CN106366076B - A kind of synthetic method of posaconazole - Google Patents
A kind of synthetic method of posaconazole Download PDFInfo
- Publication number
- CN106366076B CN106366076B CN201610755734.XA CN201610755734A CN106366076B CN 106366076 B CN106366076 B CN 106366076B CN 201610755734 A CN201610755734 A CN 201610755734A CN 106366076 B CN106366076 B CN 106366076B
- Authority
- CN
- China
- Prior art keywords
- formula
- baffle
- group
- posaconazole
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The present invention provides a kind of synthetic methods of posaconazole, itself the following steps are included: S1, using the compound as shown in Formula Il as raw material, using hydrogen as hydrogen source, under the conditions of hydrogenating debenzylation, compound shown in Formula II and catalyst and acid reagent are stirred into haptoreaction in reaction dissolvent, obtain mixed solution；S2, the mixed solution being cooled to 0-5 DEG C, the pH value of Xiang Suoshu mixed solution and dripping sodium hydroxide solution to mixed solution is 10-12, and agitation and filtration obtains filter cake, the posaconazole as shown in following formula I is dried to obtain after cleaning,
Description
Technical field
The present invention relates to pharmaceutical synthesis field, a kind of synthetic method of posaconazole.
Background technique
Posaconazole (Chinese chemical name: 4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- tri-
Azoles -1- ylmethyl) penta ring -3- base of oxa-] methoxyl group] phenyl] piperazine -1- base] phenyl] -2- [the amyl- 3- of (2S, 3S) -2- hydroxyl
Base] -1,2,4- triazole -3- ketone), there is structure shown in following formula I.
Posaconazole is developed by German Schering Plough company, trade name " Noxafil ", on October 20th, 2005 in Europe
Alliance and U.S. FDA get the Green Light the antifungal drug of listing.Oral posaconazole suspension obtains the U.S. in September, 2006 again
FDA approval weakens for immunity after bone-marrow transplantation and cancer chemotherapy causes leukopenic patient, with prevent Aspergillus and
Infection caused by candida albicans.Since it has the characteristics that high-efficiency low-toxicity, and clinical application range is wide, and curative effect is preferable, especially right
Polyenes and other triazole type drug resistances or invasive infections with fungi are effective, mention for the treatment of clinical aggressiveness fungal infection
Selection space is supplied.
Have numerous studies about the synthetic method of posaconazole in the prior art, generally finally by as shown in Formula Il
Hydrogenation of compounds debenzylation obtains posaconazole.
It is recorded in US5625064 and CN101824009A: compound shown in Formula II being cooled to 50 DEG C, 350ml first is added
Acid continues cool to 20 DEG C, and other 350ml methanol is added, and takes 85gPd/C that 350ml formic acid stirring pulp is added and reaction is added
It in bottle, is stirred overnight at 20 DEG C, is heated to 40 DEG C of reactions for 24 hours, filters, filter cake 350ml formic acid, the elution of 700ml methanol.Subtract
Solvent evaporated is pressed, 3500ml methanol and 700ml ammonium hydroxide are added into residue, is heated to reflux 1-2h, then cooling precipitation is big
Solid is measured, is filtered, filter cake is washed with 1400ml first alcohol and water (1:1), and air blast agitation obtains 300.5g final product at 40 DEG C.
Anil K.Saksena (Tetrahedron Letters 45 (2004) 8249-8251) is pointed out: by 4.03g Formula II
The compound is dissolved in 70ml formic acid, adds 5%Pd/C 8g, and reaction mixture stirs 15h at 20 DEG C, then heats
To 35-40 DEG C, it is stirred for for 24 hours.Then reaction solution is cooled to 20 DEG C, filtered, and wash filter cake with about 40ml formic acid, then use
35ml methanol washs filter cake twice, and filtrate rotates to dry that residue, column chromatography obtain posaconazole 3g, yield 84%.
The synthetic route of posaconazole is as follows in above-mentioned process
In both the above mode, formic acid is reaction dissolvent and hydrogen source.It is first reacted under 20 °, then increases temperature extremely
35-40 DEG C of reaction, total reaction time is more than 40h, and post-processing needs column chromatographic purifying sample, and quantity of solvent is too big, is not suitable for
Mass production.
It is recorded in CN102863431A: compound (8.12g) and hydrobromic acid shown in Formula II being added in 250ml there-necked flask
70ml, stirring to solid are dissolved, and 50 DEG C of reaction 2-3h are heated to, and liquid phase monitors end of reaction.Reaction solution is dilute with water (100ml)
It releases, it is about 9 that NaOH aqueous solution (100ml, 25%), which is adjusted to pH, methylene chloride (100ml) extraction, and organic phase 10%NaOH is water-soluble
Liquid (100ml) washing, water (100ml) washing, saturation NaCl aqueous solution (100ml) washing, anhydrous Na SO4It is dry, concentration, vacuum
It is dry, obtain khaki crude product, purity 93.9%.In the experimental method, hydrobromic acid is that reaction dissolvent is also hydrogen source,
It with strong quil taste and is not easy to store, easily be oxidized.And post-processing is cumbersome, yield is low, is not suitable for being applied to mass production.
In addition, being recorded in WO2013042138A2 and US2014343285A1: 42g Formula II being added in 420ml methanol
Shown compound, 5mol/l hydrochloric acid and 10%Pd-C, in 4-5kg/cm2(0.4-0.5Mpa) Hydrogen Vapor Pressure, 50 DEG C of reaction temperature
Lower reaction 5h, after reaction, Filtration of catalyst, then adjusting ph value with 4mol/L sodium hydroxide solution is 7 or so, is added
Enter water and stir 2h at 25-35 DEG C, there are a large amount of solids to be precipitated, filtering, and filter cake is washed with water, filter cake is tied again in isopropanol
Crystalline substance obtains posaconazole, yield 75%, purity 99.85%.The synthetic route of posaconazole is as follows in the process:
Although above-mentioned experimental program shortens the reaction time to a certain extent, the purity of mark product is improved.However it is
The large-scale industrial production that can be realized posaconazole, for the synthetic method of posaconazole needs to advanced optimize
And improvement, to establish a kind of reaction time is shorter and the purity and yield of posaconazole increase posaconazole
Synthetic method.
Summary of the invention
The main purpose of the present invention is to provide a kind of synthetic methods of posaconazole, in the yield for improving posaconazole
While with purity, a kind of synthetic method of posaconazole suitable for large-scale industrial production is provided.
For this purpose, providing a kind of synthetic method of posaconazole in the present invention, which includes the following steps:
S1, using the compound as shown in Formula Il as raw material, using hydrogen as hydrogen source, under the conditions of hydrogenating debenzylation, will
Compound shown in Formula II and catalyst and acid reagent stir haptoreaction in reaction dissolvent, obtain mixed solution；
S2, the mixed solution is cooled to 0-5 DEG C, Xiang Suoshu mixed solution and dripping sodium hydroxide solution is molten to mixing
The pH value of liquid is 10-12, and agitation and filtration obtains filter cake, the posaconazole as shown in following formula I is dried to obtain after cleaning.
Synthetic method according to the present invention, the purpose for adding catalyst mainly promote to hydrogenate debenzylation,
In for catalyst use there is no particular/special requirement, can promote to hydrogenate that debenzylation occurs appoints using this field
The catalyst of meaning.However in order to optimize reaction effect, the yield of posaconazole is improved, is preferably the 10% of 50wt% with water content
As catalyst, (wherein 10% palladium-carbon catalyst is the catalysis for the 10wt% that palladium content is catalyst dry weight to palladium-carbon catalyst
Agent), and the weight ratio of compound shown in the dry weight and Formula II of the 10wt% palladium-carbon catalyst is (0.05-0.1): 1, preferably
(0.08-1): 1, more preferably 0.08:1.
Synthetic method according to the present invention adds the main purpose of acid reagent to make Formula II be dissolved in reaction dissolvent
In, wherein for acid reagent use there is no particular/special requirement, can be this field it is conventional arbitrarily can satisfy above-mentioned mesh
Organic acid or inorganic acid.However in order to optimize reaction effect, improve the yield of posaconazole, the preferably described acid reagent with
The envelope-bulk to weight ratio of compound shown in Formula II is (0.5-1.5) L:1kg, more preferably 1L:1kg.
Preferably, the acid reagent is hydrochloric acid, sulfuric acid, and one of glacial acetic acid, formic acid and benzene sulfonic acid or a variety of are more excellent
Selecting the acid reagent is hydrochloric acid.For the concentration of these acid reagents, there is no particular/special requirements in the present invention, can basis
Actual needs adjustment.
Synthetic method according to the present invention, it is preferred that emphasis is be hydrogen source in hydrogen using hydrogen using compound shown in Formula II as raw material
It is stirred to react under the conditions of change debenzylation, and then while accelerating reaction efficiency, improves the yield of posaconazole, and
Simplify post-processing step.For hydrogenating debenzylation condition in step S1, there is no particular/special requirement, Ke Yican in the present invention
Corresponding conditions in the synthetic method of more solito, in the present invention preferably the hydrogenation debenzylation condition include: normal pressure,
Under the conditions of temperature is 50-55 DEG C, with the speed of 350-450rpm, it is stirred to react 2-3h.
Synthetic method according to the present invention under preferable case, promotes to walk to meet the requirement being stirred to react in step S1
Rapid S1 is carried out in the reaction kettle for being built-in with blender.This reaction kettle for being built-in with blender can be using the anti-of conventional commercial
Answer kettle.However in order to optimize mixing effect, material is promoted to be conducted heat in the case of stirring, mass transfer and reaction, and then improve
Reaction rate, in a preferred embodiment, blender includes agitating shaft and the axis along the agitating shaft in the reaction kettle
The uniformly distributed multiple groups stirring blade group in line direction, respectively include in each stirring blade group along the agitating shaft it is circumferentially uniformly distributed 1 to 3
Piece stirring blade.Preferably, stirring blade parallel arrangement or staggered in two adjacent groups stirring blade group.It is preferred described
Stirring blade is along 1/5-2/5 times, preferably 1/3 times that the length of the reaction kettle radial direction is the stirred tank radius.
Synthetic method according to the present invention promotes reaction to accelerate, the preferably described reaction to advanced optimize mixing effect
It is additionally provided at least one set of baffle group in kettle, includes the length direction of multiple baffles and each baffle in one group of baffle group
It is arranged along the axis direction for being parallel to the blender, width direction is arranged along the radial direction of the reaction kettle.It is preferred that described
Blender is arranged along the axis of the reaction kettle, and each baffle with the axis of the blender is in one group of baffle group
Vertical middle separated time is circumferentially distributed.The height of preferred each baffle is 1/2-2/3 times of stirred tank height, and width is described
1/6-1/4 times of stirred tank radius, with a thickness of 0.5-1cm.By the way that baffle group is arranged in a stirring kettle, promote to be stirred by blender
Liquid impacted with baffle, promote compound and hydrogen, catalyst and acid reagent shown in Formula II the stirring the case where
Under conducted heat, mass transfer and reaction, and then improve reaction efficiency.
In a preferred embodiment, one group of baffle group, and each baffle edge in the baffle group are equipped in the reaction kettle
The direction that its width extends, side are fixed on the inner wall of the reaction kettle, and the other side extends towards the position of the blender.
In another preferred embodiment, two groups or three groups of baffle groups, each baffle group are set in the reaction kettle
It is that vertical middle separated time is staggered in the baffle in concentric circles setting and two adjacent groups baffle group with the axis of the blender.
The mixed solution is cooled to 0-5 DEG C in step s 2 by synthetic method according to the present invention, right in this step
In selected cooling method, there is no particular/special requirements, ice cube are added directly in mixed solution preferably in the present invention to carry out
Fast cooling, this fast cooling can reduce the generation of side reaction.
In a preferred embodiment, synthetic method according to the present invention the following steps are included: S1, with such as Formula Il
Shown compound is raw material, using hydrogen as hydrogen source, in proportion by compound shown in Formula II, 10% palladium-carbon catalyst and acid reagent
(for specific ratio referring to preceding description, details are not described herein) is stirred in a kettle, at a temperature of normal pressure, 50-55 DEG C, with
The speed of 350-450rpm is stirred to react 2-3h (HPLC monitoring reaction, control reaction end), is mixed after separating catalyst
Solution；Wherein the reaction kettle be built-in with blender and optional at least one set of baffle group reaction kettle (blender and
Details are not described herein as previously described for the structure of the baffle group)；S2, the mixed solution is cooled to 0-5 DEG C, to the mixing
The pH value that alkaline reagent is added dropwise to mixed solution in solution is 10-12, and agitation and filtration obtains filter cake, is dried to obtain after cleaning such as following formula
Posaconazole shown in I.
Synthetic method according to the present invention, wherein for obtain compound shown in Formula II method there is no particular/special requirement,
It is synthesized according to conventional method in the prior art, such as: 2- [(1S, 2S) -1- ethyl-is added in 100ml there-necked flask
2- benzyloxy propyl] -2,4- dihydro -4- [4- [4- (4- hydroxy phenyl) -1- piperazinyl] phenyl] -3H-1,2,4- triazole -3-
The NaOH aqueous solution (1.6ml) of concentration 25wt% is added in ketone (4.78g) and DMSO (40ml), stirring and dissolving, is mixed 10 points
(5R-CIS)-toluene-4-sulfonic acid 5- (2,4- difluorophenyl) -5- (1H-1,2,4- triazole -1- bases) methyl tetrahydro is added in clock
Furans -3- ylmethyl ester (4.4g), 30 DEG C of mixture reaction about 14h, liquid phase monitor to end of reaction, reaction solution are poured into acutely
It in the water (240ml) of stirring, finishes, is vigorously agitated again 10min, filter, filter cake is washed with water, by filter cake recrystallisation from isopropanol
After obtain solid, vacuum drying obtains pale powder solid (Formula II).
Meanwhile a kind of posaconazole synthesized by method of the present invention is additionally provided in the present invention, it is preferably described
Purity >=99% of posaconazole.
The synthetic method of provided posaconazole is using compound shown in Formula II as raw material according to the present invention, using hydrogen as hydrogen
Source promotes compound shown in Formula II that hydrogenation debenzylation occurs under agitation.This method not only reduce reaction for
The requirement of pressure, and it has been obviously shortened the reaction time, only need 2-3h；And post-processing is easy, low temperature section ph value
To 10-12, target product posaconazole is can be obtained in centrifugation, and this method is suitable for large-scale industrial production.
Detailed description of the invention
The drawings are intended to provide a further understanding of the invention, and constitutes part of specification, with following tool
Body embodiment is used to explain the present invention together, but is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of posaconazole synthesized by embodiment 1；
Fig. 2 is the nuclear-magnetism carbon spectrogram of posaconazole synthesized by embodiment 1.
Specific embodiment
The synthetic method of the compound of structure shown in Formula II employed in embodiment 1 to 4 is as follows:
2- [(1S, 2S) -1- ethyl -2- benzyloxy propyl] -2,4- dihydro -4- [4- [4- is added in 100ml there-necked flask
(4- hydroxy phenyl) -1- piperazinyl] phenyl] -3H-1,2,4- triazole -3- ketone (4.78g) and DMSO (40ml), stirring and dissolving,
The NaOH aqueous solution (1.6ml) of concentration 25wt% is added, is mixed 10 minutes, (5R-CIS)-toluene-4-sulfonic acid 5- is added
(2,4- difluorophenyl) -5- (1H-1,2,4- triazole -1- bases) methyltetrahydrofuran -3- ylmethyl ester (4.4g), mixture 30
DEG C reaction about 14h, liquid phase monitors to end of reaction, reaction solution poured into the water (240ml) being vigorously stirred, finished, then acutely
10min, filtering are stirred, filter cake is washed with water, and solid will be obtained after filter cake recrystallisation from isopropanol, and vacuum drying obtains canescence
Powder solid (Formula II)；Through nuclear-magnetism, mass spectrum and infrared spectroscopy comprehensive detection it is found that the grey powder solid is to change described in Formula II
Object is closed, and the purity of the compound is > 99%.
Embodiment 1
For illustrate posaconazole of the present invention and its synthetic method
(1) it is built-in with the reaction kettle structure of blender:
The height of the reaction kettle is 120cm, and diameter is the 100L enamel reaction still of 50cm.It is provided with blender and one group
Baffle group, the blender be standard configuration, including along the reaction kettle axis direction setting agitating shaft and along the agitating shaft
The uniformly distributed two groups of group stirring blade groups of axis direction, each group stirring blade group is arranged in parallel, and wraps in every group of stirring blade group
Include the two panels stirring blade circumferentially uniformly distributed along the agitating shaft, length of the every stirring blade along the reaction kettle radial direction
8cm；The baffle group includes that height is 60cm, width 5cm, with a thickness of 4 baffles of 1cm, the length direction edge of each baffle
(side is fixed on the bottom wall of the reaction kettle), width direction is arranged along described anti-in the axis direction for being parallel to the blender
The radial direction of kettle is answered to be arranged, (side is fixed on the side wall of the reaction kettle each baffle, another along the direction that its width extends
Side extends towards the position of the blender), and each baffle is that vertical middle separated time is circumferentially distributed with the axis of the blender.
(2) synthesis of posaconazole
60L methanol, compound shown in 4kg Formula II are added in above-mentioned 100L enamel reaction still, 4L concentration is 36.5wt%
Hydrochloric acid, (aqueous 50%) seals reaction kettle to 10% palladium-carbon catalyst of 320g, and (mixing speed is turn on agitator
350rpm).First with air 3 times in nitrogen displacement kettle, then with hydrogen replace 3 times, Hydrogen Vapor Pressure is maintained at 0.1MPa (gauge pressure), rise
Temperature is heated to 50 DEG C, and HPLC monitoring reaction, 2h reaction terminates.Cooling is replaced 3 times with nitrogen, and the catalysis of 10% palladium carbon is obtained by filtration
Agent.Filtrate is poured into another 200L enamel reaction still, ice cube is added, is cooled to 0-5 DEG C, 2mol/L is added dropwise into filtrate
NaOH solution adjusts pH to 11, has a large amount of solids to be precipitated, after stirring 2h, centrifugation, and be washed with water filter cake 3 times, solid is put in
It is dry in 55 DEG C of air dry ovens, obtain the product of 3.32kg, attached drawing 1 shows the nucleus magnetic hydrogen spectrum figure of the product, it is attached Fig. 2 shows
The nuclear-magnetism carbon spectrogram of the product in conjunction with attached Fig. 1 and 2 it is found that the product is exactly what is needed posaconazole is computed the receipts of the product
Rate is that 93.6%, HPLC purity is 99.754%.
Embodiment 2
For illustrate posaconazole of the present invention and its synthetic method
(1) it is built-in with the reaction kettle structure of blender: with embodiment 1.
(2) synthesis of posaconazole:
It is added in the enamel reaction still of aforementioned 100L, 60L methanol, compound shown in 4kg Formula II is added, 6L concentration is
The sulfuric acid of 98wt%, (aqueous 50%) seals reaction kettle to 10% palladium-carbon catalyst of 400g, and (mixing speed is turn on agitator
400rpm).First with air 3 times in nitrogen displacement kettle, then with hydrogen replace 3 times, Hydrogen Vapor Pressure is maintained at 0.1MPa (gauge pressure), rise
Temperature is heated to 55 DEG C, and HPLC monitoring reaction, 2h reaction terminates.Cooling is replaced 3 times with nitrogen, and the catalysis of 10% palladium carbon is obtained by filtration
Agent.Filtrate is poured into another 200L enamel reaction still, ice cube is added, is cooled to 0-5 DEG C, 2mol/L is added dropwise into filtrate
NaOH solution adjusts pH to 12, has a large amount of solids to be precipitated, after stirring 2h, centrifugation, and be washed with water filter cake 3 times, solid is put in
It is dry in 55 DEG C of air dry ovens, the product of 3.27kg is obtained, by nucleus magnetic hydrogen spectrum figure nuclear-magnetism carbon spectrogram it is found that the product is exactly
Required posaconazole, it is 99.594wt% that the yield for being computed the product, which is 92.3%, HPLC purity,.
Embodiment 3
For illustrate posaconazole of the present invention and its synthetic method
(1) it is built-in with the reaction kettle structure of blender: with embodiment 1；
(2) synthesis of posaconazole:
It is added in the enamel reaction still of aforementioned 100L, 60L methanol, compound shown in 4kg Formula II is added, 4L concentration is
The hydrochloric acid of 36.5wt%, (aqueous 50%) seals reaction kettle, turn on agitator (mixing speed to 10% palladium-carbon catalyst of 200g
For 450rpm).First with air 3 times in nitrogen displacement kettle, then with hydrogen replace 3 times, Hydrogen Vapor Pressure is maintained at 0.12MPa, heating
50 DEG C are heated to, HPLC monitoring reaction, 3h reaction terminates.Cooling is replaced 3 times with nitrogen, 10% palladium-carbon catalyst is obtained by filtration
(spare).Filtrate is poured into another 200L enamel reaction still, ice cube is added, is cooled to 0-5 DEG C, is added dropwise into filtrate
2mol/L Na2CO3Solution adjusts pH to 10, has a large amount of solids to be precipitated, after stirring 2h, centrifugation, and be washed with water filter cake 3 times, it will
Solid is put in drying in 55 DEG C of air dry ovens, obtains the product of 3.24kg, it is found that should by nucleus magnetic hydrogen spectrum figure nuclear-magnetism carbon spectrogram
Product is exactly what is needed posaconazole, and it is 99.125% that the yield for being computed the product, which is 91.4%, HPLC purity,.
Embodiment 4
For illustrate posaconazole of the present invention and its synthetic method
(1) be built-in with the reaction kettle structure of blender: the height of the reaction kettle is 120cm, and diameter is that the 100L of 50cm is warded off
Porcelain reaction kettle.It is provided with blender (not baffled), the blender includes being arranged along the axis direction of the reaction kettle
Agitating shaft and the four group stirring blade groups uniformly distributed along the axis direction of the agitating shaft, each group stirring blade group are arranged in parallel, and
It include 3 stirring blades circumferentially uniformly distributed along the agitating shaft in every group of stirring blade group, stirring blade is along the reaction kettle diameter
To the length 8cm in direction.
(2) synthesis of posaconazole: the synthesis of posaconazole in reference embodiment, the reacted product for obtaining 3.19kg,
By nucleus magnetic hydrogen spectrum figure nuclear-magnetism carbon spectrogram it is found that the product is exactly what is needed posaconazole, the yield for being computed the product is
90.1%, HPLC purity are 98.565%.
, it can be seen that the compound using method synthesis formula (I) of the invention is easy easily from the result of above-described embodiment
Row, and reaction efficiency is high and yield is high.Moreover, as described above, reporting technical side in US5625064 and CN101824009A
Method needs to react 40h；Though reporting that the technology reaction time is 5h in WO2013042138A2 and US2014343285A1, target is produced
Object purity after recrystallisation from isopropanol just reaches 99.85%；Report that the post-processing of technical method is too numerous in CN102863431A
It is trivial, and purity is too low (93.9%).The present invention is by (being arranged blender and optional gear in stirring condition using hydrogen as hydrogen source
Plate) under complete hydrogenation debenzylation, hence it is evident that shorten reaction time (2-3h), and post-process it is easy, purity is high (>
98.5%).Method of the invention overcomes the support method of the prior art for the synthesis process complexity in cloth synthetic method, production
The defect of period length, is suitable for large-scale industrial production.Moreover, being utilized in the subsequent treatment process of synthesis posaconazole
The method of the invention synthesizes the introducing that can reduce impurity, is conducive to the application in pharmaceutical field.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of posaconazole, which is characterized in that the synthetic method of the posaconazole the following steps are included:
S1, using the compound as shown in Formula Il as raw material,, will be described under the conditions of hydrogenating debenzylation using hydrogen as hydrogen source
Compound shown in Formula II and catalyst and acid reagent stir haptoreaction in reaction dissolvent, obtain mixed solution；
S2, the mixed solution is cooled to 0-5 DEG C, Xiang Suoshu mixed solution and dripping sodium hydroxide solution to mixed solution
PH value is 10-12, and agitation and filtration obtains filter cake, the posaconazole as shown in following formula I is dried to obtain after cleaning,
Catalyst is the 10wt% palladium-carbon catalyst that water content is 50wt% in the step S1, and water content is 50wt%'s
The weight ratio of compound shown in 10wt% palladium-carbon catalyst and Formula II is (0.05-0.1): 1；
Acid reagent described in the step S1 is inorganic acid and/or organic acid, compound shown in the acid reagent and Formula II
Envelope-bulk to weight ratio be (0.5-1.5) L:1kg；
It includes: under conditions of normal pressure, temperature are 50-55 DEG C, with 350- that debenzylation condition is hydrogenated in the step S1
The speed of 450rpm, is stirred to react 2-3h.
2. the method according to claim 1, wherein water content is the 10wt% palladium-carbon catalyst and formula of 50wt%
The weight ratio of compound shown in II is (0.08-1): 1.
3. the method according to claim 1, wherein water content is the 10wt% palladium-carbon catalyst and formula of 50wt%
The weight ratio of compound shown in II is 0.08:1.
4. the method according to claim 1, wherein the volume weight of compound shown in the acid reagent and Formula II
Amount is than being 1L:1kg.
5. the method according to claim 1, wherein the step S1 in the reaction kettle for being built-in with blender into
Row.
6. according to the method described in claim 5, it is characterized in that, blender includes agitating shaft and along described in the reaction kettle
The uniformly distributed multiple groups stirring blade group of the axis direction of agitating shaft respectively includes in each stirring blade group circumferential along the agitating shaft
1 to 3 uniformly distributed stirring blade.
7. method according to claim 5 or 6, which is characterized in that at least one set of baffle group is additionally provided in the reaction kettle,
Length direction including multiple baffles and each baffle in one group of baffle group is along the axis side for being parallel to the blender
It is arranged to setting, width direction along the radial direction of the reaction kettle；
8. the method according to the description of claim 7 is characterized in that
The blender along the reaction kettle axis be arranged, and in one group of baffle group each baffle with the blender
Axis be vertical middle separated time be circumferentially distributed；
One group of baffle group is equipped in the reaction kettle, and each baffle is fixed along the direction that its width extends, side in the baffle group
On the inner wall of the reaction kettle, the other side extends towards the position of the blender；Or
Two groups or three groups of baffle groups are set in the reaction kettle, and each baffle group is to divide in vertical with the axis of the blender
Line is arranged in concentric circles and the baffle in two adjacent groups baffle group is staggered.
9. the method according to claim 1, wherein the acid reagent is hydrochloric acid, sulfuric acid, glacial acetic acid, formic acid
With one of benzene sulfonic acid or a variety of.
10. according to the method described in claim 9, it is characterized in that, the acid reagent is hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610755734.XA CN106366076B (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of posaconazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610755734.XA CN106366076B (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of posaconazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106366076A CN106366076A (en) | 2017-02-01 |
| CN106366076B true CN106366076B (en) | 2019-07-16 |
Family
ID=57901841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610755734.XA Active CN106366076B (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of posaconazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106366076B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106883221A (en) * | 2017-04-17 | 2017-06-23 | 兰州大学 | A kind of amorphous posaconazole and preparation method thereof |
| CN109970725B (en) * | 2019-03-29 | 2020-10-02 | 武汉朗来科技发展有限公司 | Preparation method of posaconazole |
| CN112824400A (en) * | 2019-11-20 | 2021-05-21 | 华创合成制药股份有限公司 | Preparation method of posaconazole |
| WO2023122868A1 (en) * | 2021-12-27 | 2023-07-06 | 浙江海正药业股份有限公司 | Posaconazole impurity reference substance and preparation method therefor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013042138A2 (en) * | 2011-09-19 | 2013-03-28 | Msn Laboratories Limited | Process for the preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
| CN104761555A (en) * | 2015-03-21 | 2015-07-08 | 河北国龙制药有限公司 | Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method |
-
2016
- 2016-08-29 CN CN201610755734.XA patent/CN106366076B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013042138A2 (en) * | 2011-09-19 | 2013-03-28 | Msn Laboratories Limited | Process for the preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
| CN104761555A (en) * | 2015-03-21 | 2015-07-08 | 河北国龙制药有限公司 | Tofacitinib intermediate preparation method and method for preparing tofacitinib or its salt by using tofacitinib intermediate preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106366076A (en) | 2017-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106366076B (en) | A kind of synthetic method of posaconazole | |
| CN102796052B (en) | Paeonol-1,2,3-triazole compound having antifungal activity and preparation method thereof | |
| CN104292214B (en) | The synthetic method of Chinese mugwort Fluconazole and its intermediate | |
| CN104245674B (en) | Phenyl tetrahydro isoquinoline derivative | |
| CN108794351B (en) | Preparation method of pimavanserin key intermediate | |
| WO2013020460A1 (en) | Atazanavir preparation method | |
| CN107235959A (en) | A kind of novel method for synthesizing for preparing cancer therapy drug Niraparib | |
| CN106045983A (en) | Preparing method of Afatinib | |
| CN103483324A (en) | New preparation method of lapatinib | |
| CN102367236A (en) | Synthesizing technology of donepezil hydrochloride | |
| CN105859686A (en) | Preparation technology of high-purity dabigatran etexilate | |
| CN108358900A (en) | A kind of preparation method of Afatinib and its maleate | |
| CN109810031A (en) | The preparation method of Fei Luokao former times intermediate | |
| CN108239077A (en) | A kind of novel preparation method of posaconazole and its intermediate | |
| CN106946880A (en) | A kind of method for preparing Rui Boxini intermediates | |
| CN105175317B (en) | A kind of method for preparing picosulfate sodium | |
| CN109810066A (en) | A kind of synthetic method of the ambroxol hydrochloride in relation to substance | |
| CN105367483B (en) | The preparation method of Doneppezil Hydrochloride | |
| CN106336411B (en) | The preparation technology and purposes of CDK4/6 inhibitor Pa Boxini high-purity raw medicines | |
| CN110407733A (en) | One seed sand library Ba Qu impurity compound | |
| CN107311998B (en) | A kind of preparation method of high-purity 9-hydroxy-risperidone intermediate | |
| CN104387385B (en) | 6-carboxylate methyl ester-2-oxygen-7-azaindole and preparation method thereof and application | |
| CN104230723A (en) | Synthesis method of toremifene | |
| CN105452245A (en) | Method for the preparation of (1,2,4)-triazolo(4,3-a)pyridines | |
| CN105254614B (en) | A kind of synthetic method of ZD6474 compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200603 Address after: 061100 West Zone and east side of Jingliu Road, Lingang Economic and Technological Development Zone, Cangzhou City, Hebei Province Patentee after: HEBEI GUANGXIANG PHARMACEUTICAL Co.,Ltd. Address before: 052165, Hebei, Shijiazhuang Shijiazhuang economic and Technological Development Zone, Yang Zi Road, Societe Generale Road West Patentee before: HEBEI GUOLONG PHARMACEUTICAL Co.,Ltd. |