CN106749221B - End Saperconazole monohydrate crystal form and preparation method thereof - Google Patents
End Saperconazole monohydrate crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of Chinese mugwort Saperconazole monohydrate crystal forms.Furthermore, also disclose preparation method, the method includes using (2S, 3R) (2-3-, 5- difluoro)-3- hydroxy-2-methyl-4- (1H-1,2,4- triazol-1-yl) butyronitrile, phosphordithiic acid diethylester, bromo- 4 cyano-acetophenone of 2- be raw material, by addition reaction, close the step of five-ring heterocycles and unique post-processing and crystallization processes, its Chinese mugwort Saperconazole monohydrate prepared is white crystalline solid powder, detects the solid powder with crystal form by XRPD.The Chinese mugwort Saperconazole monohydrate crystal powder that the technique is prepared has many advantages, such as that crystallization processes are simple, strong operability, stability are good, is more advantageous to industrialized production compared with previous Chinese mugwort Saperconazole amorphous powder.
Description
Technical field
The invention belongs to pharmaceutical field, it is specifically related to a kind of Chinese mugwort Saperconazole monohydrate crystal form and preparation method thereof.
Background technique
Sulfuric acid end Saperconazole (Isavuconazonium sulfate) by Astellas (Astellas, Japan) and bar
It fills in Leah (Basilea, Switzerland) to develop jointly, FDA has authorized the nitrogen azole of its qualified infectious disease product (QIDP) recognition of qulifications
Antifungal drug.On July 8th, 2014, Astellas to FDA had submitted application for quotation, and in March, 2015 is granted.Sulfuric acid Chinese mugwort Saperconazole
It is a kind of for treating the pro-drug of aggressive aspergillin infection and aggressive Mucor infection.
In blood, pro-drug is hydrolyzed to rapidly active material under the action of esterase (predominantly butyrylcholine esterase)
End Saperconazole.The mechanism of action of Chinese mugwort Saperconazole is similar with other azole antifungals, and the mechanism of action mainly reduces wheat
The synthesis of angle sterol and play a role.Ergosterol is essential substance in fungal cell's synthesis process, participates in cell
The synthesis of upper some key proteins, is necessary substance in fungal cell.It is and true after the Saperconazole that ends acts on fungal cell
14 α of lanosterol-demethylase (P45014DM) phase Competition in bacterium reduces its activity, makes intracellular lanosterol product
It is tired and ergosterol lacks, cause cell membrane that can not synthesize, to play the drug effect of Chinese mugwort Saperconazole.
The necessary key intermediate and its hydrolysis in vivo that the preparation process of sulfuric acid Chinese mugwort Saperconazole needs to use
Active constituent afterwards-Chinese mugwort Saperconazole, the chemical name for the Saperconazole that ends are as follows: 4- [2- [(1R, 2R) -2- (2,5- difluorophenyl) -2-
Hydroxyl -1- methyl -3- (1H-1,2,4- triazol-1-yls) propyl] -4- thiazolyl] benzonitrile, structural formula 6 is as follows:
According to current patent both at home and abroad and documents and materials report, the Saperconazole sheet that ends is as amorphous white powder (patent state
Border application: mention " a solid amorphous form " by page 3 in WO2016055918A1) or for colorless syrup or
The thick object of person (international application for patent: mentions " colorless heavy syrup " by page 28 in WO1999045008A1).Specially
Sharp international application: also referred in WO2016055918A1 it is a kind of end Saperconazole hydrobromate crystal form or by dissociate Ai Sha
The method of health azoles hydrobromate prepares the crystal form of three kinds of Chinese mugwort Saperconazoles, but the preparation method of these crystal forms is required to by Chinese mugwort
Prepared by Saperconazole hydrobromate, preparation process is complicated and its crystal form is not directed to hydrate.Due to amorphous powder, slurry or
The process that person's non-hydrate is precipitated without crystal during the preparation process all exists larger tired in terms of impurity and dissolvent residual removal
It is difficult.In actual fabrication process, amorphous powder be easy when solid is precipitated it is tacky, there are serious wall built-up, it is adherent, reunite etc.
Phenomenon, process is complicated, takes a long time, this is all that amorphous powder preparation process can not be broken through in industrialized production
Technical barrier.A kind of new Chinese mugwort Saperconazole crystal form is thirsted in this field, with previous Chinese mugwort Saperconazole amorphous powder or crystal form phase
Than having many advantages, such as that crystallization processes are simple, strong operability, stability are good, being more advantageous to industrialized production.
Summary of the invention
The present inventor uses (2S, 3R) -3- (2,5- difluoro) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazol-1-yl)
Bromo- 4 cyano-acetophenone of butyronitrile, phosphordithiic acid diethylester, 2- be raw material, by addition reaction, close five-ring heterocycles the step of with
And unique post-processing and crystallization processes prepare Chinese mugwort Saperconazole monohydrate white crystalline solid powder.The technique is prepared
Chinese mugwort Saperconazole monohydrate crystal powder compared with previous Chinese mugwort Saperconazole amorphous powder, have crystallization processes it is simple, can
The advantages that strong operability, stability are good, is more advantageous to industrialized production.
The object of the present invention is to provide a kind of Chinese mugwort Saperconazole monohydrate crystal forms.
A second object of the present invention is to provide the preparation methods of Chinese mugwort Saperconazole monohydrate crystal form.
In embodiments of the invention, the present invention provides a kind of new 4- [2- [(1R, 2R) -2- (2,5- difluorobenzenes
Base) -2- hydroxyl -1- methyl -3- (1H-1,2,4- triazol-1-yls) propyl] -4- thiazolyl] benzonitrile monohydrate crystal form,
Exactly end the hydrate crystal forms of Saperconazole.
In a preferred embodiment of the invention, Chinese mugwort Saperconazole monohydrate provided by the invention is crystal form, more
Preferably, in XRPD map 2 θ values 7.3 ± 0.2,13.5 ± 0.2,；14.0 ± 0.2,14.5 ± 0.2,15.7 ± 0.2,
16.1 ± 0.2,17.3 ± 0.2,19.5 ± 0.2,19.9 ± 0.2,20.5 ± 0.2,21.3 ± 0.2,21.9 ± 0.2,22.2 ±
0.2,23.6 ± 0.2,24.2 ± 0.2,24.7 ± 0.2,26.0 ± 0.2,26.6 ± 0.2,27.2 ± 0.2,27.8 ± 0.2,
28.3 ± 0.2,29.3 ± 0.2,29.9 ± 0.2,31.9 ± 0.2,32.4 ± 0.2,33.8 ± 0.2,34.4 ± 0.2,36.7 ±
There is diffraction maximum at 0.2,38.0 ± 0.2.
In more preferred of the invention, Chinese mugwort Saperconazole monohydrate crystal form provided by the invention, XRPD figure
It composes substantially as shown in Figure 1.
In more preferred of the invention, Chinese mugwort Saperconazole monohydrate crystal form provided by the invention, TGA map
It is weightless (to crystallize water decomposition weightlessness platform) that there are about the steps of 4.1%w/w between 60 DEG C -85 DEG C, opens after about 160 DEG C
Beginning gradually decomposes, and is monohydrate crystal form；Preferably, TGA map is substantially as shown in Figure 2.
In more preferred of the invention, Chinese mugwort Saperconazole monohydrate crystal form provided by the invention, DSC map
There is endothermic transition at about 74.73 DEG C, particularly preferably, DSC map is substantially as shown in Figure 3.
Second aspect, the present invention provides the preparation method of the monohydrate crystal form of above-mentioned Chinese mugwort Saperconazole, the method packets
Include following steps:
(1) 1 compound of formula and generation H2The reagent of S gas reacts, and obtains 3 compound of formula；
(2) 3 compound of formula closes five-ring heterocycles with the bromo- 4 cyano-acetophenone generation of 2- and reacts, using adjusting pH value, organic solvent
After mashing and mixed solvent crystallization, 5 compound crystal form of formula is obtained, i.e. Chinese mugwort Saperconazole monohydrate crystal form.
In embodiments of the invention, the preparation method of the monohydrate crystal form of Chinese mugwort Saperconazole provided by the invention,
In, step (1) is 1 compound of formula and generation H2The reagent of S gas reacts, the cyano and H in 1 compound structure of formula2S occurs
Addition reaction, the generation H2The reagent of S gas can be selected from phosphordithiic acid diethylester or Na2S, preferably two thio phosphorus
Diethyl phthalate.Also, in organic solvent miscible with water, under the conditions of existing for a small amount of water, addition reaction occurs, obtains formula
3 compounds, here, the organic solvent miscible with water are selected from isopropanol, ethyl alcohol, methanol, tetrahydrofuran, acetonitrile etc., preferably
Ground is isopropanol.
In a preferred embodiment of the invention, the preparation side of the monohydrate crystal form of Chinese mugwort Saperconazole provided by the invention
Method, wherein generation H described in step (1)2The reagent of S gas is using phosphordithiic acid diethylester, and uses isopropyl
Alcohol makees solvent, and the molar ratio of 1 compound of formula and phosphordithiic acid diethylester is 1:1-1:6, and the molar ratio of 1 compound of formula and water is
1:1-1:50, the temperature of addition reaction are 20 DEG C -100 DEG C, reaction time 1-48h；It is further preferred that 1 compound of formula with
The molar ratio of phosphordithiic acid diethylester is 1:4, and the molar ratio of 1 compound of formula and water is 1:10, and the temperature of addition reaction is 70
DEG C -90 DEG C, reaction time 6-15h.
In embodiments of the invention, the preparation method of the monohydrate crystal form of Chinese mugwort Saperconazole provided by the invention,
In, step (1) carries out post-processing purifying adopting after completion of the reaction with the conventional methods in the field, for example, being adjusted using inorganic base
PH is to neutrality to alkalescent, it is preferable that 10wt%NaOH solution is slowly added dropwise under stiring and adjusts pH value to 7-8.After adjusting pH
It is layered using with the immiscible solvent extraction of water, merges organic phase, it is preferable that used methylene chloride extracting and demixing, merge dichloro
It is concentrated under reduced pressure after methane phase.It crystallizes and purifies using the method for adding mixed solvent stirring that solid is precipitated after reduced pressure, it is preferable that
The mixed solvent is the mixed solvent of methylene chloride and normal heptane, and methylene chloride and normal heptane volume ratio are 1:3.
In embodiments of the invention, the monohydrate crystal form preparation method of Chinese mugwort Saperconazole provided by the invention, wherein
Step (2) are as follows: 3 compound of formula occurs pass five-ring heterocycles with bromo- 4 cyano-acetophenone of 2- and reacts, and is overregulated pH value, You Jirong
After agent mashing and mixed solvent crystallization, 5 compound crystal form of formula is obtained, i.e. Chinese mugwort Saperconazole monohydrate crystal form.Here, the pass
Five-ring heterocycles reaction carries out under solvent existence condition, and solvent for use is ethyl alcohol, methanol, acetonitrile, tetrahydrofuran, isopropanol, two
The organic solvents such as chloromethanes or ethyl acetate.The molar ratio of 3 compound of formula and bromo- 4 cyano-acetophenone of 2- is 1:0.5-1:5,
Reaction temperature is 10 DEG C -120 DEG C, and the time for closing five-ring heterocycles reaction is 1-24h.Preferably, the pass five-ring heterocycles are anti-
Answering solvent used is ethyl alcohol, and the optionally described ethyl alcohol is aqueous；3 compound of formula and bromo- 4 cyano-acetophenone of 2-
Molar ratio is 1:1-1:1.2, and the temperature for closing five-ring heterocycles reaction is 40 DEG C -80 DEG C, reaction time 1-5h.
In a preferred embodiment of the invention, the monohydrate crystal form preparation method of Chinese mugwort Saperconazole provided by the invention,
The wherein ethanol water that the reaction of pass five-ring heterocycles described in step (2) solvent used is 95 volume %；3 compound of formula and 2-
The molar ratio of bromo- 4 cyano-acetophenone is 1:1, and the temperature for closing five-ring heterocycles reaction is 80 DEG C, reaction time 1-2h.
In embodiments of the invention, the monohydrate crystal form preparation method of Chinese mugwort Saperconazole provided by the invention, wherein
Step (2) after completion of the reaction, is adjusted in pH value step, using selected from NaHCO3、Na2CO3、NaOH、Et3The inorganic base of N etc. or
PH is adjusted within the scope of 3-6 by organic base；Preferably use NaHCO3PH value is adjusted to 4-5.
In embodiments of the invention, the monohydrate crystal form preparation method of Chinese mugwort Saperconazole provided by the invention, wherein
Step (2) after completion of the reaction, in organic solvent beating process, is beaten, beating time is using organic solvents such as ethers or esters
1-10h.It is preferably beaten using isopropyl ether, beating time 2-6h.
In embodiments of the invention, the monohydrate crystal form preparation method of Chinese mugwort Saperconazole provided by the invention, wherein
After completion of the reaction, crystallization is using the poor solvents such as organic good solvents and water such as EtOH, MeCN, MeOH, THF composition for step (2)
Mixed solvent is stirred crystallization, and crystallization temperature is controlled at -20-40 DEG C；Preferably, the mixed solvent of EtOH and water are first used,
It is crystallized afterwards using the mixed solvent of MeCN and water, crystallization temperature controls within the scope of 15-25 DEG C.The mixing of EtOH and water is molten
The volume ratio of EtOH and water is 1:0.5-1:3 in agent, it is therefore preferable to 1:1-1:2.The in the mixed solvent MeCN and water of MeCN and water
Volume ratio be 1:0.5-1:5, it is therefore preferable to 1:1-1:3.
In embodiments of the invention, the monohydrate crystal form preparation method of Chinese mugwort Saperconazole provided by the invention, wherein
Step (2) is in crystallisation step after completion of the reaction, by the way of water is added dropwise after first ethyl alcohol or acetonitrile dissolution, it is preferable that second
The technique of pure and mild water crystallization is first to be dissolved 5 compound of formula using ethyl alcohol, and water is slowly added dropwise under stirring；The work of acetonitrile and water crystallization
Skill is first to be dissolved 5 compound of formula using acetonitrile, and water is slowly added dropwise under stirring.
In previous patent and document report, Chinese mugwort Saperconazole is mostly amorphous powder or slurry or for no mill base
Shape object or thick object.During actual process exploitation, it has been found that amorphous powder, slurry or non-hydrated
The process that object is gradually precipitated without crystal during the preparation process, real processes are to be initially formed grease, and rear grease is adherent viscous
Even, form adherent viscous gum in whipping process, then gradually harden and then solidify, thus this purification process in impurity and
All there is larger difficulty in dissolvent residual removal aspect.It is existing if there is serious wall built-up, adherent, reunion etc. in industrialized production
As will increase the complexity of process, taking a long time, this is all that amorphous powder preparation process can not in industrialized production
The technical barrier of realization.Separately there is international application for patent: also referring to a kind of Chinese mugwort Saperconazole hydrobromate in WO2016055918A1
Crystal form or the crystal forms of three kinds of Chinese mugwort Saperconazoles is prepared by the method for free Chinese mugwort Saperconazole hydrobromate, but these crystal forms
Preparation method is required to prepare by Chinese mugwort Saperconazole hydrobromate, and preparation needs to operate by acid-base accommodation, complex process.
The new Chinese mugwort Saperconazole crystal form of one kind of the method for the present invention preparation, with previous Chinese mugwort Saperconazole amorphous powder or crystal form
It compares, has many advantages, such as that crystallization processes are simple, strong operability, be more advantageous to industrialized production.
Detailed description of the invention
Fig. 1 shows be the embodiment of the present invention 2 obtain Chinese mugwort Saperconazole monohydrate crystal form exemplary XRPD map.
What Fig. 2 was indicated is the example T GA map of the monohydrate crystal form for the Chinese mugwort Saperconazole that the embodiment of the present invention 2 obtains.
What Fig. 3 was indicated is the exemplary DSC map of the monohydrate crystal form for the Chinese mugwort Saperconazole that the embodiment of the present invention 2 obtains.
Specific embodiment
Technical solution of the present invention is further described below by embodiment, these embodiments are illustrative, not structure
At limiting the scope of the present invention.Those skilled in the art, under the teachings of the present invention, according to the prior art to it
Middle technical characteristic, which is equivalently replaced, to be still fallen in protection scope of the present invention.
1 compound of formula, 3 compound of formula in following embodiment is Eurasian purchased from Hunan, and 2 compound of formula wishes bodyguard purchased from Shanghai
It learns, other raw materials and reagents are unless otherwise instructed ordinary commercial products.
The meaning of english abbreviation in the embodiment of the present invention:
DCM: methylene chloride, Kunshan Jin Cheng auxiliary chemicals factory, technical grade.
EtOH: ethyl alcohol, domestic technical grade.
MeCN: acetonitrile, domestic technical grade.
EA: ethyl acetate, domestic technical grade.
MeOH: methanol, domestic technical grade.
EtOH: ethyl alcohol, domestic technical grade.
Heptane: normal heptane, domestic technical grade.
XRPD detecting instrument and testing conditions:
Bruker D8Advance X-ray Diffractometer
1、Anode:Cu,2、Wavelegth1:1.5406A°,Wavelegth1:1.54443A°,3、Generator:
40kV/40mA,4、Step:0.02°/3s,5、Start Angle:3°,End Angle:40°,6、Slit:1.0/1.0/Ni/
0.2.
TGA detecting instrument and testing conditions:
TA Q500 type thermogravimetric analyzer (TGA)
240.0 DEG C of to of 10.0 DEG C/min of Ramp, N2Stream is 40mL/min.
DSC detecting instrument and testing conditions:
TA Q200 type differential scanning calorimeter (DSC)
1,25.0 DEG C of Equilibrate at, 2,200.0 DEG C 3 of 10.0 DEG C/min of Ramp to, N2Stream is 40mL/min
4, aluminium dish covers
Embodiment 1
The preparation of 3 compound of formula
2 compound of formula, i.e. phosphordithiic acid diethylester (804g), formula 1 are sequentially added into tri- mouthfuls of round-bottom reaction flasks of 5L
Compound (300g), isopropanol (1.5L) and purified water (194ml) are warming up to back flow reaction (85 DEG C of oil temperature), interior temperature under stirring
It 78 DEG C, maintains the reflux for, gradually there is a large amount of H in temperature-rise period2S gas is released, until temperature stablizes 78 DEG C of temperature inside, without a large amount of
Gas is released, and temperature stirring is kept.After 15h, sampling monitoring, TLC shows that SM1 point disappears, and new point generates.
20 DEG C are cooled to hereinafter, addition DCM (1.5L), purified water (1.5L).It is molten that 10wt%NaOH is slowly added dropwise under stirring
Liquid (about 2.3L) adjusts pH value and arrives 7-8, system flavescence in adition process, graying.Liquid separation extraction, collects lower layer DCM phase.Water phase is again
It is extracted twice with DCM (600ml).Merge organic phase, is washed with the NaCl solution of saturation, it is dry with anhydrous sodium sulfate.It depressurizes dense
Contracting obtains white to faint yellow solid, and DCM (300ml) and normal heptane (900ml), stirring and crystallizing 17h is added.After suction filtration, filter cake
It is washed with DCM: normal heptane=1:6 solution (300ml), after draining, vacuum is spin-dried for.Rewinding obtains 318g white solid, i.e. formula 3
Compound.Yield 94.5%.HPLC purity 99.68%.
Embodiment 2
The preparation of 5 compound of formula
3 compound of formula (300g), 4 compound of formula of the preparation of embodiment 1 are sequentially added into tri- mouthfuls of round-bottom reaction flasks of 5L
That is bromo- 4 cyano-acetophenone (215g) of 2- and 95% ethyl alcohol (1.5L), are warming up to 85 DEG C of oil temperature under stirring, 76 DEG C of interior temperature rises
System colour changed into yellow green, insulated and stirred 2h during temperature.Sampling monitoring, TLC show that M1 point disappears, and new point generates.
Under 20 DEG C are cooled to hereinafter, stirring, by the NaHCO of saturation3Solution is slowly added in reaction solution, adjust pH value to
4-5 has white solid precipitation, continues after stirring is precipitated completely to crystal, then water droplet added in system, reaches total Water
1.5L.It is filtered after stirring 2h, solid is washed with EtOH: water=1:1 mixed solvent.Obtained solid 1L acetonitrile is dissolved, then
2L water droplet is added in system, crystal stirs 2h after being precipitated completely, solid is washed with MeCN: water=1:2 mixed solvent.30-
50 DEG C of drying obtain solid.Yield 70.5%.HPLC purity 98.52%.
XRPD, DSC and TGA of 5 compound crystal form of formula obtained by the present embodiment are as shown in Fig. 1, Fig. 3 and Fig. 2.
Embodiment 3
The preparation of 5 compound of formula
3 compound of formula (300g), 4 compound of formula of the preparation of embodiment 1 are sequentially added into tri- mouthfuls of round-bottom reaction flasks of 5L
That is bromo- 4 cyano-acetophenone (215g) of 2- and 95% ethyl alcohol (1.5L), are warming up to 85 DEG C of oil temperature under stirring, 76 DEG C of interior temperature rises
System colour changed into yellow green, insulated and stirred 2h during temperature.Sampling monitoring, TLC show that M1 point disappears, and new point generates.
Under 20 DEG C are cooled to hereinafter, stirring, by the NaHCO of saturation3Solution is slowly added in reaction solution, adjust pH value to
4-5, then reaction solution is slowly poured into purified water (1.5L), there are a large amount of white solids to be precipitated, filter cake is dried in the air naturally to half after suction filtration
It is dry, flash-off time about 16h.DCM (1.2L) and purified water (600ml) are added into half dry solid, extraction is sufficiently stirred, point
Liquid, water phase are extracted twice with DCM (150ml), merge organic phase, are washed with saturation NaCl solution, anhydrous sodium sulfate (30g) is dry
It is dry.After filtering removal anhydrous sodium sulfate, silica gel (200g) is added into DCM solution, absorption 2h is stirred at room temperature.Filtering removal silicon
Glue, by DCM solution concentrated by rotary evaporation to light yellow oil.Above-mentioned grease is dissolved in EA (300ml) and normal heptane (1.2L), room
Solid is precipitated in temperature stirring 8h, and stirring initial stage is precipitated without solid, and as stirring is gradually had white solid precipitation, solid has adherent
Phenomenon (is scraped adherent solid with spatula, continue to stir).It filters, filter cake is washed with EA: normal heptane=1:8 solution, drained
Filter cake obtains white solid.White solid is transferred in tri- mouthfuls of round-bottom reaction flasks of 5L, 3L isopropyl ether is added, is stirred at room temperature
24h.It filters, filter cake is washed with isopropyl ether, drains to obtain white solid powder.
At 25 DEG C, obtained solid 0.5L ethyl alcohol is dissolved, then 1L water droplet is added in system, crystal stirs after being precipitated completely
Mix 2h, solid ethyl alcohol: water=1:2 mixed solvent washs.30-50 DEG C of drying obtains 330g solid.Yield 79.5%.HPLC
Purity 99.52%.
XRPD, DSC and TGA map and the resulting crystal form XRPD of embodiment 2 of 5 compound crystal form of formula obtained by this embodiment,
DSC with TGA map is consistent.
Embodiment 4
The preparation of 5 compound of formula
3 compound of formula (300g), 4 compound of formula of the preparation of embodiment 1 are sequentially added into tri- mouthfuls of round-bottom reaction flasks of 5L
That is bromo- 4 cyano-acetophenone (215g) of 2- and 95% ethyl alcohol (1.5L), are warming up to 85 DEG C of oil temperature under stirring, 76 DEG C of interior temperature rises
System colour changed into yellow green, insulated and stirred 2h during temperature.Sampling monitoring, TLC show that M1 point disappears, and new point generates.
20 DEG C are cooled to hereinafter, by the NaHCO of saturation3Solution is slowly added in reaction solution, adjusts pH value to 4-5, stirs
It mixes down, reaction solution is slowly poured into purified water (1.5L), there are a large amount of white solids to be precipitated, filter cake is dried in the air naturally to half after suction filtration
It is dry, flash-off time about 16h.DCM (1.2L) and purified water (600ml) are added into half dry solid, extraction is sufficiently stirred, point
Liquid, water phase are extracted twice with DCM (150ml), merge organic phase, are washed with saturation NaCl solution, anhydrous sodium sulfate (30g) is dry
It is dry.After filtering removal anhydrous sodium sulfate, silica gel (200g) is added into DCM solution, absorption 2h is stirred at room temperature.Filtering removal silicon
Glue, by DCM solution concentrated by rotary evaporation to light yellow oil.Above-mentioned grease is dissolved in EA (300ml) and normal heptane (1.2L), room
Solid is precipitated in temperature stirring 8h, and stirring initial stage is precipitated without solid, and as stirring is gradually had white solid precipitation, solid has adherent
Phenomenon (is scraped adherent solid with spatula, continue to stir).It filters, filter cake is washed with EA: normal heptane=1:8 solution, drained
Filter cake obtains white solid.White solid is transferred in tri- mouthfuls of round-bottom reaction flasks of 5L, 3L isopropyl ether is added, is stirred at room temperature
24h.It filters, filter cake is washed with isopropyl ether, drains to obtain white solid powder.
At 25 DEG C, obtained solid 1L acetonitrile is dissolved, then 2L water droplet is added in system, crystal stirs after being precipitated completely
2h, solid acetonitrile: water=1:2 mixed solvent washs.30-50 DEG C of drying obtains 330g solid.Yield 75.5%.HPLC is pure
Degree 98.32%.
XRPD, DSC and TGA map and the resulting crystal form XRPD of embodiment 2 of 5 compound crystal form of formula obtained by this embodiment,
DSC with TGA map is consistent.
Claims (13)
1. a kind of Chinese mugwort Saperconazole monohydrate crystal form, the XRPD map of the crystal form, 2 θ values are 7.3 ± 0.2,13.5 ± 0.2,14.0
± 0.2,14.5 ± 0.2,15.7 ± 0.2,16.1 ± 0.2,17.3 ± 0.2,19.5 ± 0.2,19.9 ± 0.2,20.5 ± 0.2,
21.3 ± 0.2,21.9 ± 0.2,22.2 ± 0.2,23.6 ± 0.2,24.2 ± 0.2,24.7 ± 0.2,26.0 ± 0.2,26.6 ±
0.2,27.2 ± 0.2,27.8 ± 0.2,28.3 ± 0.2,29.3 ± 0.2,29.9 ± 0.2,31.9 ± 0.2,32.4 ± 0.2,
There is diffraction maximum at 33.8 ± 0.2,34.4 ± 0.2,36.7 ± 0.2,38.0 ± 0.2.
2. Chinese mugwort Saperconazole monohydrate crystal form according to claim 1, wherein the XRPD map of the crystal form is substantially as schemed
Shown in 1.
3. Chinese mugwort Saperconazole monohydrate crystal form according to claim 1, wherein the TGA map of the crystal form is at 60 DEG C -85
There are about the step of 3.0-4.5%w/w weightlessness between DEG C, start gradually to decompose after about 160 DEG C, is hydrate crystal forms.
4. Chinese mugwort Saperconazole monohydrate crystal form according to claim 3, wherein the TGA map of the crystal form is substantially such as
Shown in Fig. 2.
5. Chinese mugwort Saperconazole monohydrate crystal form according to claim 1, wherein the DSC map of the crystal form is about
74.73-90 DEG C generation endothermic transition.
6. Chinese mugwort Saperconazole monohydrate crystal form according to claim 5, wherein the DSC map of the crystal form is substantially such as Fig. 3
It is shown.
7. the preparation method of Chinese mugwort Saperconazole monohydrate crystal form according to any one of claim 1 to 6, including following step
It is rapid:
(1) 1 compound of formula and generation H2The reagent of S gas reacts, and obtains 3 compound of formula, here, the generation H2The examination of S gas
Agent is selected from phosphordithiic acid diethylester or Na2S；
(2) 3 compound of formula closes five-ring heterocycles with the bromo- 4 cyano-acetophenone generation of 2- and reacts, using adjusting pH value, organic solvent
After mashing and mixed solvent crystallization, Chinese mugwort Saperconazole monohydrate crystal form is obtained；
Wherein, the adjusting pH value refers to using selected from NaHCO3、Na2CO3, NaOH or Et3The inorganic base or organic base of N will
PH is adjusted within the scope of 3-6；
The organic solvent mashing refers to be beaten using isopropyl ether, beating time 2-6h；
The mixed solvent crystallization is to be stirred crystallization using the mixed solvent of organic good solvent and poor solvent composition, is crystallized
Temperature is controlled at -20-40 DEG C；The organic good solvent is selected from EtOH, MeCN, MeOH or THF, and the poor solvent is water.
8. preparation method according to claim 7, wherein the adjusting pH value refers to using NaHCO3PH value is adjusted to 4-
5。
9. preparation method according to claim 7, wherein the mixed solvent crystallization are as follows: first using the mixed of EtOH and water
Bonding solvent is crystallized, then is crystallized using the mixed solvent of MeCN and water, and crystallization temperature controls within the scope of 15-25 DEG C.
10. preparation method according to claim 9, wherein the volume ratio of the in the mixed solvent EtOH and water of EtOH and water
For 1:0.5-1:3.
11. preparation method according to claim 10, wherein the ratio of EtOH and water is 1:1-1:2.
12. preparation method according to claim 9, wherein the ratio of the in the mixed solvent MeCN and water of MeCN and water is
1:0.5-1:5.
13. preparation method according to claim 12, wherein the ratio of MeCN and water is 1:1-1:3.
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