CN106317035A - Empagliflozin monocrystalline and preparation method and purpose thereof - Google Patents
Empagliflozin monocrystalline and preparation method and purpose thereof Download PDFInfo
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- CN106317035A CN106317035A CN201510350888.6A CN201510350888A CN106317035A CN 106317035 A CN106317035 A CN 106317035A CN 201510350888 A CN201510350888 A CN 201510350888A CN 106317035 A CN106317035 A CN 106317035A
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- gelie
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to an Empagliflozin monocrystalline and a preparation method and a purpose thereof. A chemical structural formula of Empagliflozin is shown as a formula I, according to the Empagliflozin monocrystalline, the X-ray powder diffracting at the diffraction angles 2theta of 13.33, 14.66, 18.81, 20.33, 23.44, and 26.84 has characteristic peaks. A crystal structure of the Empagliflozin monocrystalline is a monoclinic system, the space group is C2, the number Z of molecules in crystal is 4, and the Empagliflozin monocrystalline is colorless sheet-shaped crystallization at normal temperature. The monocrystalline form is good, and the purity is as high as 99%.
Description
Technical field
The invention belongs to the field of chemical synthesis, specifically, the present invention relates to a kind of clean monocrystalline of En Gelie and preparation method thereof and
Purposes.
Background technology
En Gelie clean (compound shown in Formulas I) is a kind of SGLT2 (sodium-glucose co-transporter 2) inhibitor, by suddenly
Lin Geyinge writing brush company and the cooperative development of Li Lai company, and listed by FDA approval in August, 2014.For treating into
The type 2 diabetes mellitus of year patient.
Sodium-glucose co-transporter 2, expresses in proximal tubular, and its physiological function is responsible for filtering renal tubules tube chamber
Glucose heavily absorb.En Gelie, only by suppression SGLT2, reduces and is filtered the heavily absorption of glucose and reduce kidney Portugal
Grape sugar threshold value (RTG), thus increase the excretion of urine glucose.Current evidence shows that SGLT2 inhibitor is in glycemic control side
There is a series of effect in face, reduces blood pressure including minimizing body weight, appropriateness.Additionally, also preserve Instreptozotocin Induced, improve insulin
Sensitivity.Owing to blood sugar lowering mechanism is different, SGLT2 inhibitor can be with the good use in conjunction of other types hypoglycemic medicine.
But, clean monocrystalline of current En Gelie and preparation method thereof still haves much room for improvement.
Summary of the invention
It is contemplated that solve one of above-mentioned technical problem the most to a certain extent or provide at a kind of useful business choosing
Select.To this end, it is an object of the present invention to propose a kind of clean monocrystalline of En Gelie and preparation method thereof, gained monocrystalline has no
Report, measures its crystal structure and belongs to monoclinic system, be colorless plate crystal under room temperature, and form is good, high purity 99%；
Its preparation method makes En Gelie only realize good separation, and favorable reproducibility with other impurity.Due in the clean structure of En Gelie
Containing mulitiple chiral centers, new chiral centre is had to generate in building-up process or the introducing of chiral impurity in raw material, and cannot
In building-up process chirality is completely secured, without changing, causes its structural confirmation complicated.Synthetic route according to design obtains
The clean finished product of En Gelie, determined the absolute structure of product of synthesis gained by the X-ray diffraction analysis of monocrystalline, determine with
The structure of gained expection synthesis is consistent completely, it is ensured that the correctness of the crude drug of synthesis.
Chemical reaction route clean for synthesis En Gelie is:
Step 1 is with maltonic acid-1, and 5-lactone is that raw material exists, and oxolane is solvent, and N-methylmorpholine is the condition of alkali
Lower addition trim,ethylchlorosilane reacts, and post-treated obtains intermediate 1, and reaction system is simple, and the quality of intermediate can be effective
Control.Step 2 selects (3S)-3-[4-[(2-chloro-5-iodophenyl) methyl] phenoxy group] oxolane to be starting material, through at low temperature
Lower and isopropylmagnesium chloride lithium chloride carries out Grignard reagent exchange and obtains the Grignard reagent of compound 2, further with intermediate
1 carries out nucleophilic addition, and obtains methoxy adding to take off trimethyl silicane under the conditions of hydrogen chloride methanol solution and form post processing
Base ether.This step can get the thick product of intermediate 3, and reaction yield is higher.Step 3 is with intermediate 3 as raw material, with warp
Triethyl silicane/aluminum chloride system is that reduction system carries out reduction reaction, and obtains the clean crude product of En Gelie.
It addition, CCDC (Cambridge Crystallographic Data Centre), Acta E (crystal journal E) are entered
Row crystal data is retrieved, and does not finds that mono-crystalline structures clean for En Gelie describes information.Ray crystallographic analysis can provide a chemical combination
Thing is the accurate spatial locations of all atoms in solid-state, including type of attachment, molecular conformation, accurately bond distance and the key of atom
The data such as angle, thus the information providing extensive and important is studied for chemistry, material science and life sciences etc..
According to the first aspect of the invention, the present invention proposes a kind of clean monocrystalline of En Gelie.According to embodiments of the invention, institute
State the X-ray powder diffraction of the clean monocrystalline of En Gelie the angle of diffraction 2 θ=13.33,14.66,18.81,20.33,23.44 Hes
Characteristic peak is had at 26.84 degree；This monocrystalline crystal structure belongs to monoclinic system, and space group is C2, molecular number Z=4 in brilliant bag, often
It is colorless plate crystal under temperature.
It is surprisingly found by the inventors that, the clean single crystal forms of En Gelie of the present invention is good, and purity may be up to 99%, and can lead to
Cross X-ray diffraction analysis and determine the absolute structure of the clean monocrystalline of En Gelie, thus, it is ensured that containing the medicine of the clean monocrystalline of this En Gelie
Accuracy.
According to a particular embodiment of the invention, the X-ray powder diffraction of described monocrystalline also in the following angle of diffraction 2 θ=17.92,
Characteristic peak is had at 18.29,19.15,21.17,22.06,22.68,24.31,25.17,25.62,27.21,29.37 degree.
According to a particular embodiment of the invention, described En Gelie is crystallized only and is crushed into powder, utilize X-ray diffractometer to carry out X and penetrate
Line diffraction is tested, specific as follows:
INSTRUMENT MODEL: Holland's PANalytical EMPYREAN X-ray diffractometer；Condition determination is pipe pressure: 40kV, pipe
Stream: 100mA, Cu K α radiation.X ray diffracting data experiment obtained by Computer aided analysis is smoothed,
K α 2 peak is peeled off, automatic peak-seeking location, has obtained clean for En Gelie angle of diffraction (2 θ), interplanar distance d (nm), relative abundance
(1/10) crystal parameter such as, Fig. 1 is its X-ray powder diffraction spectrum.Data are shown in Table 1.
Table 1 En Gelie clean crystal powder X-ray powder diffraction test result
Additionally choose a size of 0.20 × 0.20 × 0.20mm3Monocrystalline, with Bruker Smart Apex CCD (JY/T 008-1996)
Single crystal diffractometer detects.Measuring method is f scanning, with graphite monochromatised MoKa x radiation x, in 298K temperature
Under, in θ=1.02～31.50 ° ,-8≤h≤7 ,-13≤k≤12, accurately survey with 25 point diffractions in the range of-58≤l≤57
Determine orientation matrix and cell parameter.21371 point diffractions are collected altogether in θ=1.02～31.50 ° of sweep limitss, wherein independent
Point diffraction 6831.Analysis result shows: crystal belongs to monoclinic system, space group: C2, cell parameter: Brilliant inclusion amasssMolecule in brilliant bag
Number Z=4.Geometric calculation and difference Fourier method is utilized to resolve crystal structure, final convergence deviation factors R1=0.0408,
wR2=0.1100, finally determine that stoichiometric equation is C23H27ClO7, calculating molecular weight is 450.91, wherein comprises two molecules
Solvent methanol.Calculate crystalline density for value 1.427 gram per centimeters3The molecular structure of compound is as shown in Formulas I in description, attached
Fig. 2 is described molecule stereo structure projection.Atomic coordinates parameter and the equivalent temperature factor are shown in Table 2, the bond distance of bonding atom and
Bond angle is shown in Table 3.
Table 2 atomic coordinates (x 104) and effective homogeneity displacement parameter
The bond distance of table 3 bonding atom and bond angle
According to embodiments of the invention, the clean monocrystalline of described En Gelie has X-ray powder diffraction pattern as shown in Figure 1.
According to another aspect of the present invention, the present invention proposes a kind of method of clean monocrystalline of En Gelie preparing above-described embodiment, should
Method includes: weigh the clean crude product of En Gelie, adds recrystallisation solvent；At a predetermined temperature, slowly volatilize recrystallisation solvent, goes forward side by side
Row is cultivated, and obtains crystalline product, and described crystalline product constitutes the clean monocrystalline of described En Gelie..
It is surprisingly found by the inventors that, the clean single crystal forms of En Gelie that profit is obtained by the present invention is good, and purity may be up to
99%, and En Gelie is prone to and other magazins' layout only, and the favorable reproducibility of method.Profit is obtained by the present invention
The clean finished product of En Gelie, it is easy to determined the absolute structure of product by the X-ray diffraction analysis of monocrystalline, and then, it is ensured that containing grace
Lattice arrange the accuracy of the medicine of clean monocrystalline.
According to embodiments of the invention, described recrystallisation solvent is at least one in methanol, ethanol, isopropyl alcohol and water.
It is preferably methanol and/or the aqueous solution of ethanol.
According to embodiments of the invention, in the aqueous solution of described methanol and/or ethanol, the cumulative volume of methanol and/or ethanol and water
Volume ratio is 10:1～4:1.Thus, if methanol and/or ethanol volume ratio are too high, volatilize too fast, form the possibility of monocrystalline
Property is little.If methanol and/or ethanol volume ratio are less than normal, monocrystalline growth is slow, the longest.According to a preferred embodiment of the invention,
In the aqueous solution of described methanol and/or ethanol, the cumulative volume of methanol and/or ethanol and the volume ratio of water are 10:1.Thus, easily
In forming monocrystalline, and monocrystalline growth speed is faster, the most shorter.
According to embodiments of the invention, in every 200 milligrams of clean crude products of described En Gelie, add the described crystallization of 10-20 milliliter molten
Agent.Thus, the clean solution of En Gelie obtained in this ratio is the most fully saturated, is suitable for cultivating monocrystalline.
According to embodiments of the invention, described predetermined temperature is 10～20 degrees Celsius.It is thus, the most easily controllable,
Evaporation rate is suitable for, beneficially crystal growth.
According to embodiments of the invention, the time of described cultivation is 20～40 days.Thus, the result observed according to every day, one
As can grow into good single crystal forms at 20 days to 40 days.
According to a particular embodiment of the invention, applicant finds through repetition test research, uses the said method of the present invention not only
Can effectively prepare the clean single crystal product article of En Gelie, and use said method to have more preferable productivity.So far there is no literary composition
Offer the preparation method of the clean monocrystalline of En Gelie of report.
In accordance with a further aspect of the present invention, the invention allows for En Gelie clean monocrystalline purposes in preparing medicine, described medicine
Thing is used for preventing and treating type ii diabetes.
Additional aspect of the present invention and advantage will part be given in the following description, and part will become apparent from the description below,
Or recognized by the practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or the additional aspect of the present invention and advantage will be apparent from from combining the accompanying drawings below description to embodiment
With easy to understand, wherein:
Fig. 1 is the X-ray powder diffraction figure of the clean monocrystalline of the En Gelie according to the embodiment of the present invention；
Fig. 2 is the molecule stereo structure projection of the clean monocrystalline of the En Gelie according to the embodiment of the present invention.
Detailed description of the invention
Embodiments of the invention are described below in detail, it should be noted that the embodiments described below is exemplary, be only used for
Explain the present invention, and be not considered as limiting the invention.It addition, without clearly stating, in following embodiment
Employed in all reagent be on market commercially available, or can synthesize according to text or known method, right
In the reaction condition do not listed, also it is what those skilled in the art were readily available.
The synthesis of the clean crude product of embodiment 1 En Gelie
Synthesizing the clean crude product of En Gelie according to the following step, concrete synthetic method is as follows:
Step 1 synthesizes 2, and 3,4,6-tetra--O-trimethyls are silica-based-D-Glucose acid lactone, concrete grammar is as follows:
(1) room temperature downhill reaction bottle addition oxolane 800 grams, gluconic acid lactone 100 grams, N-methylmorpholine 454 grams,
Under nitrogen protection, start to drip trim,ethylchlorosilane 366 grams, after question response is complete, add frozen water cancellation reaction.
(2) in the reactant liquor of step (1), 2.6 kilograms of purified water and 500 grams of normal heptane are added, stirring, stratification,
And separate organic layer.
(3) have with 1.5 kilograms, 1.5 kilograms purified water of 5% biphosphate sodium water solution and 1.5 kilograms of sodium chloride solution washings respectively
Machine layer.
(4) organic layer after washing adds anhydrous magnesium sulfate, be dried, filter, be evaporated to, without fraction, obtain nothing
Color grease 2,3,4,6-tetra--O-trimethyl is silica-based-D-Glucose acid lactone 236g, i.e. intermediate 1, and yield is 90%, and gas phase is pure
Degree is 96%.
Step 2-in-1 one-tenth 1-C-[the chloro-3-of 4-[[4-[[(3S)-tetrahydrochysene-3-furyl] epoxide] phenyl] methyl] phenyl]-D-Glucopyranose.
First glycosides, specifically comprises the following steps that
(1) in the reaction bulb of dried and clean, add oxolane 125 milliliters under room temperature, add compound 2
((3S)-3-[4-[(2-chloro-5-iodophenyl) methyl] phenoxy group] oxolane) 50 grams, under nitrogen protection environment, starts to drip different
Propyl group magnesium chloride lithium chloride 150 milliliters, drips the reaction of complete laggard row, after half an hour, is sampled.
(2) temperature of reaction system is down to about-25 DEG C, starts to drip intermediate 1 (2,3,4,6-tetra--O-trimethyl silica-based-D-Portugal
Grape saccharic acid lactone).Within after dropping 1 hour, start sampling, react with hydrogen chloride methanol solution cancellation, stirring, drip saturated
Sodium carbonate liquor, adjusts pH to 7～8.
(3) methanol removed in product and oxolane are concentrated.
(4) residue is layered after adding ethyl acetate stirring, separates lower aqueous layer.
(5) in lower aqueous layer, add ethyl acetate stirring, layering, combined ethyl acetate phase, washing, ethyl acetate is used
Anhydrous sodium sulfate is dried, and filters, concentrates the filtrate to without fraction, the grease 1-C-that weighs [the chloro-3-of 4-[[4-[[(3S)-tetrahydrochysene-3-
Furyl] epoxide] phenyl] methyl] phenyl]-D-Glucopyranose. first glycosides 56 grams.Thick yield is 96%, and the thick purity of liquid phase is 84%,
The purity of this product is high, purified can not be directly used in next step.
It is clean that step 3 synthesizes En Gelie, and concrete grammar is as follows:
(1) by 41.6 grams of addition reaction bulbs of aluminum chloride, adding dichloromethane 200 milliliters, system is suspension, right
This reaction system is lowered the temperature, and is added dropwise to acetonitrile 200 milliliters.
(2) in reaction bulb, add triethyl silicane 36.2 grams.
(3) within the time of 10～15 minutes, drip in reaction bulb dissolved with compound 3 (1-C-[the chloro-3-of 4-[[4-[[(3S)-four
Hydrogen-3-furyl] epoxide] phenyl] methyl] phenyl]-D-Glucopyranose. first glycosides, 50 grams) dichloromethane and the mixed solution of acetonitrile
250 grams.
(4) temperature of control reaction system is for react under the conditions of 20～25 DEG C, and HPLC monitors response situation.
(5) after reaction completely, reaction system being cooled to 0～5 DEG C, drip purified water, cancellation is reacted.
(6) after cancellation reaction completely, concentrating under reduced pressure removes organic solvent, adds ethyl acetate extraction, and purified water is washed, subtracted
Pressure concentrates ethyl acetate and obtains grease.
(7) adding ethyl acetate 35～45 DEG C of stirred crystallization 1～2 hours in grease, the most near 18～22 DEG C are stirred
Mix 2～3 hours, filter, ethyl acetate washing filter cake, the clean crude product of get En Gelie 30 grams.Yield is 57%, and liquid phase purity is
94%.
The preparation of the clean monocrystalline of embodiment 2 En Gelie
Weigh the clean crude product of En Gelie 0.20 gram that embodiment 1 prepares, add 20 milliliters of recrystallisation solvent methanol, treat that product is complete
Dissolving, utilize the slow volatility process of solvent, temperature is set to 10～20 DEG C, cultivates 20 days, and colorless plate crystal separates out, this knot
Crystalline substance is lattice and arranges clean monocrystalline, and it is 80% that lattice arrange the yield of clean monocrystalline, and purity is 99.6%.X-ray powder diffraction instrument is utilized to detect,
En Gelie clean Single Crystal X-ray powder diagram is as shown in Figure 1.
The preparation of the clean monocrystalline of embodiment 3 En Gelie
Weigh the clean crude product of En Gelie 0.20 gram that embodiment 1 prepares, add 20 milliliters of recrystallisation solvent ethanol, treat that product is complete
Dissolving, utilize the slow volatility process of solvent, temperature is set to 10～20 DEG C, cultivates 25 days, has colorless plate crystallization, warp
Microscopic, this crystallization is lattice and arranges clean monocrystalline, and it is 84% that lattice arrange the yield of clean monocrystalline, and purity is 99.5%, utilizes X to penetrate
Line powder diffractometer detects, and En Gelie clean Single Crystal X-ray powder diagram is as shown in Figure 1.
The preparation of the clean monocrystalline of embodiment 4 En Gelie
Weigh embodiment 1 and prepare the clean crude product of En Gelie 0.20 gram, add 20 milliliters of recrystallisation solvent ethanol/waters (V/V=10:1),
Treating that product is completely dissolved, utilize the slow volatility process of solvent, temperature is set to 10～20 DEG C, cultivates 25 days, has colorless plate to tie
Partial crystallization goes out, through microscopic, this crystallization be lattice arrange clean monocrystalline, lattice arrange clean monocrystalline yield be 86%, purity is 99.4%.
The preparation of the clean monocrystalline of embodiment 5 En Gelie
Weigh embodiment 1 and prepare the clean crude product of En Gelie 0.20 gram, add 10 milliliters of recrystallisation solvent methanol/water (V/V=4:1),
Treating that product is completely dissolved, utilize the slow volatility process of solvent, temperature is set to 10～20 DEG C, cultivates 25 days, has colorless plate to tie
Partial crystallization goes out, and through microscopic, this crystallization is the clean monocrystalline of En Gelie.It is 82% that lattice arrange the yield of clean monocrystalline, and purity is 99.7%.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " concrete example "
Or specific features, structure, material or the feature bag that the description of " some examples " etc. means to combine this embodiment or example describes
It is contained at least one embodiment or the example of the present invention.In this manual, to the schematic representation of above-mentioned term not necessarily
Refer to identical embodiment or example.And, the specific features of description, structure, material or feature can be any
One or more embodiments or example combine in an appropriate manner.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is exemplary,
Being not considered as limiting the invention, those of ordinary skill in the art is without departing from the principle of the present invention and the situation of objective
Under above-described embodiment can be changed within the scope of the invention, revise, replace and modification.
Claims (10)
1. the clean monocrystalline of Yi Zhong En Gelie, chemical structural formula clean for En Gelie is shown in formula I, it is characterised in that described En Gelie
Only the X-ray powder diffraction of monocrystalline is in the angle of diffraction 2 θ=13.33,14.66,18.81,20.33,23.44 and 26.84 degree
There is characteristic peak at place；The crystal structure of the clean monocrystalline of described En Gelie is monoclinic system, and space group is C2, molecular number Z=4 in brilliant bag,
The clean monocrystalline of En Gelie the most according to claim 1, it is characterised in that the X-ray of the clean monocrystalline of described En Gelie
Powder diffraction also in the angle of diffraction 2 θ=17.92,18.29,19.15,21.17,22.06,22.68,24.31,25.17,25.62,
Characteristic peak is had at 27.21 and 29.37 degree.
The clean monocrystalline of En Gelie the most according to claim 1, it is characterised in that the clean monocrystalline of described En Gelie has as attached
X-ray powder diffraction pattern shown in Fig. 1.
4. the method for the clean monocrystalline of the En Gelie prepared described in any one of claim 1-3, it is characterised in that including:
In the clean crude product of En Gelie, add recrystallisation solvent；And
At a predetermined temperature, slowly volatilize described recrystallisation solvent, and cultivates, and obtains crystalline product, described crystalline product
Constitute the clean monocrystalline of described En Gelie.
Method the most according to claim 4, it is characterised in that described recrystallisation solvent is selected from methanol, ethanol, isopropyl
The aqueous solution of at least one in alcohol and water, preferably methanol and/or ethanol.
Method the most according to claim 5, it is characterised in that in the aqueous solution of described methanol and/or ethanol, methanol
And/or the volume ratio of the cumulative volume of ethanol and water is 10:1～4:1, preferably 10:1.
Method the most according to claim 4, it is characterised in that in every 200 milligrams of clean crude products of described En Gelie, adds
10～20 milliliters of described recrystallisation solvents.
Method the most according to claim 4, it is characterised in that described predetermined temperature is 10～20 degrees Celsius.
Method the most according to claim 4, it is characterised in that the time of described cultivation is 20～40 days.
10. the purposes in preparing medicine of the clean monocrystalline of En Gelie described in any one of claims 1 to 3, described medicine is for pre-
Prevent and treatment type ii diabetes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107163033A (en) * | 2017-06-15 | 2017-09-15 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method net high-purity Yi Palie |
| WO2020088479A1 (en) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | Method for using aqueous solution to prepare single crystal or amorphous substance |
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| CN101155794A (en) * | 2005-05-03 | 2008-04-02 | 贝林格尔·英格海姆国际有限公司 | Crystalline form of 1-chloro-4-(ss-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
| EP1888551B1 (en) * | 2005-05-03 | 2010-03-03 | Boehringer Ingelheim International GmbH | Crystalline forms of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-[4-((r)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
| CN102549005A (en) * | 2009-09-30 | 2012-07-04 | 贝林格尔.英格海姆国际有限公司 | Method for the preparation of a crystalline form of 1-chloro-4- (beta-d-glucopyranos-1-yl)-2-(4-((s)-tetrahydrofuran-3-yloxy)benzyl)benzene |
| IN2013MU01985A (en) * | 2013-06-10 | 2015-05-29 | Cadila Healthcare Ltd |
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| CN101155794A (en) * | 2005-05-03 | 2008-04-02 | 贝林格尔·英格海姆国际有限公司 | Crystalline form of 1-chloro-4-(ss-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
| EP1888551B1 (en) * | 2005-05-03 | 2010-03-03 | Boehringer Ingelheim International GmbH | Crystalline forms of 1-chloro-4-(beta-d-glucopyranos-1-yl)-2-[4-((r)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
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| IN2013MU01985A (en) * | 2013-06-10 | 2015-05-29 | Cadila Healthcare Ltd |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020088479A1 (en) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | Method for using aqueous solution to prepare single crystal or amorphous substance |
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Application publication date: 20170111 |