CN105801583A - Purification method of ticagrelor - Google Patents

Purification method of ticagrelor Download PDF

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Publication number
CN105801583A
CN105801583A CN201410844859.0A CN201410844859A CN105801583A CN 105801583 A CN105801583 A CN 105801583A CN 201410844859 A CN201410844859 A CN 201410844859A CN 105801583 A CN105801583 A CN 105801583A
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China
Prior art keywords
ticagrelor
solvent
purification
weight
crude
Prior art date
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Pending
Application number
CN201410844859.0A
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Chinese (zh)
Inventor
乔德水
鹿婷
陈�胜
高雪芹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Wanbang Biological Pharmaceutical Co Ltd
Shanghai Fosun Pharmaceutical Group Co Ltd
Xuzhou Wanbang Jinqiao Pharmaceutical Co Ltd
Original Assignee
Jiangsu Wanbang Biological Pharmaceutical Co Ltd
Shanghai Fosun Pharmaceutical Group Co Ltd
Xuzhou Wanbang Jinqiao Pharmaceutical Co Ltd
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Application filed by Jiangsu Wanbang Biological Pharmaceutical Co Ltd, Shanghai Fosun Pharmaceutical Group Co Ltd, Xuzhou Wanbang Jinqiao Pharmaceutical Co Ltd filed Critical Jiangsu Wanbang Biological Pharmaceutical Co Ltd
Priority to CN201410844859.0A priority Critical patent/CN105801583A/en
Publication of CN105801583A publication Critical patent/CN105801583A/en
Pending legal-status Critical Current

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Abstract

Belonging to the technical field of pharmaceutical industry, the invention relates to the preparation field of ticagrelor, in particular to a purification method of ticagrelor. Directed at the purification blank of ticagrelor at present, especially the blank of purification technology for the product obtained by a preparation method involved in the invention, the invention discloses a purification method of ticagrelor. The method consists of the steps of: dissolving a ticagrelor crude product in a first solvent, performing hot filtration to remove solid therein, and adding a second solvent into the filtrate while it is hot, conducting cooling till a lot of solid precipitate, carrying out low temperature heat preservation until no solid precipitate, and carrying out filtration and drying, thus obtaining a ticagrelor pure product. The purification method disclosed by the invention can decrease the total impurity content of the product from 4.5% to less than 0.2%, the purified ticagrelor has purity of more than 99.75%, and the biggest individual impurity is below 0.1%.

Description

A kind of purification process of ticagrelor
Technical field
The present invention relates to the preparation field of ticagrelor, particularly relate to the purification process of ticagrelor, belong to medical industry technical field.
Background technology
Ticagrelor (Ticagrelor, also known as Ticagrelor) belongs to cyclopenta triazolopyrimidines, chemistry by name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol, molecular formula: C23H28F2N6O4S, No. CAS: 274693-27-5, structural formula is as follows:
Ticagrelor be by U.S.'s AstraZeneca (AstraZeneca) company research and development a kind of novel, there is selective little molecule anticoagulant.This medicine can the reversibly purine 2 receptor (purinoceptor2 on vasoactive smooth muscle cell (VSMC), P2) hypotype P2Y12, the platelet aggregation that ADP is caused has obvious inhibitory action, and it is rapid to orally use rear onset, therefore can be effectively improved the symptom of acute coronary patient.And because the antiplatelet effects of ticagrelor is reversible, it needs the patient of row operation again after carrying out anticoagulant therapy in advance especially suitable for those.It is can significantly reduce cardiovascular origin and death that all reasons cause that ticagrelor compares its competitor's the most attractive advantage of clopidogrel.It it is a kind of anticoagulant having a extensive future.
As the preparation method of a kind of alternatively ticagrelor, the preparation method that the present inventor gives a kind of brand-new ticagrelor, and submitted relevant patent application, the number of accepting CN201310527897.9, the method synthetic route is as follows:
By assorted content total in the product that the method prepares 4.5%.Due to different from preparation method involved in the present invention in currently available technology, bring the impurity component in product produced by therefore into different.Therefore, based on this preparation method, a kind of applicable polishing purification technique of supporting formation, have great importance for industrialized production, but unfortunately include prior art both domestic and external in for all not relevant research of this part and report.
Summary of the invention
Purification for current ticagrelor is blank, particularly the present invention relates to the blank of the obtained purifying products technology of preparation method, the invention discloses the purification process of a kind of ticagrelor, comprising the following steps: take ticagrelor crude product heat of solution in the first solvent, heat filtering removes wherein solid, and adds the second solvent while hot in filtrate, it is cooled to low-temperature insulation when a large amount of solid precipitates out, to no longer having solid to precipitate out, filter, dry, obtain ticagrelor sterling;Described first solvent is one or more in dichloromethane, acetonitrile, acetone, methanol, ethanol, n-butyl alcohol or ethyl acetate;Described second solvent is one or more in normal hexane, hexamethylene, pentane, isobutyltrimethylmethane. or Pentamethylene..
Preferably, described first solvent is ethyl acetate;Described second solvent is normal hexane.
Preferred as one, the present invention further discloses 5 ~ 10 times that described first weight of solvent is ticagrelor crude product weight, it is preferred to 5 times.
Meanwhile, the present invention, it is also preferred that disclose that described second weight of solvent is the first weight of solvent 1 ~ 5 times, is more preferably 2 times.
Meanwhile, the invention also discloses described low temperature is less than 25 DEG C, it is preferable that this temperature is 10 DEG C ~ 15 DEG C.The low-temperature insulation time is preferably 0.5 ~ 2 hour, it is particularly preferred to ground temperature retention time is 1 hour.
Further, we, it is also preferred that dry 40 ~ 50 DEG C of vacuum dryings of finger, are wherein preferably 40 DEG C of vacuum dryings, are preferably 8 hours drying time.
As another technical scheme, we are it is also preferred that also include rinsing step after the drying, and described cleaning mixture is the first solvent and the mixed solution of the second solvent, and mixing quality is than for 1:1 ~ 5, it is preferable that this mixing quality is than for 1:2.
Further, we give a kind of preferred version, and namely described ticagrelor is dissolved in the first solvent at 30 DEG C ~ 60 DEG C, it is preferable that this temperature is 50 DEG C.
The present inventor, through substantial amounts of research, utilizes impurity and finished product dissolubility difference in mixed solvent, impurity and product is separated.
Adopting purification process disclosed in this invention by 4.5%, assorted content total in product can be reduced to less than 0.2%, purified ticagrelor purity is more than 99.75%, and maximum list is assorted below 0.1%.
After purification of the present invention, in product purity height, purifying process, product runs off few, and productivity is high.Purification process operation simple, easily controllable, purification cost is low, is suitable for industrial applications and promotes.
Detailed description of the invention
For being further appreciated by the present invention, below in conjunction with implementing technical scheme disclosed in this invention is described in detail, protection scope of the present invention is not limited by the following examples.
Experimental technique described in following example, if no special instructions, is conventional method, involved reagent and material, if no special instructions, is the commercially available prod of commercial sources.
In following embodiment, crude product used is to obtain by the following method:
According to the present inventor's patent before this, the method introduced in the number of accepting CN201310527897.9 prepares, and gained crude product is used for this purification.
Embodiment 1
By homemade 100g ticagrelor crude product (HPLC purity 95.5%, isomer 1.3%) and 500g ethyl acetate, it is warming up to 50oC stirring molten clearly.Heat filter, collects filtrate, adds 1000g normal hexane in filtrate.Finish, stirring and crystallizing of lowering the temperature, until precipitating out a large amount of white solid, 10oC~15oC insulated and stirred 1h.Filter, filter cake 150g ethyl acetate and 300g normal hexane mixed liquor drip washing.40oC vacuum drying 8 hours, obtains 87g off-white color solid, and HPLC purity reaches 99.89%, isomer 0.003%;Maximum single contaminant amount 0.005%, total impurities amount 0.011%.
Embodiment 2
By homemade 100g ticagrelor crude product (HPLC purity 95.5%, isomer 1.3%) and 600g acetone, it is warming up to 35oC stirring molten clearly.Heat filter, collects filtrate, adds 1800g isobutyltrimethylmethane. in filtrate.Finish, stirring and crystallizing of lowering the temperature, until precipitating out a large amount of white solid, 5oC~10oC insulated and stirred 2h.Filter, filter cake 200g acetone and 600g isobutyltrimethylmethane. mixed liquor drip washing.45oC vacuum drying 10 hours, obtains 83g off-white color solid, and HPLC purity reaches 99.80%, isomer 0.006%;Maximum single contaminant amount 0.008%, total impurities amount 0.020%.
Embodiment 3
By homemade 100g ticagrelor crude product (HPLC purity 95.5%, isomer 1.3%) and 700g n-butyl alcohol, it is warming up to 55oC stirring molten clearly.Heat filter, collects filtrate, adds 2800g normal hexane in filtrate.Finish, stirring and crystallizing of lowering the temperature, until precipitating out a large amount of white solid, 15oC~20oC insulated and stirred 2h.Filter, filter cake 230g n-butyl alcohol and 920g normal hexane mixed liquor drip washing.50oC vacuum drying 12 hours, obtains 83g off-white color solid, and HPLC purity reaches 99.76%, isomer 0.008%;Maximum single contaminant amount 0.009%, total impurities amount 0.024%.
Embodiment 4
By homemade 100g ticagrelor crude product (HPLC purity 95.5%, isomer 1.3%) and 800g dichloromethane, it is warming up to 40oC stirring molten clearly.Heat filter, collects filtrate, adds 800g hexamethylene in filtrate.Finish, stirring and crystallizing of lowering the temperature, until precipitating out a large amount of white solid, 25oC insulated and stirred 1h.Filter, filter cake 260g dichloromethane and 260g hexamethylene mixed liquor drip washing.40oC vacuum drying 8 hours, obtains 84g off-white color solid, and HPLC purity reaches 99.82%, isomer 0.008%;Maximum single contaminant amount 0.009%, total impurities amount 0.018%.
Embodiment 5
By the mixed liquor (mass ratio 1:1) of homemade 100g ticagrelor crude product (HPLC purity 95.5%, isomer 1.3%) with 1000g acetonitrile with methanol, it is warming up to 60oC stirring molten clearly.Heat filter, collects filtrate, adds 1000g hexamethylene in filtrate.Finish, stirring and crystallizing of lowering the temperature, until precipitating out a large amount of white solid, 25oC insulated and stirred 2h.Filter, filter cake 150g acetonitrile, 150g methanol and 300g hexamethylene mixed liquor drip washing.45oC vacuum drying 10 hours, obtains 85g off-white color solid, and HPLC purity reaches 99.83%, isomer 0.009%;Maximum single contaminant amount 0.009%, total impurities amount 0.017%.

Claims (10)

1. the purification process of a ticagrelor, it is characterized in that, comprise the following steps: take ticagrelor crude product heat of solution in the first solvent, heat filtering removes wherein solid, and in filtrate, add the second solvent while hot, it is cooled to low-temperature insulation when a large amount of solid precipitates out, to no longer having solid to precipitate out, filter, dry, obtain ticagrelor sterling;Described first solvent is one or more in dichloromethane, acetonitrile, acetone, methanol, ethanol, n-butyl alcohol or ethyl acetate;Described second solvent is one or more in normal hexane, hexamethylene, pentane, isobutyltrimethylmethane. or Pentamethylene..
2. the purification process of ticagrelor according to claim 1, is characterized in that, described first solvent is ethyl acetate.
3. the purification process of ticagrelor according to claim 1, is characterized in that, described second solvent is normal hexane.
4. the purification process of ticagrelor according to claim 1 and 2, is characterized in that, described first weight of solvent is 5 ~ 10 times of ticagrelor crude product weight.
5. the purification process of the ticagrelor according to claim 1 or 3, is characterized in that, described second weight of solvent is 1 ~ 5 times of the first weight of solvent.
6. the purification process of ticagrelor according to claim 1, is characterized in that, described low temperature is less than 25 DEG C.
7. the purification process of ticagrelor according to claim 1, is characterized in that, described 40 ~ 50 DEG C of vacuum dryings of dry finger.
8. the purification process of ticagrelor according to claim 1, is characterized in that, also includes rinsing step after drying, and described cleaning mixture is the first solvent and the mixed solution of the second solvent, and mixing quality is than for 1:1 ~ 5.
9. the purification process of ticagrelor according to claim 1, is characterized in that, described ticagrelor is dissolved in the first solvent at 30 DEG C ~ 60 DEG C.
10. the purification process of ticagrelor according to claim 1, is characterized in that, also optional one or more optimum conditions therein:
(1) described first weight of solvent is 5 times of ticagrelor crude product weight;
(2) described second weight of solvent is 2 times of the first weight of solvent;
(3) described low temperature is 10 DEG C ~ 15 DEG C;
(4) 40 DEG C of vacuum dryings of described dry finger '
(5) described cleaning mixture is the first solvent and the mixed solution of the second solvent, and mixing quality is than for 1:2;
(6) described ticagrelor is dissolved in the first solvent at 50 DEG C.
CN201410844859.0A 2014-12-31 2014-12-31 Purification method of ticagrelor Pending CN105801583A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106243108A (en) * 2015-06-03 2016-12-21 四川海思科制药有限公司 A kind of highly purified ticagrelor and preparation method thereof
CN106478636A (en) * 2016-08-30 2017-03-08 山东罗欣药业集团恒欣药业有限公司 Ticagrelor crystal formation and preparation method
CN106866677A (en) * 2017-02-17 2017-06-20 陕西必康制药集团控股有限公司 The purifying of Ticagrelor and preparation method
CN108299441A (en) * 2018-03-07 2018-07-20 于天荣 A kind of preparation method of ticagrelor
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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1680340A (en) * 2000-06-02 2005-10-12 阿斯特拉曾尼卡有限公司 Novel triazolo pyrimidine compounds
CN103664958A (en) * 2012-09-26 2014-03-26 四川海思科制药有限公司 Crystal form of ticagrelor and preparation method for crystal form
WO2014155389A2 (en) * 2013-03-25 2014-10-02 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
CN104098553A (en) * 2013-04-10 2014-10-15 江苏恒瑞医药股份有限公司 Ticagrelor intermediate and preparation method thereof and ticagrelor preparation method
CN104098570A (en) * 2013-04-07 2014-10-15 杭州领业医药科技有限公司 Crystal form of Ticagrelor Brilinta and preparation method and purpose thereof
CN104193747A (en) * 2014-08-12 2014-12-10 许彩霞 Preparation of amorphous ticagrelor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1680340A (en) * 2000-06-02 2005-10-12 阿斯特拉曾尼卡有限公司 Novel triazolo pyrimidine compounds
CN103664958A (en) * 2012-09-26 2014-03-26 四川海思科制药有限公司 Crystal form of ticagrelor and preparation method for crystal form
WO2014155389A2 (en) * 2013-03-25 2014-10-02 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
CN104098570A (en) * 2013-04-07 2014-10-15 杭州领业医药科技有限公司 Crystal form of Ticagrelor Brilinta and preparation method and purpose thereof
CN104098553A (en) * 2013-04-10 2014-10-15 江苏恒瑞医药股份有限公司 Ticagrelor intermediate and preparation method thereof and ticagrelor preparation method
CN104193747A (en) * 2014-08-12 2014-12-10 许彩霞 Preparation of amorphous ticagrelor

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106243108A (en) * 2015-06-03 2016-12-21 四川海思科制药有限公司 A kind of highly purified ticagrelor and preparation method thereof
CN106478636A (en) * 2016-08-30 2017-03-08 山东罗欣药业集团恒欣药业有限公司 Ticagrelor crystal formation and preparation method
CN106478636B (en) * 2016-08-30 2019-02-15 山东罗欣药业集团恒欣药业有限公司 Ticagrelor crystal form and preparation method
CN106866677A (en) * 2017-02-17 2017-06-20 陕西必康制药集团控股有限公司 The purifying of Ticagrelor and preparation method
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
CN108299441A (en) * 2018-03-07 2018-07-20 于天荣 A kind of preparation method of ticagrelor

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