Fluorine-containing deuterated ω-diphenyl urea or the polymorph of its salt
Technical field
The invention belongs to field of medicaments, specifically, relate to the polymorph of a kind of fluorine-containing deuterated ω-diphenyl urea or its salt, more specifically, relate to 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) polymorph of picolinamide or its salt.
Background technology
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide (4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) 3-fluorophenoxy)-2-(N-1 ', 1 ', 1 '-trideuteromethyl) picolinamide), structure is shown in formula I.
The molecular formula of compound of formula I is C21H12D3ClF4N4O3, molecular weight is 485.83, for white to off-white color crystalline powder;Odorless;Tasteless.Very easily dissolving in dimethyl sulfoxide or dimethylformamide, slightly molten in methanol, slightly soluble in acetone, dehydrated alcohol or glacial acetic acid, almost insoluble in water, fusing point is 224~230 DEG C.
Compound of formula I belongs to the suppression kinase whose compound of raf, it is adaptable to the medicine of preparation treatment cancer and relevant disease.But what be currently used for preparing relative medicine is amorphous compound, does not still develop the polymorph of compound of formula I.
Therefore, the polymorph researching and developing compound of formula I is very necessary.
Summary of the invention
It is an object of the present invention to provide a series of 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) polymorph of picolinamide or its salt.
In a first aspect of the present invention, it is provided that the polymorph of compound or its pharmaceutically acceptable salt shown in a kind of Formulas I,
In another preference, described pharmaceutically acceptable salt is toluenesulfonate.
In another preference, described polymorph is the polymorph I of compound shown in Formulas I, and wherein, described polymorph I has the X-ray powder diffraction characteristic peak that 1 or 2 selected from lower group: 7.224 ± 0.2 °, and 14.507 ± 0.2 °.
In another preference, described polymorph I also has the X-ray powder diffraction characteristic peak that 1 or 2 selected from lower group: 13.363 ± 0.2 °, 17.192 ± 0.2 °, and 19.779 ± 0.2 °.
In another preference, described polymorph I has X-ray powder diffractogram (XRPD) substantially as shown in Figure 2 a.
In another preference, the differential scanning calorimetry collection of illustrative plates of described polymorph I has peak-peak at 211.8-214.1 DEG C.
In another preference, described polymorph I has differential scanning calorimetry collection of illustrative plates (DSC) substantially as shown in Figure 2 b.
In another preference, described polymorph is the polymorph II of compound shown in Formulas I, and wherein, described polymorph II has one or more X-ray powder diffraction characteristic peaks being selected from lower group: 22.323 ± 0.2 °, 24.199 ± 0.2 °, and 24.830 ± 0.2 °.
In another preference, described polymorph II also has one or more X-ray powder diffraction characteristic peaks being selected from lower group: 18.573 ± 0.2 °, 21.671 ± 0.2 °, 23.507 ± 0.2 °, and 25.166 ± 0.2 °.
In another preference, described polymorph II has X-ray powder diffractogram (XRPD) substantially as shown in Figure 1a.
In another preference, the differential scanning calorimetry collection of illustrative plates of described polymorph II has peak-peak at 196.2-198.6 DEG C.
In another preference, described polymorph II has differential scanning calorimetry collection of illustrative plates (DSC) substantially as shown in Figure 1 b.
In another preference, described polymorph is the polymorph III of the tosilate of compound shown in Formulas I, wherein, described polymorph III has the X-ray powder diffraction characteristic peak that 1 or 2 selected from lower group: 4.476 ± 0.2 °, and 13.357 ± 0.2 °.
In another preference, described polymorph III also has one or more X-ray powder diffraction characteristic peaks being selected from lower group: 16.517 ± 0.2 °, 18.037 ± 0.2 °, 21.786 ± 0.2 ° and 22.990 ± 0.2 °.
In another preference, described polymorph III has X-ray powder diffractogram substantially as shown in Figure 3 a.
In another preference, the differential scanning calorimetry collection of illustrative plates of described polymorph III has peak-peak at 239.5-241.7 DEG C.
In another preference, described polymorph III has differential scanning calorimetry collection of illustrative plates substantially as shown in Figure 3 b.
In another preference, the tosilate of described compound of formula I is 1/1 tosilate, and wherein, the mol ratio of compound of formula I and p-methyl benzenesulfonic acid is 1:1.
In a second aspect of the present invention, it is provided that the purposes of the polymorph described in a first aspect of the present invention, it is used for preparing the pharmaceutical composition suppressing phosphokinase (such as raf kinases).
In another preference, described pharmaceutical composition is used for treating and preventing cancer.
In a third aspect of the present invention, it is provided that a kind of pharmaceutical composition, it comprises:
Polymorph described in (a) a first aspect of the present invention;With
(b) pharmaceutically acceptable carrier.
In a fourth aspect of the present invention, the preparation method providing polymorph described in a kind of a first aspect of the present invention, it includes step: by the pharmaceutically acceptable salt of compound shown in Formulas I or compound shown in Formulas I recrystallization in atent solvent, thus obtaining the polymorph described in a first aspect of the present invention.
In another preference, the method for making of described polymorph I, including step: by above-mentioned prepared polymorph II recrystallization in methanol, thus obtaining described polymorph I.
In another preference, the method for making of described polymorph III, including step: by above-mentioned prepared polymorph I and p-methyl benzenesulfonic acid recrystallization in atent solvent, thus obtaining described polymorph III.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus constituting new or preferred technical scheme.As space is limited, tired no longer one by one state at this.
Accompanying drawing explanation
Fig. 1 a shows the X-ray powder diffraction pattern of the polymorph II of embodiment 1.
Fig. 1 b shows the differential scanning calorimetry figure of the polymorph II of embodiment 1.
Fig. 1 c shows the NMR figure of the polymorph II of embodiment 1.
Fig. 2 a shows the X-ray powder diffraction pattern of the polymorph I of embodiment 2.
Fig. 2 b shows the differential scanning calorimetry figure of the polymorph I of embodiment 2.
Fig. 2 c shows the NMR figure of the polymorph I of embodiment 2.
Fig. 3 a shows the X-ray powder diffraction pattern of the polymorph III of embodiment 3.
Fig. 3 b shows the differential scanning calorimetry figure of the polymorph III of embodiment 3.
Fig. 3 c shows the NMR figure of the polymorph III of embodiment 3.
Detailed description of the invention
The present inventor is by long-term and deep research, have unexpectedly discovered that 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) the multiple polymorph of picolinamide or its salt, described Polvmorph Puritv is high, and it is highly stable, it is suitable for preparation and suppresses the pharmaceutical composition of phosphokinase (such as raf kinases), thus being more beneficial for the diseases such as treatment cancer.Additionally, the polymorph of the present invention is in the medicine manufacture processes such as subpackage, not easily kick up, easily collecting, do not easily cause waste, and contribute to the healthy of protection operator.On this basis, inventor completes the present invention.
As used herein, " compound of formula I " refer to 4-shown in structural formula as I (4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide.
Polymorph
Solid is not be exactly exist with the form of crystallization with unbodied form.When crystal form, molecule is positioned in three-dimensional lattice case.When compound crystallizes out from solution or serosity, space lattice arrangement crystallization (this character is referred to as " polymorphism ") that it can be different, form the crystal with different crystal forms, these various crystal forms are referred to as " polymorph ".The different polymorphs of given material can be different from each other (such as dissolubility and rate of dissolution, true specific gravity, crystal form, accumulation mode, mobility and/or solid-state stability) in one or more physical attributes.
Crystallization
Solution can be operated by so that the solubility limit of compound of interest is exceeded, thus completing production-scale crystallization.This can be completed by multiple method, for instance, dissolved compound at relatively high temperature, then cooling solution is to saturation limit.Or by boiling, atmospheric evaporation, vacuum drying or reduce liquid volume by some other methods.Addition solvent resistant can be passed through or compound has the solvent of low dissolubility or the mixture of such solvent wherein, reduce the dissolubility of compound of interest.Another kind of alternative is to regulate pH value to reduce dissolubility.Crystallization is referred to about the detailed description of crystallization aspect, the third edition, JWMullens, Butterworth-HeinemanLtd., 1993, ISBN0750611294.
If formation and the crystallization of expectation salt occur, if salt is less than material dissolution degree in reaction medium simultaneously, then add suitable acid or alkali may result in the direct crystallization of required salt.Equally, in the medium that the form finally wanted is less than reactant dissolubility, the completing of synthetic reaction can make end product direct crystallization.
The optimization of crystallization can include being inoculated in crystallization medium as crystal seed with the crystal of desired form.It addition, many method for crystallising use the combination of above-mentioned strategy.One embodiment is at high temperature by compound dissolution interested in a solvent, is added the solvent resistant of proper volume subsequently by controlled way, so that system is just under saturated level.Now, the crystal seed (and keeping the integrity of crystal seed) of desired form can be added, system is cooled down to complete crystallization.
As used herein, term " room temperature " refers generally to 4-30 DEG C, it is preferred that refer to 20 ± 5 DEG C.
The polymorph of the present invention
As used herein, term " polymorph of the present invention " includes compound of formula I or its salt (such as tosilate) polymorph, also includes the different polymorphs of compound of formula I.
Preferably, for the polymorph I or polymorph II of compound of formula I, or the polymorph III of 1/1 tosilate of compound of formula I, wherein, the mol ratio of compound of formula I and p-methyl benzenesulfonic acid is 1:1.
The qualification of polymorph and character
The present invention, after the polymorph of preparation I compound, adopts following various ways and instrument that its character has been studied.
X-ray powder diffraction
The method of the X-ray powder diffraction measuring crystal formation is well known in the art.Such as use the x-ray powder diffraction instrument of RigakuD/max2550VB/PC model, with scanning speed 2 ° per minute, adopt copper radiation target to obtain collection of illustrative plates.
The polymorph of the compound of formula I of the present invention, has specific crystal formation form, has specific characteristic peak in X-ray powder diffraction (XRPD) figure.
(1) polymorph I
Described polymorph I has the X-ray powder diffraction characteristic peak that 1 or 2 selected from lower group: 7.224 ± 0.2 °, and 14.507 ± 0.2 °.
In another preference, described polymorph I also has one or more X-ray powder diffraction characteristic peaks being selected from lower group: 13.363 ± 0.2 °, 17.192 ± 0.2 °, and 19.779 ± 0.2 °.
In another preference, described polymorph I has X-ray powder diffractogram substantially as shown in Figure 2 a.
(2) polymorph II
Described polymorph II has one or more X-ray powder diffraction characteristic peaks being selected from lower group: 22.323 ± 0.2 °, 24.199 ± 0.2 °, and 24.830 ± 0.2 °.
In another preference, described polymorph II also has one or more X-ray powder diffraction characteristic peaks being selected from lower group: 18.573 ± 0.2 °, 21.671 ± 0.2 °, 23.507 ± 0.2 °, and 25.166 ± 0.2 °.
In another preference, described polymorph II has X-ray powder diffractogram substantially as shown in Figure 1a.
(3) polymorph III
Described polymorph III has the X-ray powder diffraction characteristic peak that 1 or 2 selected from lower group: 4.476 ± 0.2 °, and 13.357 ± 0.2 °.
In another preference, described polymorph III also has one or more X-ray powder diffraction characteristic peaks being selected from lower group: 16.517 ± 0.2 °, 18.037 ± 0.2 °, 21.786 ± 0.2 ° and 22.990 ± 0.2 °.
In another preference, described polymorph III has X-ray powder diffractogram substantially as shown in Figure 3 a.
Differential scanning calorimetry
Also known as " differential scanning calorimetry " (DSC), it is in heating process, measures a kind of technology of relation between energy difference and the temperature between measured matter and reference substance.Peak position, shape on DSC collection of illustrative plates are relevant with the character of material with peak number order, therefore can be used for qualitatively identifying material.The method commonly used in the art detects the many kinds of parameters such as the phase transition temperature of material, glass transition temperature, reaction heat.
DSC assay method is well known in the art.Such as can use NETZSCHDSC204F1 differential scanning calorimetry (DSC), with heating rate 10 DEG C per minute, be warming up to 250 DEG C from 25 DEG C, it is thus achieved that the DSC scanning spectra of crystal formation.
The polymorph of the compound of formula I of the present invention, has specific characteristic peak in differential scanning calorimetry (DSC) figure.
(1) polymorph I
The differential scanning calorimetry collection of illustrative plates of described polymorph I has peak-peak at 211.8-214.1 DEG C.
In another preference, described polymorph I has differential scanning calorimetry collection of illustrative plates (DSC) substantially as shown in Figure 2 b.
(2) polymorph II
The differential scanning calorimetry collection of illustrative plates of described polymorph II has peak-peak at 196.2-198.6 DEG C.
In another preference, described polymorph II has differential scanning calorimetry collection of illustrative plates (DSC) substantially as shown in Figure 1 b.
(3) polymorph III
The differential scanning calorimetry collection of illustrative plates of described polymorph III has peak-peak at 239.5-241.7 DEG C.
In another preference, described polymorph III has differential scanning calorimetry collection of illustrative plates substantially as shown in Figure 3 b.
Nuclear magnetic resonance, NMR
May be used without nuclear magnetic resonance, NMR (NMR) to assist and determine crystalline structure, its assay method is well known in the art.Present invention preferably uses BrukerAvanceIIIplus-400MHz.
Active component
As used herein, term " active component " or " reactive compound " refer to the polymorph of the present invention, i.e. the polymorph of the compound shown in Formulas I, certainly include the polymorph of its pharmaceutically acceptable salt.Described pharmaceutically acceptable salt, for instance but it is not limited to toluenesulfonate.
Pharmaceutical composition and application process
Due to the polymorph of the present invention have excellence to the kinase whose inhibitory activity of phosphokinase (Kinase) such as raf, therefore the polymorph of the present invention and the pharmaceutical composition that polymorph is main active containing the present invention can be used for treating, prevent and alleviate the disease by phosphokinase (Kinase) such as raf is kinase mediated.According to prior art, the polymorph of the present invention can be used for treating following disease: cancer, cardiovascular disease, obesity, diabetes etc..
The pharmaceutical composition of the present invention comprises polymorph and pharmaceutically acceptable excipient or the carrier of the present invention in safe and effective weight range.Wherein " safe and effective amount " refers to: the amount of compound (or polymorph) is enough to be obviously improved the state of an illness, and is unlikely to produce serious side effect.Generally, pharmaceutical composition contains the polymorph/agent of the 1-2000mg present invention, more preferably, containing the polymorph/agent of the 10-200mg present invention.It is preferred that described " potion " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use and it is necessary to have enough purity and of a sufficiently low toxicity.Active component that " compatibility " referred to herein as in compositions each component energy and the present invention and they between mutually admix, and significantly reduce the drug effect of active component.Pharmaceutically acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, Talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, Fructus Canarii albi wet goods), polyhydric alcohol (such as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (such as tween), wetting agent (such as sodium lauryl sulphate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The polymorph of the present invention or the method for application of pharmaceutical composition are not particularly limited, and representational method of application includes (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and topical.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid dosage formss, active component mixes with at least one conventional inert excipients (or carrier), such as sodium citrate or dicalcium phosphate, or mixes with following compositions: (a) filler or bulking agent, such as, starch, lactose, sucrose, glucose, mannitol and silicic acid;(b) binding agent, for instance, hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum;(c) wetting agent, for instance, glycerol;(d) disintegrating agent, for instance, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate and sodium carbonate;(e) retarding solvent, for instance paraffin;F () absorbs accelerator, for instance, quaternary ammonium compound;(g) wetting agent, for instance spermol and glyceryl monostearate;(h) adsorbent, for instance, Kaolin;(i) lubricant, for instance, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, dosage form also can comprise buffer agent.
Solid dosage forms such as tablet, sugar pill, capsule, pill and granule can adopt coating and shell material to prepare, such as casing and other material well known in the art.They can comprise opacifying agent, and, in this compositions, the release of active component can release in the part of certain in digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material and Wax.If desired, active component also can with one or more formation microencapsulation form in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except active component, liquid dosage form can comprise the conventional inert diluent adopted in this area, such as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethylformamide and oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or these materials.
Except these inert diluents, compositions also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweeting agent, tender taste agent and spice.
Except active component, suspension can comprise suspending agent, for instance, the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or these materials.
Compositions for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into the sterilized powder of aseptic Injectable solution or dispersion liquid.Moisture and the nonaqueous carrier, diluent, solvent or the excipient that are suitable for include water, ethanol, polyhydric alcohol and suitable mixture thereof.
Dosage form for the polymorph of the present invention of topical includes ointment, powder, patch, propellant and inhalant.Active component aseptically with physiologically acceptable carrier and any preservative, buffer agent, or if desired be likely to need propellant be mixed together.
The polymorph of the present invention can be individually dosed, or with other pharmaceutically acceptable compound administering drug combinations.
When making pharmaceutical composition, it it is the mammal (such as people) that the polymorph of the present invention of safe and effective amount is applicable to treatment, when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day dosage is generally 1~2000mg, it is preferable that 20~500mg.Certainly, concrete dosage is it is also contemplated that the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
The major advantage of the present invention has:
1. provide series of novel 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) polymorph of picolinamide or its salt, wherein, including the polymorph I and polymorph II of compound of formula I, and the polymorph III of the toluenesulfonate of compound of formula I.
2. additionally provide the purposes of described polymorph, can be used for preparation and suppress the pharmaceutical composition of phosphokinase (such as raf kinases), thus being used for treating the diseases such as cancer.
Below in conjunction with being embodied as, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition, or according to manufacturer it is proposed that condition.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.If not the raw materials used special instruction of the present invention, all commercially.
Embodiment 1
The polymorph II of 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide
The 4-Chloro-2-Pyridyle methyl formate of 50g is dissolved in the there-necked flask of 250mL oxolane, it is separately added into the Anhydrous potassium carbonate of the deuterated methylamine hydrochloride of 31g and 80g, 25 DEG C of stirrings added 250mL water and 100mL methyl tertiary butyl ether(MTBE) after 20 hours, stirring layering, separatory, aqueous phase 100mL methyl tertiary butyl ether(MTBE) extracts, and merges organic facies and dries, and removal of solvent under reduced pressure obtains the liquid 48g of the chloro-N-of light yellow 4-deuterated picoline-2-Methanamide.
The potassium tert-butoxide of 15g is suspended in the N of 50mL, in the solution of N-dimethyl acetylamide, the N of the fluoro-4-Amino-phenol (16g) of 3-being slowly added dropwise under 0 ~ 5 degree, N-dimethyl acetylamide (50mL) solution, at room temperature stirring 20 minutes, it is warming up to 100 DEG C and is slowly added dropwise the N of the chloro-N-of 4-deuterated picoline-2-Methanamide (17g), N-dimethyl acetylamide (50mL), stirring 0.5 hour is continued after dropwising, it is cooled to 25 DEG C, in reactant liquor, add the diluted ethyl acetate of 500mL and stir 0.5 hour, it is filtered to remove inorganic salt, with the water washing of 500mL, anhydrous sodium sulfate dries, removal of solvent under reduced pressure, the ethanol of 100mL the making beating 2 hours that refluxes is added in crude product, it is cooled to 25 DEG C of 4-(4-fluoro-phenoxy groups of amino-3-being filtrated to get brown)-N-deuterated picoline-2-Methanamide solid 20g.
At 25 DEG C, chloro-for the 4-of 13g 3-trifluoromethylbenzene based isocyanate is dissolved in 70mL ethyl acetate, and by the 4-(4-fluoro-phenoxy group of amino-3-of 14g) the 350mL ethyl acetate solution of-N-deuterated picoline-2-Methanamide is slowly added dropwise to above-mentioned solution, 25 DEG C are stirred 20 hours, react complete filtration and wash twice by the ethyl acetate of 20mL, obtaining the brown solid of 13g.
Sampling warp1HNMR, X-ray powder diffraction, DSC etc. detect proof, and described solid is title compound.
1HNMR(DMSO-d6,400MHz): δ 7.06-7.10 (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 shown in Fig. 1 a, and the parameter at each peak is as shown in table 1, and differential scanning calorimetry figure (DSC) is shown in that 1c is shown in by the collection of illustrative plates of Fig. 1 b, 1HNMR.
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 |
Embodiment 2
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) the polymorph I of picolinamide
The polymorph II that the embodiment 1 of 500mg prepared adds in the acetone of 20ml, and stirring and dissolving is clarified, under room temperature, and the water of dropping 15ml, precipitate out solid, stir 30 minutes, filtration, the water washing of the solid 10ml obtained, 30 DEG C of vacuum dryings 16 hours.Sampling warp1HNMR, X-ray powder diffraction, DSC etc. detect proof, obtain title compound 200mg.
1HNMR(DMSO-d6,400MHz): δ 7.06-7.10 (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 shown in Fig. 2 a, and the parameter at each peak is as shown in table 2, and differential scanning calorimetry figure (DSC) is shown in Fig. 2 b,12c is shown in by the collection of illustrative plates of HNMR.
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 --> |
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 |
Embodiment 3
The polymorph III of 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide 1/1 tosilate
The polymorph I(10g that embodiment 2 is prepared) it is suspended in the ethanol of 150mL, add the p-methyl benzenesulfonic acid monohydrate of 1.4g, it is warming up to 80 DEG C to clarifying, filter, filtrate is heated to reflux to clarification, adds the 10mL alcoholic solution of 3.4g p-methyl benzenesulfonic acid monohydrate, constant temperature stirring 30min, it is naturally cooling to 25 DEG C, is filtrated to get the title compound of 12g.Sampling detection1HNMR, X-ray powder diffraction, DSC.
By nuclear magnetic data it can be seen that the mol ratio of compound of formula I and p-methyl benzenesulfonic acid is 1:1.
1HNMR (DMSO-d6,400MHz): δ 2.30 (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 shown in Fig. 3 a, and the parameter at each peak is as shown in table 3, and differential scanning calorimetry figure (DSC) is shown in Fig. 3 b,13c is shown in by the collection of illustrative plates of HNMR.
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 9 --> |
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 |
|
|
|
|
The stability of the polymorph I of embodiment 44-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide
After the accelerated test (experimental condition 40 DEG C, 75%RH) of 1-6 month, result shows: the crystal formation of polymorph I is sufficiently stable;And freshly prepd (0 month) the polymorph I that compares, in polymorph I, impurity content changes less than 15%.
Embodiment 5 pharmaceutical composition
4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) polymorph I (embodiment 2) 20g of picolinamide
Starch 140g
Microcrystalline Cellulose 60g
According to a conventional method, after above-mentioned substance mix homogeneously, load common gelatine capsule, obtain 1000 capsules.
Visible, multiple polymorph of the present invention is all highly stable, is highly suitable for pharmaceutical composition.And the polymorph of the present invention is in the medicine manufacture processes such as subpackage, not easily kicks up, easily collecting, do not easily cause waste, and contribute to the healthy of protection operator.
The all documents mentioned in the present invention are incorporated as reference all in this application, are individually recited as reference such just as each section of document.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application appended claims limited range equally.