CN106366076A - Posaconazole synthesis method - Google Patents

Abstract

The invention provides a posaconazole synthesis method which includes the steps: S1, taking a compound displayed by a following formula II as a raw material, taking hydrogen as a hydrogen source, stirring the compound displayed by the formula II, catalysts and acidic reagents in reaction solvents under the hydrogenation debenzylation reaction condition, and performing contact reaction to obtain mixed solution; S2, reducing the temperature of the mixed solution to range from 0 DEG C to 5 DEG C, dropping sodium hydroxide solution into the mixed solution until a pH (potential of hydrogen) value of the mixed solution is 10-12, stirring, filtering to obtain filter cakes, washing the filter cakes, and drying the washed filter cakes to obtain posaconazole as shown in the following formula I.

Description

A kind of synthetic method of posaconazole

technical field

The invention relates to the field of drug synthesis, and relates to a method for synthesizing posaconazole.

Background technique

Posaconazole (Chinese chemical name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4- Triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentyl- 3-yl]-1,2,4-triazol-3-one), has the structure shown in the following formula I.

Posaconazole is an antifungal drug developed by Schering-Plough in Germany under the trade name "Noxafil", which was approved for marketing in the European Union and the US FDA on October 20, 2005. In September 2006, posaconazole oral suspension was once again approved by the US FDA for patients with weakened immunity after bone marrow transplantation and leukopenia caused by cancer chemotherapy to prevent infections caused by Aspergillus and Candida. Because of its high efficiency and low toxicity, wide range of clinical applications, and good curative effect, it is especially effective for polyenes and other triazole-resistant or invasive fungal infections, and provides a great opportunity for the treatment of clinical invasive fungal infections. Choose a space.

There have been a lot of researches on the synthesis method of posaconazole in the prior art, and generally, posaconazole is finally obtained by hydrogenation debenzylation of the compound shown in the following formula II.

It is recorded in US5625064 and CN101824009A: cool the compound shown in formula II to 50°C, add 350ml of formic acid, continue to cool to 20°C, add another 350ml of methanol, take 85gPd/C and add 350ml of formic acid to stir into a slurry and add it to the reaction flask. Stir overnight at °C, heat to 40°C for 24 hours, filter with suction, and wash the filter cake with 350ml formic acid and 700ml methanol. Evaporate the solvent under reduced pressure, add 3500ml of methanol and 700ml of ammonia water to the residue, heat to reflux for 1-2h, then cool to precipitate a large amount of solid, filter with suction, wash the filter cake with 1400ml of methanol and water (1:1), at 40°C Blowing and irritating gave 300.5 g of the final product.

Anil K. Saksena (Tetrahedron Letters 45 (2004) 8249-8251) pointed out: 4.03g of the compound described in formula II was dissolved in 70ml of formic acid, then 5% Pd/C 8g was added, the reaction mixture was stirred at 20°C for 15h, and then Heated to 35-40°C and stirred for another 24h. Then the reaction solution was cooled to 20°C, filtered, and the filter cake was washed with about 40ml of formic acid and twice with 35ml of methanol. The rate is 84%.

The synthetic route of posaconazole in the above-mentioned processing method is as follows

In the above two methods, formic acid is the reaction solvent and hydrogen source. First react at 20°C, and then increase the temperature to 35-40°C for reaction. The total reaction time is more than 40h, and the post-processing requires column chromatography to purify the sample. The amount of solvent is too large, which is not suitable for large-scale production.

It is recorded in CN102863431A: add the compound shown by formula II (8.12g) and hydrobromic acid 70ml into a 250ml three-necked flask, stir until the solid dissolves, heat to 50°C for 2-3h, and monitor the completion of the reaction by liquid phase. The reaction solution was diluted with water (100ml), adjusted to pH about 9 with aqueous NaOH solution (100ml, 25%), extracted with dichloromethane (100ml), washed with 10% aqueous NaOH solution (100ml) of the organic phase, washed with water (100ml), washed with saturated NaCl It was washed with aqueous solution (100ml), dried over anhydrous NaSO ₄ , concentrated, and dried in vacuo to give an ocher crude product with a purity of 93.9%. In this experimental method, hydrobromic acid is both the reaction solvent and the hydrogen source, which has a strong thorny taste and is not easy to store and is easily oxidized. And post-processing is cumbersome and the yield is low, so it is not suitable for large-scale production.

In addition, it is described in WO2013042138A2 and US2014343285A1: add 42g of the compound shown in formula II to 420ml of methanol, 5mol/l hydrochloric acid and 10%Pd-C, at 4-5kg/cm ² (0.4-0.5Mpa) hydrogen pressure, reaction temperature React at 50°C for 5h. After the reaction is over, remove the catalyst by filtration, then use 4mol/L sodium hydroxide solution to adjust the pH value to about 7, add water and stir at 25-35°C for 2h, a large amount of solids precipitate, filter, and The filter cake was washed with water, and the filter cake was recrystallized in isopropanol to obtain posaconazole with a yield of 75% and a purity of 99.85%. The synthetic route of posaconazole in this processing method is as follows:

Although the above experimental scheme shortens the reaction time to a certain extent, it improves the purity of the target product. However, in order to realize the large-scale industrial production of posaconazole, the synthetic method of posaconazole needs to be further optimized and improved, so as to establish a method with shorter reaction time and the purity and yield of posaconazole Synthetic methods of posaconazole have been improved.

Contents of the invention

The main purpose of the present invention is to provide a synthetic method of posaconazole, so as to improve the yield and purity of posaconazole, and provide a synthetic method of posaconazole suitable for large-scale industrial production.

For this reason, a kind of synthetic method of posaconazole is provided in the present invention, and this synthetic method comprises the following steps:

S1. Using the compound shown in the following formula II as a raw material, using hydrogen as a hydrogen source, under the conditions of the hydrogenation debenzylation reaction, stirring and contacting the compound shown in the formula II with a catalyst and an acidic reagent in a reaction solvent to obtain a mixed solution;

S2. Cool the mixed solution to 0-5°C, add sodium hydroxide solution dropwise to the mixed solution until the pH value of the mixed solution is 10-12, stir and filter to obtain a filter cake, wash and dry to obtain the following formula I posaconazole as indicated.

According to the synthesis method of the present invention, the purpose of adding the catalyst is mainly to promote the hydrodebenzylation reaction, wherein there is no special requirement for the use of the catalyst, and any catalyst that can promote the hydrodebenzylation reaction in the art can be used. Yet in order to optimize the reaction effect, improve the yield of posaconazole, be preferably 10% palladium carbon catalyst with water content as catalyzer (wherein 10% palladium carbon catalyst is the catalyst that palladium content is 10wt% of catalyzer dry basis weight) ), and the weight ratio of the dry weight of the 10wt% palladium-carbon catalyst to the compound shown in formula II is (0.05-0.1): 1, preferably (0.08-1): 1, more preferably 0.08: 1.

According to the synthesis method of the present invention, the main purpose of adding the acidic reagent is to dissolve the formula II in the reaction solvent, wherein there is no special requirement for the use of the acidic reagent, and it can be any conventional organic acid or inorganic acid that can meet the above-mentioned purpose in the art. acid. However, in order to optimize the reaction effect and increase the yield of posaconazole, the volume-to-weight ratio of the acidic reagent to the compound represented by formula II is preferably (0.5-1.5) L: 1 kg, more preferably 1 L: 1 kg.

Preferably, the acidic reagent is one or more of hydrochloric acid, sulfuric acid, glacial acetic acid, formic acid and benzenesulfonic acid, more preferably the acidic reagent is hydrochloric acid. In the present invention, there is no special requirement for the concentration of these acidic reagents, which can be adjusted according to actual needs.

According to the synthesis method of the present invention, the focus is to use the compound shown in formula II as a raw material, and use hydrogen as a hydrogen source to carry out a stirring reaction under hydrogenation debenzylation reaction conditions, thereby increasing the yield of posaconazole while accelerating the reaction efficiency. rate and simplify the post-processing steps. In the present invention, there is no special requirement for the hydrogenation debenzylation reaction conditions in step S1, and the corresponding conditions in the conventional synthesis method can be referred to. In the present invention, the hydrogenation debenzylation reaction conditions preferably include: at normal pressure, temperature Under the condition of 50-55° C., the reaction was stirred for 2-3 hours at a speed of 350-450 rpm.

According to the synthesis method of the present invention, in order to meet the requirements of the stirring reaction in step S1, preferably, step S1 is prompted to be carried out in a reaction kettle with a built-in stirrer. This built-in reactor with agitator can adopt a conventional commercially available reactor. However, in order to optimize the stirring effect, impel the material to carry out heat transfer, mass transfer and reaction under stirring, and then increase the reaction rate, in a preferred embodiment, the stirrer in the reactor includes a stirring shaft and a stirring shaft along the Multiple sets of stirring blade groups uniformly distributed along the axial direction of the shaft, each of which includes 1 to 3 stirring blades uniformly distributed along the circumference of the stirring shaft. Preferably, the stirring blades in two adjacent groups of stirring blades are arranged in parallel or alternately. Preferably, the length of the stirring blade along the radial direction of the reactor is 1/5-2/5 times, preferably 1/3 times, the radius of the stirring tank.

According to the synthesis method of the present invention, in order to further optimize the stirring effect and accelerate the reaction, it is preferred that at least one set of baffles is also provided in the reactor, and the set of baffles includes a plurality of baffles, and each set The length direction of the baffle is set parallel to the axis of the agitator, and the width direction is set along the radial direction of the reactor. Preferably, the agitator is arranged along the axis of the reactor, and the baffles in the set of baffles are distributed in a circle with the axis of the agitator as the vertical midline. Preferably, the height of each baffle is 1/2-2/3 times the height of the stirred tank, the width is 1/6-1/4 times the radius of the stirred tank, and the thickness is 0.5-1 cm. By setting the baffle group in the stirred tank, the liquid agitated by the agitator is impelled to collide with the baffle, so as to promote the heat transfer, mass transfer and reaction of the compound shown in formula II with hydrogen, catalyst, and acidic reagent under the condition of stirring , thereby increasing the reaction efficiency.

In a preferred embodiment, a group of baffles is provided in the reaction kettle, and each baffle in the baffle group extends along its width, one side is fixed on the inner wall of the reaction kettle, and the other side is fixed on the inner wall of the reaction kettle. The side extends towards the position of the agitator.

In another preferred embodiment, two or three sets of baffles are set in the reactor, and each set of baffles is concentrically arranged with the axis of the agitator as the vertical midline and adjacent to each other. The baffles in the two groups of baffles are arranged in a staggered manner.

According to the synthesis method of the present invention, in step S2, the temperature of the mixed solution is lowered to 0-5°C. In this step, there is no special requirement for the selected cooling method. In the present invention, it is preferred to directly add ice to the mixed solution. block for rapid cooling, which can reduce the occurrence of side reactions.

In a preferred embodiment, the synthesis method according to the present invention comprises the following steps: S1, taking the compound shown in the following formula II as a raw material, using hydrogen as a hydrogen source, the compound shown in formula II, 10% palladium carbon catalyst and The acidic reagents are stirred and mixed in the reaction kettle in proportion (refer to the above description for the specific proportion, and will not be repeated here), and are stirred and reacted for 2-3 hours at a speed of 350-450 rpm under normal pressure and a temperature of 50-55 ° C (monitored by HPLC). reaction, control the reaction end point), and obtain the mixed solution after separating the catalyst; wherein the reaction kettle is a reaction kettle with a built-in agitator and at least one optional baffle group (the structure of the agitator and the baffle group As mentioned above, no more details here); S2, cooling the mixed solution to 0-5°C, adding an alkaline reagent dropwise to the mixed solution until the pH value of the mixed solution is 10-12, stirring and filtering to obtain The filter cake is washed and dried to obtain posaconazole shown in the following formula I.

According to the synthetic method of the present invention, wherein there is no special requirement for the method for obtaining the compound shown in formula II, it can be synthesized according to the conventional method in the prior art, for example: add 2-[(1S, 2S in a 100ml three-necked bottle )-1-ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H -1,2,4-Triazol-3-one (4.78g) and DMSO (40ml), stirred and dissolved, added 25wt% NaOH aqueous solution (1.6ml), mixed and stirred for 10 minutes, added (5R-CIS) -Toluene-4-sulfonic acid 5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-yl)methyltetrahydrofuran-3-ylmethyl ester ( 4.4g), the mixture was reacted at 30°C for about 14h, and the liquid phase was monitored until the reaction was completed. A solid was obtained after recrystallization from isopropanol, which was dried in vacuo to obtain an off-white powdery solid (Formula II).

At the same time, the present invention also provides posaconazole synthesized by the method of the present invention, preferably the purity of the posaconazole is ≥99%.

According to the synthesis method of posaconazole provided by the present invention, the compound represented by formula II is used as a raw material, hydrogen is used as a hydrogen source, and hydrogenation debenzylation reaction of the compound represented by formula II is promoted under stirring conditions. This method not only reduces the pressure requirements of the reaction, but also significantly shortens the reaction time, which only needs 2-3 hours; and the post-treatment is simple, and the pH value is adjusted to 10-12 at low temperature, and centrifuged to obtain the target product Posa Conazole, the method is suitable for large-scale industrial production.

Description of drawings

The accompanying drawings are used to provide a further understanding of the present invention, and constitute a part of the description, together with the following specific embodiments, are used to explain the present invention, but do not constitute a limitation to the present invention. In the attached picture:

Fig. 1 is the proton nuclear magnetic spectrum figure of the posaconazole synthesized in embodiment 1;

Figure 2 is the carbon NMR spectrum of posaconazole synthesized in Example 1.

detailed description

The synthetic method of the compound of the structure shown in the formula II adopted in embodiment 1 to 4 is as follows:

Add 2-[(1S,2S)-1-ethyl-2-benzyloxypropyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl )-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (4.78g) and DMSO (40ml), stirring and dissolving, adding NaOH aqueous solution (1.6ml ), mixed and stirred for 10 minutes, added (5R-CIS)-toluene-4-sulfonic acid 5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazole-1- base) methyltetrahydrofuran-3-ylmethyl ester (4.4g), the mixture was reacted at 30°C for about 14h, the liquid phase was monitored until the reaction was complete, the reaction solution was poured into vigorously stirred water (240ml), the addition was completed, and then vigorously Stir for 10min, filter, wash the filter cake with water, obtain a solid after the filter cake is recrystallized with isopropanol, and vacuum dry to obtain an off-white powder solid (formula II); through nuclear magnetic, mass spectrometry and infrared spectrum comprehensive detection, it can be known that this gray powder solid is The compound described in formula II, and the purity of the compound is >99%.

Example 1

For illustrating the present invention posaconazole and its synthetic method

(1) Reactor structure with built-in agitator:

The reactor has a height of 120cm and a diameter of 100L enamel reactor of 50cm. There is a stirrer and a set of baffle plates, the stirrer is standard, including a stirring shaft arranged along the axis of the reactor and two sets of stirring blades uniformly distributed along the axis of the stirring shaft Groups, each group of stirring blade groups are arranged in parallel, and each group of stirring blade groups includes two stirring blades uniformly distributed along the circumference of the stirring shaft, and the length of each stirring blade along the radial direction of the reactor is 8cm; The plate group includes a height of 60 cm, a width of 5 cm, and a thickness of 4 baffles of 1 cm. The length direction of each baffle is arranged along the axial direction parallel to the stirrer (one side is fixed on the bottom wall of the reactor. ), the width direction is arranged along the radial direction of the reactor, and each baffle is extended along the direction of its width (one side is fixed on the side wall of the reactor, and the other side extends towards the position of the agitator) , and the baffles are circumferentially distributed with the axis of the agitator as the vertical midline.

(2) Synthesis of posaconazole

Add 60L methyl alcohol in above-mentioned 100L enamel reactor, compound shown in 4kg formula II, 4L concentration is the hydrochloric acid of 36.5wt%, the 10% palladium carbon catalyst (water content 50%) of 320g, seal reactor, open agitator (stirring speed is 350rpm). First replace the air in the kettle with nitrogen for 3 times, and then replace it with hydrogen for 3 times. The hydrogen pressure is kept at 0.1 MPa (gauge pressure), and the temperature is raised to 50 ° C. The reaction is monitored by HPLC, and the reaction is completed after 2 hours. Cool down, replace with nitrogen for 3 times, and filter to obtain 10% palladium carbon catalyst. Pour the filtrate into another 200L enamel reaction kettle, add ice cubes, cool down to 0-5°C, add 2mol/L NaOH solution dropwise to the filtrate, adjust the pH to 11, a large amount of solids precipitate, stir for 2 hours, centrifuge, and The filter cake was washed with water for 3 times, and the solid was dried in a blast drying oven at 55° C. to obtain a product of 3.32 kg. Accompanying drawing 1 shows the H NMR spectrum of the product, and Accompanying drawing 2 shows the NMR of the product. The carbon spectrogram, combined with accompanying drawings 1 and 2, shows that the product is exactly the desired posaconazole, and the calculated yield of the product is 93.6%, and the HPLC purity is 99.754%.

Example 2

For illustrating the present invention posaconazole and its synthetic method

(1) Built-in reactor structure of agitator: same as embodiment 1.

(2) Synthesis of posaconazole:

Add in the enamel reactor of aforementioned 100L, add 60L methyl alcohol, compound shown in 4kg formula II, 6L concentration is the sulfuric acid of 98wt%, 10% palladium carbon catalyst (water content 50%) of 400g, seal reactor, open stirrer ( Stirring speed is 400rpm). First replace the air in the kettle with nitrogen for 3 times, then replace it with hydrogen for 3 times, keep the pressure of hydrogen at 0.1 MPa (gauge pressure), raise the temperature to 55°C, monitor the reaction by HPLC, and the reaction is completed after 2 hours. Cool down, replace with nitrogen for 3 times, and filter to obtain 10% palladium carbon catalyst. Pour the filtrate into another 200L enamel reaction kettle, add ice cubes, cool down to 0-5°C, add 2mol/L NaOH solution dropwise to the filtrate, adjust the pH to 12, a large amount of solids precipitate, stir for 2 hours, centrifuge, and The filter cake was washed with water for 3 times, and the solid was dried in a blast drying oven at 55°C to obtain 3.27 kg of the product. According to the H NMR spectrum and the C NMR spectrum, the product was exactly the desired posaconazole. After calculation The yield of the product was 92.3%, and the HPLC purity was 99.594 wt%.

Example 3

For illustrating the present invention posaconazole and its synthetic method

(1) built-in reactor structure with stirrer: same as embodiment 1;

(2) Synthesis of posaconazole:

Add in the enamel reactor of aforementioned 100L, add 60L methyl alcohol, the compound shown in 4kg formula II, 4L concentration is the hydrochloric acid of 36.5wt%, the 10% palladium carbon catalyst (water content 50%) of 200g, seal reactor, open stirrer (Stirring speed is 450rpm). First replace the air in the kettle with nitrogen for 3 times, then replace it with hydrogen for 3 times, keep the pressure of hydrogen at 0.12MPa, raise the temperature to 50°C, monitor the reaction by HPLC, and the reaction is completed in 3 hours. Cool down, replace with nitrogen for 3 times, and filter to obtain 10% palladium-carbon catalyst (standby). Pour the filtrate into another 200L enamel reaction kettle, add ice cubes, cool down to 0-5°C, add 2mol/L Na ₂ CO ₃ solution dropwise to the filtrate, adjust the pH to 10, a large amount of solids precipitate out, stir for 2 hours , centrifuged, and washed the filter cake with water for 3 times, and dried the solid in a blast oven at 55°C to obtain 3.24kg of the product. According to the H NMR spectrum and the NMR C spectrum, the product is exactly the desired posacon azole, the yield of the product was calculated to be 91.4%, and the HPLC purity was 99.125%.

Example 4

For illustrating the present invention posaconazole and its synthetic method

(1) Reactor structure with a built-in stirrer: the height of the reactor is 120cm, and the diameter is 100L enamel reactor of 50cm. Wherein a stirrer (no baffle plate) is provided, and the stirrer includes a stirring shaft arranged along the axial direction of the reaction kettle and four groups of stirring blade groups uniformly distributed along the axial direction of the stirring shaft, each group of stirring The blade groups are arranged in parallel, and each group of stirring blade groups includes 3 stirring blades uniformly distributed along the circumference of the stirring shaft, and the length of the stirring blades along the radial direction of the reactor is 8 cm.

(2) Synthesis of posaconazole: with reference to the synthesis of posaconazole in the examples, the product of 3.19kg is obtained through reaction, as can be known by the proton nuclear magnetic spectrum and the carbon nuclear magnetic spectrum, this product is exactly required posaconazole, The calculated yield of the product was 90.1%, and the HPLC purity was 98.565%.

From the results of the above examples, it can be seen that the synthesis of the compound of formula (I) by the method of the present invention is simple and easy, and the reaction efficiency is high and the yield is high. Moreover, as mentioned above, the technical method reported in US5625064 and CN101824009A needs to react for 40 hours; although the reaction time of the technology reported in WO2013042138A2 and US2014343285A1 is 5 hours, the purity of the target product reaches 99.85% after recrystallization from isopropanol; the technology reported in CN102863431A The post-processing of the method is too cumbersome, and the purity is too low (93.9%). The present invention completes the hydrogenation debenzylation reaction by using hydrogen as the hydrogen source under stirring conditions (stirrer and optional baffle are set), which obviously shortens the reaction time (2-3h), and the aftertreatment is simple and easy, and the purity is high ( >98.5%). The method of the invention overcomes the defects of complex synthesis process and long production cycle in the synthesis method of tofacitinib in the prior art, and is suitable for large-scale industrial production. Moreover, in the subsequent treatment process of synthesizing posaconazole, using the synthesis method of the present invention can reduce the introduction of impurities, which is beneficial to the application in the field of pharmacy.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (10)

1. a kind of synthetic method of posaconazole is it is characterised in that the synthetic method of described posaconazole comprises the following steps:

S1, with compound as shown in following formula ii as raw material, with hydrogen as hydrogen source, hydrogenation debenzylation under the conditions of, will be described Compound shown in formula ii stirs haptoreaction with catalyst and acid reagent in reaction dissolvent, obtains mixed solution；

S2, described mixed solution is cooled to 0-5 DEG C, to described mixed solution and dripping sodium hydroxide solution to mixed solution Ph value is 10-12, and agitation and filtration obtains filter cake, is dried to obtain the posaconazole as shown in following formula i after cleaning,

2. method according to claim 1 it is characterised in that in described step s1 catalyst be water content be 50wt% 10wt% palladium-carbon catalyst, and water content be 50wt% 10wt% palladium-carbon catalyst with the weight ratio of compound shown in formula ii be (0.05-0.1): 1, preferably (0.08-1): 1, more preferably 0.08:1.

3. method according to claim 1 it is characterised in that acid reagent described in described step s1 be mineral acid and/ Or organic acid, preferably described acid reagent is (0.5-1.5) l:1kg with the envelope-bulk to weight ratio of compound shown in formula ii, more preferably For 1l:1kg.

4. method according to claim 1 includes it is characterised in that hydrogenating debenzylation condition in described step s1: Under conditions of normal pressure, temperature are 50-55 DEG C, with the speed of 350-450rpm, stirring reaction 2-3h.

5. method according to claim 1 is it is characterised in that described step s1 is entered in the reactor be built-in with agitator OK.

6. method according to claim 5 it is characterised in that in described reactor agitator include shaft and along described The uniform multigroup stirring vane group of the axis direction of shaft, is included in each stirring vane group respectively along described shaft circumference 1 to 3 uniform stirring vane.

7. the method according to claim 5 or 6 is it is characterised in that be additionally provided with least one set baffle group in described reactor, Described one group of baffle group includes the length direction of multiple baffle plates and each described baffle plate along the axis side parallel to described agitator Arrange to setting, width along the radial direction of described reactor；

Preferably described agitator is along the axis setting of described reactor, and in described one group of baffle group, each described baffle plate is stirred with described The axis mixing device is that vertically middle separated time is circumferentially distributed.

8. method according to claim 7 it is characterised in that

It is provided with one group of baffle group, and the direction that in this baffle group, each baffle plate extends along its width, side is fixed in described reactor On the inwall of described reactor, opposite side extends towards the position of described agitator；Or

Two groups or three groups of baffle group are set in described reactor, and each described baffle group is with the axis of described agitator in vertical point Line is in that the baffle plate in concentric circular setting and two adjacent groups baffle group is crisscross arranged.

9. method according to claim 1 it is characterised in that described acid reagent be hydrochloric acid, sulphuric acid, glacial acetic acid, formic acid One or more of with benzenesulfonic acid, preferably described acid reagent is hydrochloric acid.

10. the posaconazole that in a kind of claim 1 to 9, the method synthesis described in any one obtains, preferably described pool sand health Purity >=99% of azoles.