CN110128420A - Bisulfate ion/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole monosulfate method - Google Patents
Bisulfate ion/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole monosulfate method Download PDFInfo
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Abstract
The invention discloses bisulfate ion/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole monosulfate methods; including using 1 compound of formula: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3- [((N- tertbutyloxycarbonyl-N- methylamino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester is raw material; the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole is prepared after NaI activation docking; using the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole as starting material, the preparation of Chinese mugwort Saperconazole monosulfate is realized.Present invention firstly provides the methods for being converted into monosulfate using the salt compounded of iodine that bisulfate ion/sulfate radical type anion exchange resin carries out ion exchange realization Chinese mugwort Saperconazole, the control of its Chinese mugwort Saperconazole monosulfate salt form ratio prepared is accurate, technological operation is simple, the free processing step for waiting complexity of pH value is demodulated due to avoiding tersulfate, total purity reachable 99% or more, related substance is qualified, and integrated artistic simplification is, it can be achieved that industrialized production.
Description
Technical field
The present invention relates to technical field of chemical medicine preparation, specially bisulfate ion/sulfate radical type anionexchangetechnique
The method of preparation Chinese mugwort Saperconazole monosulfate.
Background technique
Sulfuric acid end Saperconazole (Isavuconazonium sulfate) by Astellas (Astellas, Japan) and bar
It fills in Leah (Basilea, Switzerland) to develop jointly, the nitrogen azole that FDA has authorized qualified infectious disease product (QIDP) recognition of qulifications is anti-
Fungi-medicine.On July 8th, 2014, Astellas to FDA had submitted application for quotation, and in March, 2015 is granted, was a kind of for invading
Property aspergillin infection and the treatment of aggressive Mucor infection pro-drug.
In blood, pro-drug is hydrolyzed to rapidly active material under the action of esterase (predominantly butyrylcholine esterase)
End Saperconazole.The Saperconazole mechanism of action that ends is similar with other azole antifungals, and the mechanism of action mainly reduces ergot
The synthesis of sterol and play a role.Ergosterol is essential substance in fungal cell's synthesis process, is participated on cell
The synthesis of some key proteins is necessary substance in fungal cell.After the Saperconazole that ends acts on fungal cell, with fungi
Interior 14 α of lanosterol-demethylase (P45014DM) phase Competition reduces its activity, accumulates intracellular lanosterol
And ergosterol lacks, and causes cell membrane that can not synthesize, to play the drug effect of Chinese mugwort Saperconazole.
In terms of prophylactic treatment suffers from invasive infections with fungi, Fluconazole is it is verified that bone-marrow transplantation trouble can be reduced
The disease incidence of monilial infection in person.But the increase of drug resistance candida albicans increased with aspergillus infection is used for Fluconazole in recent years
Prophylactic treatment proposes challenge.Itraconazole is the more preferably selection that immunosuppressed patient prevents aggressive aspergillus infection, but mouth
The compliance defect for taking administration mode limits it and is widely applied.Due to the high mortality of aggressive aspergillus infection, researcher
Start to consider that application novel antifungal drug such as voriconazole, posaconazole replace Fluconazole pre- for High risk group
Anti- property treatment.Have that researches show that receiving patient's aspergillus infection of hematopoietic stem cell transplantation and graft versus host disease recently
In prophylactic treatment, posaconazole shows better preventive effect than Fluconazole, but high financial burden is that it is pushed away
The big obstacle of one extensively applied, thereby increases and it is possible to the adverse reactions such as gastrointestinal discomfort, dizziness, fash, liver enzyme raising occur.And sulfuric acid Ai Sha
The listing of health azoles is clinical treatment Aspergillus, read coccus and other rare fungal infections provide new selection, enriches and controls
Treatment scheme.
Sulfuric acid ends in Saperconazole preparation process, accurate control Chinese mugwort Saperconazole at salt ratio, realize by Chinese mugwort Saperconazole
Haloid be changed into monosulfate salt form conversion be technique technological difficulties, and generally acknowledged international headache.
The technique has been carried out sternly there is no the process of open salt form conversion in the patent of Yuan Yan company report at present
Lattice secrecy, the domestic process for salt form conversion are also rarely reported.Recently, the country has reported in the literature using oh type
The method of ion exchange resin prepares (2016, Inpharm studies magazine) hydroxide Chinese mugwort Saperconazole, and then uses sulphur
The de- Boc of acid realizes salt form conversion, however, Chinese mugwort Saperconazole is extremely easy in decomposition in neutral or alkaline environment, therefore hydroxide ends
The stability of Saperconazole is very poor, or even cannot be stabilized, therefore the process operability of document report is not strong, is difficult reality
Existing industrialized production.Separately have patent report " a kind of Chinese mugwort Saperconazole vitriol and preparation method thereof " (number of patent application:
201510654387.7), propose at low temperature will Chinese mugwort Saperconazole hydrochloride with alkali it is free after, by the concentrated sulfuric acid and hydrogen peroxide into
Row salt exchange, the method preparation Chinese mugwort Saperconazole vitriol finally recrystallized, equally exists Chinese mugwort Saperconazole in neutrality
Or the problem of being extremely easy in decomposition in alkaline environment, obtain sulfuric acid Chinese mugwort Saperconazole purity it is very low, cannot reach drug quality and
Industrialized requirement.
Summary of the invention
The purpose of the present invention is to provide bisulfate ion/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole list sulphur
The method of hydrochlorate, the Chinese mugwort Saperconazole monosulfate salt form ratio control prepared is accurate, and technological operation is simple, due to avoiding
Tersulfate demodulates the free equal complicated processing step of pH value, and total purity reachable 99% or more, related substance is qualified, whole
Body technology is simplified, it can be achieved that industrialized production, to solve the problems mentioned in the above background technology.
To achieve the above object, the invention provides the following technical scheme:
Bisulfate ion/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole monosulfate method, including changed using formula 1
Close object: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3- [((N- tertbutyloxycarbonyl-N- methylamino) acetoxyl group) first
Base] pyridine -2- base) carbamic acid (1- chloroethyl) ester be raw material, by NaI activation docking after prepare boc-protected Ai Sha
The salt compounded of iodine of health azoles, using the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole as starting material, using any one of following two method
It can real 3 compound of formula: the preparation of Chinese mugwort Saperconazole monosulfate: method one: first passing through de- Boc, preparation Chinese mugwort Saperconazole
Salt compounded of iodine, then ion exchange is carried out using bisulfate ion/sulfate radical type anion exchange resin and is realized the salt compounded of iodine for the Saperconazole that ends
It is converted into Chinese mugwort Saperconazole monosulfate；Method two: ion friendship is carried out using bisulfate ion/sulfate radical type anion exchange resin
The sulfate for realizing that the salt compounded of iodine by boc-protected Chinese mugwort Saperconazole is converted into boc-protected Chinese mugwort Saperconazole is changed, using de-
Boc, preparation Chinese mugwort Saperconazole monosulfate；More specifically, method one comprising the following three steps:
S101: 1 compound of formula is used: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3- [((N- tertbutyloxycarbonyl-N- methyl
Amino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be raw material, by NaI activation docking after prepare
Boc-protected 5 compound of formula out: the salt compounded of iodine for the Saperconazole that ends；
S102: 5 compound of formula is taken off into Boc in acid condition, 4 compound of preparation formula: Chinese mugwort Saperconazole salt compounded of iodine；
S103: carrying out ion exchange using bisulfate ion/sulfate radical type anion exchange resin for 4 compound of formula, by iodine bear from
Son is exchanged into HSO4 -, to convert 3 compound of formula: the monosulfate for the Saperconazole that ends for Chinese mugwort Saperconazole salt compounded of iodine；
More specifically, method two comprising the following three steps:
S201: it is identical as the S101 in method one, using 1 compound of formula: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3-
[((N- tertbutyloxycarbonyl-N- methylamino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be original
Material prepares boc-protected 5 compound of formula: the salt compounded of iodine for the Saperconazole that ends after NaI activation docking；
S202: carrying out ion exchange using bisulfate ion/sulfate radical type anion exchange resin for 5 compound of formula, by iodine bear from
Son is exchanged into HSO4 -, to convert boc-protected Chinese mugwort Saperconazole sulfate for boc-protected Chinese mugwort Saperconazole salt compounded of iodine；
S203: 6 compound of formula is taken off into Boc in acid condition, is prepared into 3 compound of formula: Chinese mugwort Saperconazole monosulfate:
Further, in S103,4 compound of formula carries out ion using bisulfate ion/sulfate radical type anion exchange resin
Exchange, is exchanged into bisulfate ion anion for iodine anion, to convert Chinese mugwort for the salt compounded of iodine (4 compound of formula) for the Saperconazole that ends
The monosulfate (3 compound of formula) of Saperconazole；The bisulfate ion/sulfate radical type anion exchange resin can be commercially available quotient
Product resin is also possible to bisulfate ion/sulfate radical type anion exchange resin made of preparing by commercial resins.
Further, in S202,5 compound of formula is carried out using bisulfate ion/sulfate radical type anion exchange resin
Iodine anion is exchanged into bisulfate ion anion by ion exchange, to convert the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole to
The sulfate (6 compound of formula) of boc-protected Chinese mugwort Saperconazole；The bisulfate ion/sulfate radical type anion exchange resin can
Think commercial goods resin, is also possible to bisulfate ion/sulfate radical type anion made of preparing by commercial resins and hands over
Change resin.
Compared with prior art, the beneficial effects of the present invention are:
Present invention firstly provides carry out ion exchange using bisulfate ion/sulfate radical type anion exchange resin to realize Ai Shakang
The method that the salt compounded of iodine of azoles is converted into monosulfate, the Chinese mugwort Saperconazole monosulfate salt form ratio control prepared is accurate,
Technological operation is simple, demodulates the free equal complicated processing step of pH value due to avoiding tersulfate, total purity reachable 99% with
On, related substance is qualified, and integrated artistic simplification is, it can be achieved that industrialized production.
Detailed description of the invention
Fig. 1 is the chemical structural drawing of 1 compound of formula of the invention, 2 compound of formula, 3 compound of formula；
Fig. 2 is the 5 compound synthesis response diagram of formula in the method for the present invention one；
Fig. 3 is the 4 compound synthesis response diagram of formula in the method for the present invention one；
Fig. 4 is the 3 compound synthesis response diagram of formula in the method for the present invention one；
Fig. 5 is the 5 compound synthesis response diagram of formula in the method for the present invention two；
Fig. 6 is the 6 compound synthesis response diagram of formula in the method for the present invention two；
Fig. 7 is the 3 compound synthesis response diagram of formula in the method for the present invention two.
The chemical structure of 3 compound of formula are as follows: 1- [ 3- (R)-[ 4- (4- cyano-phenyl) thiazol-2-yl ] -2- (R)-(2,5-
Difluorophenyl) -2- hydroxybutyl ] -4- [ 1- [ N- methyl-N- [ 3- [ 2- (methylamino) acetoxy-methyl ] pyridine -2- base ] ammonia
Base formyloxy ] ethyl ] -1H-1,2,4- triazole sulfuric esters.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
The embodiment of the present invention is first public: bisulfate ion/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole list
The method of sulfate, including use 1 compound of formula: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3- [((N- tertiary butyloxycarbonyl
Base-N- methylamino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be raw material, activated by NaI
The salt compounded of iodine that boc-protected Chinese mugwort Saperconazole is prepared after docking, using the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole as starting material,
It can real 3 compound of formula using any one of following two method: the preparation of Chinese mugwort Saperconazole monosulfate: method one:
De- Boc, preparation Chinese mugwort Saperconazole salt compounded of iodine are first passed through, then ion is carried out using bisulfate ion/sulfate radical type anion exchange resin
Exchange, which is realized, converts Chinese mugwort Saperconazole monosulfate for the salt compounded of iodine for the Saperconazole that ends；Method two: bisulfate ion/sulfate radical is used
Type anion exchange resin carries out ion exchange and realizes that the salt compounded of iodine by boc-protected Chinese mugwort Saperconazole is converted into boc-protected Chinese mugwort
The sulfate of Saperconazole, using de- Boc, preparation Chinese mugwort Saperconazole monosulfate；More specifically, method one includes following
Three steps:
S101: 1 compound of formula is used: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3- [((N- tertbutyloxycarbonyl-N- methyl
Amino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be raw material, by NaI activation docking after prepare
Boc-protected 5 compound of formula out: the salt compounded of iodine for the Saperconazole that ends；
S102: 5 compound of formula is taken off into Boc in acid condition, 4 compound of preparation formula: Chinese mugwort Saperconazole salt compounded of iodine；
S103: carrying out ion exchange using bisulfate ion/sulfate radical type anion exchange resin for 4 compound of formula, by iodine bear from
Son is exchanged into HSO4 -, to convert 3 compound of formula: the monosulfate for the Saperconazole that ends for Chinese mugwort Saperconazole salt compounded of iodine；
More specifically, method two comprising the following three steps:
S201: it is identical as the S101 in method one, using 1 compound of formula: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3-
[((N- tertbutyloxycarbonyl-N- methylamino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be original
Material prepares boc-protected 5 compound of formula: the salt compounded of iodine for the Saperconazole that ends after NaI activation docking；
S202: carrying out ion exchange using bisulfate ion/sulfate radical type anion exchange resin for 5 compound of formula, by iodine bear from
Son is exchanged into HSO4 -, to convert boc-protected Chinese mugwort Saperconazole sulfate for boc-protected Chinese mugwort Saperconazole salt compounded of iodine；
S203: 6 compound of formula is taken off into Boc in acid condition, is prepared into 3 compound of formula: Chinese mugwort Saperconazole monosulfate:
In the embodiment of the present invention, using 1 compound of formula: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3- [((the tertiary fourth oxygen of N-
Carbonyl-N-methylamino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be raw material, passed through in acetonitrile
Boc-protected 5 compound of formula: the salt compounded of iodine for the Saperconazole that ends is prepared after crossing NaI, KI activation docking, wherein activator is preferably
The molar ratio of NaI, 1 compound of formula and NaI are 1:0.8-1:3, preferably 1:1.2-1:1.5.
In the embodiment of the present invention, in S101 or S201, the molar ratio of 1 compound of formula and 2 compound of formula is 1:
0.8-1:3, the temperature of reaction are 20 DEG C -100 DEG C, reaction time 1-48h；Preferably 1 compound of formula and 2 compound of formula rubs
Your ratio is 1:1.2-1:1.5, and the temperature of reaction is 40 DEG C -80 DEG C, reaction time 1-12h；Ability is used after completion of the reaction
The method of domain routine carries out post-processing purifying, reaction solution is spin-dried for, organic extractant phase, washing, merge it is organic be concerned with dry, be spin-dried for；
Preferably use ethyl acetate, methylene chloride extracting and demixing, dry concentration after combined ethyl acetate, methylene chloride phase.
In the embodiment of the present invention, in S102,5 compound of formula uses sulfuric acid to take off Boc in organic solvent, and preparation formula 4 is changed
Close object: end Saperconazole salt compounded of iodine, and organic solvent used in the reaction is ethyl acetate, tetrahydrofuran, ethyl alcohol, methanol；Preferably
Reaction solvent for use is ethyl acetate, ethyl alcohol, and ethyl alcohol and ethyl acetate mass ratio are 1:1-1:50, preferred alcohol and ethyl acetate
Mass ratio is 1:10；Wherein, 5 compound of formula and H2SO4Molar ratio be 1:0.8-1:3, reaction temperature be -20 DEG C -90 DEG C, instead
It is 1-24h between seasonable；De- Boc after completion of the reaction, aftertreatment technology using water phase extract, organic phase washing, merge water phase after to
With.It is ethyl acetate, methylene chloride, ether, methyl tertiary butyl ether, n-hexane, normal heptane, petroleum ether used herein of organic phase
Deng.It preferably, is ethyl acetate, methylene chloride used herein of organic phase.
In the embodiment of the present invention, in S103, reaction exchange solvent used is ethyl alcohol, water, tetrahydrofuran, methanol；
Wherein, 4 compound of formula and bisulfate ion/sulfate radical type anion exchange resin mass ratio are 1:0.8-1:20, reaction temperature
It is -20 DEG C -80 DEG C, reaction time 1-24h；4 compound of preferred formula and bisulfate ion/sulfate radical type anion exchange resin
Mass ratio is 1:1-1:6, and reaction temperature is 20 DEG C -30 DEG C, reaction time 1-3h；After ion exchange, water phase is used
Organic phase is lyophilized after washing, acquisition 3 compound of high-purity formula: the monosulfate for the Saperconazole that ends, organic used in washing used
It is mutually ethyl acetate, methylene chloride, ether, methyl tertiary butyl ether, n-hexane, normal heptane, petroleum ether, preferably ethyl acetate, two
Chloromethanes and normal heptane.
In the embodiment of the present invention, used bisulfate ion/sulfate radical type anion exchange resin the preparation method is as follows:
It by commercially available anion exchange resin (chloride ion type), is eluted by sulfuric acid solution, elutes, passing through by sodium hydroxide solution
Persulfate solution elution, solution out is drenched in detection whether there is chloride ion, and after determining chloride ion exchange, hydrogen sulfate can be obtained
Root/sulfate radical type anion exchange resin.
In the embodiment of the present invention, S202 after completion of the reaction, aftertreatment technology is using filtering off sulfuric acid hydrogen radical/sulfate radical
Type anion exchange resin, organic phase is dry, is concentrated under reduced pressure, and measures the content of 6 compound of concentrate Chinese style.
In the embodiment of the present invention, in S202,5 compound of formula uses bisulfate ion/sulfate radical type anion exchange resin
Ion exchange is carried out, iodine anion is exchanged into bisulfate ion anion, so that the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole be turned
Boc-protected 6 compound of formula: the sulfate for the Saperconazole that ends is turned to, reaction exchange solvent used is ethyl alcohol, water, tetrahydro
Furans, methanol, ethyl acetate；Wherein, 6 compound of formula is with bisulfate ion/sulfate radical type anion exchange resin mass ratio
1:0.8-1:20, reaction temperature are -20 DEG C -80 DEG C, reaction time 1-24h；6 compound of preferred formula and bisulfate ion/sulfuric acid
The mass ratio of root type anion exchange resin is 1:1-1:6, and reaction temperature is 20 DEG C -30 DEG C, reaction time 1-3h.
In the embodiment of the present invention, in S203,6 compound of formula takes off Boc, preparation formula using sulfuric acid in water and organic solvent
3 compounds: Chinese mugwort Saperconazole monosulfate, organic solvent used in the reaction are ethyl acetate, tetrahydrofuran, ethyl alcohol, methanol,
It is preferred that reaction solvent for use is ethyl acetate, ethyl alcohol, water and ethyl acetate volume ratio are 1:1-1:50, and water and ethyl alcohol volume ratio are
1:1-1:50；Wherein, 6 compound of formula and H2SO4Molar ratio be 1:0.8-1:3, reaction temperature is -20 DEG C -90 DEG C, when reaction
Between be 1-24h；After completion of the reaction, aftertreatment technology is freezed after merging water phase using concentration, water phase extraction, organic phase washing
Dry, organic phase used is ethyl acetate, methylene chloride, ether, methyl tertiary butyl ether, n-hexane, normal heptane, petroleum ether；It is excellent
Selecting organic phase is ethyl acetate, methylene chloride and normal heptane.
Foregoing invention is illustrated in order to further better, following specific embodiment is also provided:
Wherein: 1 compound of formula, 2 compound of formula are commercially available chemical grade product, and unless otherwise instructed, other reagents are common city
Sell product.
Secondly, the meaning of the english abbreviation in following embodiment:
DCM: methylene chloride, Kunshan Jin Cheng auxiliary chemicals factory, technical grade；EtOH: ethyl alcohol, domestic technical grade；MeCN: acetonitrile, state
Produce technical grade；EA: ethyl acetate, domestic technical grade；MeOH: methanol, domestic technical grade；EtOH: ethyl alcohol, domestic technical grade；
THF: tetrahydrofuran, domestic technical grade；Strong-base anion-exchange resin: 201*7 strong basic polystyrene series anion exchange
Resin.
Embodiment 1
The preparation of 5 compound of formula: 1 compound of formula (50 g), 2 chemical combination of formula are sequentially added into 500ml single neck round bottom reaction flask
Object (67 g), NaI(24g) and anhydrous MeCN(250ml), nitrogen displacement, nitrogen protection；60 DEG C of oil temperature are warming up under stirring,
50 DEG C of interior temperature, insulated and stirred 12h；20 DEG C are cooled to hereinafter, filtering, filter cake are washed with EA；EA(200ml is added into filtrate) and
Purified water (500ml), stirring extraction；Liquid separation, upper layer EA phase is claret；Lower layer's water phase is extracted twice with EA(50ml), is merged
Organic phase is washed with saturation NaCl solution (50ml), and the drying of 20g anhydrous sodium sulfate is added, is concentrated under reduced pressure to give foaming solid,
It is directly used in and reacts in next step；Yield 83%, HPLC purity > 90%.
Embodiment 2
The preparation of 5 compound of formula: 1 compound of formula (75 g), 2 compound of formula are sequentially added into 1L single neck round bottom reaction flask
(99 g), KI(39 g) and anhydrous MeCN(750ml)；It is warming up to 60 DEG C of oil temperature under stirring, 48 DEG C of interior temperature, insulated and stirred 12h；
20 DEG C are cooled to hereinafter, filtering, filter cake are washed with EA；EA(300ml is added into filtrate) and purified water (750ml), stirring extraction
It takes；Liquid separation, upper layer EA phase is claret；Lower layer's water phase is extracted twice with EA(75ml), merges organic phase, with saturation NaCl solution
(75ml) washing is added the drying of 30g anhydrous sodium sulfate, is concentrated under reduced pressure to give foaming solid, is directly used in and reacts in next step.
Embodiment 3
The preparation of 4 compound of formula: the ethyl acetate solution of 2mol/L sulfuric acid is prepared in advance: 1.3Kg second is added in 0.26Kg sulfuric acid
In acetoacetic ester, heat release is paid attention in process for preparation；To double-layer glass reaction kettle be added 5 compound of 1kg formula, 2.34Kg ethyl acetate and
1.32Kg dehydrated alcohol opens mechanical stirring dissolution, and above-mentioned configured 2mol/L H is added2SO4Ethyl acetate solution, heating
To 30 ± 5 DEG C, control reaction system starts to flow back, and system color is gradually deepened, in deep claret；It is stirred to react 1h and starts TLC
Detection, end of reaction；Reaction solution, which is cooled to 20 ± 5 DEG C and is concentrated under reduced pressure into thick grease, (there are a large amount of bubbles in revolving bottle wall
Foam), weigh collection liquid weight；1.80Kg ethyl acetate is added and continues to be concentrated under reduced pressure into thick grease (in revolving bottle wall out
Now a large amount of foams), concentrate is cooled to 20 ± 5 DEG C, 2.00Kg purified water is added and 3.60Kg ethyl acetate stirs 15min,
Liquid separation extraction collects the aqueous solution that water phase obtains 4 compound of formula, is directly used in and reacts in next step.
Embodiment 4
The preparation of 4 compound of formula: the ethyl acetate solution of 2mol/L sulfuric acid is prepared in advance: 1.3KgTHF is added in 0.26Kg sulfuric acid
In, heat release is paid attention in process for preparation；It is anhydrous that 5 compound of 1kg formula, 2.34KgTHF and 1.32Kg is added to double-layer glass reaction kettle
Methanol opens mechanical stirring dissolution, and above-mentioned configured 2mol/L H is added2SO4THF solution, be warming up to 30 ± 5 DEG C, control
Reaction system starts to flow back, and system color is gradually deepened；It is stirred to react 6h and starts TLC detection, end of reaction；Reaction solution is cooled to
10 ± 5 DEG C are concentrated under reduced pressure into thick grease (a large amount of foams occur in revolving bottle wall), weigh collection liquid weight；It is added
The DCM of 1.80Kg continues to be concentrated under reduced pressure into thick grease (a large amount of foams occur in revolving bottle wall), and concentrate is cooled to
10 ± 5 DEG C, the DCM that 2.00Kg purified water and 2.50Kg is added stirs 35min, and liquid separation extraction collects water phase and obtains 4 compound of formula
Aqueous solution is directly used in and reacts in next step.
Embodiment 5
The preparation of 3 compound of formula: aqueous solution, the 2.50Kg bisulfate ion of 4 compound of 1kg formula are added to double-layer glass reaction kettle
Sulfate radical type anion exchange resin opens mechanical stirring, and 20 ± 5 DEG C of temperature control are stirred to react 0.5h, filters, filter cake 0.90Kg
Ethyl acetate elution filters to no liquid outflow, collects filtrate, the bisulfate ion sulfuric acid of 2.50Kg is added again into filtrate
Root type anion exchange resin, 20 ± 5 DEG C of temperature control stirrings, is stirred to react 0.5h, filters, and filter cake 0.90Kg ethyl acetate drenches
It washes, filters to no liquid and flow out, stirring 10min extracts liquid separation, separates organic phase, water phase uses the DCM of 2.66Kg × 3 to extract again
Washing extracts stirring 10min every time, collects water phase, and with the normal heptane extracting and washing of 0.68Kg × 3,10min is stirred in extraction every time,
Water phase is collected, 3 compound of formula, i.e. sulfuric acid Chinese mugwort Saperconazole is lyophilized to obtain in water phase.
Embodiment 6
The preparation of 3 compound of formula: the aqueous solution of 4 compound of 1kg formula and the anhydrous second of 0.5Kg are added to double-layer glass reaction kettle
Alcohol, 1.50Kg bisulfate ion sulfate radical type anion exchange resin open mechanical stirring, and 20 ± 5 DEG C of temperature control are stirred to react 0.5h,
It filters, filter cake is eluted with 0.90Kg ethyl acetate, is filtered to no liquid outflow, is collected filtrate, be added again into filtrate
The bisulfate ion sulfate radical type anion exchange resin of 2.00Kg, 20 ± 5 DEG C of temperature control stirrings, is stirred to react 0.5h, filters, filter cake
It is eluted with 0.90Kg ethyl acetate, filters to no liquid and flow out, stirring 10min extracts liquid separation, separates organic phase, water phase is used again
The DCM extracting and washing of 2.66Kg × 3, extraction stirring 10min, collects water phase every time, with the normal heptane extracting and washing of 0.68Kg × 3,
Extraction stirring 10min every time, collects water phase, and 3 compound of formula, i.e. sulfuric acid Chinese mugwort Saperconazole is lyophilized to obtain in water phase.
Embodiment 7
The preparation of 3 compound of formula: to double-layer glass reaction kettle be added 4 compound of 1kg formula aqueous solution and 0.3Kg anhydrous THF,
1.00Kg bisulfate ion sulfate radical type anion exchange resin opens mechanical stirring, and 20 ± 5 DEG C of temperature control are stirred to react 1.5h, takes out
Filter, filter cake are eluted with 0.90Kg ethyl acetate, are filtered to no liquid outflow, are collected filtrate, be added again into filtrate
The bisulfate ion sulfate radical type anion exchange resin of 3.00Kg, 20 ± 5 DEG C of temperature control stirrings, is stirred to react 1.5h, filters, filter cake
It is eluted with 0.90Kg ethyl acetate, filters to no liquid and flow out, stirring 10min extracts liquid separation, separates organic phase, water phase is used again
The DCM extracting and washing of 2.66Kg × 3, extraction stirring 10min, collects water phase every time, with the normal heptane extracting and washing of 0.68Kg × 3,
Extraction stirring 10min every time, collects water phase, and 3 compound of formula, i.e. sulfuric acid Chinese mugwort Saperconazole is lyophilized to obtain in water phase.
Embodiment 8
The preparation of 6 compound of formula: the foaming solid of 5 compound of formula after reacting in embodiment 1 is dissolved in the anhydrous second of 900ml
In alcohol, 900ml purified water is added, is placed in three mouthfuls of round-bottom reaction flasks of 3L, bisulfate ion/sulfate radical of 200g is added
Type anion exchange resin, keeps 25 DEG C of stirring 1h, and solution colour is gradually become colourless, and anion exchange resin face by yellow
Color gradually becomes yellow or brown by colourless；After completion of the reaction, 83g faint yellow solid, i.e. 6 compound of formula are concentrated to get.
Embodiment 9
The preparation of 6 compound of formula: the foaming solid of 5 compound of formula after reacting in embodiment 1 is dissolved in 900ml tetrahydro furan
In muttering, 900ml purified water is added, is placed in three mouthfuls of round-bottom reaction flasks of 3L, bisulfate ion/sulfate radical of 200g is added
Type anion exchange resin, keeps 25 DEG C of stirring 2h, and solution colour is gradually become colourless, and anion exchange resin face by yellow
Color gradually becomes yellow or brown by colourless；After completion of the reaction, 73g faint yellow solid, i.e. 6 compound of formula are concentrated to get.
Embodiment 10
The preparation of 6 compound of formula: the foaming solid of 5 compound of formula after reacting in embodiment 1 is dissolved in 900ml acetic acid second
In ester, 900ml purified water is added, is placed in three mouthfuls of round-bottom reaction flasks of 3L, bisulfate ion/sulfate radical of 200g is added
Type anion exchange resin, keeps 25 DEG C of stirring 2h, and solution colour is gradually become colourless, and anion exchange resin face by yellow
Color gradually becomes yellow or brown by colourless；After completion of the reaction, ethyl acetate phase is separated, is concentrated to get 53g faint yellow solid, i.e.,
6 compound of formula.
Embodiment 11
The preparation of 3 compound of formula:
6 compound of formula (6g), the EA(20ml prepared in embodiment 10 is sequentially added into tri- mouthfuls of round-bottom reaction flasks of 250ml),
Purified water (10ml) is cooled to 0 DEG C of ice-water bath, 0-10 DEG C of interior temperature under stirring.The H of 2M is added dropwise into solution2SO4EA solution
(3.5ml).After completion of dropwise addition, 30 DEG C are warming up to, stirs 2h；Reaction system is cooled to 15 DEG C, and it is pure that 30ml is added into reaction flask
Change water, adds 100ml EA, 15min, stratification is stirred at room temperature.The water phase separated successively use 30ml EA, 30ml DCM,
10ml Heptane washing；Gained water phase obtains 3g white to faint yellow solid using freeze-drying；Yield 57%, HPLC purity
>98%。
Embodiment 12
The preparation of 3 compound of formula:
6 compound of formula (12g), the EtOH prepared in embodiment 9 is sequentially added into tri- mouthfuls of round-bottom reaction flasks of 250ml
(80ml), purified water (10ml), is cooled to 0 DEG C of ice-water bath, 0-10 DEG C of interior temperature under stirring；The H of 2M is added dropwise into solution2SO4EA
Solution (7.0 ml)；After completion of dropwise addition, 30 DEG C are warming up to, stirs 3h；Reaction system is cooled to 15 DEG C, is added into reaction flask
60ml purified water adds 200ml EA, and 15min, stratification is stirred at room temperature；The water phase separated successively uses 60ml EA, 60ml
DCM, 20ml Heptane washing；Gained water phase obtains 5g white to faint yellow solid using freeze-drying；HPLC purity >
98%。
Embodiment 13
The preparation of bisulfate ion/sulfate radical type anion exchange resin: the 201*7 strong basic polystyrene system yin of 3.00Kg is weighed
Ion exchange resin (apparent density 0.72g/mL) first uses dilute H of 6 times of column volumes2SO4Aqueous solution rinses resin, then with pure
Change water rinse resin until soft acid；Resin is rinsed with the 5%NaOH aqueous solution of 6 times of column volumes again, is then rinsed and is set with purified water
Rouge is up to efflux to neutrality；6 times of column volume 5%H again2SO4Aqueous solution rinses resin, then with purifying water rinse resin until outflow
For liquid to soft acid, water to be purified, which no longer flows out, collects to obtain bisulfate ion/sulfate radical type anion exchange resin
In summary: the invention discloses carry out ion exchange realization by bisulfate ion/sulfate radical type anion exchange resin
The salt compounded of iodine of Chinese mugwort Saperconazole is converted into monosulfate, and ends Saperconazole monosulfate, that is, 1- [ 3- (R)-[ 4- (4- cyanogen from preparation
Base phenyl) thiazol-2-yl ] -2- (R)-(2,5- difluorophenyl) -2- hydroxybutyl ] -4- [ 1- [ N- methyl-N- [ 3- [ 2- (first ammonia
Base) acetoxy-methyl ] pyridine -2- base ] carbamoyloxy ] ethyl ] -1H-1,2,4- triazole sulfuric esters (3 compound of formula)
Process, including using Chinese mugwort Saperconazole (1 compound of formula) and N- methyl-N- (3- [((N- tertbutyloxycarbonyl-N- methylamino)
Acetoxyl group) methyl] pyridine -2- base) and carbamic acid (1- chloroethyl) ester (2 compound of formula) be raw material, by NaI activate dock
The salt compounded of iodine of boc-protected Chinese mugwort Saperconazole is prepared afterwards.Using the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole as starting material, use
Any one of lower two methods all can real 3 compound of formula, that is, method one: the preparation for the Saperconazole monosulfate that ends first passes through
De- Boc, preparation Chinese mugwort Saperconazole salt compounded of iodine are crossed, then ion exchange is carried out using bisulfate ion/sulfate radical type anion exchange resin
Realize the sulfate for converting the salt compounded of iodine for the Saperconazole that ends to Chinese mugwort Saperconazole；Method two: using bisulfate ion/sulfate radical type yin
Ion exchange resin carries out ion exchange and realizes that the salt compounded of iodine by boc-protected Chinese mugwort Saperconazole is converted into boc-protected Ai Shakang
The sulfate of azoles, using de- Boc, preparation Chinese mugwort Saperconazole monosulfate；Present invention firstly provides using bisulfate ion/
Sulfate radical type anion exchange resin carries out ion exchange and realizes the method that the salt compounded of iodine of Chinese mugwort Saperconazole is converted into monosulfate,
The Chinese mugwort Saperconazole monosulfate salt form ratio control prepared is accurate, and technological operation is simple, anti-due to avoiding tersulfate
Adjust pH value is free to wait complicated processing step, total purity reachable 99% or more, related substance is qualified, and integrated artistic simplifies, can
Realize industrialized production.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art within the technical scope of the present disclosure, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (3)
1. bisulfate ion/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole monosulfate method, which is characterized in that
It, can the real change of formula 3 using any one of following two method using the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole as starting material
It closes object: the preparation of Chinese mugwort Saperconazole monosulfate: method one: first passing through de- Boc, preparation Chinese mugwort Saperconazole salt compounded of iodine, then use sulphur
Sour hydrogen radical/sulfate radical type anion exchange resin carries out ion exchange realization and converts Chinese mugwort Saperconazole for the salt compounded of iodine for the Saperconazole that ends
Monosulfate；Method two: ion exchange realization is carried out using bisulfate ion/sulfate radical type anion exchange resin and protects Boc
The sulfate that the salt compounded of iodine of the Chinese mugwort Saperconazole of shield is converted into boc-protected Chinese mugwort Saperconazole prepares Ai Shakang using de- Boc
Azoles monosulfate；More specifically, method one comprising the following three steps:
S101: 1 compound of formula is used: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3- [((N- tertbutyloxycarbonyl-N- methyl
Amino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be raw material, by NaI activation docking after prepare
Boc-protected 5 compound of formula out: the salt compounded of iodine for the Saperconazole that ends；
S102: 5 compound of formula is taken off into Boc in acid condition, 4 compound of preparation formula: Chinese mugwort Saperconazole salt compounded of iodine；
S103: carrying out ion exchange using bisulfate ion/sulfate radical type anion exchange resin for 4 compound of formula, by iodine bear from
Son is exchanged into HSO4 -, to convert 3 compound of formula: the monosulfate for the Saperconazole that ends for Chinese mugwort Saperconazole salt compounded of iodine；
More specifically, method two comprising the following three steps:
S201: it is identical as the S101 in method one, using 1 compound of formula: Chinese mugwort Saperconazole and 2 compound of formula: N- methyl-N- (3-
[((N- tertbutyloxycarbonyl-N- methylamino) acetoxyl group) methyl] pyridine -2- base) carbamic acid (1- chloroethyl) ester be original
Material prepares boc-protected 5 compound of formula: the salt compounded of iodine for the Saperconazole that ends after NaI activation docking；
S202: carrying out ion exchange using bisulfate ion/sulfate radical type anion exchange resin for 5 compound of formula, by iodine bear from
Son is exchanged into HSO4 -, to convert boc-protected Chinese mugwort Saperconazole sulfate for boc-protected Chinese mugwort Saperconazole salt compounded of iodine
S203: 6 compound of formula is taken off into Boc in acid condition, is prepared into 3 compound of formula: Chinese mugwort Saperconazole monosulfate.
2. bisulfate ion as described in claim 1/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole monosulfate
Method, which is characterized in that in S103,4 compound of formula using bisulfate ion/sulfate radical type anion exchange resin carry out from
Son exchange, is exchanged into bisulfate ion anion for iodine anion, to convert the salt compounded of iodine (4 compound of formula) for the Saperconazole that ends to
The monosulfate (3 compound of formula) of Chinese mugwort Saperconazole；The bisulfate ion/sulfate radical type anion exchange resin can be commercially available
Resin is commercialized, is also possible to bisulfate ion/sulfate radical type anion exchange resin made of preparing by commercial resins.
3. bisulfate ion as described in claim 1/sulfate radical type anionexchangetechnique preparation Chinese mugwort Saperconazole monosulfate
Method, which is characterized in that in S202,5 compound of formula using bisulfate ion/sulfate radical type anion exchange resin carry out from
Son exchange, is exchanged into bisulfate ion anion for iodine anion, to convert the salt compounded of iodine of boc-protected Chinese mugwort Saperconazole to
The sulfate (6 compound of formula) of boc-protected Chinese mugwort Saperconazole；The bisulfate ion/sulfate radical type anion exchange resin can
Think commercial goods resin, is also possible to bisulfate ion/sulfate radical type anion made of preparing by commercial resins and hands over
Change resin.
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Application publication date: 20190816 |