CN105585523A - Novel sorafenib TsOH crystal form as well as preparation method and application thereof - Google Patents

Novel sorafenib TsOH crystal form as well as preparation method and application thereof Download PDF

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Publication number
CN105585523A
CN105585523A CN201511018488.1A CN201511018488A CN105585523A CN 105585523 A CN105585523 A CN 105585523A CN 201511018488 A CN201511018488 A CN 201511018488A CN 105585523 A CN105585523 A CN 105585523A
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bay
type crystal
sorafenib
water
water thing
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杨世琼
康立涛
李倩
赵爱平
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Anhui north card Pharmaceutical Co., Ltd.
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SHANGHAI BIOCOMPOUNDS CHEMLAB CO Ltd
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the technical field of medicine, in particular to a novel sorafenib TsOH crystal form as well as a preparation method and an application thereof, and provides a type E crystal of a sorafenib TsOH monohydrate. In an X-ray powder diffraction pattern, the type E crystal of the sorafenib TsOH monohydrate displays characteristic diffraction peaks when 2-theta is about 8.961 degrees plus/minus 0.2 degrees,13.379 degrees plus/minus 0.2 degrees, 13.939 degrees plus/minus 0.2 degrees, 19.718 degrees plus/minus 0.2 degrees, 20.658 degrees plus/minus 0.2 degrees, 22.761 degrees plus/minus 0.2 degrees, 23.561 degrees plus/minus 0.2 degrees, 24.080 degrees plus/minus 0.2 degrees and 24.881 degrees plus/minus 0.2 degrees. A compound shown in a formula (II) of the type E crystal of the sorafenib TsOH monohydrate is high in product yield and excellent in product quality and has the advantages of good stability, high crystal purity, convenience in storage and the like.

Description

Novel crystal forms of a kind of Sorafenib Tosylate and its production and use
Technical field
The present invention relates to medical technical field, particularly relate to novel crystal forms of a kind of Sorafenib Tosylate and preparation method thereofAnd purposes.
Background technology
Sorafenib Tosylate (SorafenibTsOH, molecular formula C28H24ClF3N4O6S, molecular weight 637.03) haveStructure shown in formula I, chemical name is 4-{4-[3-(the chloro-3-trifluoromethyl of 4-) uride] phenoxy group } pyridine-2-carboxamide is to firstBenzene sulfonic acid. By many target spots of one anti-cancer agent of German Bayer and Onyx exploitation listing (trade name: Nexavar, how luckyBeautiful). In December, 2005, Sorafenib Tosylate is ratified the line medicine as treatment advanced renal cell cancer fast through U.S. FDAThing Initial Public Offering. In June, 2006, Sorafenib Tosylate is used for the treatment of metastatic hepatic carcinoma indication and has obtained again FDAExamination & approval qualification fast. In August, 2009, state food and drug administration approval Bayer Bitterfeld GmbH drugmaker to tolueneSulfonic acid Sorafenib sheet formally enters Chinese market, for inoperable advanced liver cancer treatment.
Sorafenib Tosylate, as the oral anti-cancer agent of micromolecular many target spots, can not only suppress RAF-MEK-ERKPath, can also suppress the activity of the multiple receptor type tyrosine kinases such as VEGFR, PDGFR, Flt-3, C-Kit, thereby reachThe effect of inhibition tumor cell propagation and tumor angiogenesis.
The preparation side of Sorafenib Tosylate is disclosed in CN101052619, WO2009034308, US20130005980Method. CN101065360 discloses tri-kinds of crystal of I, II, III, the Sorafenib Tosylate first of Sorafenib TosylateAlcoholic solvent compound and alcohol solvent compound and corresponding preparation method. Wherein, polymorphic I is stable crystal form, and polymorphic IIBe metastable, be heated to 200 DEG C by polymorphic II, then be down to long-time stirring of room temperature with given pace and turn crystalline substance and obtain polymorphicI, is unfavorable for industry's enlarging production. It is a kind of with reflux in acetone acetonitrile mixed solvent salify, cooling that CN104177292A providesCrystallization, obtains the preparation method of polymorphic I Sorafenib Tosylate, and the method adopts mixed solvent, has increased in medicineThe possibility of dissolvent residual, although method is easy, what obtain remains polymorphic I.
The different polymorphics of a bulk drug can have different chemistry and physical characteristic, comprise fusing point, chemical reactivity, apparentSolubility, rate of dissolution, optics and engineering properties, vapour pressure and density. These characteristics can directly affect bulk drug and preparationProcessing and/or production, and can affect stability, solubility and the bioavilability of preparation. In the time there is polymorphic in compound,Because specific polymorph has specific macroscopic property and stability, therefore, in the process of preparation, understand in each agentThe crystal formation of the compound of applying in type is important, to ensure the pharmaceutical active compounds of process application same modality. Therefore,Keeping pharmaceutical active compounds is that single crystal formation or the known mixture of some crystal formations is necessary.
The discovery of the new polymorph of pharmaceutical active compounds provides the machine that improves medicine physical characteristic or prepare new formulationMeeting, has expanded whole character of material, and for example different polymorphs may have different solubility or pharmacokineticsMatter, can know the research of pharmaceutical active compounds and preparation thereof better. And in the time judging that whether which kind of crystal formation preferred,Much character and the preferred polymorph that must compare them make a choice based on many physical propertys. Completely possibleA kind of polymorphic in some aspects as difficulty or ease, the stability etc. of preparation to be considered under critical condition be preferred.
Therefore, Sorafenib Tosylate one water thing (SorafenibnTsOHmonohydrate, molecular formula provided by the inventionC21H16ClF3N4O3·nC7H8O3SH2O, molecular weight 464.82+172.20n+18.01) there is the structure shown in formula II, chemistryName is called 4-{4-[3-(the chloro-3-trifluoromethyl of 4-) uride] phenoxy group } polymorphic of pyridine-2-carboxamide p-methyl benzenesulfonic acid one hydrationThing has commercial value and researching value in the manufacture of medicine and application thereof.
Summary of the invention
The shortcoming of prior art in view of the above, the object of the present invention is to provide Sorafenib Tosylate novel crystal forms andPreparation Method And The Use, for solving the problems of the prior art.
For achieving the above object and other relevant objects, the invention provides a kind of E type crystalline substance of Sorafenib Tosylate one water thingBody, in X-ray powder diffraction (XRPD), described E type crystal is in approximately 8.961 ± 0.2 ° of 2-θ, 13.379 ± 0.2°,13.939±0.2°,19.718±0.2°,20.658±0.2°,22.761±0.2°,23.561±0.2°,24.080±0.2°,Locate indicating characteristic diffraction maximum for 24.881 ± 0.2 °.
Described X-ray powder diffraction adopts Cu-K α radiation.
Preferably, the E type crystal of described Sorafenib Tosylate one water thing is in approximately 8.961 ± 0.2 ° of 2-θ, 13.379 ± 0.2°,13.939±0.2°,17.120±0.2°，19.718±0.2°,20.658±0.2°,22.761±0.2°,23.561±0.2°,24.080±0.2°,24.881±0.2°,25.720±0.2°,27.041±0.2°,27.361±0.2°,28.278±0.2°Place's indicating characteristic diffraction maximum.
Preferred, the E type crystal of described Sorafenib Tosylate one water thing is approximately 8.961 ± 0.2 ° of 2-θ, 13.379 ±0.2°,13.939±0.2°,17.120±0.2°,19.718±0.2°,20.658±0.2°,22.761±0.2°,23.561±0.2°,24.080±0.2°,24.881±0.2°,25.720±0.2°,27.041±0.2°,27.361±0.2°,28.278±0.2 °, 31.702 ± 0.2 °, locate indicating characteristic diffraction maximum for 36.180 ± 0.2 °.
In an embodiment of the present invention, the X-ray powder diffraction of the E type crystal of Sorafenib Tosylate one water thing asShown in accompanying drawing 1, and there is feature as shown in table 1:
Table 1
Preferably, the E type crystal of described Sorafenib Tosylate one water thing, in thermogravimetry (TGA), adds hot temperatureDegree, from 25～350 DEG C, loses weight 3.334% left and right at 75～138 DEG C.
The result of thermogravimetry is further determined and illustrates that this crystal is not solvate, being a water thing.
Preferably, in the E type crystal of described Sorafenib Tosylate one water thing, p-methyl benzenesulfonic acid: BAY 43-9006 free alkaliAverage molecular mol ratio be (0.50～0.52): 1.
Second aspect present invention provides the preparation method of the E type crystal of described Sorafenib Tosylate one water thing, comprises as followsStep:
1) prepare BAY 43-9006 solution;
2) a hydration p-methyl benzenesulfonic acid is added in BAY 43-9006 solution, react 0.5～1h at 70～95 DEG C;
3), by step 2 gained reactant liquor cooling, crystallization, obtain the E of described Sorafenib Tosylate one water thing after dryType crystal.
Preferably, the solution that described BAY 43-9006 solution is BAY 43-9006 free alkali (CASNo.284461-73-0).
Preferably, in described step 1, the solvent of BAY 43-9006 solution be selected from a kind of in Isosorbide-5-Nitrae-dioxane, water, DMF orMultiple combination.
Preferred, the solvent of described BAY 43-9006 solution is mixed solvent or the DMF of Isosorbide-5-Nitrae-dioxane and water. Isosorbide-5-Nitrae-In the mixed solvent of dioxane and water, the volume ratio of water and Isosorbide-5-Nitrae dioxane is 1:(3～10).
Preferably, in described step 1, time prepared by BAY 43-9006 solution, can adopt the method for heating to make system molten clear.
Those skilled in the art can, according to the actual conditions of reaction, adjust the solvent load of BAY 43-9006 solution, real in the present invention oneExecute in example, time prepared by the solution of BAY 43-9006 free alkali, 1g BAY 43-9006 free alkali uses 8～22ml mixed solvent (above-mentioned waterMixed solvent with Isosorbide-5-Nitrae dioxane composition) dissolve, and system is made at 20～80 DEG C system molten clear rapidly, at thisInvent in another embodiment, 1g BAY 43-9006 free alkali uses 1～2mlDMF to dissolve.
Preferably, in described step 2, at 70～95 DEG C, a hydration p-methyl benzenesulfonic acid is added in BAY 43-9006 solution, preferablyFor a hydration p-methyl benzenesulfonic acid is added in BAY 43-9006 solution fast.
In described step 2, those skilled in the art can choose suitable method by a hydration pair according to the concrete condition of reaction systemToluenesulfonic acid adds in BAY 43-9006 solution fast, in an embodiment of the present invention, a hydration p-methyl benzenesulfonic acid is added to rope fastConcrete grammar in La Feini solution is: a hydration p-methyl benzenesulfonic acid is dissolved in to appropriate and suitable solvent (as Isosorbide-5-Nitrae-dioxane)Middle acquisition, to benzene methanesulfonic acid solution, then will add in BAY 43-9006 solution benzene methanesulfonic acid solution fast.
Preferably, in described step 2, the mol ratio of a hydration p-methyl benzenesulfonic acid and BAY 43-9006 is 1:(0.49～1.02).
In a hydration p-methyl benzenesulfonic acid and step 1 that the mol ratio of described benzene methanesulfonic acid and BAY 43-9006 specifically refers to add in step 2The mol ratio of the BAY 43-9006 (being BAY 43-9006 free alkali in one embodiment of the invention) using while preparing BAY 43-9006 solution.
Preferably, in described step 3, step 2 gained reactant liquor is cooled to-5～18 DEG C.
In described step 3, those skilled in the art can choose suitable method according to the concrete condition of reaction system reactant liquor is fallenTemperature, in an embodiment of the present invention, by the concrete grammar of reactant liquor cooling is: first reactant liquor naturally stirred and is cooled to room temperature,Stir borehole cooling at freezing liquid again.
Preferably, in described step 3, the actual conditions of crystallization is: by the reactant liquor room temperature of first naturally lowering the temperature, then fall with freezing liquidTemperature is to-5～18 DEG C, and insulation crystallization 3～25h, divides isolated crystal. Described insulation crystallization is preferably and stirs insulation crystallization, analysesThe brilliant time is preferably 15～25h.
Those skilled in the art can, according to the concrete condition of reaction system, adjust the temperature and time of crystallization.
Preferably, in described step 3, dry actual conditions is: dry at 50～80 DEG C, preferably dry at 50～60 DEG C.
Third aspect present invention provides the E type crystal (formula (II) compound) of described Sorafenib Tosylate one water thing to existPreparation or screening are treated tumour medicine or prepare the purposes in diagnosing tumor medicine.
Preferably, described tumour is selected from kidney, liver cancer, lung cancer, cancer of pancreas, thyroid cancer and intestinal cancer.
It should be noted that, in X-ray powder diffraction spectrum (XRPD), the diffraction spectrogram pair being obtained by crystalline compoundsDistinctive often in specific crystal formation, wherein the relative intensity of bands of a spectrum (especially at low angle) may be because of crystal barThe difference of part, particle diameter and other condition determinations and the advantage orientation effect that produces and change. Therefore the relative intensity of diffraction maximum is to instituteFor crystal formation be not distinctive, judge whether when identical with known crystal formation, should be noted that the relative position at peakInstead of their relative intensity. In addition, for any given crystal formation, may there is slight error in the position at peak,This is also known in crystallography field. For example, the variation of temperature during due to analytic sample, the movement of sample or instrumentDemarcate etc., the position at peak can be moved, and the error of 2 θ values is approximately decided to be sometimes ± and 0.2 °. Therefore determining when every kind of crystalline texture,This error should be taken into account.
Fourth aspect present invention provides a kind of pharmaceutical composition, and wherein said composition does not produce unacceptable side effect, comprises and controllingTreat the E type crystal of the described Sorafenib Tosylate one water thing of effective dose.
Preferably, described pharmaceutical composition also comprises pharmaceutically acceptable carrier, diluent or excipient.
Described pharmaceutical composition can be by suitable mode administration, for example, by oral, non-enteron aisle, lung, nose, hypogloeeis, tongue,Rectum, skin, the administrations such as conjunctiva. And the contained p-methyl benzenesulfonic acid of formula (II) compound of E crystal formation thing of the present inventionMolecular number tend towards stability, based on the stability of E crystal formation thing, with and specific physicochemical properties, the formula (II) of E crystal formation thingCompound has potential using value in the manufacture of medicine.
The inventor, through extensive and deep research, has found that the novel crystal formation thing of BAY 43-9006 tosilate is (right unexpectedlyFormula (II) compound of the E type crystal of Sorafenib Tosylate one water thing also further provides the preparation method of this crystal formation. InstituteState that preparation method is simple to operate, mild condition, step is few and do not need transformation of crystal, salify is directly prepared the crystalline substance that purity is higherFormula (II) the compound Sorafenib Tosylate one water thing of type E. In addition, its whole course of reaction of this preparation method withoutHigh temperature, deep cooling, and do not use high toxicity reagent, whole preparation process stablize controlled, save the energy and and environmental friendliness, haveThe features such as energy consumption is low, yield good, process safety, its product preparing is without potential safety issue. By this preparation sideFormula (II) compound products yield and the product quality of the E type crystal of the Sorafenib Tosylate one water thing that method preparesGood, have good stability, crystallization purity high, be convenient to the advantages such as storage.
Brief description of the drawings
Fig. 1 is shown as formula (II) chemical combination of the p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal that the embodiment of the present invention 1 preparesThing X-ray powder diffraction pattern.
Fig. 2 is shown as formula (II) chemical combination of the p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal that the embodiment of the present invention 1 preparesThing TGA figure.
Fig. 3 is shown as formula (II) chemical combination of the p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal that the embodiment of the present invention 3 preparesThing X-ray powder diffraction pattern.
Fig. 4 is shown as formula (II) chemical combination of the p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal that the embodiment of the present invention 4 preparesThing X-ray powder diffraction pattern.
Fig. 5 is shown as formula (II) chemical combination of the p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal that the embodiment of the present invention 5 preparesThing X-ray powder diffraction pattern.
Fig. 6 is shown as formula (II) compounds X-penetrating of the p-methyl benzenesulfonic acid BAY 43-9006 I type crystal that the embodiment of the present invention 6 preparesLine powder diagram.
Formula (II) the compound N MR figure of the p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal that Fig. 7 embodiment 3 prepares.
Formula (II) the compound N MR figure of the p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal that Fig. 8 embodiment 4 prepares.
Detailed description of the invention
Below, by specific instantiation explanation embodiments of the present invention, those skilled in the art can be disclosed by this descriptionContent understand easily other advantages of the present invention and effect. The present invention can also add by other different detailed description of the inventionTo implement or application, the every details in this description also can, based on different viewpoints and application, not deviate from essence of the present inventionUnder god, carry out various modifications or change.
Notice, process equipment or device concrete not dated in the following example all adopt conventional equipment or the device in this area.
In addition should be understood that one or more method steps of mentioning in the present invention do not repel before and after described combination step all rightBetween the step that has additive method step or clearly mention at these, can also insert additive method step, except as otherwise noted;The relation that is connected between one or more equipment/devices of mentioning in the present invention of should also be understood that is not repelled in described combination and is establishedBetween two equipment/devices that can also have other equipment/devices before and after standby/device or clearly mention at these, can also insert itHis equipment/device, except as otherwise noted. And except as otherwise noted, the numbering of various method steps is only for differentiating various method stepsConvenient tool, but not for the ordering of restriction various method steps or limit the present invention enforceable scope, its relativenessChange or adjust, in the situation that changing technology contents without essence, when being also considered as the enforceable category of the present invention.
Embodiment 1.
Formula (II) the compound preparation of p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal:
2g BAY 43-9006 free alkali is dissolved in Isosorbide-5-Nitrae-dioxane of 15ml and the deionized water of 5ml, stirs, and is warming up to 78 DEG C,The fast instant Isosorbide-5-Nitrae dioxane solution 3ml that adds 1g mono-hydration p-methyl benzenesulfonic acid after clear of system, insulation continues to stir 30 minutes.System is cooled to room temperature naturally, then is cooled to-5～0 DEG C with freezing liquid, continues stirring and crystallizing 20 hours. Suction filtration, use Isosorbide-5-Nitrae-Dioxane washing, collects filter cake, and 50 DEG C of forced air dryings 72 hours, survey moisture 3.0 after drying, and obtain 2.4g p-methyl benzenesulfonic acid ropeLa Feini mono-water thing, yield 88%, purity 98.79%, fusing point: 127.3～134.8 DEG C, X-ray powder diffraction pattern is as Fig. 1Shown in, TGA schemes as shown in Figure 2.
Embodiment 2.
Formula (II) the compound preparation of p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal:
2.2g BAY 43-9006 free alkali is dissolved in Isosorbide-5-Nitrae-dioxane of 44ml and the deionized water of 4.4ml, stirs, and is warming up to 76DEG C, system is the molten Isosorbide-5-Nitrae dioxane solution 3ml that adds 1g mono-hydration p-methyl benzenesulfonic acid after clear rapidly, continues to stir 30 minutes.Naturally be cooled to room temperature, then low temperature is cooled to-5～0 DEG C, continuation stirring and crystallizing 25 hours. Suction filtration, washes with Isosorbide-5-Nitrae-dioxaneFilter cake, collects filter cake. 60 DEG C of forced air dryings 16 hours, survey moisture 3.22 after drying, and obtain 2.5g p-methyl benzenesulfonic acid BAY 43-9006One water thing, yield 84%. Purity 98.59%, fusing point: 126.0～135.1 DEG C.
Embodiment 3
Formula (II) the compound preparation of p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal:
1g BAY 43-9006 free alkali is dissolved in Isosorbide-5-Nitrae-dioxane of 8ml and the deionized water of 2ml, stirs, and is warming up to 76 DEG C,System is the molten Isosorbide-5-Nitrae dioxane solution 2ml that adds 0.4g mono-hydration p-methyl benzenesulfonic acid after clear rapidly, continues to stir 1 hour. FromSo be cooled to room temperature (15～18 DEG C), stirring and crystallizing 17 hours. Suction filtration, with Isosorbide-5-Nitrae-dioxane filter wash cake, collects filter cake.60 DEG C of forced air dryings 6 hours, survey moisture 3.20 after drying, and obtain 0.9g p-methyl benzenesulfonic acid BAY 43-9006 one water thing, yield 90%.Purity 98.86%, fusing point: 133.2-136.9 DEG C, X-ray powder diffraction pattern as shown in Figure 3,1H-NMR testing result is as figure(DMSO-d shown in 76,400MHzδppm＝2.29(s,1.5H),2.83(s,3H),5.79(br,2.5H),7.17～7.21(m,3H), 7.25～7.27(m,1H),7.58～7.70(m,6H),8.14(d,1H),8.57(d,1H),9.03(d,1H),9.27(s,1H)，9.45(s,1H)。Known according to Fig. 7, in the E type crystal of described Sorafenib Tosylate one water thing, p-methyl benzenesulfonic acid: BAY 43-9006 is freeThe mol ratio of alkali is 0.51:1.
Embodiment 4
Formula (II) the compound preparation of p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal:
2g BAY 43-9006 free alkali is dissolved in Isosorbide-5-Nitrae-dioxane of 14ml and the deionized water of 2ml, stirs, and is warming up to 70 DEG C,System is the molten Isosorbide-5-Nitrae dioxane solution 3ml that adds 1g mono-hydration p-methyl benzenesulfonic acid after clear rapidly, continues to stir 45 minutes. NatureBe cooled to room temperature, then low temperature is cooled to 0～5 DEG C, stirring and crystallizing 17 hours. Suction filtration, with Isosorbide-5-Nitrae-dioxane filter wash cake, receivesCollection filter cake. 60 DEG C of forced air dryings 6 hours, survey moisture 3.25 after drying, and obtain 1.4g p-methyl benzenesulfonic acid BAY 43-9006 one water thing, receiveRate 70%. Purity 98.74%, fusing point: 129.2-132.5 DEG C, X-ray powder diffraction pattern as shown in Figure 4,1H-NMR detectsResult as shown in Figure 8 (DMSO-d6,400MHz δ ppm=2.28 (s, 1.5H), 2.83 (s, 3H), 5.82 (br, 2.5H),7.17～7.21(m,3H),7.26～7.27(m,1H),7.56～7.70(m,6H),8.14(d,1H),8.57(d,1H),9.06(d,1H),9.30 (s, 1H), 9.48 (s, 1H)). Known according to Fig. 8, in the E type crystal of described Sorafenib Tosylate one water thing,One hydration p-methyl benzenesulfonic acid: the mol ratio of BAY 43-9006 free alkali is 0.50:1.
Embodiment 5
Formula (II) the compound preparation of p-methyl benzenesulfonic acid BAY 43-9006 one water thing E type crystal:
1.2g BAY 43-9006 free alkali is dissolved in the DMF of 2.6ml, stirs, and is warming up to 95 DEG C, and system is rapidly molten to add after clearThe DMF solution 3ml of 1g mono-hydration p-methyl benzenesulfonic acid, continues to stir 30 minutes. Naturally be cooled to room temperature, then low temperature is cooled to0～5 DEG C, stirring and crystallizing 15 hours. Suction filtration, with DMF filter wash cake, collects filter cake. 60 DEG C of forced air dryings 16 hours, dryAfter dry, survey moisture 3.41, obtain 1.2g p-methyl benzenesulfonic acid BAY 43-9006 one water thing, yield 100%. Purity 98.79%, fusing point:126.8-132.2 DEG C, X-ray powder diffraction pattern is as shown in Figure 5.
Embodiment 6
The preparation (comparative example) of p-methyl benzenesulfonic acid BAY 43-9006 I type crystal:
2g BAY 43-9006 free alkali is dissolved in the absolute ethyl alcohol of 48ml, is warming up to 80 DEG C under stirring, refluxes and moltenly adds after clear until system1g mono-hydration p-methyl benzenesulfonic acid is dissolved in the solution 3ml in ethanol, adds follow-up continuous insulated and stirred 30 minutes. System is lowered the temperature naturallyTo room temperature, then be cooled to 0～5 DEG C with frozen water, continue stirring and crystallizing 2 hours. Suction filtration 3mL absolute ethanol washing. 60 DEG C of drumsAir-dry dry 8 hours, after drying, survey moisture 0.16, obtain p-methyl benzenesulfonic acid BAY 43-9006 I type crystal 2.1g, yield: 77%, pureDegree 99.60%, X-ray powder diffraction pattern as shown in Figure 6.
In sum, the present invention has effectively overcome various shortcoming of the prior art and tool high industrial utilization.
Above-described embodiment is illustrative principle of the present invention and effect thereof only, but not for limiting the present invention. Anyly be familiar with this skillThe personage of art all can, under spirit of the present invention and category, modify or change above-described embodiment. Therefore, such asUnder have in technical field conventionally know the knowledgeable do not depart under disclosed spirit and technological thought, complete all etc.Effect is modified or is changed, and must be contained by claim of the present invention.

Claims (10)

1. an E type crystal for Sorafenib Tosylate one water thing, in X-ray powder diffraction, described to toluene sulphurThe E type crystal of acid Sorafenib one water thing is approximately 8.961 ± 0.2 ° of 2-θ, and 13.379 ± 0.2 °, 13.939 ± 0.2 °,19.718±0.2°,20.658±0.2°,22.761±0.2°,23.561±0.2°,24.080±0.2°,24.881±0.2°Place's indicating characteristic diffraction maximum.
2. the E type crystal of a kind of Sorafenib Tosylate one water thing as claimed in claim 1, is characterized in that, described to firstThe E type crystal of benzene sulfonic acid Sorafenib one water thing is approximately 8.961 ± 0.2 ° of 2-θ, and 13.379 ± 0.2 °, 13.939 ± 0.2 °,17.120±0.2°，19.718±0.2°,20.658±0.2°,22.761±0.2°,23.561±0.2°,24.080±0.2°, 24.881 ± 0.2 °, 25.720 ± 0.2 °, 27.041 ± 0.2 °, 27.361 ± 0.2 °, locate diffraction for 28.278 ± 0.2 °Peak.
3. the E type crystal of a kind of Sorafenib Tosylate one water thing as claimed in claim 2, is characterized in that, described to firstThe E type crystal of benzene sulfonic acid Sorafenib one water thing is approximately 8.961 ± 0.2 ° of 2-θ, and 13.379 ± 0.2 °, 13.939 ± 0.2 °,17.120±0.2°,19.718±0.2°,20.658±0.2°,22.761±0.2°,23.561±0.2°,24.080±0.2°,24.881±0.2°,25.720±0.2°,27.041±0.2°,27.361±0.2°,28.278±0.2°,31.702±0.2°,Locate diffraction maximum for 36.180 ± 0.2 °.
4. the E type crystal of a kind of Sorafenib Tosylate one water thing as claimed in claim 1, is characterized in that, described to firstIn the E type crystal of benzene sulfonic acid Sorafenib one water thing, p-methyl benzenesulfonic acid: the average molecular mol ratio of BAY 43-9006 free alkali is(0.50～0.52)：1。
5. the preparation method of the E type crystal of the Sorafenib Tosylate one water thing as described in claim as arbitrary in claim 1-4,Comprise the steps:
1) prepare BAY 43-9006 solution;
2) a hydration p-methyl benzenesulfonic acid is added in BAY 43-9006 solution, react 0.5～1h at 70～95 DEG C;
3), by step 2 gained reactant liquor cooling, crystallization, obtain the E of described Sorafenib Tosylate one water thing after dryType crystal.
6. preparation method as claimed in claim 5, is characterized in that, described BAY 43-9006 solution is the solution of BAY 43-9006 free alkali;And/or the solvent of described BAY 43-9006 solution is selected from one or more the combination in Isosorbide-5-Nitrae dioxane, water, DMF.
7. preparation method as claimed in claim 6, is characterized in that, the solvent of described BAY 43-9006 solution be Isosorbide-5-Nitrae-dioxane andThe mixed solvent of water or DMF; In the mixed solvent of Isosorbide-5-Nitrae-dioxane and water, the volume ratio of water and Isosorbide-5-Nitrae dioxaneFor 1:(3～10).
8. preparation method as claimed in claim 5, is characterized in that, in described step 2, at 70～95 DEG C by a hydration pairBenzene methanesulfonic acid adds in BAY 43-9006 solution fast;
And/or in described step 2, the mol ratio of a hydration p-methyl benzenesulfonic acid and BAY 43-9006 is 1:(0.49～1.02);
And/or, in described step 3, step 2 gained reactant liquor is cooled to-5～18 DEG C;
And/or in described step 3, the actual conditions of crystallization is: reactant liquor is cooled to-5～18 DEG C, stirring and crystallizing 15-25Hour, point isolated crystal;
And/or in described step 3, dry actual conditions is: dry at 50～80 DEG C.
9. the E type crystal of the Sorafenib Tosylate one water thing as described in claim as arbitrary in claim 1-4 is in preparation or screeningAnti-tumor medicine or prepare the purposes in diagnosing tumor medicine.
10. a pharmaceutical composition, comprises the p-methyl benzenesulfonic acid as described in the claim as arbitrary in claim 1-4 for the treatment of effective doseThe E type crystal of Sorafenib one water thing.
CN201511018488.1A 2015-12-29 2015-12-29 Novel sorafenib TsOH crystal form as well as preparation method and application thereof Pending CN105585523A (en)

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CN109796400A (en) * 2017-11-16 2019-05-24 四川科伦药物研究院有限公司 A kind of toluenesulfonic acid Sorafenib crystal form and preparation method thereof
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EP3390362A4 (en) * 2015-12-14 2019-06-26 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof
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