CN106478636A - Ticagrelor crystal formation and preparation method - Google Patents
Ticagrelor crystal formation and preparation method Download PDFInfo
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- CN106478636A CN106478636A CN201610765692.8A CN201610765692A CN106478636A CN 106478636 A CN106478636 A CN 106478636A CN 201610765692 A CN201610765692 A CN 201610765692A CN 106478636 A CN106478636 A CN 106478636A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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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Abstract
The invention belongs to medicinal chemistry art, is related to ticagrelor crystal formation and preparation method.Ticagrelor crude product is added in mixed solvent of the ethyl acetate with isopropyl ether, 65 DEG C are warming up to, segmentation cooling crystallization, obtain ticagrelor crystal formation.The ticagrelor crystal formation that the present invention is provided has solubility improvement, the feature of stable crystal form.
Description
Technical field
The present invention relates to ticagrelor crystal formation and preparation method.
Background technology
Ticagrelor (Ticagrelor), entitled (1S, 2S, 3R, 5S) -3- [7- [(1R, 2S) -2- (3, the 4- difluoros of chemistry
Phenyl) cyclopropylamino] -5- (thiopropyl) -3H- [1,2,3] triazole [4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl-oxethyl) ring
Pentane -1,2- glycol, structural formula are as shown in Equation 1：
Ticagrelor (Ticagrelor) belongs to cyclopenta triazolopyrimidines, is that once Buddhist nun's card is public by Astra
A kind of new, the selective small molecule anticoagulant of department's exploitation.The medicine can reversibly vasoactive smooth muscle
2 receptor subtype P2Y12 of purine on cell, has obvious inhibitory action to the platelet aggregation that ADP causes, and after orally using
Onset is rapid, therefore can be effectively improved the symptom of acute coronary patient.And as the antiplatelet effects of ticagrelor are
Reversible, its for those need to after anticoagulant therapy is carried out in advance again the patient of row operation especially suitable.
Patent CN1247583C of Astrazeneca AB discloses four crystal formations (crystal formation I, crystal formation II, the crystalline substance of ticagrelor
Type III, crystal formation IV) and amorphous state and preparation method thereof, this four kinds of crystal formations and amorphous be all " anhydrous " state.Either
Which kind of crystal formation above-mentioned, solubility very little of the ticagrelor in water, II solubility in water of the ticagrelor on market
Also only have 16 μ g/ml, for this purpose, ticagrelor crystal formation has more preferable solubility and stability obtained in the present invention.
Content of the invention
It is an object of the invention to provide a kind of ticagrelor crystal formation, the crystal formation has solubility improvement, and stability is high, reappears
The good feature of property, it is easy to large-scale production.
The present invention provides a kind of ticagrelor crystal formation, is radiated using Cu-K α, with the X-ray powder diffraction that 2 θ angles represent
5.17 ± 0.2 °, 7.22 ± 0.2 °, 10.28 ± 0.2 °, 11.98 ± 0.2 °, 15.35 ± 0.2 °, 17.28 ± 0.2 °, 18.21
±0.2°、21.41±0.2°22.49±0.2°、24.99±0.2°、26.08±0.2°、27.82±0.2°、28.95±
0.2 °, 29.99 ± 0.2 °, have characteristic peak at 31 ± 0.2 °.
Further, ticagrelor crystal formation has X-ray powder diffraction spectrogram as shown in Figure 1.
Further, the ticagrelor crystal formation that the present invention is provided, its preparation method comprise the steps：
Ticagrelor crude product is added in the mixed solvent of ethyl acetate and isopropyl ether organic solvent, 65 DEG C is warming up to,
Molten clear after add activated carbon stirring, hot suction filtration removes activated carbon, gained filtrate lowered the temperature using segmentation by the way of stirring and crystallizing, temperature
10 DEG C are progressively down to, and stirring and crystallizing is complete；Filter, obtain ticagrelor crystal formation；
The mode stirring and crystallizing process of described segmentation cooling is：
1) 45 DEG C of insulated and stirred 20 minutes；
2) 35 DEG C of insulated and stirred are cooled to 40 minutes；
3) 25 DEG C of insulated and stirred are cooled to 30 minutes；
4) 10 DEG C are finally cooled to and continue insulated and stirred 2 hours.
Further, described ticagrelor crude product with the mass volume ratio of ethyl acetate and isopropyl ether mixed solvent is
1:3～5g/ml, the volume ratio of the ethyl acetate and isopropyl ether organic solvent is 5～2:1.
Ethyl acetate of the present invention, isopropyl ether are the 3rd or the 4th class solvent of low toxicity, and solvent toxicity is little, medicine
Safe, be not in the sticky phenomenon of crystallizing system, with low cost, be conducive to industry to amplify and medicine production.
The present invention can both avoid, as crystallization speed is soon by impurity comprising in product, obtaining again using segmentation cooling method
The crystal formation of favorable reproducibility.
The present inventors have additionally discovered that ticagrelor compares existing crystal formation water solubility being improved, be conducive to the use of clinic.
The present invention is studied to the stability of ticagrelor, ticagrelor in 25 ± 2 DEG C of temperature, humidity 60% ±
Kept sample under the conditions of 10% for a long time, after 12 months, its content has no substantially reduction to study on the stability, and maximum list is miscellaneous to have no substantially increasing
Plus, indices have no significant change, and illustrate that this product has good stability, and reappearance is easy to long term storage, clinical application
Safer.
Description of the drawings
Fig. 1 is ticagrelor crystal formation X-ray powder diffraction collection.
Fig. 2 is ticagrelor crystal formation thermogravimetric analysis collection of illustrative plates.
Specific embodiment
Following examples are only used for further illustrating the present invention, but do not limit the present invention.
The preparation of 1 ticagrelor crystal formation of embodiment
30g ticagrelor crude product, 75ml ethyl acetate, 15ml isopropyl ether are added in 1000ml flask, be warming up to 65 DEG C；
After molten clear after add activated carbon stirring；Hot suction filtration, filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, cooling
To 35 DEG C of insulated and stirred crystallizations 40 minutes, 25 DEG C of insulated and stirred crystallizations are down to 30 minutes, being cooled to 10 DEG C, to continue insulated and stirred 2 little
When abundant crystallization, suction filtration, dry ticagrelor crystal formation 28.5g, HPLC purity 99.93%.
Gained crystal formation is determined through X-ray powder diffraction collection, as a result as Fig. 1, is penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction represent
Line powder diffraction spectrum collection of illustrative plates 5.17 ± 0.2 °, 7.22 ± 0.2 °, 10.28 ± 0.2 °, 11.98 ± 0.2 °, 15.35 ± 0.2 °,
17.28±0.2°、18.21±0.2°、21.41±0.2°22.49±0.2°、24.99±0.2°、26.08±0.2°、27.82
± 0.2 °, 28.95 ± 0.2 °, 29.99 ± 0.2 °, have characteristic peak at 31 ± 0.2 °.Thermogravimetric analysis collection of illustrative plates is as shown in Fig. 2 crystal formation
Fusing point is 132-138 DEG C, the zero gravity loss before degrading of ticagrelor crystal formation, may infer that the nothing for ticagrelor is hydrated
Thing.
The preparation of 2 ticagrelor crystal formation of embodiment
30g ticagrelor crude product, 60ml ethyl acetate, 30ml isopropyl ether are added in 1000ml flask, be warming up to 65 DEG C；
After molten clear after add activated carbon stirring；Hot suction filtration, filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, cooling
To 35 DEG C of insulated and stirred crystallizations 40 minutes, 25 DEG C of insulated and stirred crystallizations are down to 30 minutes, being cooled to 10 DEG C, to continue insulated and stirred 2 little
When abundant crystallization, suction filtration, dry ticagrelor crystal formation 28.7g, HPLC purity 99.95%.
According to XPRD data, gained crystal formation is consistent with crystal formation in embodiment 1.Using Perkin-Elmer company of U.S. PE
The thermogravimetric analysis collection of illustrative plates that Pyris Diamond TG thermogravimetric analyzer is obtained is consistent with embodiment 1.
The preparation of 3 ticagrelor crystal formation of embodiment
30g ticagrelor crude product, 125ml ethyl acetate, 25ml isopropyl ether are added in 1000ml flask, be warming up to 65
℃；After molten clear after add activated carbon stirring；Hot suction filtration, filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, drop
Temperature is down to 25 DEG C of insulated and stirred crystallizations 30 minutes, is cooled to 10 DEG C of continuation insulated and stirred 2 to 35 DEG C of insulated and stirred crystallizations 40 minutes
Hour abundant crystallization, suction filtration, dry ticagrelor crystal formation 29.3g, HPLC purity 99.96%.
According to XPRD data, gained crystal formation is consistent with crystal formation in embodiment 1.Using Perkin-Elmer company of U.S. PE
The thermogravimetric analysis collection of illustrative plates that Pyris Diamond TG thermogravimetric analyzer is obtained is consistent with embodiment 1.
The preparation of 4 ticagrelor crystal formation of embodiment
30g ticagrelor crude product, 100ml ethyl acetate, 50ml isopropyl ether are added in 1000ml flask, be warming up to 65
℃；After molten clear after add activated carbon stirring；Hot suction filtration, filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, drop
Temperature is down to 25 DEG C of insulated and stirred crystallizations 30 minutes, is cooled to 10 DEG C of continuation insulated and stirred 2 to 35 DEG C of insulated and stirred crystallizations 40 minutes
Hour abundant crystallization, suction filtration, dry ticagrelor crystal formation 29.5g, HPLC purity 99.98%.
According to XPRD data, gained crystal formation is consistent with crystal formation in embodiment 1.Using Perkin-Elmer company of U.S. PE
The thermogravimetric analysis collection of illustrative plates that Pyris Diamond TG thermogravimetric analyzer is obtained is consistent with embodiment 1.
Test example 1
Solubility test
The test example has investigated dissolubility of the ticagrelor crystal formation of the present invention with the ticagrelor of prior art in water.
Sample number into spectrum is as follows：
Sample 1：Ticagrelor obtained in the embodiment of the present invention 1；
Sample 2：Ticagrelor obtained in the embodiment of the present invention 2；
Sample 3：Ticagrelor obtained in the embodiment of the present invention 3；
Sample 4：Ticagrelor obtained in the embodiment of the present invention 4；
Sample 5：According to the embodiment 1 of patent CN1247583C method obtained in ticagrelor polymorphic I；
Sample 6：According to the embodiment 2 of patent CN1247583C method obtained in ticagrelor polymorphs；
Sample 7：According to the embodiment 3 of patent CN1247583C method obtained in ticagrelor polymorphic III；
Sample 8：According to the embodiment 4 of patent CN1247583C method obtained in ticagrelor polymorphic IV；
Sample 9：According to the embodiment 5 of patent CN1247583C method obtained in ticagrelor amorphous；
Solubility test method：
The method specified according to the version two of Chinese Pharmacopoeia 2010 " note on the use " has done the solubility test of following several solvents.
Method：Weigh be ground into fine powder each sample appropriate (being accurate to ± 2.0%), add the water of a certain amount of volume, 25
Shook 30 seconds every 5 minutes under ± 2 DEG C of room temperatures, observation dissolved situation in 30 minutes, the results are shown in Table 1.
1 solubility test result of table
As can be seen from the test results, compared with prior art, obtained in the present invention, ticagrelor crystal formation is in water for the present invention
In dissolubility increase.
Test example 2
Stability test
In order to investigate the long-time stability of ticagrelor crystal formation further, the present invention is for the ticagrelor of embodiment 1～4
Crystal formation is kept sample under the conditions of humidity 60% ± 10% for a long time in 25 ± 2 DEG C of temperature, and, after 12 months, result of the test is such as study on the stability
Shown in table 2.
2 stability test result of table
As a result show, in 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10% is placed 12 months, and indices are all Wu bright
Aobvious change, illustrates that this product has good stability, and reappearance is easy to long term storage, and clinical application is safer.
Claims (4)
1. ticagrelor crystal formation shown in a kind of formula I, is radiated using Cu-K α, it is characterised in that the crystal formation is with 2 θ ± 0.2 ° diffraction
X-ray powder diffraction spectrogram that angle represents spectrum 5.17 ± 0.2 °, 7.22 ± 0.2 °, 10.28 ± 0.2 °, 11.98 ± 0.2 °,
15.35±0.2°、17.28±0.2°、18.21±0.2°、21.41±0.2°22.49±0.2°、24.99±0.2°、26.08
± 0.2 °, 27.82 ± 0.2 °, 28.95 ± 0.2 °, 29.99 ± 0.2 °, have characteristic peak at 31 ± 0.2 °.
2. ticagrelor crystal formation as claimed in claim 1, it is characterised in that ticagrelor crystal formation has X- as shown in Figure 1 and penetrates
Line powder diffractogram.
3. ticagrelor crystal formation as claimed in claim 1, its preparation method comprise the steps：
Ticagrelor crude product is added in the mixed solvent of ethyl acetate and isopropyl ether, 65 DEG C are warming up to, molten clear rear addition is lived
Property charcoal stirring, hot suction filtration removes activated carbon, gained filtrate lowered the temperature using segmentation by the way of stirring and crystallizing, temperature is progressively down to 10
DEG C, stirring and crystallizing is complete；Filter, obtain ticagrelor crystal formation；
The mode stirring and crystallizing process of described segmentation cooling is：
1) 45 DEG C of insulated and stirred 20 minutes；
2) 35 DEG C of insulated and stirred are cooled to 40 minutes；
3) 25 DEG C of insulated and stirred are cooled to 30 minutes；
4) 10 DEG C are finally cooled to and continue insulated and stirred 2 hours.
4. the preparation method of ticagrelor crystal formation as claimed in claim 3, it is characterised in that described ticagrelor crude product and second
The mass volume ratio of acetoacetic ester and isopropyl ether mixed solvent is 1:3～5g/ml, the volume ratio of the ethyl acetate and isopropyl ether is
5～2:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109705123A (en) * | 2017-10-26 | 2019-05-03 | 郑州泰丰制药有限公司 | A kind of purification process of ticagrelor |
| CN112898304A (en) * | 2019-11-19 | 2021-06-04 | 北京四环制药有限公司 | Preparation method of high-purity ticagrelor crystal form II |
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| CN104098571A (en) * | 2013-04-08 | 2014-10-15 | 博瑞生物医药技术(苏州)有限公司 | Crystal form of Ticagrelor Brilinta and preparation method thereof |
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| CN104370912A (en) * | 2013-08-13 | 2015-02-25 | 开原亨泰制药股份有限公司 | Ticagrelor polycrystal and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109705123A (en) * | 2017-10-26 | 2019-05-03 | 郑州泰丰制药有限公司 | A kind of purification process of ticagrelor |
| CN112898304A (en) * | 2019-11-19 | 2021-06-04 | 北京四环制药有限公司 | Preparation method of high-purity ticagrelor crystal form II |
| CN112898304B (en) * | 2019-11-19 | 2023-10-31 | 北京四环制药有限公司 | Preparation method of ticagrelor crystal form II |
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