CN104177308B - Three kinds of novel Febustat pharmaceutical co-crystals and preparation method thereof - Google Patents
Three kinds of novel Febustat pharmaceutical co-crystals and preparation method thereof Download PDFInfo
- Publication number
- CN104177308B CN104177308B CN201410371582.4A CN201410371582A CN104177308B CN 104177308 B CN104177308 B CN 104177308B CN 201410371582 A CN201410371582 A CN 201410371582A CN 104177308 B CN104177308 B CN 104177308B
- Authority
- CN
- China
- Prior art keywords
- febustat
- crystal
- pharmaceutical
- eutectic
- organic pharmaceutical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of three kinds of novel Febustat organic pharmaceutical co-crystal and the preparation method of pharmaceutical co-crystals.The invention discloses a kind of Febustat organic pharmaceutical co-crystal 1,2 and 3, the water solubility of three kinds of eutectics of Febustat of the present invention all improves a lot than Febustat, and especially Febustat meglumine eutectic and Febustat arginine eutectic is to improve the eutectic that Febustat solubility degree is the highest at present.It addition, three kinds of eutectic purity of Febustat of the present invention are high, impurity content is few, good stability, in preparation production and storage process, crystal transfer will not occur for raw material with it, and keep stablizing of preparation crystal formation, be the necessary condition that the quality of the pharmaceutical preparations is stable.The preparation method of eutectic of the present invention is simple and easy to do, mild condition and being easily controlled, favorable reproducibility, easily realizes large-scale industrial production, and production cost is low, has great commercial application value.
Description
Technical field
The invention belongs to technical field of organic pharmaceutical co-crystal, be specifically related to three kinds of novel Febustat organic pharmaceutical co-crystal and medicine is total to
Brilliant preparation method.
Background technology
Pharmaceutical co-crystals is based on supramolecular chemistry principle, the molecular recognition i.e. carried out by intermolecular mutual synergy and oversubscription
Sub-self assembly.Active constituents of medicine (API) is with suitable eutectic formation (cocrystal former, CCF) by hydrogen bond certainly
Assemble, or the non-covalent bond (such as aromatic hydrocarbons or the Van der Waals force of phenyl ring, π-πconjugation and halogen key) with saturability and directionality
Assemble a kind of new structure formed, i.e. pharmaceutical co-crystals.In November, 2011, FDA has issued that " pharmaceutical co-crystals management classification refers to
South " (Guidance forIndustry:Regulatory Classification of Pharmaceutical Cocrystals), it is indicated that work as medicine
Formed after eutectic with certain auxiliary material, pharmaceutical co-crystals can be managed as " preparation intermediate " and controls, thus eutectic without
Register separately as medicine.In recent years, pharmaceutical co-crystals research was increasingly paid close attention to by people.Present stage, the most right
The research of pharmaceutical co-crystals starts gradually to increase and go deep into;And it is domestic the most relatively fewer to its research.For imitation medicine, medicine
The research of eutectic can also break the patent protection to drug crystal forms of the Yuan Yan medicine company, is beneficial to introduce imitation medicine to the market.Therefore,
Obtain more there is novelty, practical and creative pharmaceutical co-crystals has important practical significance, particularly some water insoluble drugs
Thing, is conducive to improving the water solubility of medicine and bioavilability.
Febustat, molecular formula is C16H16N2O3S, chemistry is entitled: 2-[(3-cyano-4-isobutoxy) phenyl]-4-methyl-5-thiophene
Triazole carboxylic acid (2-(3-cyano-4-isobutoxyphenyl)-5-methyl-1,3-thiazole-4-carboxylicacid), for novel non-
Purines xanthine oxidase (XO) inhibitor, clinically for preventing and treat the gout of hyperuricemia and initiation thereof.Non-cloth
Take charge of him as xanthine oxidase inhibitor, there is high selectivity, the generation of uric acid can be reduced, effectively treat gout.Japan Supreme Being
People company at the beginning of 2004 Japanese publication list, the end of the year in the same year U. S. application list, in October, 2008 Europe EMEA
(Europe medical product appraisal agency) approval Febustat sheet listing.On in February, 2009 U.S. FDA approval Febustat sheet
City.
Domestic patent CN1275126 discloses five kinds of crystal formations A, B, C, D, G of Febustat and a kind of amorphousness,
Wherein A crystalline substance is wherein relative to stable crystal form;Patent CN 101139325A discloses two kinds of crystal formations of Febustat I, II;Patent
CN 1970547A discloses three kinds of crystal formations H, I and J of Febustat;Patent CN 101386605A discloses Febustat
A kind of novel crystal forms K;Patent CN 101648926A discloses a kind of new crystal form Q of Febustat;Patent CN101671314A
Disclose Febustat alpha-crystal form;Patent CN 101525319A discloses Febustat 2 crystal formation;Patent CN 101684107A
Disclose Febustat X, Y, Z crystal formation;CN101085761 discloses a kind of novel crystal forms, prepares with ethyl acetate for solvent;
CN 101805310A discloses novel crystal forms δ;Patent CN 101824007A discloses new crystal form M;CN 101891703 is public
Cloth novel crystal forms N;CN101928260A provides three kinds of novel crystal forms R, S, T;International monopoly WO2010144685A1 is public
Cloth Febuxostat crystal form F1-F14 totally 14 kinds of crystal formations;International monopoly WO 2012/098501 A1 discloses Febustat and three
Plant eutectic formation urea, niacinamide, the eutectic of caffeine formation.Febustat solubility in water is 5mg/L (room
Temperature), poorly water-soluble, it is therefore desirable to prepare the eutectic that can improve its solubility, improves its dissolubility and bioavilability.
Summary of the invention
Febustat organic pharmaceutical co-crystal that it is an object of the invention to provide three kinds of new structures and preparation method thereof, and brilliant to it
Body structure is measured, and characterizes its character.
The present invention select active constituents of medicine (API) be Febustat, eutectic presoma (CCF) be nicotimine, meglumine,
Arginine, prepares the pharmaceutical co-crystals of three kinds of new structures.
Febustat (Febuxostat) as the active constituents of medicine of the present invention, chemical name is: 2-[(3-cyano group-4-isobutyl oxygen
Base) phenyl]-4-methyl-5-thiazole carboxylic acid, molecular formula is C16H16N2O3S.Its structural formula is as shown in a;Selected in the present invention
Eutectic presoma nicotimine, molecular formula is C6H6N2O, its structural formula is shown as b;Eutectic presoma meglumine, molecular formula is
C7H18NO5, its structural formula is as shown by c;Eutectic presoma arginine, molecular formula is C6H14N4O2, its structural formula such as d institute
Show.
The present invention is achieved through the following technical solutions:
The invention discloses a kind of Febustat organic pharmaceutical co-crystal 1, pharmaceutical co-crystals 1 is to become using Febustat as pharmaceutically active
Point, with nicotimine for eutectic presoma, a Febustat molecule and a nicotimine molecular composition Febustat pharmaceutical co-crystals
Basic structural unit, this pharmaceutical co-crystals belongs to monoclinic system, P21/ n space group, cell parameter is: β=106.943 (10) °,Z=4, Dx=1.345, point
Minor is: C16H16N2O3S·C6H6N2O。
As improving further, crystal formation 1 of the present invention has X-ray powder diffraction pattern as shown in Figure 1, to spread out
Firing angle 2 θ ° ± 0.1 is expressed as: 6.2,11.4,12.4,12.8,13.4,13.9,14.6,15.7,17.6,18.3,19.2,
19.4,20.2,21.1,21.9,22.5,22.9,23.6,24.9,25.1,25.7,26.7,28.0 etc. have characteristic diffraction peak.
The invention also discloses the preparation method of a kind of Febustat organic pharmaceutical co-crystal 1, step is as follows:
(1) by Febustat and the nicotimine of mol ratio 1:1, join in ketone or nitrile, be heated to reflux dissolving, in reaction system
The ratio of weight g of solute and the volume ml of solvent is 1:10~40;
(2) temperature dissolved is at 30~85 DEG C;
(3) after dissolving clarification, slow cooling crystallization or left at room temperature crystallization, there is light yellow crystal to separate out after 1~72 hour,
I.e. Febustat organic pharmaceutical co-crystal 1.
As improving further, solvent of the present invention is acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl tert-butyl
One or several mixed solvent in base ketone, cyclohexanone.
The invention discloses a kind of Febustat organic pharmaceutical co-crystal 2, pharmaceutical co-crystals 2 is with Febustat as active constituents of medicine,
With meglumine for eutectic presoma, a Febustat molecule and a meglumine molecular composition Febustat organic pharmaceutical co-crystal 2
Basic structural unit.
As improving further, crystal formation 2 of the present invention has X-ray powder diffraction pattern as shown in Figure 6, with
The angle of diffraction 2 θ ° ± 0.1 is expressed as: 2.3, and 4.7,7.1,9.4,12.3,12.4,13.0,14.2,15.7,16.6,
16.8,17.3,18.5,19.0,21.4,22.1,22.9,23.8,24.3,25.1 etc. have characteristic diffraction peak.
The invention also discloses the preparation method of a kind of Febustat organic pharmaceutical co-crystal 2, it is characterised in that step is as follows:
(1) Febustat and meglumine that mol ratio is 1:1 are added acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl
In one or several mixed solvent in isobutyl ketone, cyclohexanone, quality g of solute and the volume of solvent in reaction system
The ratio of ml is 1:20~80;
(2) 40~85 DEG C are heated to reflux, and after clarifying to solution, stop stirring, slow cooling or room temperature and stand crystallization, 0.5h~24h
Having crystal to separate out, precipitate is described Febustat organic pharmaceutical co-crystal 2.
The invention discloses a kind of Febustat organic pharmaceutical co-crystal 3, pharmaceutical co-crystals 3 is with Febustat as active constituents of medicine,
With arginine for eutectic presoma, a Febustat molecule and an arginine molecule form Febustat organic pharmaceutical co-crystal
Basic structural unit.
As improving further, crystal formation 3 of the present invention has X-ray powder diffraction pattern as shown in Figure 10, with
The angle of diffraction 2 θ ° ± 0.1 is expressed as: 3.3, and 6.7,8.9,9.4,10.0,11.2,13.3,13.6,14.9,15.9,16.3,
17.9,18.8,19.2,19.8,20.1,20.9,21.3,22.3,23.3,24.4,26.7,32.5 etc. have characteristic diffraction peak.
The invention also discloses the preparation method of a kind of Febustat organic pharmaceutical co-crystal 3, it is characterised in that step is as follows:
(1) Febustat and arginine that mol ratio is 1:1 are added acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl
In one or several mixed solvent in isobutyl ketone, cyclohexanone, quality g of solute and the volume of solvent in reaction system
Ml ratio is 1:10~60;
(2) 40~85 DEG C are heated to reflux, and after clarifying to solution, stop stirring, slow cooling or room temperature and stand crystallization, 0.5h~48h
Having crystal to separate out, precipitate is described Febustat organic pharmaceutical co-crystal 3.
Beneficial effects of the present invention is as follows:
Febustat molar solubility in 37 DEG C of water is only 0.0235mmol/L (being i.e. practically insoluble in water), and the present invention
Mole dissolving in 37 DEG C of water of Febustat-nicotimine eutectic, Febustat-meglumine eutectic and Febustat-arginine eutectic
Degree is respectively 1.3 times of Febustat, 1087 times and 990 times.Visible, the water solubility of three kinds of eutectics of Febustat of the present invention
All improving a lot than Febustat, especially Febustat-meglumine eutectic and Febustat-arginine eutectic are to carry at present
The eutectic that high Febustat solubility degree is the highest.Febustat is a Biopharmaceutics Classification system II class medicine (low dissolving
Degree, high osmosis), dissolving is its rate-limiting step absorbed, and improves the solubility of Febustat by the way of forming eutectic, can
To significantly improve body absorption and the bioavilability of Febustat, preferably play its curative effect.
It addition, three kinds of eutectic purity of Febustat of the present invention are high, impurity content is few, good stability, is that raw material is at preparation with it
Produce and storage process will not occur crystal transfer, and keeping stablizing of preparation crystal formation, being the necessary condition that the quality of the pharmaceutical preparations is stable.
The preparation method of eutectic of the present invention is simple and easy to do, mild condition and being easily controlled, favorable reproducibility, easily realizes large-scale industry
Producing, production cost is low, has great commercial application value.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRD) figure of Febustat organic pharmaceutical co-crystal 1;
Fig. 2 is Febustat organic pharmaceutical co-crystal 1 three-dimensional structure diagram;
Fig. 3 is Febustat organic pharmaceutical co-crystal 1 hydrogen bond connection figure;
Fig. 4 is Febustat organic pharmaceutical co-crystal 1 means of differential scanning calorimetry figure (DSC);
Fig. 5 is Febustat organic pharmaceutical co-crystal 1 infrared spectrogram (IR);
Fig. 6 is X-ray powder diffraction (XRD) figure of Febustat organic pharmaceutical co-crystal 2;
Fig. 7 is Febustat organic pharmaceutical co-crystal 2 means of differential scanning calorimetry figure (DSC);
Fig. 8 is Febustat organic pharmaceutical co-crystal 2 thermogravimetric analysis figure (TG);
Fig. 9 is Febustat organic pharmaceutical co-crystal 2 infrared spectrogram (IR);
Figure 10 is X-ray powder diffraction (XRD) figure of Febustat organic pharmaceutical co-crystal 3;
Figure 11 is Febustat organic pharmaceutical co-crystal 3 means of differential scanning calorimetry figure (DSC);
Figure 12 is Febustat organic pharmaceutical co-crystal 3 thermogravimetric analysis figure (TG);
Figure 13 is Febustat organic pharmaceutical co-crystal 3 infrared spectrogram (IR);
Figure 14 is Febustat organic pharmaceutical co-crystal 1 and Febustat solubility comparison diagram;
Figure 15 is Febustat organic pharmaceutical co-crystal 2 and Febustat solubility comparison diagram;
Figure 16 is Febustat organic pharmaceutical co-crystal 3 and Febustat solubility comparison diagram.
Detailed description of the invention
Below by specific embodiment, in conjunction with Figure of description, technical scheme is described in further detail:
Fig. 1 is X-ray powder diffraction (XRD) figure of Febustat organic pharmaceutical co-crystal 1;Fei Busi of the present invention
The X-ray diffraction spectral line of his organic pharmaceutical co-crystal 1 is in the angle of diffraction (2 θ ° ± 0.1): 6.2,11.4,12.4,12.8,13.4,
13.9、14.6、15.7、17.6、18.3、19.2、19.4、20.2、21.1、21.9、22.5、22.9、23.6、24.9、25.1、
25.7,26.7,28.0 etc. have characteristic diffraction peak.
Fig. 2 is Febustat organic pharmaceutical co-crystal 1 three-dimensional structure diagram;Febustat organic pharmaceutical co-crystal 1 is by a non-cloth
Take charge of his molecule, the basic structural unit of a nicotimine molecular composition Febustat organic pharmaceutical co-crystal, belong to monoclinic system, P21/n
Space group, crystallographic parameters is as shown in table 1, and atomic coordinates and temperature factor are as shown in table 2.Carboxylic acid group in Febustat molecule
The hydroxyl of group and the carbonylic oxygen atom of amide group in nicotimine molecule form hydrogen bond, and two nicotimine molecules are by amide groups glob
Become intermolecular hydrogen bonding, join end to end, infinitely extend along a direction of principal axis, form chain-like molecular structure in a zigzag.Fig. 3 is non-cloth
Take charge of his organic pharmaceutical co-crystal 1 hydrogen bond connection figure;The carbonyl of each nicotimine molecule respectively from different Febustat molecules hydroxyl groups shapes
Become intermolecular hydrogen bonding to connect, and extend along a direction of principal axis, form undulatory stacking.Fig. 4 is that Febustat organic drug is total to
Brilliant 1 means of differential scanning calorimetry figure (DSC);Thus show the endothermic peak that only one of which is stronger in the range of room temperature to 220 DEG C, show
Eutectic 1 is single crystal form, and fusing point (summit value) is 166.8 DEG C, is different from the fusing point (Febustat of Febustat and nicotimine
Fusing point 210.1 DEG C, nicotimine fusing point is 155-158 DEG C), the melt initiation temperature degree of eutectic 1 is 165.5 DEG C, and melting enthalpy is 140.8J/g.
Fig. 5 is Febustat organic pharmaceutical co-crystal 1 infrared spectrogram (IR);Thus the infared spectrum analysis result of eutectic 1 shows,
Infrared spectrum characteristic peak positions 2968,2221,1694,1511cm-1Etc., C O in Febustat and nicotimine molecule
Stretching vibration disappears the most, at 1694cm-1There is new C O stretching vibration absworption peak in place.Medicine and auxiliary material when forming eutectic
Carbonyl be involved in formed hydrogen bond so that the absworption peak of carbonyl has significantly different.
The crystallographic parameters table of table 1 Febustat nicotimine eutectic
The atomic coordinates of table 2 Febustat organic pharmaceutical co-crystal 1 and temperature factor
The invention further relates to the preparation method of Febustat organic pharmaceutical co-crystal 1: by Febustat and nicotimine with mol ratio 1:1,
Join a kind of in acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl iso-butyl ketone (MIBK), cyclohexanone or their mixing
In solvent, preferred solvent is acetonitrile.The temperature of heating for dissolving is 30~85 DEG C, preferably 50~80 DEG C, makes solute all be dissolved to
After clarification, slow cooling crystallization or left at room temperature crystallization, there is light yellow crystal to separate out after 1~72 hour, Best Times is
1h~12h, obtains Febustat organic pharmaceutical co-crystal 1.It is easy to operation that the method prepares eutectic, it is simple to realizes industry metaplasia
Produce.
Specifically comprise the following steps that
(1) Febustat and nicotimine that mol ratio is 1:1 are added acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl
In a kind of in isobutyl ketone, cyclohexanone or their mixed solvent, in reaction system, the ratio of solute and solvent is 1:10~40
(g:mL);
(2) 50~80 DEG C are heated to reflux, stir, and are further continued for stirring 0.5h after being completely dissolved;
(3) stop stirring, be naturally cooling to room temperature, after 1~12 hour, have light yellow crystal to separate out, be i.e. Febustat organic drug
Eutectic 1.
Fig. 6 is X-ray powder diffraction (XRD) figure of Febustat organic pharmaceutical co-crystal 2;Febustat organic drug is altogether
The X-ray diffraction spectral line of brilliant 2 is in the angle of diffraction (2 θ ° ± 0.1): 2.3,4.7,7.1,9.4,12.3,12.4,13.0,
14.2,15.7,16.6,16.8,17.3,18.5,19.0,21.4,22.1,22.9,23.8,24.3,25.1 etc.
There is characteristic diffraction peak.
Febustat organic pharmaceutical co-crystal 2 of the present invention is by a Febustat molecule, a meglumine group of molecules patent medicine
The basic structural unit of thing eutectic, Fig. 7 is Febustat organic pharmaceutical co-crystal 2 means of differential scanning calorimetry figure (DSC);Eutectic 2
Differential scanning calorimetry (DSC) analysis result show, the endothermic peak that only one of which is stronger in the range of room temperature to 220 DEG C,
Show eutectic 2 for single crystal form, fusing point (summit value) is 142.9 DEG C, and eutectic melting point and Febustat fusing point (210.1 DEG C)
All different with meglumine fusing point (128~132 DEG C), the melt initiation temperature degree of eutectic 2 is 140.4 DEG C, and melting enthalpy is 102.8J/g.
Fig. 8 is Febustat organic pharmaceutical co-crystal 2 thermogravimetric analysis figure (TG);The thermogravimetry analysis result of eutectic 2 shows eutectic
Only one of which weightlessness peak, without solvent in its structure, for anhydrous eutectic.Fig. 9 is that Febustat organic pharmaceutical co-crystal 2 is infrared
Spectrogram (IR);The infared spectrum of eutectic 2 show eutectic 3432,2967,2229,1533,1087,1514cm-1Deng
There is characteristic absorption peak at place, and in Febustat molecule, C O stretching vibration disappears, and eutectic is at 1533cm-1There is new carboxylate in place
C O stretching vibration absworption peak, 693cm-1The COO-on-plane surface angle weak absorbing peak at place also demonstrates the formation of carboxylate.Shape
The secondary amine group generation proton translocation of carbonyl and the meglumine of medicine when becoming eutectic so that the absworption peak of carbonyl has significantly different (non-
The carbonyl absorption peak of Bu Sita is 1678cm-1)。
The invention further relates to the preparation method of Febustat organic pharmaceutical co-crystal 2: by Febustat and meglumine with 1:1 mole
Than joining a kind of in acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl iso-butyl ketone (MIBK), cyclohexanone or theirs is mixed
In bonding solvent, preferably acetonitrile.It is heated to 40~85 DEG C, most preferably 60~85 DEG C, makes solute all be dissolved to clarification, crystallization of lowering the temperature,
Recrystallization temperature is room temperature, and through 0.5h~24h, Best Times is 3~12h, obtains described Febustat meglumine eutectic 2.System
Preparation Method is simple and easy to do, it is simple to realize industrialized production.
Specifically comprise the following steps that
(1) Febustat and meglumine that mol ratio is 1:1 are added acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl
In a kind of in isobutyl ketone, cyclohexanone or their mixed solvent, in reaction system, the ratio of solute and solvent is 1:20~80
(g:mL);
(2) 60~85 DEG C are heated to reflux and stir, and after clarifying to solution, continue stirring 0.5h;
(3) stopping stirring, slow cooling or room temperature and stand crystallization, 3~12h have crystal to separate out, and precipitate is described non-cloth
Take charge of his meglumine eutectic 2.
Figure 10 is X-ray powder diffraction (XRD) figure of Febustat organic pharmaceutical co-crystal 3;Fei Busi of the present invention
The X-ray diffraction spectral line of his organic pharmaceutical co-crystal 3 is in the angle of diffraction (2 θ ° ± 0.1): 3.3, and 6.7,8.9,9.4,10.0,11.2,
13.3,13.6,14.9,15.9,16.3,17.9,18.8,19.2,19.8,20.1,20.9,21.3,22.3,23.3,24.4,
26.7,32.5 etc. have characteristic diffraction peak.
Febustat organic pharmaceutical co-crystal 3 of the present invention is by a Febustat molecule, an arginine molecule and one
The basic structural unit of hydrone composition pharmaceutical co-crystals.Figure 11 is Febustat organic pharmaceutical co-crystal 3 means of differential scanning calorimetry figure
(DSC);The differential scanning calorimetry analysis result of eutectic 3 shows, eutectic 3 is single crystal form, 56.5 DEG C, 77.9 DEG C,
Having three endothermic peaks at 154.7 DEG C, wherein 56.5 DEG C, 77.9 DEG C should be eutectic dehydration peak, should be phase transformation peak at 154.7 DEG C, melted
Temperature is 199.3 DEG C (summit values), is different from Febustat fusing point (210.1 DEG C) and arginine fusing point (222 DEG C), melts
Beginning temperature is 194.5 DEG C, and melting enthalpy is 68.55J/g.Figure 12 is Febustat organic pharmaceutical co-crystal 3 thermogravimetric analysis figure (TG);
The thermogravimetry analysis result of eutectic 3 shows, eutectic is in the range of 100 DEG C, and its weightlessness is 3.60%, should be dehydration process,
Show the water Han a part in eutectic molecule, for Febustat-arginine monohydrate.Figure 13 is Febustat organic pharmaceutical co-crystal
3 infrared spectrograms (IR);The infared spectrum of eutectic 3 shows, eutectic 3 3368,2963,2229,1644,1291,
1524cm-1Etc. have characteristic absorption peak, 1644cm-1There is new C O stretching vibration peak in place, medicine when being owing to forming eutectic
The carbonyl of thing, arginic carbonyl, arginic primary amine group are involved in forming hydrogen bond so that the absworption peak of carbonyl has the most not
With (Febustat, arginic carbonyl absorption peak are respectively 1678cm-1、1676cm-1)。
The invention further relates to the preparation method of Febustat organic pharmaceutical co-crystal 3: by Febustat and arginine with 1:1 mole
Than one or several mixing joined in acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl iso-butyl ketone (MIBK), cyclohexanone
In solvent, preferably acetone.It is heated to 40~85 DEG C, most preferably 50~75 DEG C, makes solute all be dissolved to clarification, crystallization of lowering the temperature,
Recrystallization temperature is slow cooling or room temperature standing crystallization, and through 0.5h~48h, Best Times is 3~12h, obtains described non-cloth
Take charge of his arginine eutectic 3.Preparation method is simple and easy to do, it is simple to realize industrialized production.
Specifically comprise the following steps that
(1) Febustat and arginine that mol ratio is 1:1 are added acetonitrile, benzene acetonitrile, cyanophenyl, acetone, butanone, methyl
In a kind of in isobutyl ketone, cyclohexanone or their mixed solvent, in reaction system, the ratio of solute and solvent is 1:10~60
(g:mL);
(2) 50~75 DEG C are heated to reflux, and after clarifying to solution, stop stirring, slow cooling or room temperature and stand crystallization, and 3~12h have
Crystal separates out, and precipitate is described Febustat organic pharmaceutical co-crystal 3.
Solubility and Dissolution experiments with water as dissolution medium show, Febustat solubility in 37 DEG C of water is only
7.448mg/L, molar solubility is 0.0235mmol/L;The solubility of Febustat organic pharmaceutical co-crystal 1 more than Febustat (as
Figure 14), improving to 13.11mg/L, molar solubility is 1.3 times of Febustat;Febustat organic pharmaceutical co-crystal 2 molten
Xie Du is more than Febustat (such as Figure 15), and for 13101mg/L, molar solubility is 1087 times of Febustat;Febustat
The solubility of organic pharmaceutical co-crystal 3 is more than Febustat (such as Figure 16), and for 570.8mg/L, molar solubility is Febustat
990 times.
Three kinds of Febustat organic pharmaceutical co-crystal that the present invention prepares remain the pharmacologically active of Febustat, solubility,
Stability and bioavilability aspect all have clear improvement.
The instrument detecting pharmaceutical co-crystals structure and performance in the present invention is as follows:
Single crystal diffraction characterizes: RigakuR-AXIS-RAPID single crystal diffractometer, uses MoK αRay,
Structure elucidation and correction is carried out with SHELXS97 and SHELXL97.Diamond and Mercury software is used to obtain structure
Figure.
Powder x-ray diffraction (XRD) characterizes: instrument: RigakuD/Max-2550PC, CuK α radiates, power 40kV,
250mA, sweep limits 2 θ are 3~40 °, step width (stepwidth) 0.02 °, 5 °/min of sweep speed.
Thermogravimetric analysis (TG) characterizes: instrument: TA company SDTQ600, purge gas: nitrogen 120ml/min, programming rate:
10 DEG C/min, temperature range: room temperature~380 DEG C.
Differential scanning calorimetric analysis (DSC) characterizes: instrument: TA company DSCQ100, purge gas: nitrogen 50mL/min,
Programming rate: 10 DEG C/min, temperature range: room temperature~200 DEG C.
Specific embodiments:
Embodiment 1: take Febustat 3.16g (10mmol), nicotimine 1.22g (10mmol) joins in 100mL acetonitrile,
Stirring, is heated to reflux to 85 DEG C, and solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 4h separates out completely,
Suction filtration, dries, obtains flaxen pressed powder, for Febustat organic pharmaceutical co-crystal 1.
Embodiment 2: take Febustat 0.316g (1mmol), nicotimine 0.122g (1mmol) joins in 30mL cyanophenyl, stirs
Mixing, be heated to reflux to 50 DEG C, solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 48h separates out completely, takes out
Filter, dries, obtains flaxen crystal, for Febustat organic pharmaceutical co-crystal 1.
Embodiment 3: take Febustat 0.316g (1mmol), nicotimine 0.122g (1mmol) joins in 40mL benzene acetonitrile,
Stirring, is heated to reflux to 70 DEG C, and solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 48h separates out completely,
Suction filtration, dries, obtains flaxen crystal, for Febustat organic pharmaceutical co-crystal 1.
Embodiment 4: take Febustat 15.8g (50mmol), nicotimine 6.1g (50mmol) joins in 500mL acetone, stirs
Mixing, be heated to reflux to 50 DEG C, solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 2h separates out completely, takes out
Filter, dries, obtains flaxen crystal, for Febustat organic pharmaceutical co-crystal 1.
Embodiment 5: take Febustat 3.16g (10mmol), nicotimine 1.22g (10mmol) joins in 150mL butanone,
Stirring, is heated to reflux to 70 DEG C, and solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 6h separates out completely,
Suction filtration, dries, obtains flaxen crystal, for Febustat organic pharmaceutical co-crystal 1.
Embodiment 6: take Febustat 1.58g (5mmol), nicotimine 0.61g (5mmol) joins 100mL methyl-isobutyl
In ketone, stirring, it is heated to reflux to 85 DEG C, solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, treat that 24h has separated out
Quan Hou, suction filtration, dry, obtain flaxen crystal, for Febustat organic pharmaceutical co-crystal 1.
Embodiment 7: take Febustat 1.58g (5mmol), nicotimine 0.61g (5mmol) joins in 100mL cyclohexanone,
Stirring, is heated to reflux to 80 DEG C, and solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 48h separates out completely,
Suction filtration, dries, obtains flaxen crystal, for Febustat organic pharmaceutical co-crystal 1.
Embodiment 8: take Febustat 3.16g (10mmol), meglumine 1.96g (10mmol) joins in 300mL acetonitrile,
Stirring, is heated to reflux to 75 DEG C, and solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 2h separates out completely,
Suction filtration, dries, obtains white solid powder, for Febustat organic pharmaceutical co-crystal 2.
Embodiment 9: take Febustat 0.316g (1mmol), meglumine 0.196g (1mmol) joins in 40mL cyanophenyl,
Stirring, is heated to reflux to 70 DEG C, and solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 12h separates out completely,
Suction filtration, dries, obtains white solid powder, for Febustat organic pharmaceutical co-crystal 2.
Embodiment 10: take Febustat 0.316g (1mmol), meglumine 0.196g (1mmol) joins 40mL benzene acetonitrile
In, stirring, it is heated to reflux to 70 DEG C, solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, treat that 24h has separated out
Quan Hou, suction filtration, dry, obtain white solid powder, for Febustat organic pharmaceutical co-crystal 2.
Embodiment 11: take Febustat 3.16g (10mmol), meglumine 1.96g (10mmol) joins 100mL acetone
In, stirring, it is heated to reflux to 50 DEG C, solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, treat that 2h has separated out
Quan Hou, suction filtration, dry, obtain white solid powder, for Febustat organic pharmaceutical co-crystal 2.
Embodiment 12: take Febustat 0.632g (2mmol), meglumine 0.392g (2mmol) joins in 40mL butanone,
Stirring, is heated to reflux to 70 DEG C, and solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, after 24h separates out completely,
Suction filtration, dries, obtains white solid powder, for Febustat organic pharmaceutical co-crystal 2.
Embodiment 13: take Febustat 0.316g (1mmol), that meglumine 0.196g (1mmol) joins 20mL methyl is different
In butyl ketone, stirring, it is heated to reflux to 70 DEG C, solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, treat 24h
After separating out completely, suction filtration, dry, obtain white solid powder, for Febustat organic pharmaceutical co-crystal 2.
Embodiment 14: take Febustat 0.316g (1mmol), meglumine 0.196g (1mmol) joins 20mL cyclohexanone
In, stirring, it is heated to reflux to 85 DEG C, solution is clarified, and after continuing stirring 0.5h, takes out and stands in normal temperature, treat that 24h has separated out
Quan Hou, suction filtration, dry, obtain white solid powder, for Febustat organic pharmaceutical co-crystal 2.
Embodiment 15: take Febustat 6.32g (20mmol), arginine 3.48g (20mmol) joins 200mL acetone
In, stirring, it is heated to reflux to 50 DEG C, solution is clarified, and takes out and stands in normal temperature, after 2h separates out completely, suction filtration, dry
Obtain white solid powder, for Febustat organic pharmaceutical co-crystal 3.
Embodiment 16: take Febustat 3.16g (10mmol), arginine 1.74g (10mmol) joins 200mL acetonitrile
In, stirring, it is heated to reflux to 70 DEG C, solution is clarified, and takes out and stands in normal temperature, after 24h separates out completely, suction filtration, dry
Obtain white solid powder, for Febustat organic pharmaceutical co-crystal 3.
Embodiment 17: take Febustat 1.58g (5mmol), arginine 0.87g (5mmol) joins in 150mL butanone,
Stirring, is heated to reflux to 70 DEG C, and solution is clarified, and takes out and stands in normal temperature, after 12h separates out completely, and suction filtration, drying
White solid powder, for Febustat organic pharmaceutical co-crystal 3.
Embodiment 18: take Febustat 0.316g (1mmol), that arginine 0.174g (1mmol) joins 30mL methyl is different
In butyl ketone, stirring, it is heated to reflux to 85 DEG C, solution is clarified, and takes out and stands in normal temperature, after 48h separates out completely, suction filtration,
Drying white solid powder, for Febustat organic pharmaceutical co-crystal 3.
Embodiment 19: take Febustat 0.316g (1mmol), arginine 0.174g (1mmol) joins 30mL cyclohexanone
In, stirring, it is heated to reflux to 85 DEG C, solution is clarified, and takes out and stands in normal temperature, after 48h separates out completely, suction filtration, dry
Obtain white solid powder, for Febustat organic pharmaceutical co-crystal 3.
Embodiment 20: take Febustat 0.316g (1mmol), arginine 0.174g (1mmol) joins 20mL benzene acetonitrile
In, stirring, it is heated to reflux to 70 DEG C, solution is clarified, and takes out and stands in normal temperature, after 12h separates out completely, suction filtration, dry
Obtain white solid powder, for Febustat organic pharmaceutical co-crystal 3.
Embodiment 21: take Febustat 0.316g (1mmol), arginine 0.174g (1mmol) joins in 20mL cyanophenyl,
Stirring, is heated to reflux to 70 DEG C, and solution is clarified, and takes out and stands in normal temperature, after 12h separates out completely, and suction filtration, drying
White solid powder, for Febustat organic pharmaceutical co-crystal 3.
Finally, in addition it is also necessary to it is noted that listed above is only that the several of the present invention are embodied as example.Obviously, the present invention is not
It is limited to above example, it is also possible to have many deformation.Those of ordinary skill in the art can be direct from present disclosure
The all deformation derived or associate, are all considered as protection scope of the present invention.
Claims (4)
1. a Febustat organic pharmaceutical co-crystal 2, it is characterised in that pharmaceutical co-crystals 2 is with Febustat as medicine
Active component, with meglumine for eutectic presoma, a Febustat molecule and a meglumine molecular composition are non-
The basic structural unit of Bu Sita organic pharmaceutical co-crystal 2, the X that described crystal formation 2 has as shown in Figure 6 penetrates
Line powder diffraction spectrum, is expressed as with the angle of diffraction 2 θ ° ± 0.1: 2.3,4.7,7.1,9.4,12.3,
12.4,13.0,14.2,15.7,16.6,16.8,17.3,18.5,19.0,21.4,22.1,22.9,
Characteristic diffraction peak is had at 23.8,24.3,25.1.
2. the preparation method of a Febustat organic pharmaceutical co-crystal 2 as claimed in claim 1, it is characterised in that
Step is as follows:
(1) Febustat and meglumine that mol ratio is 1:1 are added acetonitrile, benzene acetonitrile, cyanophenyl, acetone, fourth
In one or several mixed solvent in ketone, methyl iso-butyl ketone (MIBK), cyclohexanone, solute in reaction system
The ratio of the volume ml of quality g and solvent is 1:20~80;
(2) 40~85 DEG C are heated to reflux, and after clarifying to solution, stop stirring, slow cooling or room temperature and stand crystallization,
0.5h~24h has crystal to separate out, and precipitate is described Febustat organic pharmaceutical co-crystal 2.
3. a Febustat organic pharmaceutical co-crystal 3, it is characterised in that pharmaceutical co-crystals 3 is with Febustat as medicine
Active component, with arginine for eutectic presoma, a Febustat molecule and an arginine molecule composition are non-
The basic structural unit of Bu Sita organic pharmaceutical co-crystal 3, the X that described crystal formation 3 has as shown in Figure 10 penetrates
Line powder diffraction spectrum, is expressed as with the angle of diffraction 2 θ ° ± 0.1: 3.3,6.7,8.9,9.4,10.0,11.2,
13.3,13.6,14.9,15.9,16.3,17.9,18.8,19.2,19.8,20.1,20.9,21.3,22.3,
Characteristic diffraction peak is had at 23.3,24.4,26.7,32.5.
4. the preparation method of a Febustat organic pharmaceutical co-crystal 3 as claimed in claim 3, it is characterised in that
Step is as follows:
(1) Febustat and arginine that mol ratio is 1:1 are added acetonitrile, benzene acetonitrile, cyanophenyl, acetone, fourth
In one or several mixed solvent in ketone, methyl iso-butyl ketone (MIBK), cyclohexanone, solute in reaction system
The volume ml ratio of quality g and solvent is 1:10~60;
(2) 40~85 DEG C are heated to reflux, and after clarifying to solution, stop stirring, slow cooling or room temperature and stand crystallization,
0.5h~48h has crystal to separate out, and precipitate is described Febustat organic pharmaceutical co-crystal 3.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410371582.4A CN104177308B (en) | 2014-07-31 | 2014-07-31 | Three kinds of novel Febustat pharmaceutical co-crystals and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410371582.4A CN104177308B (en) | 2014-07-31 | 2014-07-31 | Three kinds of novel Febustat pharmaceutical co-crystals and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104177308A CN104177308A (en) | 2014-12-03 |
CN104177308B true CN104177308B (en) | 2016-08-24 |
Family
ID=51958689
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410371582.4A Active CN104177308B (en) | 2014-07-31 | 2014-07-31 | Three kinds of novel Febustat pharmaceutical co-crystals and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104177308B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105832690A (en) * | 2016-05-12 | 2016-08-10 | 河北仁合益康药业有限公司 | Febuxostat coated tablet composition and preparation method thereof |
CN107056607B (en) * | 2016-12-01 | 2020-02-07 | 北京理工大学 | Gemfibrozil eutectic crystal and preparation method thereof |
CN108530382A (en) * | 2018-03-20 | 2018-09-14 | 华南理工大学 | A kind of Febuxostat ligustrazine eutectic and its preparation method and application |
CN112638866B (en) * | 2018-07-06 | 2023-06-09 | 艾科西斯有限责任公司 | Co-crystals of sorafenib derivatives and process for preparing same |
CN113292621B (en) * | 2021-05-19 | 2022-03-08 | 国家卫生健康委科学技术研究所 | Pharmaceutical crystal form of progesterone and application thereof |
CN115838343A (en) * | 2022-11-22 | 2023-03-24 | 天津大学 | belinostat-L-proline zwitter-ion eutectic and preparation method and application thereof |
CN116199590A (en) * | 2022-12-26 | 2023-06-02 | 湖北美林药业有限公司 | Dobutamine hydrochloride and injection thereof |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102372679A (en) * | 2010-08-27 | 2012-03-14 | 北京润德康医药技术有限公司 | Febuxostat water-soluble derivative and preparation method thereof |
WO2012098501A1 (en) * | 2011-01-21 | 2012-07-26 | Ranbaxy Laboratories Limited | Febuxostat co-crystals |
CN103058951A (en) * | 2013-01-24 | 2013-04-24 | 吉林化工学院 | Novel febuxostat pharmaceutical co-crystal and preparation method thereof |
CN103044353B (en) * | 2013-01-24 | 2014-06-11 | 吉林三善恩科技开发有限公司 | Febuxostat pharmaceutical co-crystal and preparation method thereof |
-
2014
- 2014-07-31 CN CN201410371582.4A patent/CN104177308B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN104177308A (en) | 2014-12-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104177308B (en) | Three kinds of novel Febustat pharmaceutical co-crystals and preparation method thereof | |
CN102875529B (en) | Dabigatran derivatives and preparation method thereof | |
CN106543094A (en) | The preparation method of high-purity gadobutrol | |
CN108299294A (en) | A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity | |
CN104736540B (en) | The preparation method of pemetrexed and its lysine salt | |
Wang et al. | Crystal structure, dissolution and hygroscopicity of a novel cocrystal hydrate of berberine hydrochloride with L (+)-lactic acid | |
CN109476609A (en) | The manufacturing method of pyrazole-amide compounds | |
CN105085328B (en) | A kind of synthetic method of Peramivir trihydrate | |
CN104072492A (en) | Synthetic method of anti-tumor targeting therapy drug Tivozanib | |
WO2023174449A1 (en) | Method for preparing n-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide | |
US20230203001A1 (en) | Solid forms of fasoracetam | |
CN107365298A (en) | A kind of preparation method of the benzyl propionate derivant of 2 methyl 2 ' | |
CN101928277B (en) | Preparation method of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amino]benzoic acid, related intermediate and application thereof | |
CN107298683B (en) | A kind of synthetic method of chirality benzodiazepine * compound | |
CN107188799B (en) | Fenbufen eutectic crystal and preparation method and application thereof | |
WO2021230198A1 (en) | Cocrystal of dihydroquinolinone compound | |
Su et al. | The supramolecular assemblies of 7-amino-2, 4-dimethylquinolinium salts and the effect of a variety of anions on their luminescent properties | |
WO2021259051A1 (en) | Method for improving synthesis process of hypidone free base | |
KR20180105926A (en) | Quinazoline, Quinoline Derivatives and Their Use as EGFR Kinase Inhibitors | |
CN108929217B (en) | Preparation method of 2-methyl-5-fluorobenzoic acid | |
CN103601726B (en) | Two kinds of ticagrelor pharmaceutical co-crystals and preparation method thereof | |
CN104130245A (en) | Pazopanib hydrochloride N crystal form and preparation thereof | |
TWI787751B (en) | Processes for producing amide compounds, and their crystalline and salt form | |
EP2540717B1 (en) | Lamivudine oxalate and preparation method thereof | |
WO2023197978A1 (en) | Crystal form of fgfr4 selective inhibitor compound, and preparation method therefor and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |