CN106366076A - Posaconazole synthesis method - Google Patents
Posaconazole synthesis method Download PDFInfo
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- CN106366076A CN106366076A CN201610755734.XA CN201610755734A CN106366076A CN 106366076 A CN106366076 A CN 106366076A CN 201610755734 A CN201610755734 A CN 201610755734A CN 106366076 A CN106366076 A CN 106366076A
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- 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
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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
Technical field
The present invention relates to pharmaceutical synthesis field, a kind of synthetic method of posaconazole.
Background technology
Posaconazole (Chinese chemical name: 4- [4- [4- [4- [[(3r, 5r) -5- (2,4 difluorobenzene base) -5- (1,2,4- tri-
Azoles -1- ylmethyl) oxa- penta ring -3- base] 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 to be developed by German Schering Plough company, and trade name " noxafil ", on October 20th, 2005 in Europe
Alliance and U.S. fda get the Green Light the antifungal drug of listing.Posaconazole Oral Suspension obtains the U.S. again in September, 2006
Fda ratifies to weaken for immunity after bone marrow transplantation and causes leukopenic patient with cancer chemotherapy, with prevent aspergillosiss and
The microbial infection of beads.Because it has high-efficiency low-toxicity, and clinical application range is wide, and curative effect is preferably, especially right
Effectively, the treatment for clinical invasive infections with fungi carries for Polyenes and other triazole type drug resistances or invasive infections with fungi
Supply selection space.
With regard to the existing numerous studies of synthetic method of posaconazole in prior art, typically finally by as shown in following formula ii
Hydrogenation of compounds debenzylation obtains posaconazole.
Described in us5625064 and cn101824009a: compound shown in formula ii is cooled to 50 DEG C, adds 350ml first
Acid, continues cool to 20 DEG C, adds other 350ml methanol, takes 85gpd/c to add 350ml formic acid stirring pulp to add reaction
In bottle, it is stirred overnight at 20 DEG C, be heated to 40 DEG C of reaction 24h, sucking filtration, filter cake 350ml formic acid, 700ml methanol drip washing.Subtract
Pressure solvent evaporated, adds 3500ml methanol and 700ml ammonia in residue, is heated to the 1-2h that flows back, and then cooling precipitation is big
Amount solid, sucking filtration, filter cake is washed with 1400ml first alcohol and water (1:1), and at 40 DEG C, air blast agitation obtains 300.5g end-product.
Anil k.saksena (tetrahedron letters 45 (2004) 8,249 8251) points out: by 4.03g formula ii
Described compound is dissolved in 70ml formic acid, adds 5%pd/c 8g, and reactant mixture stirs 15h at 20 DEG C, then heats
To 35-40 DEG C, it is stirred for 24h.Then reactant liquor is cooled to 20 DEG C, filters, and wash filter cake with about 40ml formic acid, then use
Twice, filtrate revolving, to doing to obtain residue, column chromatography, obtains posaconazole 3g to 35ml methanol washing filter cake, and yield is 84%.
In above-mentioned process, the synthetic route of posaconazole is as follows
In both the above mode, formic acid is reaction dissolvent, is also hydrogen source.First react under 20 °, then rise high-temperature extremely
35-40 DEG C of reaction, total reaction time is all more than 40h, and post processing needs column chromatography purification of samples, and quantity of solvent is too big, is not suitable for
Big production.
Described in cn102863431a: add compound (8.12g) and hydrobromic acid shown in formula ii in 250ml there-necked flask
70ml, stirs to solid dissolving, is heated to 50 DEG C of reaction 2-3h, and liquid phase monitoring reaction finishes.Reactant liquor is dilute with water (100ml)
Release, naoh aqueous solution (100ml, 25%) adjusts and is about 9 to ph, and dichloromethane (100ml) extracts, and organic faciess 10%naoh are water-soluble
Liquid (100ml) washs, and water (100ml) washs, and saturation nacl aqueous solution (100ml) washs, anhydrous naso4It is dried, concentrate, vacuum
It is dried, obtains khaki crude product, purity is 93.9%.In this experimental technique, it is also hydrogen source that hydrobromic acid is reaction dissolvent, its
There is strong Spina jujubae taste and be difficult to store, easily oxidized.And post processing is loaded down with trivial details, yield is low, is not suitable for being applied to produce greatly.
Additionally, described in wo2013042138a2 and us2014343285a1: add 42g formula ii 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 terminates, Filtration of catalyst, then adjusting ph value with 4mol/l sodium hydroxide solution is 7 about, plus
Enter water and stir 2h at 25-35 DEG C, have a large amount of solids to separate out, filter, and wash filter cake with water, filter cake is tied in isopropanol again
Crystalline substance obtains posaconazole, and yield is 75%, and purity is 99.85%.In this process, the synthetic route of posaconazole is as follows:
Although above-mentioned experimental program shortens the response time to a certain extent, improve the purity of mark product.But be
It is capable of the large-scale industrial production of posaconazole, synthetic method for posaconazole needs to optimize further
And improvement, to establish the posaconazole that a kind of response time is shorter and the purity of posaconazole and yield all increase
Synthetic method.
Content of the invention
Present invention is primarily targeted at providing a kind of synthetic method of posaconazole, with the yield improving posaconazole
While with purity, provide a kind of synthetic method of the posaconazole being applied to large-scale industrial production.
For this reason, providing a kind of synthetic method of posaconazole in the present invention, this synthetic method 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
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, molten to mixing to described mixed solution and dripping sodium hydroxide solution
The ph value of liquid is 10-12, and agitation and filtration obtains filter cake, is dried to obtain the posaconazole as shown in following formula i after cleaning.
According to the synthetic method of the present invention, the purpose adding catalyst mainly promotes to hydrogenate debenzylation generation, its
In for catalyst using not particular/special requirement, can promote to hydrogenate that debenzylation occurs times using this area
The catalyst of meaning.But in order to optimize reaction effect, improve the yield of posaconazole, 10% preferably with water content as 50wt%
Palladium-carbon catalyst is as the catalyst (catalysis of the 10wt% that wherein 10% palladium-carbon catalyst is catalyst butt weight for palladium content
Agent), and the dry weight of described 10wt% palladium-carbon catalyst is (0.05-0.1) with the weight ratio of compound shown in formula ii: 1, preferably
(0.08-1): 1, more preferably 0.08:1.
According to the synthetic method of the present invention, the main purpose adding acid reagent is in order that formula ii is dissolved in reaction dissolvent
In, wherein for acid reagent using not particular/special requirement, can be this area conventional arbitrarily disclosure satisfy that above-mentioned mesh
Organic acid or mineral acid.But in order to optimize reaction effect, improve the yield of posaconazole, 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, described acid reagent is hydrochloric acid, sulphuric acid, and one or more of glacial acetic acid, formic acid and benzenesulfonic acid are more excellent
Described acid reagent is selected to be hydrochloric acid.Concentration for these acid reagents does not have particular/special requirement in the present invention, can basis
It is actually needed adjustment.
Synthetic method according to the present invention, it is preferred that emphasis is with compound shown in formula ii as raw material, with hydrogen for hydrogen source in hydrogen
It is stirred under the conditions of changing debenzylation reacting, and then while accelerating reaction efficiency, improve the yield of posaconazole, and
Simplify post-processing step.Do not have particular/special requirement, Ke Yican for hydrogenation debenzylation condition in step s1 in the present invention
Corresponding conditionses in the synthetic method of more solito, in the present invention preferably described hydrogenation debenzylation condition include: normal pressure,
Under the conditions of temperature is 50-55 DEG C, with the speed of 350-450rpm, stirring reaction 2-3h.
According to the synthetic method of the present invention, in order to meet the requirement of stirring reaction in step s1, under preferable case, promote to walk
Rapid s1 is carried out in the reactor be built-in with agitator.This reactor being built-in with agitator can adopt the anti-of conventional commercial
Answer kettle.But in order to optimize mixing effect, promote material to carry out conducting heat in the case of stirring, mass transfer and reaction, and then improve
Reaction rate, in a preferred embodiment, in described reactor, agitator includes shaft and the axle along described shaft
The uniform multigroup stirring vane group in line direction, is included in each stirring vane group respectively along described shaft circumference uniform 1 to 3
Piece stirring vane.Preferably, stirring vane parallel arrangement or staggered in two adjacent groups stirring vane group.Preferably described
Stirring vane is 1/5-2/5 times of described stirred tank radius along the length of described reactor radial direction, preferably 1/3 times.
According to the synthetic method of the present invention, in order to optimize mixing effect further, reaction is promoted to accelerate, preferably described reaction
It is additionally provided with least one set baffle group, described one group of baffle group includes multiple baffle plates and the length direction of each described baffle plate in kettle
Arrange along the axis direction setting parallel to described agitator, 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 with the axis of described agitator is
Vertically middle separated time is circumferentially distributed.The height of preferably each described baffle plate is 1/2-2/3 times of stirred tank height, and width is described
1/6-1/4 times of stirred tank radius, thickness is 0.5-1cm.By arranging baffle group in stirred tank, promote to be stirred by agitator
Liquid impact with baffle plate, promote compound and hydrogen, catalyst and acid reagent shown in formula ii in the situation of stirring
Under carry out conducting heat, mass transfer and reaction, and then improve reaction efficiency.
In a preferred embodiment, it is provided with one group of baffle group in described reactor, and each baffle plate edge in this baffle group
The direction that its width extends, side is fixed on the inwall of described reactor, and opposite side extends towards the position of described agitator.
In another kind of preferred implementation, two groups or three groups of baffle group, each described baffle group are set in described reactor
Axis with described agitator be vertically middle separated time be in concentric circular arrange and two adjacent groups baffle group in baffle plate be crisscross arranged.
According to the synthetic method of the present invention, in step s2, described mixed solution is cooled to 0-5 DEG C, right in this step
Do not have particular/special requirement in selected cooling method, in mixed solution, preferably directly add ice cube in the present invention to carry out
Fast cooling, this fast cooling can reduce the generation of side reaction.
In a preferred embodiment, comprised the following steps according to the synthetic method of the present invention: s1, with such as following formula ii
Shown compound is raw material, with hydrogen as hydrogen source, by compound shown in formula ii, 10% palladium-carbon catalyst and acid reagent in proportion
(concrete ratio, with reference to preceding description, will not be described here) stirring mixing in a kettle., at a temperature of normal pressure, 50-55 DEG C, with
The speed of 350-450rpm, stirring reaction 2-3h (hplc monitoring reaction, control reaction end), mixed after separating catalyst
Solution；Wherein said reactor be built-in with agitator and optional least one set baffle group reactor (described agitator and
The structure of described baffle group will not be described here as previously mentioned)；S2, described mixed solution is cooled to 0-5 DEG C, to described mixing
In solution, Deca alkaline reagent is 10-12 to the ph value of mixed solution, and agitation and filtration obtains filter cake, is dried to obtain as following formula after cleaning
Posaconazole shown in i.
According to the synthetic method of the present invention, the wherein method for compound shown in formula ii of acquisition does not have particular/special requirement,
It synthesizes according to conventional method of the prior art, for example: in 100ml there-necked flask add 2- [(1s, 2s) -1- ethyl -
2- benzyloxy propyl group] -2,4- dihydro -4- [4- [4- (4- hydroxy phenyl) -1- piperazinyl] phenyl] -3h-1,2,4- triazole -3-
Ketone (4.78g) and dmso (40ml), stirring and dissolving, add the naoh aqueous solution (1.6ml) of concentration 25wt%, 10 points of mix and blend
Clock, adds (5r-cis)-toluene-4-sulfonic acid 5- (2,4 difluorobenzene base) -5- (1h-1,2,4- triazole -1- bases) methyl tetrahydrochysene
Furan -3- ylmethyl ester (4.4g), 30 DEG C of reaction about 14h of mixture, liquid phase is monitored and is finished to reaction, reactant liquor is poured into acutely
In the water (240ml) of stirring, finish, be vigorously agitated again 10min, filter, filter cake washes with water, by filter cake recrystallisation from isopropanol
After obtain solid, vacuum drying obtains pale powder solid (formula ii).
Meanwhile, additionally provide a kind of posaconazole being synthesized by method of the present invention in the present invention, preferably described
Purity >=99% of posaconazole.
Synthetic method according to posaconazole provided by the present invention compound shown in formula ii as raw material, with hydrogen as hydrogen
Source, promotes compound shown in formula ii that hydrogenation debenzylation occurs under agitation.The method not only reduce reaction for
The requirement of pressure, and substantially shorten the response time, only need 2-3h；And post processing is easy, low temperature section ph value
To 10-12, it is centrifuged, you can obtain target product posaconazole, the method is applied to large-scale industrial production.
Brief description
Accompanying drawing is used to provide a further understanding of the present invention, and constitutes the part of description, with following tool
Body embodiment is used for explaining 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 the posaconazole synthesized by embodiment 1；
Fig. 2 is the nuclear-magnetism carbon spectrogram of the posaconazole synthesized by embodiment 1.
Specific embodiment
Shown in formula ii employed in embodiment 1 to 4, the synthetic method of the compound of structure is as follows:
2- [(1s, 2s) -1- ethyl -2- benzyloxy propyl group] -2,4- dihydro -4- [4- [4- is added in 100ml there-necked flask
(4- hydroxy phenyl) -1- piperazinyl] phenyl] -3h-1,2,4- triazoles -3- ketone (4.78g) and dmso (40ml), stirring and dissolving,
Add the naoh aqueous solution (1.6ml) of concentration 25wt%, mix and blend 10 minutes, add (5r-cis)-toluene-4-sulfonic acid 5-
(2,4 difluorobenzene base) -5- (1h-1,2,4- triazole -1- bases) methyltetrahydrofuran -3- ylmethyl ester (4.4g), mixture 30
DEG C reaction about 14h, liquid phase is monitored and is finished to reaction, reactant liquor is poured in the water (240ml) being stirred vigorously, finishes, more acutely
Stirring 10min, filters, and filter cake washes with water, will obtain solid after filter cake recrystallisation from isopropanol, and vacuum drying obtains canescence
Powder solid (formula ii)；Understand through nuclear-magnetism, mass spectrum and infrared spectrum comprehensive detection, this Lycoperdon polymorphum Vitt powder solid is to change described in formula ii
Compound, and the purity of this compound is > 99%.
Embodiment 1
For illustrate posaconazole of the present invention and its synthetic method
(1) it is built-in with the reactor structure of agitator:
The height of this reactor is 120cm, the 100l enamel reaction still of a diameter of 50cm.It is provided with agitator and one group
Baffle group, described agitator be standard configuration, including along described reactor axis direction setting shaft and along described shaft
The uniform two groups of group stirring vane groups of axis direction, each group stirring vane group be arranged in parallel, and wraps in every group of stirring vane group
Include two panels along the described shaft uniform stirring vane of circumference, every stirring vane is along the length of described reactor radial direction
8cm；It is 60cm that described baffle group includes height, and width is 5cm, and thickness is 4 baffle plates of 1cm, the length direction edge of each baffle plate
Axis direction parallel to described agitator arranges (side is fixed on the diapire of described reactor), width along described anti-
The radial direction answering kettle is arranged, and the direction that each baffle plate extends along its width is (on the side wall that side is fixed on described reactor, another
Side extends towards the position of described agitator), and each baffle plate is circumferentially distributed with the axis of described agitator for vertically middle separated time.
(2) synthesis of posaconazole
Add 60l methanol, compound shown in 4kg formula ii in above-mentioned 100l enamel reaction still, 4l concentration is 36.5wt%
Hydrochloric acid, ((mixing speed is turn on agitator 10% palladium-carbon catalyst of 320g for aqueous 50%), sealed reactor
350rpm).First use air 3 times in nitrogen displacement kettle, then with hydrogen exchange 3 times, Hydrogen Vapor Pressure is maintained at 0.1mpa (gauge pressure), liter
Temperature is heated to 50 DEG C, hplc monitoring reaction, and 2h reaction terminates.Cooling, with nitrogen displacement 3 times, is filtrated to get 10% palladium carbon catalysis
Agent.Filtrate is poured in another 200l enamel reaction still, adds ice cube, be cooled to 0-5 DEG C, Deca 2mol/l in filtrate
Naoh solution, adjusts ph to 11, has a large amount of solids to separate out, after stirring 2h, centrifugation, and wash filter cake 3 times with water, solid is put in
It is dried in 55 DEG C of air dry ovens, obtain the product of 3.32kg, accompanying drawing 1 shows the nucleus magnetic hydrogen spectrum figure of this product, accompanying drawing 2 illustrates
The nuclear-magnetism carbon spectrogram of this product, understands, this product is exactly what is needed posaconazole, be computed the receipts of this product in conjunction with attached Fig. 1 and 2
Rate is 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 reactor structure of agitator: with embodiment 1.
(2) synthesis of posaconazole:
The enamel reaction still of aforementioned 100l adds, adds 60l methanol, compound shown in 4kg formula ii, 6l concentration is
The sulphuric acid of 98wt%, ((mixing speed is turn on agitator 10% palladium-carbon catalyst of 400g for aqueous 50%), sealed reactor
400rpm).First use air 3 times in nitrogen displacement kettle, then with hydrogen exchange 3 times, Hydrogen Vapor Pressure is maintained at 0.1mpa (gauge pressure), liter
Temperature is heated to 55 DEG C, hplc monitoring reaction, and 2h reaction terminates.Cooling, with nitrogen displacement 3 times, is filtrated to get 10% palladium carbon catalysis
Agent.Filtrate is poured in another 200l enamel reaction still, adds ice cube, be cooled to 0-5 DEG C, Deca 2mol/l in filtrate
Naoh solution, adjusts ph to 12, has a large amount of solids to separate out, after stirring 2h, centrifugation, and wash filter cake 3 times with water, solid is put in
It is dried in 55 DEG C of air dry ovens, obtain the product of 3.27kg, by nucleus magnetic hydrogen spectrum figure nuclear-magnetism carbon spectrogram, this product is exactly
Required posaconazole, the yield being computed this product is 99.594wt% for 92.3%, hplc purity.
Embodiment 3
For illustrate posaconazole of the present invention and its synthetic method
(1) it is built-in with the reactor structure of agitator: with embodiment 1；
(2) synthesis of posaconazole:
The enamel reaction still of aforementioned 100l adds, adds 60l methanol, compound shown in 4kg formula ii, 4l concentration is
The hydrochloric acid of 36.5wt%, 10% palladium-carbon catalyst (aqueous 50%), sealed reactor, the turn on agitator (mixing speed of 200g
For 450rpm).First use air 3 times in nitrogen displacement kettle, then with hydrogen exchange 3 times, Hydrogen Vapor Pressure is maintained at 0.12mpa, intensification
It is heated to 50 DEG C, hplc monitoring reaction, 3h reaction terminates.Cooling, with nitrogen displacement 3 times, is filtrated to get 10% palladium-carbon catalyst
(standby).Filtrate is poured in another 200l enamel reaction still, adds ice cube, be cooled to 0-5 DEG C, the Deca in filtrate
2mol/l na2co3Solution, adjusts ph to 10, has a large amount of solids to separate out, after stirring 2h, centrifugation, and wash filter cake 3 times with water, will
Solid is put in 55 DEG C of air dry ovens and is dried, and obtains the product of 3.24kg, by nucleus magnetic hydrogen spectrum figure nuclear-magnetism carbon spectrogram, should
Product is exactly what is needed posaconazole, and the yield being computed this product is 99.125% for 91.4%, hplc purity.
Embodiment 4
For illustrate posaconazole of the present invention and its synthetic method
(1) it is built-in with the reactor structure of agitator: the height of this reactor is 120cm, the 100l of a diameter of 50cm wards off
Porcelain reactor.It is provided with agitator (not baffled), described agitator includes the axis direction setting along described reactor
Shaft and along four groups of uniform stirring vane groups of the axis direction of described shaft, each group stirring vane group be arranged in parallel, and
Every group of stirring vane group includes 3 along the uniform stirring vane of described shaft circumference, and stirring vane is along described reactor footpath
Length 8cm to direction.
(2) synthesis of posaconazole: the synthesis of posaconazole in reference embodiment, the reacted product obtaining 3.19kg,
By nucleus magnetic hydrogen spectrum figure nuclear-magnetism carbon spectrogram, this product is exactly what is needed posaconazole, and the yield being computed this product is
90.1%, hplc purity is 98.565%.
It can be seen that the compound using method of the present invention synthesis type (i) is easy easily from the result of above-described embodiment
OK, and reaction efficiency is high and yield is high.And, as described above, in us5625064 and cn101824009a, report technical side
Method needs to react 40h；Though the report technology response time is 5h in wo2013042138a2 and us2014343285a1, target is produced
Thing purity after recrystallisation from isopropanol just reaches 99.85%；Report in cn102863431a that the post processing of technical method is too numerous
Trivial, and purity too low (93.9%).The present invention passes through with hydrogen as hydrogen source, in stirring condition (setting agitator and optional gear
Plate) under complete to hydrogenate debenzylation hence it is evident that shortening the response time (2-3h), and post processing is easy, purity height (>
98.5%).The expelling pathogens by strengthening vital QI that the method for the present invention overcomes prior art replaces the synthesis process in cloth synthetic method complicated, produces
The defect of cycle length, is suitable for large-scale industrial production.And, in the subsequent treatment process of synthesis posaconazole, utilize
The method of the invention synthesis can reduce the introducing of impurity, is conducive to the application in pharmaceutical field.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.All within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the 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.
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Cited By (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 |
| CN109970725A (en) * | 2019-03-29 | 2019-07-05 | 武汉朗来科技发展有限公司 | The 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 |
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| CN106883221A (en) * | 2017-04-17 | 2017-06-23 | 兰州大学 | A kind of amorphous posaconazole and preparation method thereof |
| CN109970725A (en) * | 2019-03-29 | 2019-07-05 | 武汉朗来科技发展有限公司 | The 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 |
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