CN105601614A - Ceritinib crystal form and preparation method thereof - Google Patents
Ceritinib crystal form and preparation method thereof Download PDFInfo
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- CN105601614A CN105601614A CN201410675278.9A CN201410675278A CN105601614A CN 105601614 A CN105601614 A CN 105601614A CN 201410675278 A CN201410675278 A CN 201410675278A CN 105601614 A CN105601614 A CN 105601614A
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Abstract
The invention discloses a ceritinib crystal form C, an amorphous substance, preparation methods and an application thereof. Concretely, the invention relates to the ceritinib amorphous substance and the crystal form C, and respective preparation methods of the ceritinib amorphous substance and the crystal form C. The ceritinib amorphous substance provided by the invention has good dissolvability, and the ceritinib crystal form C has good thermostability.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, particularly, the present invention relates to a kind of look auspicious crystal formation and nothing for Buddhist nunSetting thing and its production and use.
Background technology
Look auspicious to be developed by Novartis Co.,Ltd for Buddhist nun, and commodity are called Zykadia, the chemistry chloro-N of 5-by name2-(2-isopropylOxygen base-5-methyl-4-(piperidin-4-yl) phenyl)-N4-(2-(propane-2-sulfonic group)-phenyl) pyrimidine-2,4-Diamines, its structural formula is as follows:
Look auspicious is ALK inhibitor (AnaplasticLymphomaKinase) for Buddhist nun, in April, 201429 Nikkei U.S. FDA approval listings, for after gram azoles is for Buddhist nun's treatment, sb.'s illness took a turn for the worse or replace Buddhist nun not resistance to gram azolesThe anaplastic lymphoma kinase positive (ALK+) Metastatic Nsclc (NSCLC) patient who is subject to controlsTreat. At least accept in the 400mg look auspicious NSCLC patient for Buddhist nun's treatment in every day, the Progression free survival phase is 7Individual month. In the NSCLC patient that ALK resets late, comprise that acceptance gram azoles replaces Buddhist nun to treat rear existing disease and entersNo matter whether the patient of exhibition, there is ALK medicament-resistant mutation, and look auspicious is all highly effective for Buddhist nun.
Only have at present WO2012/082972 to report look auspicious two kinds of crystal formations---crystal form A and crystal form B for Buddhist nun.Wherein, the fusing point of crystal form A is 174 DEG C, and its preparation method is: under environment temperature by look auspicious for Buddhist nun's hydrochlorideJoin in the acetone/water of first part, in approximately 20 minutes, be heated to 55 ± 3 DEG C. Filter while hot, add secondAcetone/water. Time segment adds the NaOH aqueous solution in batches again, is then cooled to the time period of 45 minutes20 ± 3 DEG C, add deionized water. Filter, deionized water washing leaching cake, dry under 50 ± 3 DEG C and 10 millibars of vacuumWithin dry 17 hours, obtain crystal form A. In above-mentioned preparation method, solvent and aqueous slkali all need gradation to add, heating andThe cooling time all needs to control, and final drying stage, because wet product kind major part is water, needs higherTemperature and vacuum, and very long drying time.
The fusing point of the crystal form B of reporting in above-mentioned document is 162 DEG C, and its preparation method is: at 30-40 DEG CFirst be prepared into hydrochloride by look auspicious for Buddhist nun, be then cooled to 20-23 DEG C, within approximately 20 minutes, drip the NaOH aqueous solution.The dregs obtaining is heated to 40-42 DEG C and stirs 2 hours, and be heated to subsequently 50-55 DEG C and stir again 2 hours.Finally gained slurries are cooled to room temperature, filter, water washing filter cake, vacuum drying obtains crystal form B. This preparation sideIn method, need gradient increased temperature, complex operation, and also filter cake also washes with water, and dry temperature and vacuum areHeight, drying time is long.
Therefore, this area is needed the auspicious Buddhist nun's novel crystal forms that replaces of the more easy look of a kind of preparation means of exploitation badly.
Summary of the invention
The inventor, improving in existing crystal form A preparation method's experimental study, has surprisingly obtained look auspicious for Buddhist nunNovel crystal forms---crystal C, this crystal formation has good heat endurance, agent of low hygroscopicity, and has found another simultaneouslyA kind of novel crystal forms---look auspicious is for Buddhist nun's amorphous substance, and this crystal formation has good dissolubility, and can be very squareJust prepare crystal C.
In a first aspect of the present invention, provide a kind of look auspicious the crystal C for Buddhist nun, the X of described crystal CRay powder diffraction comprises that 3 or 3 are selected from the 2 θ values of lower group above: 4.96 °, 8.90 °,9.99°、10.3°、12.23°、13.95°、14.31°、14.90°、15.60°、15.96°、16.51°、16.77°、18.05°、18.74°、19.18°、19.93°、20.72°、23.16°、24.60°、24.92°、26.37°、27.05°、28.01°±0.2°。
In another preference, the X-ray powder diffraction collection of illustrative plates of the described look auspicious crystal C for Buddhist nun is basic as figure1 institute characterizes.
In another preference, the described look auspicious crystal C for Buddhist nun has the one or more spies that are selected from lower groupLevy:
Its differential scanning calorimetry is analyzed collection of illustrative plates and have characteristic peak in 198 DEG C of-207 scope;
Its differential scanning calorimetry is analyzed collection of illustrative plates substantially as Fig. 2 characterizes;
Its thermogravimetric analysis collection of illustrative plates is substantially as Fig. 3 characterizes.
Its infrared Fourier conversion spectrum has absworption peak in following position:
3417.7、3325.9、3191.5、2978.2、2936.57、2780.1、1593.9、1569.9、1539.2、1507.2、1487.9、1468.74、1445.1、1410.8、1317.8、1287.2、1260.3、1221.3、1199.3、1141.5、1122.9、1066.6、944.1、882.3、846.3、771.8、 734.9、703.9、675.7、587.9、509.4±2cm-1；
Its infrared Fourier conversion spectrum substantially as shown in Figure 4.
In another preference kind, in the thermogravimetric analysis collection of illustrative plates of the described look auspicious crystal C for Buddhist nun, decomposition point is positioned atWithin the scope of 261.43 ± 2 DEG C.
In another preference, described preparation method comprises the steps:
(i) in organic solvent, turn brilliant by look auspicious for Buddhist nun's raw material, form described replace of look auspicious thereby separate outBuddhist nun's crystal C,
Wherein said organic solvent is selected from lower group: acetone, esters solvent, alcohols solvent or its combination;
(ii) isolate the described look auspicious Buddhist nun's crystal C that replaces;
Wherein, described look auspicious is selected from for Buddhist nun's raw material: the look auspicious crystal form A for Buddhist nun's amorphous substance, the look auspicious Buddhist nun of replacing,Look auspicious crystal form B or its combination for Buddhist nun.
In another preference, described method comprises the one or more features that are selected from lower group:
In step (i), at 35-45 DEG C and stir and within 10～30 hours, turn brilliant;
In step (i), the described look auspicious w/v for Buddhist nun's raw material and described organic solvent is about 1g:5－20ml；
Described step (ii) comprising: be cooled to after 10-25 DEG C, filter, thereby obtain the look auspicious crystalline substance for Buddhist nunType C;
Described esters solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate and combination thereof;
Described alcohols solvent is selected from isopropyl alcohol, n-butanol, ethanol and combination thereof.
In another preference, enter under anhydrous or low moisture content condition at the crystalline substance that turns described in step (i)OK, for example, water content≤5% of described organic solvent, more preferably < 3%, more preferably < 1%, best <1%; In another preference, described method comprises: by look auspicious for Buddhist nun's crystal form A or crystal form B at acetone, esterIn kind solvent or alcohols solvent, stir and turn brilliant, obtain crystal C.
In another preference, described method comprises: mix with acetone for Buddhist nun's amorphous substance look auspicious, bothW/v is 1g:5-20ml, stirs at 35-45 DEG C, is cooled to after 10-25 DEG C, filters 30-40At DEG C, vacuum drying obtains the look auspicious crystal C for Buddhist nun.
In a second aspect of the present invention, provide a kind of look auspicious for Buddhist nun's amorphous substance, described look auspicious for Buddhist nun withoutSetting thing is between approximately 10 °-30 ° of the 2 θ number of degrees of X-ray powder diffraction collection of illustrative plates, and its x-ray powderDiffracting spectrum is substantially as Fig. 5 characterizes.
In another preference, described look auspicious has for Buddhist nun's amorphous substance the one or more spies that are selected from lower groupLevy:
Its differential scanning calorimetry is analyzed collection of illustrative plates and has been located characteristic peak at 66.7 ± 2 DEG C;
Its differential scanning calorimetry is analyzed collection of illustrative plates substantially as Fig. 6 characterizes;
Its thermogravimetric analysis collection of illustrative plates shows that its decomposition point is 269.47 ± 2 DEG C;
Its thermogravimetric analysis collection of illustrative plates is substantially as Fig. 7 characterizes;
Its infrared Fourier conversion spectrum has absworption peak in following position:
3415.7、2975.6、2935.7、2808.8、2723.8、2490.5、1600.1、1569.6、1508.5、1483.2、1448.1、1412.5、1316.5、1287.8、1262.9、1219.6、1196.0、1140.4、1123.9、1083.9、1053.2、1018.4、950.9、873.9、775.7、735.3、706.3、677.6、652.9、543.8、519.9、170.8±2cm-1；
Its infrared Fourier conversion spectrum is substantially as Fig. 8 characterizes.
In another preference, described method comprises the steps:
(1) preparation look auspicious is for Buddhist nun's dihydrochloride aqueous solution, at 0～20 DEG C with inorganic base aqueous solution furnishing pH8-9;
(2) gained solution extracts with esters solvent;
(3) organic layer of gained system is separated, pressure reducing and steaming solvent at 15～20 DEG C, obtains look auspiciousFor Buddhist nun's amorphous substance.
In another preference, the inorganic base described in above-mentioned steps (1) is to be selected from one or more of lower group:
NaOH, potassium hydroxide, sodium carbonate, potash, sodium acid carbonate, saleratus.
In another preference, the inorganic base described in step (1) is to be selected from one or more of lower group: hydrogenSodium oxide molybdena, potassium hydroxide.
In another preference, the esters solvent described in step (2) is to be selected from one or more of lower group:
Ethyl formate, methyl acetate, ethyl acetate or isopropyl acetate.
In another preference, the esters solvent described in step (2) is: ethyl acetate.
In a third aspect of the present invention, a kind of medical composition is provided, described composition comprises (a) originallyThe auspicious look for the crystallization of Buddhist nun's crystal C, second aspect present invention of the look of invention first aspect auspicious for Buddhist nun's amorphous substance withAnd (b) pharmaceutically acceptable supporting agent.
In a fourth aspect of the present invention, provide the look of first aspect present invention auspicious for Buddhist nun's crystal C or the present inventionThe look auspicious purposes for Buddhist nun's amorphous substance described in second aspect, as preparing medicine.
In another preference, described medicine is used for the treatment of cancer.
In another preference, as preparing the look auspicious raw material for Buddhist nun's crystal C.
Look provided by the invention is auspicious for Buddhist nun's crystal C, has the advantage such as Heat stability is good, stable storing. ThisBright look auspicious is 206.76 DEG C 206 for Buddhist nun's crystal C fusing point, than crystal form A and the crystal formation of WO2012/082972 reportThe fusing point of B is high, and physicochemical property is more stable. Especially technological operation is simple, do not need strictly to control temperature andTime, and shorten dramatically the drying time of product, production cost reduced. Look provided by the invention is auspicious to be replacedIt is auspicious for Buddhist nun's crystal C that Buddhist nun's amorphous substance can prepare look of the present invention easily.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and at below (as embodiment)In can combine mutually between specifically described each technical characterictic, thereby form new or preferred technical sideCase. As space is limited, this is no longer going to repeat them.
Brief description of the drawings
Fig. 1 has shown the look auspicious X-ray powder diffraction spectrogram (XRPD) for Buddhist nun's crystal C.
Fig. 2 has shown the look auspicious differential scanning calorimetric analysis spectrogram (DSC) for Buddhist nun's crystal C.
Fig. 3 has shown the look auspicious thermogravimetic analysis (TGA) spectrogram (TGA) for Buddhist nun's crystal C.
Fig. 4 has shown the look auspicious infrared Fourier conversion spectrum figure (FT-IR) for Buddhist nun's crystal C.
Fig. 5 has shown the look auspicious X-ray powder diffraction spectrogram (XRPD) for Buddhist nun's amorphous substance.
Fig. 6 has shown the look auspicious differential scanning calorimetric analysis spectrogram (DSC) for Buddhist nun's amorphous substance.
Fig. 7 has shown the look auspicious thermogravimetic analysis (TGA) spectrogram (TGA) for Buddhist nun's amorphous substance.
Fig. 8 has shown the look auspicious infrared Fourier conversion spectrum figure (FT-IR) for Buddhist nun's amorphous substance.
Detailed description of the invention
For existing defect in prior art, the inventor, through extensive and deep research, obtains firstA kind of look auspicious crystal C and its amorphous substance for Buddhist nun, and corresponding preparation method. Look of the present invention is auspicious for Buddhist nunCrystal C has good heat endurance, agent of low hygroscopicity, and the auspicious Buddhist nun's amorphous substance that replaces of the look making is first as thisThe intermediate forms of bright method, also has good dissolubility, more easily and is easily converted into that required look auspicious to be replacedBuddhist nun's crystal C. Preparation method provided by the invention, simple to operate and can scale implement. Inventor on this basisComplete the present invention.
It is a kind of taking the auspicious pharmaceutical composition of Buddhist nun's crystal C as active component that replace of look of the present invention that the present invention also provides.
As used herein, " crystal of the present invention ", " crystal formation of the present invention ", " crystal C of the present invention "," crystal C of the present invention ", " look of the present invention auspicious for Buddhist nun's crystal C ", " look auspicious is for Buddhist nun's crystal C ", " look auspiciousFor Buddhist nun's crystal C " be used interchangeably.
Active component
The auspicious X-ray powder diffraction collection of illustrative plates for Buddhist nun's crystal C of look of the present invention comprises that 3 or 3 are selected from aboveThe 2 θ values of lower group: 4.96 °, 8.90 °, 9.99 °, 10.3 °, 12.23 °, 13.95 °, 14.31°、14.90°、15.60°、15.96°、16.51°、16.77°、18.05°、18.74°、19.18°、19.93°、20.72°、23.16°、24.60°、24.92°、26.37°、27.05°、28.01° ± 0.2 °; More preferably, the X-ray powder diffraction collection of illustrative plates of described crystal is substantially as Fig. 1 characterizes.
In another preference, the described look auspicious crystal C for Buddhist nun has the one or more spies that are selected from lower groupLevy:
Its differential scanning calorimetry is analyzed collection of illustrative plates and have characteristic peak within the scope of 206.76 ± 2 DEG C;
Its differential scanning calorimetry is analyzed collection of illustrative plates substantially as Fig. 2 characterizes;
In its thermogravimetric analysis collection of illustrative plates, decomposition point is positioned at 261.43 ± 2 DEG C of scopes;
Its thermogravimetric analysis collection of illustrative plates is substantially as Fig. 3 characterizes.
Its infrared Fourier conversion spectrum has absworption peak in following position:
3417.7、3325.9、3191.5、2978.2、2936.57、2780.1、1593.9、1569.9、1539.2、1507.2、1487.9、1468.74、1445.1、1410.8、1317.8、1287.2、1260.3、1221.3、1199.3、1141.5、1122.9、1066.6、944.1、882.3、846.3、771.8、734.9、703.9、675.7、587.9、509.4±2cm-1；
Its infrared Fourier conversion spectrum substantially as shown in Figure 4.
Preparation method
The invention provides a kind of look auspicious for Buddhist nun's crystal C. Those skilled in the art can be with reference to WO2012/082972Prepare this look as the look auspicious raw material for Buddhist nun's crystal C auspicious for Buddhist nun's crystal form A and crystal form B.
Those skilled in the art also can prepare the look auspicious amorphous substance for Buddhist nun with reference to instruction of the present invention,As preparing the look auspicious raw material for Buddhist nun's crystal C.
First, the invention provides a kind of look auspicious method for Buddhist nun's crystal C, comprise step:
1) under environment temperature, join in organic solvent for Buddhist nun's raw material look auspicious, stir;
In another preference, described organic solvent is selected from lower group: acetone, esters solvent or alcohols solvent.Described esters solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate and combination thereof; Described alcoholsSolvent is selected from isopropyl alcohol, n-butanol, ethanol and combination thereof.
In another preference, the described look auspicious w/v for Buddhist nun's raw material and organic solvent is 1:5-20(g/ml), preferred 1:5-10 (g/ml).
The present invention " look auspicious is for Buddhist nun's raw material " used can be that look auspicious is for Buddhist nun's amorphous substance or any known formLook auspicious for Buddhist nun; Preferred: look auspicious replaces Buddhist nun's crystal form A, crystal form B for Buddhist nun's amorphous substance and Se Rui.
2) be warming up to 35～45 DEG C, continue to stir 10～30 hours;
3) be cooled to 10-25 DEG C, filter, thereby obtain the look auspicious crystal C for Buddhist nun;
Preferably, can do further dry processing for Buddhist nun's crystal C by auspicious the look obtaining, as uniform temperature (as30～40 DEG C) under carry out vacuum drying.
Secondly, the present invention also provides a kind of look auspicious for the unbodied method of Buddhist nun, comprises step:
(1) preparation look auspicious is for Buddhist nun's dihydrochloride aqueous solution, at 0～20 DEG C with inorganic base aqueous solution furnishing pH8-9;
(2) gained solution extracts with esters solvent;
(3) organic layer of gained system is separated, pressure reducing and steaming solvent at 15～20 DEG C, obtains look auspiciousFor Buddhist nun's amorphous substance.
In another preference, the inorganic base described in above-mentioned steps (1) is to be selected from one or more of lower group:NaOH, potassium hydroxide, sodium carbonate, potash, sodium acid carbonate, saleratus. Preferred NaOH,Potassium hydroxide.
In another preference, the esters solvent described in step (2) is to be selected from one or more of lower group:Ethyl formate, methyl acetate, ethyl acetate or isopropyl acetate. Ethyl acetate.
Pharmaceutical composition
Pharmaceutical composition of the present invention, taking the auspicious Buddhist nun's crystal C that replaces of look of the present invention as active component, also can contain medicineAcceptable salt on.
" pharmaceutically acceptable carrier " refers to: one or more compatibility solids or liquid filler orGelatinous mass, they are suitable for people's use, and must have enough purity and enough low toxicity. " phaseCapacitive " referred to herein as in composition between each component energy and compound of the present invention and they and mutually mixWith, and the drug effect of not obvious reduction compound. Pharmaceutically acceptable carrier part example have cellulose andIts derivative (as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum,Kollag (as stearic acid, dolomol), calcium sulfate, vegetable oil (as soya-bean oil, sesame oil, peanut oil,Olive wet goods), polyalcohol (as propane diols, glycerine, sweet mellow wine, sorbierite etc.), emulsifying agentWetting agent (as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizing agent, antioxidant, anticorrisive agent,Apirogen water etc.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited. The compounds of this invention canIndividually dosed, or with other pharmaceutically acceptable compound administering drug combinations.
Below in conjunction with specific embodiment, further set forth the present invention. Should be understood that these embodiment are only for explanationThe present invention and being not used in limits the scope of the invention. The experiment side of unreceipted actual conditions in the following exampleMethod, conventionally according to normal condition, or the condition of advising according to manufacturer. Unless otherwise indicated, otherwisePercentage and umber are calculated by weight.
Raw material and universal method
In following examples, raw materials used look auspicious Buddhist nun's crystal form A and the crystal form B of replacing is all with reference to WO2012/082972 systemStandby; Look auspicious is commercially available conventionally form for Buddhist nun's dihydrochloride.
X-ray powder diffraction instrument: Dedye～ScherrerINELCPS～120X-ray powder diffractionInstrument; Radiation source: α 1=α2＝Strength ratio α 1/ α 2 is 0.5; OccurDevice (Generator) kv:40kv; Generator (Generator) mA:30mA; 2 initial θ: 2.000 °,Sweep limits: 2.0000～50.000 °.
Differential scanning calorimetry (DSC) instrument: the Q2000 type of TA company of the U.S., within the scope of 20～450 DEG C,10 DEG C/min of the rate of heat addition, nitrogen flow rate 50ml/min.
Thermogravimetric analysis (TGA) instrument: the SDTQ600 type of TA company of the U.S., within the scope of 20～450 DEG C, adds10 DEG C/min of hot speed, nitrogen flow rate 100ml/min.
The preparation for Buddhist nun's amorphous substance of embodiment 1 look auspicious
Be added in 200mL deionized water for Buddhist nun's dihydrochloride (37.0g) look auspicious, control temperature at 0-5DEG C, drip the 2NNaOH aqueous solution, be adjusted to pH=8. In reactant liquor, add ethyl acetate (100ml) extractionThree times; Combined ethyl acetate phase, anhydrous sodium sulfate drying, filters. Filtrate, at 15-20 DEG C, is reduced pressure denseBe reduced to dryly, obtain 31.5g white solid, yield 96%.
Result: the x-ray diffractogram of powder of gained solid is substantially as Fig. 5 characterizes, differential scanning spectrogram baseOriginally as shown in Figure 6, substantially as shown in Figure 7, infrared Fourier conversion spectrum is basic as Fig. 8 institute in thermogravimetric analysisShow.
The look obtaining is auspicious for Buddhist nun's amorphous substance, approximately 10 ° to 30 ° of the 2 θ number of degrees of its X-ray powder diffraction collection of illustrative platesBetween, due to aperiodicity structure, can not produce diffraction effect to X ray, be the bulge of steamed bun shape. ItsDifferential scanning calorimetry is analyzed collection of illustrative plates and has been located characteristic peak at 66.7 DEG C, and its thermogravimetric analysis collection of illustrative plates shows its decomposition pointBe 269.47 DEG C, its infrared Fourier conversion spectrum 3415.7,2975.6,2935.7,2808.8,2723.8、2490.5、1600.1、1569.6、1508.5、1483.2、1448.1、1412.5、1316.5、1287.8、1262.9、1219.6、1196.0、1140.4、1123.9、1083.9、1053.2、1018.4、950.9、873.9、775.7、735.3、706.3、677.6、652.9、543.8、519.9、170.8±2There is absworption peak at cm-1 place.
The preparation for Buddhist nun's crystal C of embodiment 2 looks auspicious
Join in the acetone solvent of 100mL for Buddhist nun's amorphous substance (20.0g) look auspicious, mixture is at 35-40At DEG C, stir 24 hours. Gained slurries are cooled to room temperature, filter. Filter cake washs with a small amount of acetone,At 30-35 DEG C, vacuum drying obtains 19.1g white solid, yield 96%.
Result:
Its x-ray diffractogram of powder substantially as shown in Figure 1, differential scanning spectrogram substantially as shown in Figure 2, heatSubstantially as shown in Figure 3, infrared Fourier conversion spectrum substantially as shown in Figure 4 for weight analysis.
The look obtaining is auspicious for Buddhist nun's crystal C, and the characteristic peak of its X-ray powder diffraction collection of illustrative plates mainly contains (2 θ):4.96°、8.90°、9.99°、10.3°、12.23°、13.95°、14.31°、14.90°、15.60°、15.96°、16.51°、16.77°、18.05°、18.74°、19.18°、19.93°, 20.72 °, 23.16 °, 24.60 °, 24.92 °, 26.37 °, 27.05 °, 28.01 °. ItsDifferential scanning calorimetry is analyzed collection of illustrative plates and has been located characteristic peak at 206.76 DEG C, and its thermogravimetric analysis collection of illustrative plates shows its decompositionPoint is 261.43 DEG C, its infrared Fourier conversion spectrum 3417.7,3325.9,3191.5,2978.2,2936.57、2780.1、1593.9、1569.9、1539.2、1507.2、1487.9、1468.74、1445.1、1410.8、1317.8、1287.2、1260.3、1221.3、1199.3、1141.5、1122.9、1066.6、944.1、882.3、846.3、771.8、734.9、703.9、675.7、587.9、509.4±2cm-1There is absworption peak at place.
The preparation for Buddhist nun's crystal C of embodiment 3 looks auspicious
Join in the n-butanol of 100mL for Buddhist nun's amorphous substance (20.0g) look auspicious, mixture is at 35-40At DEG C, stir 16 hours. Gained slurries are cooled to room temperature, filter. Filter cake washs with a small amount of n-butanol,At 35-40 DEG C, vacuum drying obtains 18.6g white solid, yield 93%.
Result: substantially as shown in Figure 1, differential scanning spectrogram is basic as Fig. 2 institute for its x-ray diffractogram of powderShow, substantially as shown in Figure 3, infrared Fourier conversion spectrum substantially as shown in Figure 4 in thermogravimetric analysis.
The preparation for Buddhist nun's crystal C of embodiment 4 looks auspicious
Join in the ethyl acetate of 15mL for Buddhist nun's amorphous substance (2.0g) look auspicious, mixture is at 40-45At DEG C, stir 12 hours. Gained slurries are cooled to room temperature, filter. Filter cake is washed with a small amount of ethyl acetateWash, vacuum drying obtains 1.6g white solid, yield 80% at 35-40 DEG C.
Result: substantially as shown in Figure 1, differential scanning spectrogram is basic as Fig. 2 institute for its x-ray diffractogram of powderShow, substantially as shown in Figure 3, infrared Fourier conversion spectrum substantially as shown in Figure 4 in thermogravimetric analysis.
The preparation for Buddhist nun's crystal C of embodiment 4 looks auspicious
Be added in the ethyl acetate solvent of 15mL for Buddhist nun's crystal form A (2.0g) look auspicious, mixture is at 35-40At DEG C, stir 24 hours. Gained slurries are cooled to room temperature, filter. Filter cake is washed with a small amount of ethyl acetateWash, vacuum drying obtains 1.7g white solid, yield 85% at 35-40 DEG C.
Result: substantially as shown in Figure 1, differential scanning spectrogram is basic as Fig. 2 institute for its x-ray diffractogram of powderShow, substantially as shown in Figure 3, infrared Fourier conversion spectrum substantially as shown in Figure 4 in thermogravimetric analysis.
The preparation for Buddhist nun's crystal C of embodiment 5 looks auspicious
Be added in the ethanol of 10mL for Buddhist nun's crystal form A (2.0g) look auspicious, mixture at 30-35 DEG C,Stir 30 hours. Gained slurries are cooled to room temperature, filter. Filter cake washs with a small amount of ethanol, 35-40 DEG CLower vacuum drying obtains 1.6g white solid, yield 80%.
Result: substantially as shown in Figure 1, differential scanning spectrogram is basic as Fig. 2 institute for its x-ray diffractogram of powderShow, substantially as shown in Figure 3, infrared Fourier conversion spectrum substantially as shown in Figure 4 in thermogravimetric analysis.
The preparation for Buddhist nun's crystal C of embodiment 6 looks auspicious
Be added in the ethyl acetate solvent of 10mL for Buddhist nun's crystal form B (2.0g) look auspicious, mixture is at 40-45At DEG C, stir 20 hours. Gained slurries are cooled to room temperature, filter. Filter cake is washed with a small amount of ethyl acetateWash, vacuum drying obtains 1.8g white solid, yield 90% at 35-40 DEG C.
Result: substantially as shown in Figure 1, differential scanning spectrogram is basic as Fig. 2 institute for its x-ray diffractogram of powderShow, substantially as shown in Figure 3, infrared Fourier conversion spectrum substantially as shown in Figure 4 in thermogravimetric analysis.
Discuss
As fully visible, the look auspicious Buddhist nun's crystal C that replaces that prepared by the present invention all has good heat endurance and more existing skillThe look that art provides is auspicious for the lower fusing point of Buddhist nun's crystal. Can be used as reality and look prepared by the present invention is auspicious for Buddhist nun's amorphous substanceExecute the intermediate forms of method provided by the present invention, also there is good dissolubility, more easily and be easily converted intoRequired look auspicious is for Buddhist nun's crystal C.
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each section of documentQuoted separately as a reference. In addition should be understood that after having read above-mentioned instruction content of the present invention,Those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within this Shen equallyPlease appended claims limited range.
Claims (10)
1. a look auspicious crystal C for Buddhist nun, is characterized in that the X-ray powder diffraction of described crystal CCollection of illustrative plates comprises that 3 or 3 are selected from the 2 θ values of lower group above: 4.96 °, 8.90 °, 9.99 °, 10.3°、12.23°、13.95°、14.31°、14.90°、15.60°、15.96°、16.51°、16.77°、18.05°、18.74°、19.18°、19.93°、20.72°、23.16°、24.60°、24.92°、26.37°、27.05°、28.01°±0.2°。
2. the auspicious crystal C for Buddhist nun of look as claimed in claim 1, is characterized in that, described look auspicious is for Buddhist nun'sThe X-ray powder diffraction collection of illustrative plates of crystal C is substantially as Fig. 1 characterizes.
3. the auspicious crystal C for Buddhist nun of look as claimed in claim 1, is characterized in that, described look auspicious is for Buddhist nunCrystal C there are the one or more features that are selected from lower group:
Its differential scanning calorimetry is analyzed collection of illustrative plates and have characteristic peak in 198 DEG C of-207 scope;
Its differential scanning calorimetry is analyzed collection of illustrative plates substantially as Fig. 2 characterizes;
Its thermogravimetric analysis collection of illustrative plates is substantially as Fig. 3 characterizes;
Its infrared Fourier conversion spectrum has absworption peak in following position:
3417.7、3325.9、3191.5、2978.2、2936.57、2780.1、1593.9、1569.9、1539.2、1507.2、1487.9、1468.74、1445.1、1410.8、1317.8、1287.2、1260.3、1221.3、1199.3、1141.5、1122.9、1066.6、944.1、882.3、846.3、771.8、734.9、703.9、675.7、587.9、509.4±2cm-1；
Its infrared Fourier conversion spectrum substantially as shown in Figure 4.
4. the preparation method of the auspicious crystal C for Buddhist nun of look as claimed in claim 1, is characterized in that, described inPreparation method comprise the steps:
(i) in organic solvent, turn brilliant by look auspicious for Buddhist nun's raw material, form described replace of look auspicious thereby separate outBuddhist nun's crystal C,
Wherein said organic solvent is selected from lower group: acetone, esters solvent, alcohols solvent or its combination;
(ii) isolate the described look auspicious Buddhist nun's crystal C that replaces;
Wherein, described look auspicious is selected from for Buddhist nun's raw material: the look auspicious crystal form A for Buddhist nun's amorphous substance, the look auspicious Buddhist nun of replacing,Look auspicious crystal form B or its combination for Buddhist nun.
5. preparation method as claimed in claim 4, is characterized in that, described method comprises and is selected from lower groupOne or more features:
In step (i), at 35-45 DEG C and stir and within 10～30 hours, turn brilliant;
In step (i), the described look auspicious w/v for Buddhist nun's raw material and described organic solvent is about 1g: 5－20ml；
Described step (ii) comprising: be cooled to after 10-25 DEG C, filter, thereby obtain the look auspicious crystalline substance for Buddhist nunType C;
Described esters solvent is selected from ethyl acetate, methyl acetate, isopropyl acetate and combination thereof;
Described alcohols solvent is selected from isopropyl alcohol, n-butanol, ethanol and combination thereof.
6. look auspicious is characterized in that for Buddhist nun's amorphous substance, and the described look auspicious Buddhist nun's amorphous substance that replaces is at XBetween approximately 10 °-30 ° of the 2 θ number of degrees of ray powder diffraction, and its X-ray powder diffraction collection of illustrative plates baseIn basis as Fig. 5 characterizes.
7. look as claimed in claim 6 is auspicious is characterized in that for Buddhist nun's amorphous substance, and described look auspicious to be replacedBuddhist nun's amorphous substance has the one or more features that are selected from lower group:
Its differential scanning calorimetry is analyzed collection of illustrative plates and has been located characteristic peak at 66.7 ± 2 DEG C;
Its differential scanning calorimetry is analyzed collection of illustrative plates substantially as Fig. 6 characterizes;
Its thermogravimetric analysis collection of illustrative plates shows that its decomposition point is 269.47 ± 2 DEG C;
Its thermogravimetric analysis collection of illustrative plates is substantially as Fig. 7 characterizes;
Its infrared Fourier conversion spectrum has absworption peak in following position:
3415.7、2975.6、2935.7、2808.8、2723.8、2490.5、1600.1、1569.6、1508.5、1483.2、1448.1、1412.5、1316.5、1287.8、1262.9、1219.6、1196.0、1140.4、1123.9、1083.9、1053.2、1018.4、950.9、873.9、775.7、735.3、706.3、677.6、652.9、543.8、519.9、170.8±2cm-1；
Its infrared Fourier conversion spectrum is substantially as Fig. 8 characterizes.
8. the auspicious preparation method for Buddhist nun's amorphous substance of look as claimed in claim 6, is characterized in that instituteThe method of stating comprises the steps:
(1) preparation look auspicious is for Buddhist nun's dihydrochloride aqueous solution, at 0～20 DEG C with inorganic base aqueous solution furnishing pH8-9;
(2) gained solution extracts with esters solvent;
(3) organic layer of gained system is separated, pressure reducing and steaming solvent at 15～20 DEG C, obtains look auspiciousFor Buddhist nun's amorphous substance.
9. a medical composition, is characterized in that, described composition comprises described in (a) claim 1The look auspicious look for the crystallization of Buddhist nun's crystal C, claim 6 auspicious for Buddhist nun's amorphous substance and (b) pharmaceutically acceptableSupporting agent.
10. the auspicious purposes for Buddhist nun's amorphous substance of look as claimed in claim 6, is characterized in that, as systemThe standby look auspicious raw material for Buddhist nun's crystal C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017152858A1 (en) * | 2016-03-11 | 2017-09-14 | 苏州晶云药物科技有限公司 | Crystal form of ceritinib and preparation method thereof |
| WO2021143819A1 (en) * | 2020-01-17 | 2021-07-22 | 山东轩竹医药科技有限公司 | Crystal form of polycyclic anaplastic lymphoma kinase inhibitor |
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| CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
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| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017152858A1 (en) * | 2016-03-11 | 2017-09-14 | 苏州晶云药物科技有限公司 | Crystal form of ceritinib and preparation method thereof |
| WO2021143819A1 (en) * | 2020-01-17 | 2021-07-22 | 山东轩竹医药科技有限公司 | Crystal form of polycyclic anaplastic lymphoma kinase inhibitor |
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