content of 5.6%, So pl. 139-140°C.

Example 5

The synthesis of the crystalline modification II of fluconazole

6,12 g (0.02 mol) of anhydrous fluconazole was dissolved in 60 ml of isopropanol with stirring at 70°and then the solution was cooled. P is after the temperature reached 50° C, the cooling rate was 10°C/hour. The deposition of crystals began at about 40°C. After 5 hours, when the temperature reached 0°C, the crystalline modification II of fluconazole was filtered and dried at 50°until then, until the mixture became constant, with the receipt of 5.85 g (91.2 per cent) of the connection specified in the header. So pl. 139-141°C.

Example 6

The synthesis of the crystalline modification II of fluconazole

6,12 g (0.02 mol) of fluconazole was dissolved in 25 ml of ethanol with stirring at 50°s, then the solution was slowly cooled at a constant speed (10°C/hour) to °C. the Deposition of crystals began at about 40°C. the Precipitated crystalline modification II of fluconazole was filtered and dried at 50°until then, until the mixture became constant, obtaining 5,23 g (85,5%) of the compound indicated in the title. So pl. 139-140°C.

Example 7

The synthesis of the crystalline modification II of fluconazole

6,12 g (0.02 mol) of fluconazole was dissolved in 60 ml of sec-butanol at 60°s, then the solution was cooled to 0°With a speed of 10°C/hour. The precipitation started at about 42°C. the Crystals were filtered and dried at 50°until then, until the mixture became constant, obtaining 5,70 g (93.1%) are the connection specified in the header. So pl. 139-140°C.

Example 8

The synthesis of the crystalline modification II of fluconazole

With the offer of 7.5 g (0.02 mol) of 2-(2,4-differenl)-1,3-bis(1,2,4-triazole-1-yl)-2-(trimethylsilyloxy)propane, 40 ml of methanol, 3 ml of water and 0.1 g of sodium hydroxide was stirred at room temperature for 1 hour. After adding 300 ml of water the solution was concentrated to a volume of 50 ml by vacuum distillation. The resulting suspension was cooled to 0°and filtered. Got to 6.00 g of the monohydrate of fluconazole, the water content is accounted for 11.0%. It was placed in a flask of 100 ml and was added 0.1 g of seed crystals of the crystalline modification II of fluconazole. The compound was dried in a rotary evaporator at a pressure of 13.3 kPa, so that the crystals of the monohydrate was heated for 3 hours from 30 to 70°C and kept at this temperature until, until the mixture became constant (approximately 2 hours). Got to 5.4 g of compound indicated in the title. So pl. 139-141°C. figure 7 shows the data of x-ray powder diffraction for monohydrate.

1. The method of synthesis monohydrate fluconazole formula (I)

characterized in that carry out the hydrolysis derived salelologa ether of the formula (II)

where a value of R²represents hydrogen or C₁-C₁₀alkyl or phenyl group, R³and R⁴independently of one another represent C₁-C₁₀alkyl or phenyl group, or at pH below 3, if the above about 8, in aqueous solution,

then cool the reaction mixture containing fluconazole formula (I), and allocate the besieged monohydrate of fluconazole.

2. The method according to claim 1, characterized in that the hydrolysis is derived salelologa ether of the formula (II), where the values of R², R³and R⁴such as defined in claim 1, carried out in aqueous methanol solution in the presence of sodium hydroxide.

3. The method according to claim 1, characterized in that the hydrolysis is derived salelologa ether of the formula (II), where the values of R², R³and R⁴such as defined in claim 1, carried out in aqueous sodium hydroxide solution.

4. The method according to claims 1 to 3, characterized in that as starting material used is derived salelologa ether of the formula (II), where R², R³and R⁴represent a methyl group.

5. The method of synthesis of the crystalline modification II of fluconazole formula I

characterized in that

anhydrous fluconazole or its monohydrate dissolved in₁-C₄-alcohol with a straight or branched chain at boiling point and cooling the solution with a speed of 5-15°S/h

6. The method according to claim 5, characterized in that the monohydrate of fluconazole obtained by hydrolysis silyl-fluconazole as defined in claim 1.

7. The method according to claim 5, characterized the eat, the anhydrous solution of fluconazole or its monohydrate in isopropanol obtained at the boiling point, cooled at a rate of 10°S/h

8. The method according to claim 5, characterized in that the anhydrous solution of fluconazole or its monohydrate in ethanol, obtained at the boiling point, cooled at a rate of 10°S/h

9. The method according to claim 5, characterized in that the anhydrous solution of fluconazole or its monohydrate in sec-butanol obtained at the boiling point, cooled at a rate of 10°C/hour.

10. The method according to claims 7 to 9, characterized in that the solution cooled to 0°C.

11. The method of synthesis of the crystalline modification II of fluconazole formula (I)

characterized in that

monohydrate fluconazole dried at 30-70°C.

12. The method according to claim 11, characterized in that the monohydrate of fluconazole dried in the presence of seed crystals of the crystalline modification II.

13. The method according to item 12, wherein the specified drying is carried out under stirring in vacuum at 40°C for 2 h and then at 70°C for 4 hours

14. The method of synthesis of the crystalline modification I of fluconazole formula (I)

characterized in that the monohydrate of fluconazole dried at 80°C.

15. The method according to 14, characterized in that the mono is igrat fluconazole dried in the presence of seed crystals of the crystalline modification I.

16. The method according to item 15, wherein the specified drying is carried out under stirring in vacuum at 80°C for 4 h before until the mixture becomes constant.