CN110483551A - A kind of Laura replaces the crystal of Buddhist nun's free alkali - Google Patents

A kind of Laura replaces the crystal of Buddhist nun's free alkali Download PDF

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CN110483551A
CN110483551A CN201910812912.1A CN201910812912A CN110483551A CN 110483551 A CN110483551 A CN 110483551A CN 201910812912 A CN201910812912 A CN 201910812912A CN 110483551 A CN110483551 A CN 110483551A
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crystal
diaza
pyrazolo
fluoro
bright
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CN110483551B (en
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赵紫岭
王守亮
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Beijing Saisiyuan Biomedical Technology Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention discloses a kind of (10R) -7- amino -12- fluoro- 2,10,16- trimethyl -15- oxos -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] crystal of the bright-coloured ring -3- formonitrile HCN of benzo oxa- diaza 14 (Laura replace Buddhist nun) free alkali in the X-ray powder diffraction collection that the crystal is measured using Cu-Ka ray, includes at least following characteristics peak: the angle of diffraction 2θValue is 7.85 ± 0.2 °, 12.21 ± 0.2 °, 17.16 ± 0.2 °, 17.92 ± 0.2 °, 20.59 ± 0.2 ° and 23.44 ± 0.2 °；Resulting crystal stability is good, is suitable for industrialized production.In addition, the present invention also provides the preparation method of the crystal and Pharmaceutical compositions.

Description

A kind of Laura replaces the crystal of Buddhist nun's free alkali
Technical field
The present invention relates to the crystal of medical compounds, in particular to (10R) -7- amino -12- fluoro- 2,10,16- trimethyls - 15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 bright-coloured ring -3- formonitrile HCN crystal and preparation method thereof and Pharmaceutical composition.
Background technique
A kind of chemical substance for inhibiting abnormal cell growth is described in United States Patent (USP) US20160115178, especially The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- (methine bridge) Bright-coloured ring -3- formonitrile HCN the solvate of pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14.On November 2nd, 2018, The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- (methine bridge) Bright-coloured ring -3- the formonitrile HCN of pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 (Laura replaces Buddhist nun, trade name: Lorbrena), Belong to third generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), for treatment receiving gram azoles for Buddhist nun and extremely Disease deteriorates after a kind of few other ALK inhibitor for treating, or receives Ai Le for Buddhist nun (Alectinib) or Ceritinib (Ceritinib) as first ALK inhibitor for treating but the ALK positive metastatic non-small cell lung cancer of disease progression (NSCLC) patient.
A kind of method of the cancer cell multiplication of inhibition ALK driving is described in United States Patent (USP) US8680111, especially with Fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- (the secondary first of compound (10R) -7- amino -12- Ji Qiao) bright-coloured ring -3- the formonitrile HCN of pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14, for treating the transfer of the ALK positive Property Patients with Non-small-cell Lung, validity is more preferably.
Pfizer Inc. (Pfizer) describes in Chinese patent application file CN107849060A (publication number) The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- (methine bridge) The crystal form of the bright-coloured ring -3- formonitrile HCN of pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 (Laura replaces Buddhist nun) free alkali And preparation method, pharmaceutical composition and the side using composition treatment abnormal cell growth such as cancer has been further described Method.
The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- is (secondary Methyl bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 bright-coloured ring -3- formonitrile HCN have it is certain fat-soluble but difficult It is dissolved in water, is had differences without isomorphous solubility, to influence the external dissolution of its pharmaceutical composition, release, Jin Erying It rings and arrives the bioavilability of drug in vivo.So research and preparation (10R) -7- amino -12- fluoro- 2,10,16- trimethyls - 15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza The different shape crystallization of 14 bright-coloured ring -3- formonitrile HCNs has immeasurable prospect.
Summary of the invention
Primary and foremost purpose of the present invention is to provide one kind fluoro- oxo -10 2,10,16- trimethyl -15- (10R) -7- amino -12-, Bright-coloured ring-the 3- of 15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 Formonitrile HCN crystal, the crystal have many advantages, such as fat-soluble good, better stability, are convenient for industrialized production.
It is another object of the present invention to provide the fluoro- 2,10,16- trimethyls-of (10R) -7- amino -12- described in one kind 15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza The preparation method of 14 bright-coloured ring -3- formonitrile HCN crystal, the method achieve at low cost, high income and impurity are controllable.
A further object of the present invention is to provide the Pharmaceutical composition containing above-mentioned crystal.
The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- of (10R) -7- amino -12- provided by the present invention Bright-coloured ring -3- formonitrile HCN the crystal of tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14, Radiated using Cu-Ka, x-ray diffraction pattern, 2 θ being expressed in degrees 7.85 ± 0.2 °, 12.21 ± 0.2 °, 14.75 ± 0.2 °, 17.16 ± 0.2 °, 17.92 ± 0.2 °, 20.59 ± 0.2 °, 23.44 ± 0.2 °, 24.45 ± 0.2 ° and 24.98 ± 0.2 ° There is diffraction maximum at place.In particular, 7.85 ± 0.2 °, 12.21 ± 0.2 °, 17.16 ± 0.2 °, 17.92 ± 0.2 °, 20.59 ± 0.2 ° and 23.44 ± 0.2 ° there are one or multiple (in any combination, including two or more, or all) diffraction maximums；Crystal X-ray diffracting spectrum it is as shown in Figure 1.
In addition, fluoro- 2,10,16- trimethyl -15- oxo -10,15 of (10R) -7- amino -12- of the invention, 16,17- tetra- Bright-coloured ring -3- formonitrile HCN the crystal of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is used The infrared absorption pattern that KBr tabletting measures, it is characterized in that in about 3469cm-1, 3332cm-1, 2998cm-1, 2944cm-1, 2229cm-1, 1627cm-1, 1492cm-1, 1419cm-1, 1369cm-1, 1253cm-1, 1199cm-1, 1166cm-1, 1070cm-1, 1049cm-1, 948cm-1, 887cm-1, 835cm-1, 636cm-1, 570cm-1, 441cm-1Etc. have absorption peak；See Fig. 2.
In specific implementation case, the present invention provides fluoro- 2,10,16- trimethyl -15- oxygen of (10R) -7- amino -12- Generation -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 Bright-coloured ring -3- formonitrile HCN crystal, has19F solid-state nmr spectrum, it is described19F solid-state nmr spectrum includes resonance value selected from the following :- 59.4, -82.5, -86.5, -104.9, -127.0 and -168.0ppm ± 0.2ppm；As shown in Figure 3.
The present invention also provides one kind fluoro- oxo -10,15,16 2,10,16- trimethyl -15- (10R) -7- amino -12-, Bright-coloured ring -3- the formonitrile HCN of 17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is brilliant The step of preparation method of body, realization includes: first by fluoro- 2,10,16- trimethyl -15- oxo of (10R) -7- amino -12- - 10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is bright-coloured Ring -3- formonitrile HCN is dissolved under stiring in 5~10 times of ((v/v)) dioxane, is added 12~16 times of (v/v) water, is placed at room temperature for Until crystal is slowly precipitated；Collect obtained solid；Filtration drying obtained solid to get arrive (10R) -7- amino -12- Fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2, 5,11] the bright-coloured ring -3- formonitrile HCN crystal of benzo oxa- diaza 14.
Crystal is fat-soluble good, increases the usage amount of organic solvent, and product quality promotion is limited, and yield reduction is larger, instead And whole production cost can be improved.
In the present invention, X- powder diffraction test equipment according to the present invention and test condition are as follows: x-ray diffractometer Rigaku D/max-rA type (Rigaku)；Cu target, graphite curved-crystal monochromator, tube voltage 40kv, tube current 100mA, wavelength3~70 ° of scanning range.
Related substance high performance liquid chromatography detection condition and method according to the present invention are as follows: chromatographic condition and system are applicable in Property is filler with octadecylsilane chemically bonded silica；Mobile phase is 0.1% aqueous formic acid and methanol, carries out isocratic elution (0.1% formic acid solution: methanol=63:37；Runing time: 30min；Flow velocity: 1ml/min)；Detection wavelength 254nm；Theoretical tower Plate number presses fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- (the secondary first of (10R) -7- amino -12- Ji Qiao) the bright-coloured ring -3- formonitrile HCN peak of pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14, which calculates, should be not less than 8000. The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- (methine bridge) Bright-coloured ring -3- formonitrile HCN the peak of pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 and the separating degree at other impurities peak should accord with It closes and requires.
The determination condition and method of dissolution rate: it is measured according to four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method.
Tablet made of this product is taken, is molten with acetate buffer solution (adjusting pH value to 4.5) 900ml according to dissolution method Medium out, revolving speed are 100 turns per minute, operate according to methods, when through 60 minutes, take solution appropriate, filter, discard primary filtrate, take continuous Test solution is used as after filtrate dilution.Another precision weighs the fluoro- 2,10,16- trimethyl -15- oxo-of (10R) -7- amino -12- 10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is bright-coloured Ring -3- formonitrile HCN reference substance is appropriate, is made in every 1ml with water containing about fluoro- 2,10,16- trimethyl -15- of (10R) -7- amino -12- Oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza ten The solution of four bright-coloured 10 μ g of ring -3- formonitrile HCN, as reference substance solution.Above two solution is taken, according to UV-VIS spectrophotometry (four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method measures absorbance, by external standard method with absorbance at 225nm wavelength Calculate the amount of dissolution of every (or piece).
The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- is (secondary Methyl bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 bright-coloured ring -3- formonitrile HCN crystal property measurement.
One, stability
Test sample: the fluoro- 2,10,16- trimethyl -15- oxo-of (10R) -7- amino -12- prepared by embodiment 1 10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is bright-coloured Ring -3- formonitrile HCN crystal.
1, water or solvent effect test
By the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal of (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 and appropriate amount of auxiliary materials are mixed Merging and carries out wet granulation, gained sample measures X-ray diffracting spectrum, (10R) -7- amino -12- fluoro- 2 before comparing granulation, 10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] Bright-coloured ring -3- formonitrile HCN the crystal of benzo oxa- diaza 14 does not find to influence or change.As a result such as referring to X-ray diffracting spectrum Shown in Fig. 4.
2, test is crushed
Take sample appropriate, the method crushed using high speed disintegrator is measured by sampling after crushing, and test index simultaneously will knot Fruit the results are shown in Table 1 compared with before crushing.
Table 1 crushes test
3, with auxiliary material combined experiments
Weigh the quantitative fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro-of (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the portion of 2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 and appropriate Claim 5 described in auxiliary material, then cross 80 meshes and mix three times, the sample that mixes with auxiliary material of crystal is made.By gained Sample carries out X-ray diffraction detection with mixed accessories used in the present invention, and testing result is as shown in Figure 6.
4, exposure experiments to light (5000lxs)
It takes sample appropriate, sets and place 30 days under the conditions of illumination relative intensity 5000lxs, sampled respectively at the 10th day, 30 days Measurement, and by result compared with 0 day appearance character, the results are shown in Table 2.
2 exposure experiments to light of table
5, accelerated test (40 DEG C)
It takes sample appropriate, sets under the conditions of temperature is 40 DEG C and place 30 days, be measured by sampling respectively at the 10th day, 30 days, sampling It measures crystal powder data, after comparing appearance, test index and by result compared with 0 day, the results are shown in Table 3.
3 accelerated test of table (40 DEG C)
6, high humidity test
By the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal raw material of (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is uniformly shared Into open culture dish, thickness≤5mm is placed in room temperature (25 DEG C or so), the constant temperature and humidity incubator that relative humidity is 90 ± 5% In, it is measured respectively at the 10th day, sampling in 30 days, and is compareed with 0 day result, the results are shown in Table 4.
4 high humidity test of table (room temperature, relative humidity: 90 ± 5%)
Two, dissolubility
It is tested referring to Chinese Pharmacopoeia two notes on the use of version in 2015.Method: it is fluoro- that precision weighs (10R) -7- amino -12- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5, 11] the bright-coloured ring -3- formonitrile HCN crystal of benzo oxa- diaza 14 is appropriate, a certain amount of solvent is slowly added to, every 5 minutes strong oscillatings It shakes 30 seconds, the dissolution situation in observation 30 minutes the results are shown in Table 5.
The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of table 5 (10R) -7- amino -12- The test of the bright-coloured ring -3- formonitrile HCN Crystal solubility of (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14
Solvent Test sample amount (g) It is added quantity of solvent (ml) Dissolve situation Conclusion
DMA 1.00215 Less than 10ml Dissolution It is readily soluble
DMF 1.00108 Less than 10ml Dissolution It is readily soluble
Dioxane 1.01043 Less than 10ml Dissolution It is readily soluble
THF 1.00057 Less than 10ml Dissolution It is readily soluble
Ethyl alcohol 1.00806 Less than 10ml Dissolution It is readily soluble
Methanol 1.02143 Less than 30ml Dissolution Dissolution
Water 1.01872 Greater than 10000ml It is insoluble It is almost insoluble
0.1M Hcl 1.00209 Less than 30ml Dissolution Dissolution
0.1M NaOH 1.00075 Greater than 10000ml It is insoluble It is almost insoluble
Verified by a series of experiments, research high temperature, illumination, pressure, mechanical shear stress and with auxiliary material effect etc. conditions Under stability.It can be seen that fluoro- 2,10,16- trimethyl -15- oxo -10,15 of (10R) -7- amino -12- of the invention, 16, Bright-coloured ring -3- the formonitrile HCN of 17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is brilliant Body is suitble to be prepared into preparation.
Detailed description of the invention
Fig. 1 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 X-ray diffracting spectrum.
Fig. 2 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 Infrared spectroscopy map.
Fig. 3 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 1419F solid-state nmr map.
Fig. 4 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN crystal the system of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 X-ray diffracting spectrum after grain.
Fig. 5 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal powder of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 X-ray diffracting spectrum after broken.
Fig. 6 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 with Auxiliary material mixing X-ray diffracting spectrum.
Fig. 7 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN crystal the light of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 According to 10 days test X-ray diffracting spectrums.
Fig. 8 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN crystal the light of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 According to 30 days test X-ray diffracting spectrums.
Fig. 9 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal 40 of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 DEG C accelerate 10 days test X-ray diffracting spectrums.
Figure 10 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal 40 of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 DEG C accelerate 30 days test X-ray diffracting spectrums.
Figure 11 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is high Wet 10 days test X-ray diffracting spectrums.
Figure 12 is the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four of the present invention (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is high Wet 30 days test X-ray diffracting spectrums.
Specific embodiment
Following embodiment and attached drawing make more specifically description to the present invention, but the present invention is not limited in following embodiment Content.
Embodiment 1
The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8 of 10g (10R) -7- amino -12- is taken, Bright-coloured ring -3- the formonitrile HCN of 4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is dissolved in 5 times under stiring In ((v/v)) dioxane, 12 times of (v/v) water are added, are placed at room temperature for until crystal is slowly precipitated；It is solid obtained by filtration drying Body, products obtained therefrom X-ray diffracting spectrum are as shown in Figure 1.
Embodiment 2
The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8 of 30g (10R) -7- amino -12- is taken, Bright-coloured ring -3- the formonitrile HCN of 4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is dissolved in 10 under stiring Again in ((v/v)) dioxane, 12 times of (v/v) water are added, are placed at room temperature for until crystal is slowly precipitated；It is solid obtained by filtration drying Body, products obtained therefrom X-ray diffraction spectrogram and embodiment 1 are almost the same.
The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8 of 50g (10R) -7- amino -12- is taken, Bright-coloured ring -3- the formonitrile HCN of 4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 is dissolved in 10 under stiring Again in ((v/v)) dioxane, 16 times of (v/v) water are added, are placed at room temperature for until crystal is slowly precipitated；It is solid obtained by filtration drying Body, products obtained therefrom X-ray diffraction spectrogram and embodiment 1 are almost the same.
The prescription and preparation process of 3 tablet of embodiment:
As follows with several excipient by the above-mentioned fluoro- 2,10,16- trimethyl -15- oxygen of (10R) -7- amino -12- Generation -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 Bright-coloured ring -3- formonitrile HCN crystal is configured to every tablet of tablet containing 25mg, the results are shown in Table 6.
6 prescription situation of table
Preparation process: the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- four containing (10R) -7- amino -12- Bright-coloured ring -3- formonitrile HCN the crystal wafer of hydrogen -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 The manufacturing method of agent is by above-mentioned excipient (except magnesium stearate) and the fluoro- 2,10,16- trimethyl-of (10R) -7- amino -12- 15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 bright-coloured ring -3- formonitrile HCN crystal are uniformly mixed in mixing machine, dry granulation, and magnesium stearate is added in Xiang Shangshu dry particl, are mixed Close uniformly tabletting.Reference crystal mixed, pelletized using identical method, tabletting.Tablet formulation dissolution determination result pair Than being shown in Table 7.
7 tablet formulation dissolution determination Comparative result of table
Time (min) Reference crystal New crystal
30 80.6% 81.9%
45 86.2% 88.1%
60 101.3% 101.8%
The present invention is not limited in the content of above-described embodiment.Other are any using technical solution of the present invention and method Conceive the insubstantial improvement made, or not improved the technical solution of invention and inventive concept is directly applied into other occasions , all belong to the scope of protection of the present invention within.

Claims (9)

1. the fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- of one kind (10R) -7- amino -12- The crystal of the bright-coloured ring -3- formonitrile HCN of (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14, the crystal make Radiated with Cu-Ka, x-ray diffraction pattern, 2 θ being expressed in degrees 7.85 ± 0.2 °, 12.21 ± 0.2 °, 14.75 ± 0.2 °, Have at 17.16 ± 0.2 °, 17.92 ± 0.2 °, 20.59 ± 0.2 °, 23.44 ± 0.2 °, 24.45 ± 0.2 ° and 24.98 ± 0.2 ° Diffraction maximum.
2. crystal described in claim 1, the infrared absorption pattern measured with KBr tabletting, it is characterized in that in about 3469cm-1, 3332cm-1, 2998cm-1, 2944cm-1, 2229cm-1, 1627cm-1, 1492cm-1, 1419cm-1, 1369cm-1, 1253cm-1, 1199cm-1, 1070cm-1, 948cm-1, 887cm-1, 835cm-1, 570cm-1, 441cm-1Etc. have absorption peak.
3. crystal described in claim 1, which is characterized in that described19F solid-state nmr spectrum includes resonance value selected from the following :- 104.9 and -168.0ppm ± 0.2ppm.
4. crystal described in claim 1-3, crystal data is constant after mixing with auxiliary material.
5. auxiliary material as claimed in claim 4 includes that auxiliary material is selected from lactose, sucrose, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose Element, pregelatinized starch etc. do filler, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium etc. Cooking disintegrating agent, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carmethose, povidone etc. make adhesive, stearic acid, Magnesium stearate, calcium stearate etc. do lubricant, and talcum powder, polyethylene glycol, polyvinyl alcohol, titanium dioxide, iron oxide etc., which are done, to be coated Material and other pharmaceutically acceptable auxiliary materials.
6. the preparation method of crystal described in claim 1-3, it is characterised in that: by (10R) -7- amino -12- fluoro- 2,10,16- Trimethyl -15- oxo -10,15,16,17- tetrahydro -2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxygen Bright-coloured ring -3- the formonitrile HCN of miscellaneous diaza 14 is dissolved in dioxane under stiring, adds suitable quantity of water, is placed at room temperature for until crystal is slow It is slow to be precipitated；Collect obtained solid.
7. dioxane amount ratio as claimed in claim 6 is 1:5 ~ 1:10 (v/v), preferably 1:7；Water consumption ratio is 1:12 ~ 1: 16 (v/v), preferably 1:13 ~ 1:14；.
8. a kind of Pharmaceutical composition comprising crystal described in any claim in claims 1 to 3.
9. Pharmaceutical composition according to claim 8, wherein the Pharmaceutical composition unit dose contains claims 1 to 33 The fluoro- 2,10,16- trimethyl -15- oxo -10,15,16,17- tetrahydro-of (10R) -7- amino -12- described in middle any claim Bright-coloured ring -3- formonitrile HCN crystal the 1- of 2H-8,4- (methine bridge) pyrazolo [4,3-h] [2,5,11] benzo oxa- diaza 14 200mg。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104169286A (en) * 2012-03-06 2014-11-26 辉瑞大药厂 Macrocyclic derivatives for the treatment of proliferative diseases
WO2014207606A1 (en) * 2013-06-28 2014-12-31 Pfizer Inc. Solid forms of a macrocyclic kinase inhibitor
CN107849060A (en) * 2015-07-31 2018-03-27 辉瑞公司 Laura replaces the crystal form of Buddhist nun's free alkali

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104169286A (en) * 2012-03-06 2014-11-26 辉瑞大药厂 Macrocyclic derivatives for the treatment of proliferative diseases
WO2014207606A1 (en) * 2013-06-28 2014-12-31 Pfizer Inc. Solid forms of a macrocyclic kinase inhibitor
CN107849060A (en) * 2015-07-31 2018-03-27 辉瑞公司 Laura replaces the crystal form of Buddhist nun's free alkali

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