CN106478636B - Ticagrelor crystal form and preparation method - Google Patents
Ticagrelor crystal form and preparation method Download PDFInfo
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- CN106478636B CN106478636B CN201610765692.8A CN201610765692A CN106478636B CN 106478636 B CN106478636 B CN 106478636B CN 201610765692 A CN201610765692 A CN 201610765692A CN 106478636 B CN106478636 B CN 106478636B
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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
Abstract
The invention belongs to field of medicinal chemistry, are related to ticagrelor crystal form and preparation method.Ticagrelor crude product is added to the in the mixed solvent of ethyl acetate and isopropyl ether, is warming up to 65 DEG C, segmented cooling crystallization obtains ticagrelor crystal form.The characteristics of ticagrelor crystal form provided by the invention improves with solubility, stable crystal form.
Description
Technical field
The present invention relates to ticagrelor crystal form and preparation methods.
Background technique
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 blocks public affairs by Astra
Novel, the selective small molecule anticoagulant of one kind of department's exploitation.The medicine can reversibly vasoactive smooth muscle
2 receptor subtype P2Y12 of purine on cell, has apparent inhibiting effect to platelet aggregation caused by ADP, and after being administered orally
It works rapidly, therefore can effectively improve the symptom of acute coronary patient.And since the antiplatelet effects of ticagrelor are
Reversible, the patient to perform the operation that need to go again after carrying out anticoagulant therapy in advance for those is especially suitable.
The patent CN1247583C of Astrazeneca AB discloses four crystal forms (crystal form I, crystal form II, the crystalline substance of ticagrelor
Type III, crystal form IV) and amorphous state and preparation method thereof, this four kinds of crystal forms and it is amorphous be " anhydrous " state.Either
Which kind of above-mentioned crystal form, the solubility very little of ticagrelor in water, the solubility of the II of ticagrelor in the market in water
Also there was only 16 μ g/ml, for this purpose, ticagrelor crystal form produced by the present invention has better solubility and stability.
Summary of the invention
It is an object of the invention to provide a kind of ticagrelor crystal form, which improves with solubility, and stability is high, reappears
The good feature of property, is easy to large-scale production.
The present invention provides a kind of ticagrelor crystal form, is radiated using Cu-K α, the X-ray powder diffraction indicated with 2 θ angles
In 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±
There is characteristic peak at 0.2 °, 29.99 ± 0.2 °, 31 ± 0.2 °.
Further, ticagrelor crystal form has X-ray powder diffraction spectrogram as shown in Figure 1.
Further, ticagrelor crystal form provided by the invention, preparation method include the following steps:
Ticagrelor crude product is added to the in the mixed solvent of ethyl acetate and isopropyl ether organic solvent, is warming up to 65 DEG C,
Active carbon stirring is added after dissolved clarification, heat, which filters, removes active carbon, gained filtrate stirring and crystallizing by the way of segmented cooling, temperature
10 DEG C are gradually down to, stirring and crystallizing is complete；Filtering, obtains ticagrelor crystal form；
The mode stirring and crystallizing process of the segmented cooling is:
1) 45 DEG C insulated and stirred 20 minutes；
2) 35 DEG C of insulated and stirreds are cooled to 40 minutes；
3) 25 DEG C of insulated and stirreds are cooled to 30 minutes；
4) 10 DEG C of continuation insulated and stirred 2 hours are finally cooled to.
Further, the ticagrelor crude product and the mass volume ratio of ethyl acetate and isopropyl ether mixed solvent are
The volume ratio of 1:3~5g/ml, the ethyl acetate and isopropyl ether organic solvent is 5~2:1.
Ethyl acetate of the present invention, isopropyl ether are the third or the 4th class solvent of low toxicity, and solvent toxicity is small, drug
It is highly-safe, it is not in the sticky phenomenon of crystallizing system, it is low in cost, be conducive to industry amplification and drug production.
The present invention not only can avoid using segmented cooling mode due to crystallization speed including fastly that but also can obtain in product by impurity
The crystal form of favorable reproducibility.
The present inventors have additionally discovered that ticagrelor is improved compared to existing crystal form water solubility, be conducive to clinical use.
The present invention studies the stability of ticagrelor, ticagrelor in 25 ± 2 DEG C of temperature, humidity 60% ±
Keep sample for a long time under the conditions of 10%, after study on the stability 12 months, content, which has no, to be substantially reduced, and largest single impurity has no obvious increasing
Add, indices have no significant change, and illustrate that this product is with good stability, and reproducibility is convenient for long term storage, clinical application
It is safer.
Detailed description of the invention
Fig. 1 is ticagrelor crystal form X-ray powder diffraction collection.
Fig. 2 is ticagrelor crystal form thermogravimetric analysis map.
Specific embodiment
Following embodiment is only used for further illustrating the present invention, but does not limit the present invention.
The preparation of 1 ticagrelor crystal form of embodiment
30g ticagrelor crude product, 75ml ethyl acetate, 15ml isopropyl ether are added into 1000ml flask, is warming up to 65 DEG C；
Active carbon stirring is added after dissolved clarification；Heat filters, and filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, cools down
To 35 DEG C insulated and stirred crystallization 40 minutes, be down to 25 DEG C of insulated and stirred crystallizations 30 minutes, it is small to be cooled to 10 DEG C of continuation insulated and stirreds 2
When abundant crystallization, filter, dry ticagrelor crystal form 28.5g, HPLC purity 99.93%.
Gained crystal form is measured through X-ray powder diffraction collection, as a result such as Fig. 1, is penetrated with the X- that the 2 θ ± 0.2 ° angles of diffraction indicate
Line powder diffraction spectrum map 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
There is characteristic peak at ± 0.2 °, 28.95 ± 0.2 °, 29.99 ± 0.2 °, 31 ± 0.2 °.Thermogravimetric analysis map is as shown in Fig. 2, crystal form
Fusing point is 132-138 DEG C, and ticagrelor crystal form before degrading lose by zero gravity, be may infer that as ticagrelor without hydration
Object.
The preparation of 2 ticagrelor crystal form of embodiment
30g ticagrelor crude product, 60ml ethyl acetate, 30ml isopropyl ether are added into 1000ml flask, is warming up to 65 DEG C；
Active carbon stirring is added after dissolved clarification；Heat filters, and filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, cools down
To 35 DEG C insulated and stirred crystallization 40 minutes, be down to 25 DEG C of insulated and stirred crystallizations 30 minutes, it is small to be cooled to 10 DEG C of continuation insulated and stirreds 2
When abundant crystallization, filter, dry ticagrelor crystal form 28.7g, HPLC purity 99.95%.
According to XPRD data, gained crystal form is consistent with crystal form in embodiment 1.Using Perkin-Elmer company of U.S. PE
The thermogravimetric analysis map and embodiment 1 that Pyris Diamond TG thermogravimetric analyzer obtains are consistent.
The preparation of 3 ticagrelor crystal form of embodiment
30g ticagrelor crude product, 125ml ethyl acetate, 25ml isopropyl ether are added into 1000ml flask, is warming up to 65
℃；Active carbon stirring is added after dissolved clarification；Heat filters, and filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, drops
Temperature to 35 DEG C insulated and stirred crystallization 40 minutes, be down to 25 DEG C of insulated and stirred crystallizations 30 minutes, be cooled to 10 DEG C of continuation insulated and stirreds 2
Hour abundant crystallization filters, dry ticagrelor crystal form 29.3g, HPLC purity 99.96%.
According to XPRD data, gained crystal form is consistent with crystal form in embodiment 1.Using Perkin-Elmer company of U.S. PE
The thermogravimetric analysis map and embodiment 1 that Pyris Diamond TG thermogravimetric analyzer obtains are consistent.
The preparation of 4 ticagrelor crystal form of embodiment
30g ticagrelor crude product, 100ml ethyl acetate, 50ml isopropyl ether are added into 1000ml flask, is warming up to 65
℃；Active carbon stirring is added after dissolved clarification；Heat filters, and filtrate is placed in 45 DEG C of hot baths, insulated and stirred crystallization 20 minutes, drops
Temperature to 35 DEG C insulated and stirred crystallization 40 minutes, be down to 25 DEG C of insulated and stirred crystallizations 30 minutes, be cooled to 10 DEG C of continuation insulated and stirreds 2
Hour abundant crystallization filters, dry ticagrelor crystal form 29.5g, HPLC purity 99.98%.
According to XPRD data, gained crystal form is consistent with crystal form in embodiment 1.Using Perkin-Elmer company of U.S. PE
The thermogravimetric analysis map and embodiment 1 that Pyris Diamond TG thermogravimetric analyzer obtains are consistent.
Test example 1
Solubility test
The test example has investigated the dissolubility of the ticagrelor of ticagrelor crystal form of the present invention and the prior art in water.
Sample number into spectrum is as follows:
Sample 1: ticagrelor made from the embodiment of the present invention 1；
Sample 2: ticagrelor made from the embodiment of the present invention 2；
Sample 3: ticagrelor made from the embodiment of the present invention 3；
Sample 4: ticagrelor made from the embodiment of the present invention 4；
Sample 5: ticagrelor polymorphic I made from the method according to the embodiment 1 of patent CN1247583C；
Sample 6: ticagrelor polymorphs made from the method according to the embodiment 2 of patent CN1247583C；
Sample 7: ticagrelor polymorphic III made from the method according to the embodiment 3 of patent CN1247583C；
Sample 8: ticagrelor polymorphic IV made from the method according to the embodiment 4 of patent CN1247583C；
Sample 9: ticagrelor made from the method according to the embodiment 5 of patent CN1247583C is amorphous；
Solubility test method:
The solubility test of following several solvents has been done according to method as defined in Chinese Pharmacopoeia 2010 version two " note on the use ".
Method: weigh be ground into fine powder each sample it is appropriate (being accurate to ± 2.0%), the water of a certain amount of volume is added, 25
± 2 DEG C shook 30 seconds every 5 minutes at room temperature, and 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, the present invention ticagrelor crystal form produced by the present invention is in water
In dissolubility increase.
Test example 2
Stability test
In order to further investigate the long-time stability of ticagrelor crystal form, the present invention is directed to the ticagrelor of Examples 1 to 4
Crystal form keeps sample for a long time under the conditions of 25 ± 2 DEG C of temperature, humidity 60% ± 10%, and after study on the stability 12 months, test result is such as
Shown in table 2.
2 stability test result of table
The results show that relative humidity 60% ± 10% is placed 12 months, and indices are without bright at 25 DEG C ± 2 DEG C of temperature
Aobvious variation, illustrates that this product is with good stability, and reproducibility is convenient for long term storage, and clinical application is safer.
Claims (3)
1. ticagrelor crystal form shown in a kind of formula I, is radiated using Cu-K α, which is characterized in that the crystal form is with 2 θ ± 0.2 ° diffraction
Angle indicate X-ray powder diffraction spectrogram 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
There is characteristic peak at ± 0.2 °, 27.82 ± 0.2 °, 28.95 ± 0.2 °, 29.99 ± 0.2 °, 31 ± 0.2 °；
2. ticagrelor crystal form as described in claim 1, which is characterized in that there is ticagrelor crystal form X- as shown in Figure 1 to penetrate
Line powder diffractogram.
3. a kind of preparation method of ticagrelor crystal form as described in claim 1, includes the following steps:
Ticagrelor crude product is added to the in the mixed solvent of ethyl acetate and isopropyl ether, is warming up to 65 DEG C, is added and lives after dissolved clarification
Property charcoal stirring, heat, which filters, removes active carbon, gained filtrate stirring and crystallizing by the way of segmented cooling, and temperature is gradually down to 10
DEG C, stirring and crystallizing is complete；Filtering, obtains ticagrelor crystal form；The ticagrelor crude product and ethyl acetate and isopropyl ether mixes
The mass volume ratio of bonding solvent is 1:3~5g/ml, and the volume ratio of the ethyl acetate and isopropyl ether is 5~2:1；
The mode stirring and crystallizing process of the segmented cooling is:
1) 45 DEG C insulated and stirred 20 minutes；
2) 35 DEG C of insulated and stirreds are cooled to 40 minutes；
3) 25 DEG C of insulated and stirreds are cooled to 30 minutes；
4) 10 DEG C of continuation insulated and stirred 2 hours are finally cooled to.
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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 |
| 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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| EP2816043A1 (en) * | 2013-06-21 | 2014-12-24 | LEK Pharmaceuticals d.d. | Spherical ticagrelor particles |
| 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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| CN104710425A (en) * | 2013-12-16 | 2015-06-17 | 石药集团中奇制药技术（石家庄）有限公司 | Ticagrelor new crystal and preparation method thereof |
| CN105669673A (en) * | 2014-11-20 | 2016-06-15 | 天津汉瑞药业有限公司 | Stable Ticagrelor compound |
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|---|---|---|---|---|
| WO2013150495A2 (en) * | 2012-04-05 | 2013-10-10 | Dr. Reddy's Laboratories Limited | Preparation of ticagrelor |
| 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 |
| EP2816043A1 (en) * | 2013-06-21 | 2014-12-24 | LEK Pharmaceuticals d.d. | Spherical ticagrelor particles |
| 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 |
| WO2015037016A2 (en) * | 2013-09-10 | 2015-03-19 | Laurus Labs Private Limited | An improved process for the preparation of ticagrelor and intermediates thereof |
| CN104710425A (en) * | 2013-12-16 | 2015-06-17 | 石药集团中奇制药技术（石家庄）有限公司 | Ticagrelor new crystal and preparation method thereof |
| CN104193748A (en) * | 2014-08-14 | 2014-12-10 | 严白双 | Method for synthesizing ticagrelor |
| CN105669673A (en) * | 2014-11-20 | 2016-06-15 | 天津汉瑞药业有限公司 | Stable Ticagrelor compound |
| CN105801583A (en) * | 2014-12-31 | 2016-07-27 | 徐州万邦金桥制药有限公司 | Purification method of ticagrelor |
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