CN103923001A - Regorafenib salt, crystal thereof and preparation method of crystal - Google Patents
Regorafenib salt, crystal thereof and preparation method of crystal Download PDFInfo
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- CN103923001A CN103923001A CN201410181182.7A CN201410181182A CN103923001A CN 103923001 A CN103923001 A CN 103923001A CN 201410181182 A CN201410181182 A CN 201410181182A CN 103923001 A CN103923001 A CN 103923001A
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- NNCNMULVIHULID-UHFFFAOYSA-N Cc(cc1)c(C(F)(F)F)cc1NC(Nc(c(F)c1)ccc1Oc1cc(C(NC)=O)ncc1)=O Chemical compound Cc(cc1)c(C(F)(F)F)cc1NC(Nc(c(F)c1)ccc1Oc1cc(C(NC)=O)ncc1)=O NNCNMULVIHULID-UHFFFAOYSA-N 0.000 description 1
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- 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
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Abstract
The invention relates to two regorafenib organic acid salt as shown in formulas (I, II), namely 2-isethionate(isethionate) and esilate of regorafenib, and relates to two regorafenib isethionate (formula I) crystals named as a crystal A and a crystal B, two regorafenib esilate (formula II) crystals named as a crystal alpha and a crystal Beta and a novel regorafenib tosilate crystal named as a crystal N-1. The invention also relates to preparation methods of the regorafenib isethionate crystals A, B, the regorafenib esilate crystals alpha and beta and the novel regorafenib tosilate crystal N-1. The regorafenib isethionate crystals A, B, the regorafenib esilate crystals alpha and beta and the novel regorafenib tosilate crystal N-1 which are disclosed by the invention have X-ray powder diffraction characteristic absorption peaks and DSC (Differential Scanning Calorimeter) characteristic absorption peaks; and the regorafenib isethionate crystal A, the regorafenib esilate crystal beta and the novel regorafenib tosilate crystal N-1 which are disclosed by the invention have the advantages of stability, difficulty in moisture absorption and good solubility.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field.Be specifically related to be commonly called Rui Gefeini (Regorafenib); be the pharmacy acceptable salt of N-(the chloro-3-of 4-(trifluoromethyl) phenyl)-N '-2-fluoro-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea, crystal formation and preparation method thereof.
Background technology
The Chinese of Rui Gefeini (Regorafenib) is by name: N-(the chloro-3-of 4-(trifluoromethyl) phenyl)-N '-2-fluoro-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea, English by name:
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea。Trade(brand)name: Stivarga.Structural formula is as follows:
Rui Gefeini (Regorafenib) is a kind of novel many kinase inhibitor, can block the plurality of enzymes that promotes tumor growth, is found and is developed by Bayer (Bayer) company.In September, 2012, U.S. FDA is ratified it and is used for the treatment of metastatic colorectal carcinoma.It is granted that its new indication of in February, 2013 (patients with advanced gastrointestinal stromal tumors) is preferentially evaluated program by FDA.This medicine obtains Orphan drug qualification because being used for the treatment of rare disease simultaneously.
The crystal formation report of Rui Gefeini (Regorafenib) is less, and patent WO2005009961 discloses the preparation method of Rui Gefeini and salt thereof for the first time.The crystal formation of pointing out the Rui Gefeini (Regorafenib) of gained in compound patent WO2005009961 in patent WO2008043446 is Form I, also discloses for the first time Rui Gefeini (Regorafenib) hydrate (compounds Ⅳ) and preparation method thereof simultaneously.The pharmaceutical composition that contains Rui Gefeini (Regorafenib) hydrate and the purposes of controlling illness thereof are also disclosed simultaneously.But the preparation of disclosed Rui Gefeini (Regorafenib) hydrate need to be transformed by the stirring in long-time (1-2 week) by the specific crystal formation of Rui Gefeini (Regorafenib) free alkali (Form I) in water-containing solvent (acetone, acetonitrile etc.) in patent WO2008043446, production cycle is long, poor repeatability, is unfavorable for realizing suitability for industrialized production.Although disclose a kind of industrialized process for preparing of Rui Gefeini monohydrate in patent WO2011128261, but Rui Gefeini monohydrate less stable, in organic solvent, very easily lose crystal water and become the worse Rui Gefeini free alkali of solvability, and the water absorbability of Rui Gefeini monohydrate is larger, limits it and applied on preparation.
Xarelto (Sorafenib) and Rui Gefeini (Regorafenib) belong to many kinase inhibitor of same type, are all the exploitation of Bayer (Bayer) company.Xarelto (Sorafenib) goes on the market in the U.S. in December, 2005, and in September, 2006 is in Discussion on Chinese Listed.Commodity are by name: Nexavar.The medicinal substance form of Xarelto (Sorafenib) is Xarelto tosilate (SorafenibTosylate, compound V).Xarelto tosilate has the stability of better solvability and Geng Gao than Xarelto itself, be more suitable for for preparation.
Rui Gefeini and Xarelto structure very close (in structure, only differing from a F atom), belong to again many kinase inhibitor of same type.And Rui Gefeini monohydrate poorly soluble, has limited its application on preparation.Therefore, find and develop pharmaceutically acceptable other salt of a kind of Rui Gefeini (Regorafenib), and study and find that a kind of stability is high, solvability good, the stable crystal form that draws moist low pharmaceutical salts is very necessary.
Summary of the invention
Technical problem to be solved by this invention is, works out a kind of good stability, Rui Gefeini pharmaceutical salts and crystal formation thereof that solvability is good.
Technical problem of the present invention is achieved through the following technical solutions:
Rui Gefeini isetionate, its structural formula is suc as formula shown in (I):
Rui Gefeini ethyl sulfonate, its structural formula is suc as formula shown in (II):
The invention provides the unformed crystal formation of described Rui Gefeini isetionate, crystal form A and crystal form B, the crystal formation α of Rui Gefeini ethyl sulfonate, crystal formation β, and Rui Gefeini tosilate crystal formation N-1, and their preparation method.
A unformed crystal formation for Rui Gefeini isetionate, its X-ray powder diffraction collection of illustrative plates is as Fig. 1.
The unformed crystal formation of described Rui Gefeini isetionate, has substantially differential scanning calorimeter (DSC) collection of illustrative plates as shown in Figure 7.
DSC collection of illustrative plates shows: the unformed crystal formation of described Rui Gefeini isetionate has obvious exothermic peak 150 DEG C of left and right, and 199～205 DEG C of fusing endotherm(ic)peaks, maximum heat absorption melt temperature is 203 DEG C of left and right.
The unformed crystal formation of described Rui Gefeini isetionate, has substantially infrared (IR) collection of illustrative plates as shown in figure 13.
A crystal form A for Rui Gefeini isetionate, its X-ray powder diffraction collection of illustrative plates is 4.88,10.74,11.42,14.76,15.16 at 2 θ, 15.44,17.04,18.22,19.34,21.40,21.72,22.98,24.58,24.89, locate to there is characteristic peak for 26.84 and 31.22 ± 0.2 °.
Described Rui Gefeini isetionate crystal form A has substantially its X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 2.
Described Rui Gefeini isetionate crystal form A has substantially differential scanning calorimeter (DSC) collection of illustrative plates as shown in Figure 8.
DSC collection of illustrative plates shows: described Rui Gefeini isetionate crystal form A has 192～199 DEG C of fusing endotherm(ic)peaks, and maximum heat absorption melt temperature is 196 DEG C of left and right.
Described Rui Gefeini isetionate crystal form A has substantially infrared (IR) collection of illustrative plates as shown in figure 14.
The present invention also provides the preparation method of the crystal form A of described Rui Gefeini isetionate, has following steps:
(1), at the temperature of 0～50 DEG C, Rui Gefeini dissolution of solid, in organic solvent, is obtained to Rui Gefeini solution; Described organic solvent is the combination of one or more in alcohol, ketones solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably, and this alcohol also comprises moisture alcohol (purity that is alcohol can not be 100%); Ketones solvent is preferably from acetone, butanone or its combination; Described organic solvent is the mixture of one or several in ethanol, Virahol, acetone more preferably;
(2) the temperature of 0～50 DEG C, the 2-hydroxyethyl sulfonic acid aqueous solution is joined to step (1) gained Rui Gefeini solution;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) to wash;
(4) by the solid drying separating, obtain Rui Gefeini 2-hydroxyethyl sulfonate crystal form A; The preferred loft drier that uses is dry; Drying temperature is preferably 30-80 DEG C.
A crystal form B for Rui Gefeini isetionate, its X-ray powder diffraction collection of illustrative plates at 2 θ is: 7.24,8.56,11.49,13.37,14.74,15.57,16.48,17.20,18.79,19.84,23.42,25.86,26.36,27.40,31.62, locate to there is characteristic peak for 42.28 and 43.16 ± 0.2 °.
Described Rui Gefeini isetionate crystal form B has substantially its X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 3.
Described Rui Gefeini isetionate crystal form B has substantially differential scanning calorimeter (DSC) collection of illustrative plates as shown in Figure 9.
DSC collection of illustrative plates shows: described Rui Gefeini isetionate crystal form B has 207～213 DEG C of fusing endotherm(ic)peaks, and maximum heat absorption melt temperature is 210 DEG C of left and right.
Described Rui Gefeini isetionate crystal form B has substantially infrared (IR) collection of illustrative plates as shown in figure 15.
The preparation method who the invention provides two kinds of described Rui Gefeini isetionate crystal form Bs, the first preparation method comprises the steps:
(1) at 40 DEG C to solvent boiling point temperature, Rui Gefeini solid is joined to organic solvent, or in the mixed solvent of organic solvent and water, obtains Rui Gefeini solution; Described organic solvent is the combination of one or several in alcohol, esters solvent preferably; Described alcoholic solvent is the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably, and this alcohol also comprises moisture alcohol; Described esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in ethanol, Virahol, ethyl acetate more preferably;
(2) at 40 DEG C to solvent boiling point temperature, 2-hydroxyethyl sulfonic acid is added in the Rui Gefeini solution of above-mentioned steps (1) gained, be down to below room temperature;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, washs with the described organic solvent of step (1);
(4) by the solid drying separating, obtain Rui Gefeini 2-hydroxyethyl sulfonate crystal form B; Preferably, use loft drier dry; Drying temperature is preferably 30-80 DEG C.
The second preparation method, comprises the steps:
(1), at 0～40 DEG C of temperature, unformed Rui Gefeini isetionate crystal formation or crystal form A are dissolved in to optimum organic solvent and obtain Rui Gefeini isetionate solution; Described optimum organic solvent is preferably DMF (DMF), DMAc (N,N-dimethylacetamide), one or several mixtures in DMSO (dimethyl sulfoxide (DMSO));
(2), at 0～40 DEG C of temperature, in step (1) gained Rui Gefeini isetionate solution, be added dropwise to anti-solvent; Anti-solvent is preferably water, methyl tertiary butyl ether, one or several mixtures in heptane;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, with the described optimum organic solvent washing of step (1);
(4) by the solid drying separating, obtain Rui Gefeini 2-hydroxyethyl sulfonate crystal form B; Preferably, use loft drier dry; Drying temperature is preferably 30-80 DEG C.
A crystal formation α for Rui Gefeini ethyl sulfonate, its X-ray powder diffraction collection of illustrative plates is 7.22,8.28,9.92 at 2 θ, 12.14,16.74,17.04,18.42,20.02,20.67,22.32,24.28,27.06,29.14,29.50,33.40, locate to there is characteristic peak for 34.34,36.36,42.16 ± 0.2 °.
Described Rui Gefeini ethyl sulfonate crystal formation α has substantially its X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 4.
Described Rui Gefeini ethyl sulfonate crystal formation α has substantially differential scanning calorimeter (DSC) collection of illustrative plates as shown in figure 10.
DSC collection of illustrative plates shows: described Rui Gefeini ethyl sulfonate crystal formation α has obvious endotherm(ic)peak 80～100 DEG C of left and right, and 198～202 DEG C of fusing endotherm(ic)peaks, maximum heat absorption melt temperature is 198 DEG C of left and right.
Described Rui Gefeini ethyl sulfonate crystal formation α has substantially infrared (IR) collection of illustrative plates as shown in figure 16.
The preparation method who the invention provides the crystal formation α of described Rui Gefeini esilate, comprises the steps:
(1) at 40 DEG C to solvent boiling point temperature, Rui Gefeini solid is joined to moisture organic solvent, or obtains Rui Gefeini solution in the mixed solvent of organic solvent and water; Described organic solvent is the combination of one or several in alcohol, esters solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably, and this alcohol also comprises moisture alcohol; Esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in ethanol, Virahol, ethyl acetate more preferably;
(2) at 40 DEG C to solvent boiling point temperature, ethylsulfonic acid or the ethylsulfonic acid aqueous solution are added in the Rui Gefeini solution of step (1) gained, be down to room temperature;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) to wash;
(4) by the solid drying separating, obtain Rui Gefeini ethyl sulfonate crystal formation α; The preferred loft drier that uses is dried; Drying temperature is preferably 30-80 DEG C.
A crystal formation β for Rui Gefeini ethyl sulfonate, its X-ray powder diffraction collection of illustrative plates is 8.02,8.72,10.10 at 2 θ, 11.98,12.80,15.06,15.98,17.68,18.64,20.18,21.12,21.86,23.46,24.38,25.74,26.04,28.18, locate to there is characteristic peak for 30.37,32.20,37.56 and 40.90 ± 0.2 °.
Described Rui Gefeini ethyl sulfonate crystal formation β has substantially its X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 5.
Described Rui Gefeini ethyl sulfonate crystal formation β has substantially differential scanning calorimeter (DSC) collection of illustrative plates as shown in figure 11.
DSC collection of illustrative plates shows: described Rui Gefeini ethyl sulfonate crystal formation β has 201～207 DEG C of fusing endotherm(ic)peaks, and maximum heat absorption melt temperature is 205 DEG C of left and right.
Described Rui Gefeini ethyl sulfonate crystal formation β has substantially infrared (IR) collection of illustrative plates as shown in figure 17.
The preparation method who the invention provides the crystal formation β of described Rui Gefeini esilate, comprises the steps:
(1), at the temperature of 0～50 DEG C, Rui Gefeini solid and the ethylsulfonic acid aqueous solution are joined in organic solvent; Described organic solvent has one or several the combination being selected from alcohol, ketones solvent; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably, and this alcohol also comprises moisture alcohol; Ketones solvent is preferably from acetone, butanone or its combination; Described organic solvent is the mixture of one or several in methyl alcohol, ethanol, n-propyl alcohol, acetone more preferably; Described temperature is preferably room temperature to 45 DEG C;
(2) at the temperature of 0～50 DEG C, be stirred to and occur precipitation; Described temperature is preferably room temperature to 45 DEG C;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) to wash;
(4) by the solid drying separating, obtain Rui Gefeini ethyl sulfonate crystal formation β; The preferred loft drier that uses is dried; Drying temperature is preferably 30-80 DEG C.
A crystal formation N-1 for Rui Gefeini tosilate, its X-ray powder diffraction collection of illustrative plates is 4.34,13.22,14.68 at 2 θ, 16.44,17.96,18.79,19.62,20.03,20.72,21.70,22.24,22.92,26.76,28.06,28.90,29.98,31.34, locate to there is characteristic peak for 34.30,40.62,46.08 ± 0.2 °.
Described Rui Gefeini tosilate crystal formation N-1 has substantially its X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 6.
Described Rui Gefeini tosilate crystal formation N-1 has substantially differential scanning calorimeter (DSC) collection of illustrative plates as shown in figure 12.
DSC collection of illustrative plates shows: described Rui Gefeini tosilate crystal formation N-1 has 239～243 DEG C of fusing endotherm(ic)peaks, and maximum heat absorption melt temperature is 241 DEG C of left and right.
Described Rui Gefeini tosilate crystal formation N-1 has substantially infrared (IR) collection of illustrative plates as shown in figure 18.
The preparation method who the invention provides the crystal formation N-1 of described Rui Gefeini tosilate, comprises the steps:
(1) in room temperature to solvent boiling point temperature, Rui Gefeini solid is joined in organic solvent, obtain Rui Gefeini solution; Described organic solvent is the combination of one or several in alcohol, ketone, esters solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably, and this alcohol also comprises moisture alcohol; Ketones solvent is preferably from acetone, butanone or its combination; Esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in methyl alcohol, ethanol, n-propyl alcohol, acetone, ethyl acetate more preferably;
(2) in room temperature to solvent boiling point temperature, the solution of tosic acid solid or its organic solvent is added in the Rui Gefeini solution of step (1) gained, occur precipitation after, continue stir be not less than 1 hour; Described organic solvent is the combination of one or several in alcohol, ketone, esters solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably, and this alcohol also comprises moisture alcohol; Ketones solvent is preferably from acetone, butanone or its combination; Esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in methyl alcohol, ethanol, n-propyl alcohol, acetone, ethyl acetate more preferably;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) or (2) to wash;
(4) by the solid drying separating, obtain Rui Gefeini tosilate crystal formation N-1; Be preferably loft drier dry; Drying temperature is preferably 30-80 DEG C.
Room temperature of the present invention is 25 DEG C of left and right.
Rui Gefeini isetionate crystal form A of the present invention, Rui Gefeini ethyl sulfonate crystal formation β and Rui Gefeini tosilate crystal formation N-1 be not all containing crystal water and solvent, not static electrification, good stability, be difficult for the moisture absorption, solvability is good, and its character is obviously better than Rui Gefeini monohydrate of the prior art, is more conducive to preparation work.
And the Rui Gefeini isetionate crystal form A the present invention relates to, Rui Gefeini ethyl sulfonate crystal formation β and Rui Gefeini tosilate crystal formation N-1, its preparation method is simple, technique does not need specific installation, reproducible, easy and simple to handle, product utilization rate is high, and purity is high, is applicable to industrialization.
Brief description of the drawings
The XRPD figure of the unformed crystal formation of Fig. 1 embodiment 1.1 Rui Gefeini isetionates;
The XRPD figure of Fig. 2 embodiment 2.1 Rui Gefeini isetionate crystal form As;
The XRPD figure of Fig. 3 embodiment 3.1 Rui Gefeini isetionate crystal form Bs;
The XRPD figure of Fig. 4 embodiment 4.1 Rui Gefeini ethyl sulfonate crystal formation α;
The XRPD figure of Fig. 5 embodiment 5.1 Rui Gefeini ethyl sulfonate crystal formation β;
The XRPD figure of Fig. 6 embodiment 6.1 Rui Gefeini tosilate crystal formation N-1;
The DSC figure of the unformed crystal formation of Fig. 7 embodiment 1.1 Rui Gefeini isetionates;
The DSC figure of Fig. 8 embodiment 2.1 Rui Gefeini isetionate crystal form As;
The DSC figure of Fig. 9 embodiment 3.1 Rui Gefeini isetionate crystal form Bs;
The DSC figure of Figure 10 embodiment 4.1 Rui Gefeini ethyl sulfonate crystal formation α;
The DSC figure of Figure 11 embodiment 5.1 Rui Gefeini ethyl sulfonate crystal formation β;
The DSC figure of Figure 12 embodiment 6.1 Rui Gefeini tosilate crystal formation N-1;
The IR figure of the unformed crystal formation of Figure 13 embodiment 1.1 Rui Gefeini isetionates;
The IR figure of Figure 14 embodiment 2.1 Rui Gefeini isetionate crystal form As;
The IR figure of Figure 15 embodiment 3.1 Rui Gefeini isetionate crystal form Bs;
The IR figure of Figure 16 embodiment 4.1 Rui Gefeini ethyl sulfonate crystal formation α;
The IR figure of Figure 17 embodiment 5.1 Rui Gefeini ethyl sulfonate crystal formation β;
The IR figure of Figure 18 embodiment 6.1 Rui Gefeini tosilate crystal formation N-1;
Figure 19 embodiment 2.1 Rui Gefeini isetionate crystal form A illumination DSC collection of illustrative plates of 6 days;
Figure 20 embodiment 2.1 Rui Gefeini isetionate crystal form A high temperature are placed the DSC collection of illustrative plates of 6 days;
Figure 21 embodiment 2.1 Rui Gefeini isetionate crystal form A high humiditys are placed the DSC collection of illustrative plates of 6 days;
Figure 22 embodiment 3.1 Rui Gefeini isetionate crystal form B illumination DSC collection of illustrative plates of 6 days;
Figure 23 embodiment 3.1 Rui Gefeini isetionate crystal form B high temperature are placed the DSC collection of illustrative plates of 6 days;
Figure 24 embodiment 3.1 Rui Gefeini isetionate crystal form B high humiditys are placed the DSC collection of illustrative plates of 6 days;
Figure 25 embodiment 4.1 Rui Gefeini ethyl sulfonate crystal formation α illumination DSC collection of illustrative plates of 6 days;
Figure 26 embodiment 4.1 Rui Gefeini ethyl sulfonate crystal formation α high temperature are placed the DSC collection of illustrative plates of 6 days;
Figure 27 embodiment 4.1 Rui Gefeini ethyl sulfonate crystal formation α high humiditys are placed the DSC collection of illustrative plates of 6 days;
Figure 28 embodiment 5.1 Rui Gefeini ethyl sulfonate crystal formation β illumination DSC collection of illustrative plates of 6 days;
Figure 29 embodiment 5.1 Rui Gefeini ethyl sulfonate crystal formation β high temperature are placed the DSC collection of illustrative plates of 6 days;
Figure 30 embodiment 5.1 Rui Gefeini ethyl sulfonate crystal formation β high humiditys are placed the DSC collection of illustrative plates of 6 days;
Figure 31 embodiment 6.1 Rui Gefeini tosilate crystal formation N-1 illumination DSC collection of illustrative plates of 6 days;
Figure 32 embodiment 6.1 Rui Gefeini tosilate crystal formation N-1 high temperature are placed the DSC collection of illustrative plates of 6 days;
Figure 33 embodiment 6.1 Rui Gefeini tosilate crystal formation N-1 high humiditys are placed the DSC collection of illustrative plates of 6 days;
The XRPD figure of Figure 34 comparative example 1 Rui Gefeini monohydrate;
The IR figure of Figure 35 comparative example 1 Rui Gefeini monohydrate.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this.
Analyzing and testing condition of the present invention is as follows:
1, X-ray powder diffraction is to be recorded by RigakuD/max2550VB-pc diffractometer, employing Cu/K-alphal (λ=
) radiation, power: 40kV × 100mA gathers associated diffraction data in 0 ° of-60 ° of scope of 2 θ, walk wide 0.02 °, 6 °/min of sweep velocity.
2, DSC is detected by the resistance to DSC200F3 of speeding of Germany, temperature range 30-350 DEG C, and heat-up rate 10.0K/min, hole, nitrogen environment are pricked in sealing.
3, infrared spectra (IR) is detected by PEspectrumRXI, and temperature is 23 DEG C, and humidity is 54%.
In the Rui Gefeini referenced patent WO2005009961 using in the embodiment of the present invention prepared by embodiment 1.
The preparation of the unformed crystal formation of embodiment 1 Rui Gefeini isetionate
Embodiment 1.1
1.0g Rui Gefeini is joined in 10ml ethyl acetate and 1ml water, be warming up to 40 DEG C of dissolvings.0.33g2-hydroxyethyl sulfonic acid is joined in reaction solution, be not less than 40 DEG C of reactions 2 hours.Be cooled to after room temperature without Precipitation, reaction solution is concentrated into the dry unformed crystal formation of get Rui Gefeini isetionate.
1H-NMR(400MHz,DMSO)：δ2.65-2.68(t,J＝2.8Hz,2H)，2.80(d,J＝4.8Hz,3H)，3.64(t,J＝2.8Hz,2H)，6.71(broads,1H)，7.07-7.10(dd,J
1＝8.8Hz,J
2＝1.2Hz,1H)，7.26(t,J＝2.8Hz,1H)，7.34-7.37(dd,J
1＝11.6Hz,J
2＝2.8Hz,1H)，7.54(d,J＝2.0Hz,1H)，7.63(s,2H)，8.16(m,2H)，8.57(d,J＝5.6Hz,1H)，8.80(s,1H)，8.91(s,1H)，9.57(s,1H)。
Embodiment 1.2
Adopt the method identical with embodiment 1.1, but solvent for use ethyl acetate 10ml is replaced with to acetone 20ml.
The preparation of embodiment 2 Rui Gefeini isetionate crystal form As
Embodiment 2.1
3.0g Rui Gefeini is joined in 30ml acetone, be warming up to 40 DEG C.At this temperature, be added dropwise to 2-hydroxyethyl sulphur aqueous acid, maintain 40～45 DEG C of reactions 2 hours after having solid to separate out.Filter, and with 1ml washing with acetone filter cake, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini isetionate crystal form As.
Rui Gefeini isetionate crystal form A also can be made by following methods:
Embodiment 2.2
1.0g Rui Gefeini is joined in 10ml acetone, under room temperature, be added dropwise to 2-hydroxyethyl sulphur aqueous acid, have solid to separate out rear continuation and stir 2 hours.Filter, collect filter cake in 50 DEG C of forced air drying get Rui Gefeini isetionate crystal form As.
Embodiment 2.3
1.0g Rui Gefeini is joined in 10ml ethanol, under room temperature, be added dropwise to 2-hydroxyethyl sulphur aqueous acid, have solid to separate out rear continuation and stir 2 hours.Filter, collect filter cake in 50 DEG C of forced air drying get Rui Gefeini isetionate crystal form As.
The preparation of embodiment 3 Rui Gefeini isetionate crystal form Bs
Embodiment 3.1
1.0g Rui Gefeini is joined in 13ml Virahol, be heated to 50 DEG C.Be added dropwise to 2-hydroxyethyl sulphur aqueous acid (0.4g2-hydroxyethyl sulfonic acid is dissolved in 1ml water) at 50 DEG C.Be cooled to room temperature, have Precipitation, filter, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini isetionate crystal form Bs.
Embodiment 3.2
1.0g Rui Gefeini is joined in 10ml ethyl acetate and 1ml water, and being warming up to refluxes dissolves.0.33g2-hydroxyethyl sulfonic acid is joined in reaction solution, be not less than 40 DEG C of reactions 2 hours, be cooled to rapidly 0 DEG C, have a small amount of solid to separate out rear continuation and stir 1 hour, filter, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini isetionate crystal form Bs.
Embodiment 3.3
1.0g Rui Gefeini is joined in 5ml ethanol and 10ml Virahol, be heated to 50 DEG C above molten clear.Be added dropwise to above 2-hydroxyethyl sulphur aqueous acid (0.4g2-hydroxyethyl sulfonic acid is dissolved in 1ml water) at 50 DEG C.Be cooled to room temperature, have Precipitation, filter, with ethanol 1ml washing leaching cake, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini isetionate crystal form Bs.
Embodiment 3.4
By the unformed dissolution of solid of gained Rui Gefeini isetionate in 1.0g embodiment 1.1 in 2.5mlDMF, under stirring at room temperature, be added dropwise to wherein 2.5ml water, there is solid to separate out rear continuation and stir 2 hours, filter, collect filter cake in 50 DEG C of forced air drying get Rui Gefeini isetionate crystal form Bs.
Embodiment 3.5
Gained Rui Gefeini isetionate crystal form A in 1.0g embodiment 2.1 is dissolved in 2.5mlDMF, under stirring at room temperature, be added dropwise to wherein 2.5ml water, there is solid to separate out rear continuation and stir 3 hours, filter, collect filter cake in 50 DEG C of forced air drying get Rui Gefeini isetionate crystal form Bs.
Embodiment 3.6
By the unformed dissolution of solid of gained Rui Gefeini isetionate in 1.0g embodiment 1.1 in 3mlDMAc, under stirring at room temperature, be added dropwise to wherein 4ml water, having solid to separate out rear continuation stirs 2 hours, filter, water 1ml washing leaching cake, collects filter cake in 80 DEG C of forced air drying get Rui Gefeini isetionate crystal form Bs.
Embodiment 3.7
Gained Rui Gefeini isetionate crystal form A in 1.0g embodiment 2.1 is dissolved in 2.5mlDMSO, under stirring at room temperature, be added dropwise to wherein 5ml heptane, having solid to separate out rear continuation stirs 2 hours, filter, with heptane 2ml washing leaching cake, collect filter cake in 50 DEG C of forced air drying get Rui Gefeini isetionate crystal form Bs.
The preparation of embodiment 4 Rui Gefeini ethyl sulfonate crystal formation α
Embodiment 4.1
1.0g Rui Gefeini is joined in 10ml ethyl acetate and 1ml water, be warming up to reflux molten clear after, add 0.23g ethylsulfonic acid.Be cooled to room temperature, separate out rear continuation of precipitation and stir 2 hours, filter, with 1ml ethyl acetate washing leaching cake, collection filter cake is in 50～80 DEG C of forced air dryings to constant weight get Rui Gefeini ethyl sulfonate crystal formation α.
1H-NMR(400MHz,DMSO)：δ1.09(t,J＝7.6Hz,3H)，2.52(m,2H)，2.80(d,J＝8Hz,3H)，6.32(broads,1H)，7.07-7.09(dd,J
1＝8.8Hz,J
2＝1.6Hz,1H)，7.23-7.25(dd,J
1＝5.6Hz,J
2＝2.4Hz,1H)，7.33-7.37(dd,J1＝11.6Hz,J
2＝2.4Hz,1H)，7.51(d,J＝2.4Hz,1H)，7.63(s,2H)，8.14(m,2H)，8.56(d,J＝5.6Hz,1H)，8.33(s,1H)，8.89(d,J＝4.4Hz,1H)，9.60(s,1H)。
Water content: KF=3.3%
Embodiment 4.2
1.0g Rui Gefeini is joined in 10ml Virahol, be warming up to 50 DEG C, be added dropwise to the aqueous solution (0.23g ethylsulfonic acid is dissolved in 1ml water) of ethylsulfonic acid, be cooled to room temperature, separate out rear continuation of precipitation and stir 2 hours.Filter, collect filter cake in 50 DEG C of forced air drying get Rui Gefeini ethyl sulfonate crystal formation α.
Embodiment 4.3
1.0g Rui Gefeini is joined in the mixed solvent of 5ml ethanol and 20ml ethyl acetate, be warming up to more than 50 DEG C, the aqueous solution (0.23g ethylsulfonic acid is dissolved in 1ml water) that is added dropwise to ethylsulfonic acid, is cooled to room temperature, separates out rear continuation of precipitation and stirs 2 hours.Filter, with 2ml ethyl acetate washing leaching cake, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini ethyl sulfonate crystal formation α.
The preparation of embodiment 5 Rui Gefeini ethyl sulfonate crystal formation β
Embodiment 5.1
1.0g Rui Gefeini and 0.23g ethylsulfonic acid are joined in 10ml acetone, and stirring at room temperature, first moltenly separates out again precipitation after clear, continues to stir 2 hours.Filter, with 1ml washing with acetone filter cake, collect filter cake in 40～50 DEG C of forced air drying get Rui Gefeini ethyl sulfonate crystal formation β.
Embodiment 5.2
1.0g Rui Gefeini and 0.23g ethylsulfonic acid are joined in 10ml methyl alcohol, and stirring at room temperature, first moltenly separates out again precipitation after clear, continues to stir 2 hours.Filter, with 1ml methanol wash filter cake, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini ethyl sulfonate crystal formation β.
Embodiment 5.3
1.0g Rui Gefeini is joined in 20ml ethanol, be warming up to 45 DEG C, add after 0.23g ethylsulfonic acid, be down to stirring at room temperature more than 2 hours, filter, with ethanol 1ml washing leaching cake, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini ethyl sulfonate crystal formation β.
Embodiment 5.4
1.0g Rui Gefeini and 0.23g ethylsulfonic acid are joined in 5ml acetone and 3ml methyl alcohol, and stirring at room temperature, first moltenly separates out again precipitation after clear, continues to stir more than 2 hours.Filter, with 1ml washing with acetone filter cake, collect filter cake in 40～50 DEG C of forced air drying get Rui Gefeini ethyl sulfonate crystal formation β.
The preparation of embodiment 6 Rui Gefeini tosilate crystal formation N-1
Embodiment 6.1
1.0g Rui Gefeini is joined in 13ml n-propyl alcohol, add 0.4g tosic acid, be warming up to 50 DEG C and be moltenly cooled to room temperature after clear, continue to stir 4 hours after separating out precipitation.Filter, with 1ml n-propyl alcohol washing leaching cake, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini tosilate crystal formation N-1.
Embodiment 6.2
1.0g Rui Gefeini is joined in 10ml dehydrated alcohol, be added dropwise to the ethanol solution (0.4g tosic acid is dissolved in 1ml dehydrated alcohol) of tosic acid, first moltenly separate out again precipitation after clear, continue to stir 2 hours.Filter, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini tosilate crystal formation N-1.
Embodiment 6.3
1.0g Rui Gefeini is joined in the mixed solvent of 10ml ethyl acetate and 0.75ml water, be warming up to backflow, add the aqueous solution (0.4g tosic acid is dissolved in 0.75ml water) of tosic acid, be down to room temperature, separate out rear continuation of precipitation and stir 2 hours.Filter, collect filter cake in 50～80 DEG C of forced air drying get Rui Gefeini tosilate crystal formation N-1.
Embodiment 6.4
1.0g Rui Gefeini is joined in 10ml acetone, under room temperature, be added dropwise to acetone (5ml) solution of tosic acid (0.4g), first moltenly separate out again precipitation after clear, continue to stir 2 hours, filter, collect filter cake in 40～50 DEG C of forced air drying get Rui Gefeini tosilate crystal formation N-1.
Embodiment 6.5
1.0g Rui Gefeini is joined in the mixed solvent of 5ml acetone and 15ml Virahol, under room temperature, be added dropwise to acetone (5ml) solution of tosic acid (0.4g), first moltenly separate out again precipitation after clear, continue to stir 2 hours, filter, collect filter cake in 40～50 DEG C of forced air drying get Rui Gefeini tosilate crystal formation N-1.
The preparation of comparative example 1 Rui Gefeini monohydrate
The Rui Gefeini monohydrate using in the present invention is " work embodiment-stage 3 " method preparation in referenced patent WO2011128261 (Chinese patent CN102947271 of the same clan).
Test case 1 electrostatic detection
Contact respectively each crystal formation of the Rui Gefeini salt that embodiment 1.1, embodiment 2.1, embodiment 3.1, embodiment 4.1, embodiment 5.1, embodiment 6.1 and comparative example 1 obtain with the glass stick after friction, whether observe static electrification, the results are shown in Table 1.
The electrostatic detection result of each crystal formation of table 1 Rui Gefeini salt
| Crystal formation type | Embodiment 1.1 | Embodiment 2.1 | Embodiment 3.1 | Embodiment 4.1 | Embodiment 5.1 | Embodiment 6.1 | Comparative example 1 |
| Static | Nothing | Nothing | Nothing | Nothing | Nothing | Nothing | Nothing |
Test case 2 solvabilities detect
The solubleness detected result of each crystal formation of table 2 Rui Gefeini salt in different solvents
Remarks: the pH4.1 aqueous solution is: get 2.99g Sodium acetate trihydrate, accurately weighed, to 1L water, adjust pH=4.1 with acetic acid.
Conclusion: Rui Gefeini isetionate crystal form A, the solvability of Rui Gefeini ethyl sulfonate crystal formation α, crystal formation β and Rui Gefeini tosilate crystal formation N-1 is all better than Rui Gefeini monohydrate of the prior art.
Test case 3 draws moist detection
The each crystal formation that in humidity is the Rui Gefeini salt that under 80% condition, embodiment 2.1, embodiment 3.1, embodiment 4.1, embodiment 5.1, embodiment 6.1 and comparative example 1 obtained is placed 24 hours, detects the moisture absorption weightening finish of each crystal formation of Rui Gefeini salt.
The water absorbability detected result of each crystal formation of table 3 Rui Gefeini salt
Conclusion: Rui Gefeini isetionate crystal form A, crystal form B, Rui Gefeini ethyl sulfonate crystal formation α, the water absorbability of crystal formation β and Rui Gefeini tosilate crystal formation N-1 is all lower than Rui Gefeini monohydrate.The water absorbability minimum of the Ge Feini of its China and Sweden isetionate crystal form B and Rui Gefeini ethyl sulfonate crystal formation β, is conducive to preparation work.
Test case 4 Detection of Stability
Each crystal formation of the Rui Gefeini salt of embodiment 2.1, embodiment 3.1, embodiment 4.1, embodiment 5.1, embodiment 6.1 gained is placed in respectively to high light (45001x ± 5001x), high temperature, high humidity environment, within 6 days, does purity (HPLC) detection and DSC detection in placement respectively.
Test condition is:
Illumination condition: exposure intensity 45001x ± 5001x
Hot conditions: temperature 60 C;
Super-humid conditions: humidity 95% (saturated potassium nitrate solution), 25 DEG C of temperature.
Result shows:
The Rui Gefeini isetionate crystal form A of embodiment 2.1 is at illumination (45001x ± 5001x), high temperature (60 DEG C), high humidity (95% (saturated potassium nitrate solution), 25 DEG C of temperature) environment in place 0 day consistent with the DSC collection of illustrative plates of 6 days, as Fig. 8,19-21, there is no the moisture absorption, there is not any variation, prove at its stable crystal form of this condition.
The Rui Gefeini isetionate crystal form B of embodiment 3.1 is at illumination (45001x ± 5001x), high temperature (60 DEG C), high humidity (95% (saturated potassium nitrate solution), 25 DEG C of temperature) environment in place 0 day consistent with the DSC collection of illustrative plates of 6 days, as Fig. 9,22-24, there is no the moisture absorption, there is not any variation, prove at its stable crystal form of this condition.
The Rui Gefeini ethyl sulfonate crystal formation α of embodiment 4.1 is at illumination (45001x ± 5001x), high temperature (60 DEG C), high humidity (95% (saturated potassium nitrate solution), 25 DEG C of temperature) environment in place DSC collection of illustrative plates after 6 days and place the DSC of 0 day consistent, as Figure 10,25-27, there is no the moisture absorption, there is not any variation, prove at its stable crystal form of this condition.
The Rui Gefeini ethyl sulfonate crystal formation β of embodiment 5.1 is at illumination (45001x ± 5001x), high temperature (60 DEG C), high humidity (95% (saturated potassium nitrate solution), 25 DEG C of temperature) environment in place 0 day consistent with the DSC collection of illustrative plates of 6 days, as, 11,28-30, there is no the moisture absorption, there is not any variation, prove at its stable crystal form of this condition.
The Rui Gefeini tosilate crystal formation N-1 of embodiment 6.1 is at illumination (45001x ± 5001x), high temperature (60 DEG C), high humidity (95% (saturated potassium nitrate solution), 25 DEG C of temperature) environment in place 0 day consistent with the DSC collection of illustrative plates of 6 days, as Figure 12,31-33, there is no the moisture absorption, there is not any variation, prove at its stable crystal form of this condition.
The above; it is only the specific embodiment of the present invention; but protection scope of the present invention is not limited to this; any those of ordinary skill in the art are in disclosed technical scope; the variation that can expect without creative work or replacement, within all should being encompassed in protection scope of the present invention.
Claims (24)
1. Rui Gefeini isetionate, its structural formula is suc as formula shown in (I):
2. Rui Gefeini ethyl sulfonate, its structural formula is suc as formula shown in (II):
3. the unformed crystal formation of Rui Gefeini isetionate described in claim 1, is characterized in that: have X-ray powder diffraction collection of illustrative plates as shown in Figure 1.
4. the crystal form A of Rui Gefeini isetionate described in claim 1, is characterized in that: diffraction angle 2 θ of its X-ray powder diffraction figure are 4.88,10.74,11.42,14.76,15.16,15.44,17.04,18.22,19.34,21.40,21.72,22.98, locate to there is characteristic peak for 24.58,24.89,26.84 and 31.22 ± 0.2 °.
5. the crystal form A of Rui Gefeini isetionate as claimed in claim 4, is characterized in that: have substantially XRPD collection of illustrative plates as shown in Figure 2.
6. the crystal form A of Rui Gefeini isetionate as claimed in claim 4, is characterized in that: have infared spectrum as shown in figure 14.
7. the preparation method of the crystal form A of Rui Gefeini isetionate described in any one in claim 4-6, is characterized in that having following steps:
(1), at the temperature of 0～50 DEG C, Rui Gefeini dissolution of solid, in organic solvent, is obtained to Rui Gefeini solution; Described organic solvent is the combination of one or more in alcohol, ketones solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably; Ketones solvent is preferably from acetone, butanone or its combination; Described organic solvent is the mixture of one or several in ethanol, Virahol, acetone more preferably;
(2) the temperature of 0～50 DEG C, the 2-hydroxyethyl sulfonic acid aqueous solution is joined to step (1) gained Rui Gefeini solution;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) to wash;
(4) by the solid drying separating, obtain Rui Gefeini 2-hydroxyethyl sulfonate crystal form A; The preferred loft drier that uses is dry; Drying temperature is preferably 30-80 DEG C.
8. the crystal form B of Rui Gefeini isetionate described in claim 1, is characterized in that: diffraction angle 2 θ of its X-ray powder diffraction figure are 7.24,8.56,11.49,13.37,14.74,15.57,16.48,17.20,18.79,19.84,23.42,25.86,26.36,27.40, locate to there is characteristic peak for 31.62,42.28 and 43.16 ± 0.2 °.
9. the crystal form B of Rui Gefeini isetionate as claimed in claim 8, is characterized in that: have XRPD collection of illustrative plates as shown in Figure 3.
10. the crystal form B of Rui Gefeini isetionate as claimed in claim 8, is characterized in that: have infared spectrum as shown in figure 15.
In 11. claim 8-10, the preparation method of the crystal form B of described Rui Gefeini isetionate described in any one, is characterized in that, comprises the following steps:
(1) at 40 DEG C to solvent boiling point temperature, Rui Gefeini solid is joined to organic solvent, or in the mixed solvent of organic solvent and water, obtains Rui Gefeini solution; Described organic solvent is the combination of one or more in alcohol, esters solvent preferably; Described alcoholic solvent is the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably; Described esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in ethanol, Virahol, ethyl acetate more preferably;
(2) at 40 DEG C to solvent boiling point temperature, 2-hydroxyethyl sulfonic acid is added in the Rui Gefeini solution of above-mentioned steps (1) gained, be down to below room temperature;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, washs with the described organic solvent of step (1);
(4) by the solid drying separating, obtain Rui Gefeini 2-hydroxyethyl sulfonate crystal form B; Preferably, use loft drier dry; Drying temperature is preferably 30-80 DEG C;
Or
(1), at 0～40 DEG C of temperature, unformed Rui Gefeini isetionate crystal formation or crystal form A are dissolved in to optimum organic solvent and obtain Rui Gefeini isetionate solution; Described optimum organic solvent is preferably DMF, N,N-dimethylacetamide, one or several mixtures in dimethyl sulfoxide (DMSO);
(2), at 0～40 DEG C of temperature, in step (1) gained Rui Gefeini isetionate solution, be added dropwise to anti-solvent; Anti-solvent is preferably water, methyl tertiary butyl ether, one or several mixtures in heptane;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, with the described optimum organic solvent washing of step (1);
(4) by the solid drying separating, obtain Rui Gefeini 2-hydroxyethyl sulfonate crystal form B; Preferably, use loft drier dry; Drying temperature is preferably 30-80 DEG C.
The crystal formation α of Rui Gefeini ethyl sulfonate described in 12. claims 2, is characterized in that: diffraction angle 2 θ of its X-ray powder diffraction figure are 7.22,8.28,9.92,12.14,16.74,17.04,18.42,20.02,20.67,22.32,24.28,27.06,29.14,29.50,33.40, locate to there is characteristic peak for 34.34,36.36,42.16 ± 0.2 °.
The 13. crystal formation α of Rui Gefeini esilate as claimed in claim 12, is characterized in that: have XRPD collection of illustrative plates as shown in Figure 4.
The 14. crystal formation α of Rui Gefeini esilate as claimed in claim 12, is characterized in that: have differential scanning calorimeter collection of illustrative plates as shown in figure 10; It has endotherm(ic)peak at 80-100 DEG C, has fusing endotherm(ic)peak at 198-202 DEG C, and maximum heat absorption melt temperature is 198 DEG C.
The 15. crystal formation α of Rui Gefeini esilate as claimed in claim 12, is characterized in that: have infared spectrum as shown in figure 16.
In 16. claim 12-15, the preparation method of the crystal formation α of Rui Gefeini esilate described in any one, is characterized in that, comprises the steps:
(1) at 40 DEG C to solvent boiling point temperature, Rui Gefeini solid is joined to moisture organic solvent, or obtains Rui Gefeini solution in the mixed solvent of organic solvent and water; Described organic solvent has one or more the combination being selected from alcohol, esters solvent; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably; Esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in ethanol, Virahol, ethyl acetate more preferably;
(2) at 40 DEG C to solvent boiling point temperature, ethylsulfonic acid or the ethylsulfonic acid aqueous solution are added in the Rui Gefeini solution of step (1) gained, be down to room temperature;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) to wash;
(4) by the solid drying separating, obtain Rui Gefeini ethyl sulfonate crystal formation α; The preferred loft drier that uses is dried; Drying temperature is preferably 30-80 DEG C.
The crystal formation β of Rui Gefeini esilate described in 17. claims 2, is characterized in that: diffraction angle 2 θ of its X-ray powder diffraction figure are 8.02,8.72,10.10,11.98,12.80,15.06,15.98,17.68,18.64,20.18,21.12,21.86,23.46,24.38,25.74,26.04,28.18, locate to there is characteristic peak for 30.37,32.20,37.56 and 40.90 ± 0.2 °.
The 18. crystal formation β of Rui Gefeini esilate as claimed in claim 17, is characterized in that: have XRPD collection of illustrative plates as shown in Figure 5.
The 19. crystal formation β of Rui Gefeini esilate as claimed in claim 17, is characterized in that: have infared spectrum as shown in figure 17.
In 20. claim 17-19, the preparation method of the crystal formation β of Rui Gefeini esilate described in any one, is characterized in that, comprises the steps:
(1), at the temperature of 0～50 DEG C, Rui Gefeini solid and the ethylsulfonic acid aqueous solution are joined in organic solvent; Described organic solvent is the one or more combination in alcohol, ketones solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably; Ketones solvent is preferably from acetone, butanone or its combination; Described organic solvent is the mixture of one or several in methyl alcohol, ethanol, n-propyl alcohol, acetone more preferably; Described temperature is preferably room temperature to 45 DEG C;
(2) at the temperature of 0～50 DEG C, be stirred to and occur precipitation; Described temperature is preferably room temperature to 45 DEG C;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) to wash;
(4) by the solid drying separating, obtain Rui Gefeini ethyl sulfonate crystal formation β; The preferred loft drier that uses is dried; Drying temperature is preferably 30-80 DEG C.
The crystal formation N-1 of 21. Rui Gefeini tosilate, is characterized in that: diffraction angle 2 θ of its X-ray powder diffraction figure are 4.34,13.22,14.68,16.44,17.96,18.79,19.62,20.03,20.72,21.70,22.24,22.92,26.76,28.06,28.90,29.98,31.34, locate to there is characteristic peak for 34.30,40.62,46.08 ± 0.2 °.
The 22. crystal formation N-1 of Rui Gefeini tosilate as claimed in claim 21, is characterized in that: have XRPD collection of illustrative plates as shown in Figure 6.
The 23. crystal formation N-1 of Rui Gefeini tosilate as claimed in claim 21, is characterized in that: have infared spectrum as shown in figure 18.
In 24. claim 21-23, the preparation method of the crystal formation N-1 of Rui Gefeini tosilate described in any one, is characterized in that, comprises the steps:
(1) in room temperature to solvent boiling point temperature, Rui Gefeini solid is joined in organic solvent, obtain Rui Gefeini solution; Described organic solvent is the combination of one or more in alcohol, ketone, esters solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably; Ketones solvent is preferably from acetone, butanone or its combination; Esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in methyl alcohol, ethanol, n-propyl alcohol, acetone, ethyl acetate more preferably;
(2) in room temperature to solvent boiling point temperature, the solution of tosic acid solid or its organic solvent is added in the Rui Gefeini solution of step (1) gained, occur precipitation after, continue stir be not less than 1 hour; Described organic solvent is the combination of one or more in alcohol, ketone, esters solvent preferably; Alcoholic solvent is wherein the combination of one or more in methyl alcohol, ethanol, Virahol, n-propyl alcohol preferably; Ketones solvent is preferably from acetone, butanone or its combination; Esters solvent is the combination of one or more in ethyl formate, butyl formate, ethyl acetate, methyl acetate, butylacetate, isopropyl acetate preferably; Described organic solvent is the mixture of one or several in methyl alcohol, ethanol, n-propyl alcohol, acetone, ethyl acetate more preferably;
(3) solid is separated from suspension liquid; Preferably, described separation also comprises filtration, uses the described organic solvent of step (1) or (2) to wash;
(4) by the solid drying separating, obtain Rui Gefeini tosilate crystal formation N-1; Be preferably loft drier dry; Drying temperature is preferably 30-80 DEG C.
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| CN111777551A (en) * | 2020-07-21 | 2020-10-16 | 天津理工大学 | Eutectic of regorafenib and suberic acid and preparation method thereof |
| CN111777552A (en) * | 2020-07-22 | 2020-10-16 | 天津理工大学 | Eutectic of regorafenib and pimelic acid and preparation method thereof |
| CN111995571A (en) * | 2020-08-07 | 2020-11-27 | 天津理工大学 | Eutectic crystal of regorafenib and maleic acid and preparation method thereof |
| CN111777551B (en) * | 2020-07-21 | 2024-11-19 | 天津理工大学 | Eutectic of regorafenib and suberic acid and preparation method thereof |
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| CN105985287B (en) * | 2015-02-13 | 2018-07-17 | 上海京新生物医药有限公司 | A kind of Rui Gefeini novel crystal forms |
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| CN105879049A (en) * | 2016-05-13 | 2016-08-24 | 浙江大学 | Clathrate compound of regorafenib-beta-cyclodextrin (RG-beta-CD) and preparation method thereof |
| CN105879049B (en) * | 2016-05-13 | 2019-03-26 | 浙江大学 | A kind of Rui Gefeini and the inclusion compound of beta-cyclodextrin and preparation method thereof |
| CN111116462A (en) * | 2020-01-13 | 2020-05-08 | 青岛市中心医院 | Regorafenib and wogonin co-crystal and application thereof |
| CN111777551A (en) * | 2020-07-21 | 2020-10-16 | 天津理工大学 | Eutectic of regorafenib and suberic acid and preparation method thereof |
| CN111777551B (en) * | 2020-07-21 | 2024-11-19 | 天津理工大学 | Eutectic of regorafenib and suberic acid and preparation method thereof |
| CN111777552A (en) * | 2020-07-22 | 2020-10-16 | 天津理工大学 | Eutectic of regorafenib and pimelic acid and preparation method thereof |
| CN111777552B (en) * | 2020-07-22 | 2024-11-19 | 天津理工大学 | Eutectic crystal of regorafenib and pimelic acid and preparation method thereof |
| CN111995571A (en) * | 2020-08-07 | 2020-11-27 | 天津理工大学 | Eutectic crystal of regorafenib and maleic acid and preparation method thereof |
| CN111995571B (en) * | 2020-08-07 | 2021-12-03 | 天津理工大学 | Eutectic crystal of regorafenib and maleic acid and preparation method thereof |
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| Publication number | Publication date |
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| CN103923001B (en) | 2016-02-10 |
| CN104829523B (en) | 2017-10-31 |
| WO2015165320A1 (en) | 2015-11-05 |
| CN104829523A (en) | 2015-08-12 |
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