CN103387536A - Polymorphs of fluorine-containing deuterium-substituted omega-diphenylcarbamide or polymorphs of salts of fluorine-containing deuterium-substituted omega-diphenylcarbamide - Google Patents
Polymorphs of fluorine-containing deuterium-substituted omega-diphenylcarbamide or polymorphs of salts of fluorine-containing deuterium-substituted omega-diphenylcarbamide Download PDFInfo
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Abstract
The invention relates to polymorphs of fluorine-containing deuterium-substituted omega-diphenylcarbamide or a salt of fluorine containing deuterated omega-diphenylcarbamide, and particularly provides the polymorphs of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluoro-phenoxy)-2-(N 1', 1', 1'-trideuteromethyl)picolinamide. The polymorphs include a polymorph I, a polymorph II and a polymorph III of 4-toluenesulfonate salt of the 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluoro-phenoxy)-2-(N 1', 1', 1'-trideuteromethyl) picolinamide. The polymorphs are suitable for use in the preparation of pharmaceutical compositions that inhibit phosphokinase (such as raf kinase).
Description
Technical field
The invention belongs to field of medicaments, particularly, relate to the polymorphic form of a kind of fluorine-containing deuterium for ω-diphenyl urea or its salt, more specifically, relate to 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuteriums are for methyl) polymorphic form of picolinamide or its salt.
Background technology
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuteriums are for methyl) picolinamide (4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) 3-fluorophenoxy)-2-(N-1 ', 1 ', 1 '-trideuteromethyl) picolinamide), structure is suc as formula shown in I.
The molecular formula of formula I compound is C
21H
12D
3ClF
4N
4O
3, molecular weight is 485.83, for white to the off-white color crystalline powder; Odorless; Tasteless.Very easily dissolve in methyl-sulphoxide or dimethyl formamide, slightly molten in methyl alcohol, slightly soluble in acetone, dehydrated alcohol or Glacial acetic acid, almost insoluble in water, fusing point is 224～230 ℃.
Formula I compound belongs to and suppresses the kinase whose compound of raf, is applicable to prepare the medicine for the treatment of cancer and relative disease.But, at present for the preparation of the amorphous compound that is of relative medicine, still do not develop the polymorphic form of formula I compound.
Therefore, the polymorphic form of research and development formula I compound is very necessary.
Summary of the invention
An object of the present invention is to provide the polymorphic form of a series of 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuteriums are for methyl) picolinamide or its salt.
In a first aspect of the present invention, the polymorphic form of compound shown in a kind of formula I or its pharmacy acceptable salt is provided,
In another preference, described pharmacy acceptable salt is toluenesulfonate.
In another preference, described polymorphic form is the polymorphic form I of compound shown in formula I, and wherein, described polymorphic form I has 1 or 2 X-ray powder diffraction characteristic peak that is selected from lower group: 7.224 ± 0.2 °, and 14.507 ± 0.2 °.
In another preference, described polymorphic form I also has 1 or 2 X-ray powder diffraction characteristic peak that is selected from lower group: 13.363 ± 0.2 °, and 17.192 ± 0.2 °, and 19.779 ± 0.2 °.
In another preference, described polymorphic form I has X-ray powder diffraction spectrogram (XRPD) substantially as shown in Figure 2 a.
In another preference, the dsc collection of illustrative plates of described polymorphic form I has peak-peak at 211.8-214.1 ℃.
In another preference, described polymorphic form I has dsc collection of illustrative plates (DSC) substantially as shown in Figure 2 b.
In another preference, described polymorphic form is the polymorphic form II of compound shown in formula I, and wherein, described polymorphic form II has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 22.323 ± 0.2 °, 24.199 ± 0.2 °, and 24.830 ± 0.2 °.
In another preference, described polymorphic form II also has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 18.573 ± 0.2 °, and 21.671 ± 0.2 °, 23.507 ± 0.2 °, and 25.166 ± 0.2 °.
In another preference, described polymorphic form II has X-ray powder diffraction spectrogram (XRPD) substantially as shown in Figure 1a.
In another preference, the dsc collection of illustrative plates of described polymorphic form II has peak-peak at 196.2-198.6 ℃.
In another preference, described polymorphic form II has dsc collection of illustrative plates (DSC) substantially as shown in Figure 1 b.
In another preference, described polymorphic form is the polymorphic form III of the tosilate of compound shown in formula I, wherein, described polymorphic form III has 1 or 2 X-ray powder diffraction characteristic peak that is selected from lower group: 4.476 ± 0.2 °, and 13.357 ± 0.2 °.
In another preference, described polymorphic form III also has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 16.517 ± 0.2 °, and 18.037 ± 0.2 °, 21.786 ± 0.2 ° and 22.990 ± 0.2 °.
In another preference, described polymorphic form III has basic X-ray powder diffraction spectrogram as shown in Fig. 3 a.
In another preference, the dsc collection of illustrative plates of described polymorphic form III has peak-peak at 239.5-241.7 ℃.
In another preference, described polymorphic form III has basic dsc collection of illustrative plates as shown in Fig. 3 b.
In another preference, the tosilate of described formula I compound is 1/1 tosilate, and wherein, the mol ratio of formula I compound and tosic acid is 1:1.
In a second aspect of the present invention, provide the purposes of the described polymorphic form of a first aspect of the present invention, for the preparation of the pharmaceutical composition that suppresses phosphokinase (as the raf kinases).
In another preference, described pharmaceutical composition is used for the treatment of and preventing cancer.
In a third aspect of the present invention, a kind of pharmaceutical composition is provided, it comprises:
(a) the described polymorphic form of a first aspect of the present invention; With
(b) pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, the preparation method of the described polymorphic form of a kind of a first aspect of the present invention is provided, it comprises step: with pharmacy acceptable salt recrystallization in inert solvent of compound shown in compound shown in formula I or formula I, thereby obtain the described polymorphic form of a first aspect of the present invention.
In another preference, the method for making of described polymorphic form I comprises step: with the above-mentioned polymorphic form II recrystallization in methyl alcohol that makes, thereby obtain described polymorphic form I.
In another preference, the method for making of described polymorphic form III comprises step: with the above-mentioned polymorphic form I that makes and tosic acid recrystallization in inert solvent, thereby obtain described polymorphic form III.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tire out and state no longer one by one at this.
Description of drawings
Fig. 1 a has shown the X-ray powder diffraction pattern of the polymorphic form II of embodiment 1.
Fig. 1 b has shown the dsc figure of the polymorphic form II of embodiment 1.
Fig. 1 c has shown the NMR figure of the polymorphic form II of embodiment 1.
Fig. 2 a has shown the X-ray powder diffraction pattern of the polymorphic form I of embodiment 2.
Fig. 2 b has shown the dsc figure of the polymorphic form I of embodiment 2.
Fig. 2 c has shown the NMR figure of the polymorphic form I of embodiment 2.
Fig. 3 a has shown the X-ray powder diffraction pattern of the polymorphic form III of embodiment 3.
Fig. 3 b has shown the dsc figure of the polymorphic form III of embodiment 3.
Fig. 3 c has shown the NMR figure of the polymorphic form III of embodiment 3.
Embodiment
The inventor is by long-term and deep research, be surprised to find that 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuteriums are for methyl) the multiple polymorphic form of picolinamide or its salt, described polymorphic form purity is high, and highly stable, be suitable for preparation and suppress the pharmaceutical composition of phosphokinase (as the raf kinases), thereby more be conducive to treat the disease such as cancer.In addition, polymorphic form of the present invention in the medicine manufacturing processedes such as packing, is difficult for kicking up, and easily collecting is difficult for causing waste, and helps to protect that operator's is healthy.On this basis, the contriver has completed the present invention.
As used herein, " formula I compound " refers to the 4-shown in structural formula as I (4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuteriums are for methyl) picolinamide.
Polymorphic form
Solid is not to be exactly that form with crystallization exists with unbodied form.In the situation that crystallized form, molecule is positioned in the three-dimensional lattice case.When compound crystallized out from solution or slurries, the space lattice that it can be different was arranged crystallization (this character is known as " polymorphism "), formed the crystal with different crystallized forms, and these various crystallized forms are known as " polymorphic form ".The different polymorphic forms of given material can differ from one another in (as solubleness and dissolution rate, true specific gravity, crystalline form, accumulation mode, mobility and/or solid-state stability) aspect one or more physical attributes.
Crystallization
Can pass through working solution, make the solubility limit of compound of interest be exceeded, thereby complete production-scale crystallization.This can complete by several different methods, for example, dissolved compound at relatively high temperature, then cooling solution is to saturation limit.Perhaps by boiling, atmospheric evaporation, vacuum-drying or by other certain methods, reduce liquid volume.Can have therein the solvent of low solubleness or the mixture of such solvent by adding anti-solvent or compound, reduce the solubleness of compound of interest.Another kind of optional method is to regulate the pH value to reduce solubleness.The detailed description of relevant crystallization aspect sees also Crystallization, the third edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN0750611294.
If formation and the crystallization of expectation salt occur simultaneously,, if salt is less than material dissolution degree in reaction medium, add so suitable acid or alkali can cause the direct crystallization of required salt.Equally, in the form of finally the wanting medium less than reactants dissolved degree, completing of building-up reactions can make the final product direct crystallization.
The optimization of crystallization can comprise with the crystal of desired form and being inoculated in crystallization medium as crystal seed.In addition, many crystallization method use the combination of above-mentioned strategy.Embodiment be at high temperature with interested compound dissolution in solvent, add subsequently the anti-solvent of proper volume by controlled way, so that system is just in time under saturated level.At this moment, can add the crystal seed integrity of crystal seed (and keep) of desired form, system is cooling to complete crystallization.
As used herein, term " room temperature " refers generally to 4-30 ℃, preferably refers to 20 ± 5 ℃.
Polymorphic form of the present invention
As used herein, term " polymorphic form of the present invention " comprises formula I compound or its salt (as tosilate) polymorphic form, also comprises the different polymorphic forms of formula I compound.
Preferably, be polymorphic form I or the polymorphic form II of formula I compound, or the polymorphic form III of 1/1 tosilate of formula I compound, wherein, the mol ratio of formula I compound and tosic acid is 1:1.
The evaluation of polymorphic form and character
The present invention after the polymorphic form of preparation I compound, adopts following various ways and instrument to be studied its character.
X-ray powder diffraction
The method of measuring the X-ray powder diffraction of crystal formation is well known in the art.For example use the x-ray powder diffraction instrument of RigakuD/max 2550VB/PC model,, with the sweep velocity of 2 ° of per minutes, adopt the copper radiation target to obtain collection of illustrative plates.
The polymorphic form of formula I compound of the present invention, have specific crystal formation form, has specific characteristic peak in X-ray powder diffraction (XRPD) figure.
(1) polymorphic form I
Described polymorphic form I has 1 or 2 X-ray powder diffraction characteristic peak that is selected from lower group: 7.224 ± 0.2 °, and 14.507 ± 0.2 °.
In another preference, described polymorphic form I also has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 13.363 ± 0.2 °, and 17.192 ± 0.2 °, and 19.779 ± 0.2 °.
In another preference, described polymorphic form I has X-ray powder diffraction spectrogram substantially as shown in Figure 2 a.
(2) polymorphic form II
Described polymorphic form II has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 22.323 ± 0.2 °, and 24.199 ± 0.2 °, and 24.830 ± 0.2 °.
In another preference, described polymorphic form II also has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 18.573 ± 0.2 °, and 21.671 ± 0.2 °, 23.507 ± 0.2 °, and 25.166 ± 0.2 °.
In another preference, described polymorphic form II has X-ray powder diffraction spectrogram substantially as shown in Figure 1a.
(3) polymorphic form III
Described polymorphic form III has 1 or 2 X-ray powder diffraction characteristic peak that is selected from lower group: 4.476 ± 0.2 °, and 13.357 ± 0.2 °.
In another preference, described polymorphic form III also has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 16.517 ± 0.2 °, and 18.037 ± 0.2 °, 21.786 ± 0.2 ° and 22.990 ± 0.2 °.
In another preference, described polymorphic form III has basic X-ray powder diffraction spectrogram as shown in Fig. 3 a.
Differential scanning calorimetry
Claiming " differential scanning calorimetry " (DSC) again, is in heat-processed, the energy difference between measurement measured matter and reference substance and a kind of technology of temperature Relations Among.Peak position on the DSC collection of illustrative plates, shape and peak number order are relevant with the character of material, therefore can be used for qualitatively identifying material.This area is commonly used the method and is carried out the many kinds of parameters such as the transformation temperature of detection material, second-order transition temperature, reaction heat.
The DSC measuring method is well known in the art.For example can use NETZSCH DSC 204F1 differential scanning calorimeter,, with the temperature rise rate of 10 ℃ of per minutes, from 25 ℃, be warming up to 250 ℃, the DSC scanning spectra of acquisition crystal formation.
The polymorphic form of formula I compound of the present invention, have specific characteristic peak in differential scanning calorimetry (DSC) figure.
(1) polymorphic form I
The dsc collection of illustrative plates of described polymorphic form I has peak-peak at 211.8-214.1 ℃.
In another preference, described polymorphic form I has dsc collection of illustrative plates (DSC) substantially as shown in Figure 2 b.
(2) polymorphic form II
The dsc collection of illustrative plates of described polymorphic form II has peak-peak at 196.2-198.6 ℃.
In another preference, described polymorphic form II has dsc collection of illustrative plates (DSC) substantially as shown in Figure 1 b.
(3) polymorphic form III
The dsc collection of illustrative plates of described polymorphic form III has peak-peak at 239.5-241.7 ℃.
In another preference, described polymorphic form III has basic dsc collection of illustrative plates as shown in Fig. 3 b.
Nucleus magnetic resonance
Also can adopt nucleus magnetic resonance (NMR) to carry out the auxiliary crystalline structure of determining, its measuring method is well known in the art.The present invention preferably adopts Bruker Avance III plus-400MHz.
Activeconstituents
As used herein, term " activeconstituents " or " active compound " refer to polymorphic form of the present invention, i.e. the polymorphic form of the compound shown in formula I comprises the polymorphic form of its pharmacy acceptable salt certainly.Described pharmacy acceptable salt, such as but not limited to toluenesulfonate.
Pharmaceutical composition and application process
Excellent for example kinase whose inhibitions of raf is active to phosphokinase (Kinase) because polymorphic form of the present invention has, therefore polymorphic form of the present invention and to contain polymorphic form of the present invention be that the pharmaceutical composition of main active ingredient can be used for treatment, prevention and alleviation by to phosphokinase (Kinase) the kinase mediated disease of raf for example.According to prior art, polymorphic form of the present invention can be used for treating following disease: cancer, cardiovascular disorder, obesity, diabetes etc.
The polymorphic form of the present invention that pharmaceutical composition of the present invention comprises in safe and effective weight range reaches pharmaceutically acceptable vehicle or carrier.Wherein " safe and effective amount " refers to: the amount of compound (or polymorphic form) is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-2000mg polymorphic form/agent of the present invention, more preferably, contains 10-200mg polymorphic form/agent of the present invention.Preferably, described " potion " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." consistency " referred to herein as each component energy and activeconstituents of the present invention and blending mutually between them in composition, and the drug effect of not obvious reduction activeconstituents.Pharmaceutically acceptable carrier part example has Mierocrystalline cellulose and derivative (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as tween
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
The method of application of polymorphic form of the present invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): in oral, knurl, rectum, parenteral (intravenously, intramuscular or subcutaneous) and topical.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, activeconstituents mixes with at least a conventional inert excipient (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or with following compositions, mixes: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that in this composition, the release of activeconstituents can postpone certain part in digestive tube.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, activeconstituents also can with above-mentioned vehicle in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except activeconstituents, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.
Except activeconstituents, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion, and is used for again being dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprises water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the polymorphic form of the present invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.
Polymorphic form of the present invention can be individually dosed, perhaps with other pharmaceutically acceptable compound Combined Preparation.
While making pharmaceutical composition, the polymorphic form of the present invention of safe and effective amount need to be applicable to the Mammals (as the people) for the treatment of, the effective dosage of dosage for pharmaceutically thinking while wherein using, for the people of 60kg body weight, day dosage is generally 1～2000mg, preferred 20～500mg.Certainly, concrete dosage also should be considered the factors such as route of administration, patient health situation, and these are all within the skilled practitioners skill.
Major advantage of the present invention has:
1. provide the 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group) of series of novel-2-(N-1 ', 1 ', 1 '-three deuteriums are for methyl) polymorphic form of picolinamide or its salt, wherein, the polymorphic form I and the polymorphic form II that comprise formula I compound, and the polymorphic form III of the toluenesulfonate of formula I compound.
2. the purposes of described polymorphic form also is provided, has can be used for preparation and suppress the pharmaceutical composition of phosphokinase (as the raf kinases), thereby be used for the treatment of the disease such as cancer.
, below in conjunction with concrete enforcement, further set forth the present invention.Should be understood that these embodiment only are not used in and limit the scope of the invention for explanation the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.If not the raw materials used special instruction of the present invention, all commercially available obtaining.
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuterium is for methyl) the polymorphic form II of picolinamide
The 4-Chloro-2-Pyridyle methyl-formiate of 50g is dissolved in the there-necked flask of 250mL tetrahydrofuran (THF), add respectively the Anhydrous potassium carbonate of 31g deuterium for methylamine hydrochloride and 80g, 25 ℃ of stirrings added 250mL water and 100mL methyl tertiary butyl ether after 20 hours, stir layering, separatory, water, with the extraction of 100mL methyl tertiary butyl ether, merges organic phase and dry, and removal of solvent under reduced pressure obtains the liquid 48g of light yellow 4-chloro-N-deuterium for picoline-2-methane amide.
the potassium tert.-butoxide of 15g is suspended in the N of 50mL, in the solution of N-N,N-DIMETHYLACETAMIDE, the N of the 3-fluoro-4-amino-phenol (16g) that slowly drips under 0 ~ 5 degree, N-N,N-DIMETHYLACETAMIDE (50mL) solution, at room temperature stirred 20 minutes, be warming up to 100 ℃ and also slowly drip the N of 4-chloro-N-deuterium for picoline-2-methane amide (17g), N-N,N-DIMETHYLACETAMIDE (50mL), dropwising rear continuation stirred 0.5 hour, be cooled to 25 ℃, add the ethyl acetate of 500mL dilute and stirred 0.5 hour in reaction solution, remove by filter inorganic salt, water washing with 500mL, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, add the ethanol of 100mL and the making beating 2 hours that refluxes in crude product, be cooled to the 4-(4-amino that 25 ℃ of filtrations obtain brown-3-fluoro-phenoxy group)-the N-deuterium is for picoline-2-methane amide solid 20g.
Under 25 ℃, the 4-chloro-3-trifluoromethylbenzene based isocyanate of 13g is dissolved in the 70mL ethyl acetate, and with the 4-(4-of 14g amino-3-fluoro-phenoxy group)-the N-deuterium slowly drops in above-mentioned solution for the 350mL ethyl acetate solution of picoline-2-methane amide, 25 ℃ were stirred 20 hours, react complete filtration and with the ethyl acetate of 20mL, wash twice, obtain the light brown solid of 13g.
The sampling warp
1H NMR, X-ray powder diffraction, DSC etc. detect proof, and described solid is title compound.
1H NMR（DMSO-d6，400MHz）:δ7.06-7.10(m,1H),7.19(dd,J=2.4Hz,5.6Hz,1H),7.35(dd,J=2.8Hz,12Hz,1H),7.43(d,J=2.4Hz,1H),7.63(m,2H),8.14(br,1H),8.17(t,J=8.8Hz,1H),8.53(d,J=5.6Hz,1H),8.75(d,J=1.6Hz,1H),8.78(br,1H),9.54(br,1H).
Its X-ray powder diffraction pattern is seen Fig. 1 a, and the parameter at each peak is as shown in table 1, and dsc figure (DSC) sees Fig. 1 b, and the collection of illustrative plates of 1H NMR is seen 1c.
Table 1
| Peak number | 2θ(°) | Peak height | Relative intensity (I%) | Peak number | 2θ(°) | Peak height | Relative intensity (I%) |
| 1 | 6.627 | 907 | 3.81 | 22 | 24.199 | 23808 | 100.00 |
| 2 | 9.828 | 3116 | 13.09 | 23 | 24.830 | 11204 | 47.06 |
| 3 | 10.778 | 1495 | 6.28 | 24 | 25.166 | 3926 | 16.49 |
| 4 | 11.388 | 3255 | 13.67 | 25 | 26.548 | 1805 | 7.58 |
| 5 | 12.336 | 4600 | 19.32 | 26 | 28.327 | 1117 | 4.69 |
| 6 | 12.938 | 860 | 3.61 | 27 | 29.173 | 2725 | 11.45 |
| 7 | 13.267 | 1910 | 8.02 | 28 | 30.004 | 3103 | 13.03 |
| 8 | 13.599 | 3263 | 13.71 | 29 | 31.580 | 1732 | 7.27 |
| 9 | 14.230 | 2782 | 11.69 | 30 | 31.974 | 940 | 3.95 |
| 10 | 14.761 | 2998 | 12.59 | 31 | 32.726 | 1747 | 7.34 |
| 11 | 15.451 | 3245 | 13.63 | 32 | 33.869 | 1276 | 5.36 |
| 12 | 15.969 | 1245 | 5.23 | 33 | 34.071 | 1255 | 5.27 |
| 13 | 17.032 | 1270 | 5.33 | 34 | 34.819 | 970 | 4.07 |
| 14 | 17.745 | 2310 | 9.70 | 35 | 36.795 | 1113 | 4.67 |
| 15 | 18.573 | 5092 | 21.39 | 36 | 37.305 | 993 | 4.17 |
| 16 | 19.067 | 2115 | 8.88 | 37 | 38.213 | 802 | 3.37 |
| 17 | 19.974 | 2053 | 8.62 | 38 | 38.845 | 890 | 3.74 |
| 18 | 21.671 | 6374 | 26.77 | 39 | 39.498 | 914 | 3.84 |
| 19 | 22.323 | 12716 | 53.41 | 40 | 40.583 | 1069 | 4.49 |
| 20 | 23.054 | 2736 | 11.49 | 41 | 42.617 | 813 | 3.41 |
| 21 | 23.507 | 5938 | 24.94 | 42 | 43.823 | 779 | 3.27 |
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuterium is for methyl) the polymorphic form I of picolinamide
The polymorphic form II of the embodiment of 500mg 1 preparation is added in the acetone of 20ml, and the stirring and dissolving clarification, under room temperature, drip the water of 15ml, separates out solid, stirred 30 minutes, filters the solid that the obtains water washing of 10ml, 30 ℃ of vacuum-drying 16 hours.The sampling warp
1H NMR, X-ray powder diffraction, DSC etc. detect proof, obtain title compound 200mg.
1H NMR（DMSO-d6，400MHz）:δ7.06-7.10(m,1H),7.19(dd,J=2.4Hz,5.6Hz,1H),7.35(dd,J=2.8Hz,12Hz,1H),7.43(d,J=2.4Hz,1H),7.63(m,2H),8.14(br,1H),8.17(t,J=8.8Hz,1H),8.53(d,J=5.6Hz,1H),8.75(d,J=1.6Hz,1H),8.78(br,1H),9.54(br,1H).
Its X-ray powder diffraction pattern is seen Fig. 2 a, and the parameter at each peak is as shown in table 2, and dsc figure (DSC) sees Fig. 2 b,
1The collection of illustrative plates of H NMR is seen 2c.
Table 2
| Peak number | 2θ(°) | Peak height | Relative intensity (I%) | Peak number | 2θ(°) | Peak height | Relative intensity (I%) |
| 1 | 7.224 | 30657 | 100.00 | 19 | 24.182 | 1855 | 6.05 |
| 2 | 8.563 | 1491 | 4.86 | 20 | 24.754 | 1919 | 6.26 |
| 3 | 10.602 | 856 | 2.79 | 21 | 25.858 | 4496 | 14.67 |
| 4 | 12.018 | 717 | 2.34 | 22 | 26.292 | 3434 | 11.20 |
| 5 | 13.363 | 8592 | 28.03 | 23 | 27.397 | 4076 | 13.30 |
| 6 | 14.507 | 20969 | 68.40 | 24 | 28.090 | 1268 | 4.14 |
| 7 | 14.705 | 3685 | 12.02 | 25 | 29.274 | 1813 | 5.91 |
| 8 | 15.573 | 2735 | 8.92 | 26 | 30.339 | 1440 | 4.70 |
| 9 | 16.005 | 1146 | 3.74 | 27 | 31.561 | 2721 | 8.88 |
| 10 | 16.496 | 2431 | 7.93 | 28 | 32.666 | 1036 | 3.38 |
| 11 | 17.192 | 5855 | 19.10 | 29 | 34.998 | 1758 | 5.73 |
| 12 | 18.554 | 2950 | 9.62 | 30 | 35.726 | 1025 | 3.34 |
| 13 | 18.792 | 3858 | 12.58 | 31 | 38.709 | 1123 | 3.66 |
| 14 | 19.779 | 6442 | 21.01 | 32 | 39.731 | 1307 | 4.26 |
| 15 | 21.850 | 1216 | 3.97 | 33 | 40.938 | 1125 | 3.67 |
| 16 | 22.761 | 1128 | 3.68 | 34 | 42.338 | 1194 | 3.89 |
| 17 | 23.370 | 4126 | 13.46 | 35 | 43.127 | 1187 | 3.87 |
| 18 | 23.765 | 2448 | 7.99 | 36 | 43.819 | 933 | 3.04 |
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuterium is for methyl) the polymorphic form III of picolinamide 1/1 tosilate
The polymorphic form I(10g that embodiment 2 is made) be suspended in the ethanol of 150mL, the tosic acid monohydrate that adds 1.4g, be warming up to 80 ℃ to clarification, filter, the filtrate reflux, to clarification, is added the 10mL ethanolic soln of 3.4g tosic acid monohydrate, and constant temperature stirs 30min, naturally be cooled to 25 ℃, filter the title compound that obtains 12g.Sampling detects
1H NMR, X-ray powder diffraction, DSC.
By nuclear magnetic data as can be known, the mol ratio of formula I compound and tosic acid is 1:1.
1H NMR(DMSO-d6，400MHz):δ2.30(s,3H),7.09-7.15(m,3H),733-7.40(m,2H),7.53(d,J=8Hz,2H),7.52(d,J=8Hz,2H),7.61-7.67(m,3H),8.14-8.21(m,2H),8.61(d,J=5.6Hz,1H),8.88(s,1H),9.06(d,J=4.8Hz,1H),9.63(s,1H),13.5(br,1H).
Its X-ray powder diffraction pattern is seen Fig. 3 a, and the parameter at each peak is as shown in table 3, and dsc figure (DSC) sees Fig. 3 b,
1The collection of illustrative plates of H NMR is seen 3c.
Table 3
| Peak number | 2θ(°) | Peak height | Relative intensity (I%) | Peak number | 2θ(°) | Peak height | Relative intensity (I%) |
| 1 | 4.476 | 29534 | 91.89 | 27 | 26.879 | 3459 | 10.76 |
| 2 | 8.913 | 1398 | 4.35 | 28 | 27.118 | 1811 | 5.63 |
| 3 | 10.952 | 1040 | 3.24 | 29 | 27.687 | 2448 | 7.62 |
| 4 | 11.429 | 1307 | 4.07 | 30 | 28.138 | 3770 | 11.73 |
| 5 | 12.178 | 903 | 2.81 | 31 | 28.637 | 2141 | 6.66 |
| 6 | 13.357 | 32139 | 100.00 | 32 | 28.989 | 3849 | 11.98 |
| 7 | 14.761 | 1840 | 5.73 | 33 | 29.526 | 1672 | 5.20 |
| 8 | 15.153 | 798 | 2.48 | 34 | 29.996 | 2103 | 6.54 |
| 9 | 16.222 | 2040 | 6.35 | 35 | 31.451 | 1346 | 4.19 |
| 10 | 16.517 | 7203 | 22.41 | 36 | 31.674 | 1421 | 4.42 |
| 11 | 18.037 | 15686 | 48.81 | 37 | 32.402 | 1096 | 3.41 |
| 12 | 18.883 | 3902 | 12.14 | 38 | 32.997 | 1065 | 3.31 |
| 13 | 19.242 | 1534 | 4.77 | 39 | 33.571 | 1603 | 4.99 |
| 14 | 19.690 | 3790 | 11.79 | 40 | 33.906 | 1708 | 5.31 |
| 15 | 20.107 | 4607 | 14.33 | 41 | 34.319 | 2078 | 6.47 |
| 16 | 20.327 | 3671 | 11.42 | 42 | 35.501 | 900 | 2.80 |
| 17 | 20.838 | 4477 | 13.93 | 43 | 36.404 | 896 | 2.79 |
| 18 | 21.786 | 15975 | 49.71 | 44 | 36.964 | 985 | 3.06 |
| 19 | 22.320 | 2403 | 7.48 | 45 | 38.168 | 1001 | 3.11 |
| 20 | 22.990 | 8363 | 26.02 | 46 | 38.677 | 1101 | 3.43 |
| 21 | 23.665 | 1871 | 5.82 | 47 | 39.406 | 1052 | 3.27 |
| 22 | 23.976 | 2432 | 7.57 | 48 | 40.633 | 1476 | 4.59 |
| 23 | 24.472 | 1989 | 6.19 | 49 | 41.304 | 1752 | 5.45 |
| 24 | 24.907 | 1786 | 5.56 | 50 | 41.875 | 1844 | 5.74 |
| 25 | 25.597 | 1690 | 5.26 | 51 | 44.363 | 1403 | 4.37 |
| 26 | 26.087 | 1486 | 4.62 |
Embodiment 44-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuterium is for methyl) stability of the polymorphic form I of picolinamide
After the accelerated test (40 ℃ of test conditionss, 75%RH) through 1-6 month, result shows: the crystal formation of polymorphic form I is very stable; And freshly prepd (0 month) the polymorphic form I that compares, in polymorphic form I, foreign matter content changes less than 15%.
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride)-3-fluoro-phenoxy group)-2-(N-1 ', 1 ', 1 '-three deuterium is for methyl) polymorphic form I (embodiment 2) 20g of picolinamide
Starch 140g
Microcrystalline Cellulose 60g
According to a conventional method, after above-mentioned substance was mixed, the common gelatine capsule of packing into, obtained 1000 capsules.
As seen, multiple polymorphic form of the present invention is all highly stable, is suitable for very much pharmaceutical composition.And polymorphic form of the present invention in the medicine manufacturing processedes such as packing, is difficult for kicking up, and easily collecting is difficult for causing waste, and helps to protect that operator's is healthy.
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (11)
1. the polymorphic form of compound shown in a formula I or its pharmacy acceptable salt,
2. polymorphic form as claimed in claim 1, it is characterized in that, described polymorphic form is the polymorphic form I of compound shown in formula I, wherein, described polymorphic form I has 1 or 2 X-ray powder diffraction characteristic peak that is selected from lower group: 7.224 ± 0.2 °, and 14.507 ± 0.2 °.
3. polymorphic form as claimed in claim 2, is characterized in that, the dsc collection of illustrative plates of described polymorphic form I has peak-peak at 211.8-214.1 ℃.
4. polymorphic form as claimed in claim 1, it is characterized in that, described polymorphic form is the polymorphic form II of compound shown in formula I, wherein, described polymorphic form II has one or more X-ray powder diffraction characteristic peaks that is selected from lower group: 22.323 ± 0.2 °, 24.199 ± 0.2 °, and 24.830 ± 0.2 °.
5. polymorphic form as claimed in claim 4, is characterized in that, the dsc collection of illustrative plates of described polymorphic form II has peak-peak at 196.2-198.6 ℃.
6. polymorphic form as claimed in claim 1, it is characterized in that, described polymorphic form is the polymorphic form III of the tosilate of compound shown in formula I, wherein, described polymorphic form III has 1 or 2 X-ray powder diffraction characteristic peak that is selected from lower group: 4.476 ± 0.2 °, and 13.357 ± 0.2 °.
7. polymorphic form as claimed in claim 6, is characterized in that, the dsc collection of illustrative plates of described polymorphic form III has peak-peak at 239.5-241.7 ℃.
8. the purposes as the arbitrary described polymorphic form of claim 1-7, is characterized in that, for the preparation of the pharmaceutical composition that suppresses phosphokinase.
9. purposes as claimed in claim 8, is characterized in that, described pharmaceutical composition is used for the treatment of and preventing cancer.
10. a pharmaceutical composition, is characterized in that, comprises:
(a) the arbitrary described polymorphic form of claim 1-7; With
(b) pharmaceutically acceptable carrier.
11. preparation method as the described polymorphic form of claim 1-7 any one, it is characterized in that, comprise step: with pharmacy acceptable salt recrystallization in inert solvent of compound shown in compound shown in formula I or formula I, thereby obtain the described polymorphic form of claim 1-7 any one.
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| US20090069388A1 (en) * | 2007-09-11 | 2009-03-12 | Protia, Llc | Deuterium-enriched sorafenib |
| WO2010135579A1 (en) * | 2009-05-22 | 2010-11-25 | Concert Pharmaceuticals, Inc. | Fluorinated diaryl urea derivatives |
| WO2011113368A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Preparation method of fluoro-substituted deuterated diphenylurea |
| WO2011113370A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Deuterium-substituted omega-diphenylurea and derivatives thereof and pharmaceutical compositions comprising these compounds |
| CN102459180A (en) * | 2009-06-09 | 2012-05-16 | 江苏迈度药物研发有限公司 | Urea derivatives as kinase inhibitors |
| CN102675018A (en) * | 2011-03-17 | 2012-09-19 | 苏州泽璟生物制药有限公司 | Method for preparing deuterated diphenyl urea |
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| US20090069388A1 (en) * | 2007-09-11 | 2009-03-12 | Protia, Llc | Deuterium-enriched sorafenib |
| WO2010135579A1 (en) * | 2009-05-22 | 2010-11-25 | Concert Pharmaceuticals, Inc. | Fluorinated diaryl urea derivatives |
| CN102459180A (en) * | 2009-06-09 | 2012-05-16 | 江苏迈度药物研发有限公司 | Urea derivatives as kinase inhibitors |
| WO2011113368A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Preparation method of fluoro-substituted deuterated diphenylurea |
| WO2011113370A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Deuterium-substituted omega-diphenylurea and derivatives thereof and pharmaceutical compositions comprising these compounds |
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| CN113788758A (en) * | 2021-09-13 | 2021-12-14 | 安徽昊帆生物有限公司 | Preparation method and preparation device of deuterated low-carbon amine |
| CN113788758B (en) * | 2021-09-13 | 2024-09-17 | 安徽昊帆生物有限公司 | Preparation method and preparation device of deuterated low-carbon amine |
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