CN107382735A - A kind of synthetic method of ticagrelor intermediate - Google Patents
A kind of synthetic method of ticagrelor intermediate Download PDFInfo
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- CN107382735A CN107382735A CN201710603936.7A CN201710603936A CN107382735A CN 107382735 A CN107382735 A CN 107382735A CN 201710603936 A CN201710603936 A CN 201710603936A CN 107382735 A CN107382735 A CN 107382735A
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- anhydrous
- ticagrelor
- compound
- catalyst
- rhodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention provides a kind of ticagrelor intermediate（1）Novel synthesis：By compound（2）Reacted through rhodium catalysis asymmetry three-membered ring（New catalyst system and catalyzing）Ticagrelor midbody compound is made（1）.Method provided by the invention is easy to operate, and production cost is low, good product quality, is adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of synthetic method of ticagrelor intermediate.
Background technology
Ticagrelor (common name：Ticagrelor, trade name BRILINTA), entitled (1S, 2S, 3R, the 5S) -3- of chemistry
[7- [(1R, 2S) -2- (3,4- difluorophenyls) cyclopropane amino] -5- (propane sulfydryl) -3H- [1,2,3] triazole [4,5-d]
Pyridin-3-yl] -5- (2- hydroxyl ethanes oxygen) pentamethylene -1,2- glycol.The molecular weight of ticagrelor：522.57；CAS registration numbers：
274693-27-5 ；Structural formula is shown in formula 1：
Formula 1
Ticagrelor is researched and developed by AstraZeneca AB.A kind of platelet aggregation inhibitor of the FDA of in September, 2015 approvals, for lattice
Rui Luo is approved for the Antiplatelet therapy of ACS patient in the U.S..
Prior art literature
Patent document：
Patent document：WO 2008018822A1
Patent document：WO 2008018823A1
The present inventor study find, the compound 1 being shown below can be used as synthesis ticagrelor important intermediate so that
Provide new process route prepared by a kind of ticagrelor.This method is simple and easy, and cost is relatively low, and yield is higher, product matter
Amount is preferable, is adapted to big industrialized production.
The important intermediate of ticagrelor.
The content of the invention
It is an object of the invention to provide a kind of ticagrelor midbody compound（1）Novel synthesis.
The purpose of the present invention can be realized by following measures：
A kind of ticagrelor intermediate（1）Synthetic method：Compound（2）Reacted through rhodium catalysis asymmetry three-membered ring（New catalysis
System）Ticagrelor midbody compound is made（1）, its reaction equation is as follows：
。
The reaction dissolvent of shown preparation method is anhydrous tetrahydro furan, absolute ether, anhydrous methyl tertbutyl ether, anhydrous
Dichloromethane, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans, absolute methanol, absolute ethyl alcohol, anhydrous isopropyl
One or more in alcohol, anhydrous propanone and anhydrous acetonitrile, wherein preferred solvent are anhydrous methylene chloride;Reaction temperature is -80
DEG C~20 DEG C, wherein preferable temperature is -30 DEG C~-25 DEG C;Rhodium catalyst is selected from Rh2(pfb)4、Rh2(OAc)4、RhCl3、Rh2
(OCOt-Bu)4, mandelic acid rhodium, trifluoroacetic acid rhodium and [Rh (cod)2]BF4, wherein preferred catalyst is Rh2(OAc)4；Part is：；The ratio of catalyst and part is 1:1.
The invention provides a kind of new method of synthesis ticagrelor intermediate, compared with prior art, its remarkable advantage is：
This method has the advantages that synthetic yield height, good product purity, raw material are cheap and easy to get and are suitable for industrialized production.
Embodiment
For ease of understanding, the present invention will be described in detail by specific embodiment below.Need to particularly point out
, instantiation is merely to explanation, it is clear that one of ordinary skill in the art can be according to illustrating, the present invention's herein
In the range of various amendments are made to the present invention.
The method of intermediate HPLC of the present invention detection purity：
Test apparatus：The high performance liquid chromatographs of Agilent 1100（DAD detectors）.
Chromatographic condition：With OB-H (4.6 × 250mm, 5 μm) for chromatographic column, flow velocity：0.5ml/min.
Mobile phase A：Isopropanol；Mobile phase B：Normal heptane
According to the form below carries out linear gradient elution：
Ultraviolet detection wavelength：254nm.
Embodiment 1
The preparation of compound 1
The mL of reaction dissolvent anhydrous methylene chloride 500 and 185 g (1.0 mol) compound are added into 2L four round flask
（2）, it is 4.4 g to add catalyst（1 mmol）Rh2(OAc)4With the g of part 7.1（1 mmol）, reaction solution is cooled after adding
To -30 DEG C or so, the dichloromethane solution of diazomethane is then slowly added into（550 mL, 2M dichloromethane solution, 6 is small
When）, TLC tracking reactions, react and terminate after 3 hours, be warmed to room temperature, through the compound that is concentrated under reduced pressure to obtain（1）Crude product.Above-mentioned crude product warp
Compound is made in re crystallization from toluene（1）Fine work 197.1g.
Mass yield is 106%, HPLC detection purity：99.17%.
1H NMR (500 MHz, DMSO-d6) δ 7.39 – 6.79 (m, 3H), 3.92 (td, J = 9.3,
8.3 Hz, 1H), 2.37 (td, J = 10.2, 8.2 Hz, 1H), 1.26 (ddd, J = 12.4, 10.2, 9.3
Hz, 1H), 1.01 (ddd, J = 12.4, 10.3, 9.5 Hz, 1H).
13C NMR (125 MHz, DMSO-d6) δ 154.37 (dd, J = 251.8, 20.0 Hz), 149.41 (dd,J = 251.8, 20.0 Hz), 137.74, 126.81, 116.02 (dd, J = 20.0, 8.6 Hz), 113.79
(dd, J = 19.6, 8.1 Hz), 55.87, 23.38, 16.70.
ESI+ [M+H]+=200.
Embodiments of the invention are the foregoing is only, are not intended to limit the scope of the invention, it is every to be said using the present invention
The equivalent structure or equivalent flow conversion that bright book content is made, or other related technical fields are directly or indirectly used in,
Similarly it is included within the scope of the present invention.
Claims (2)
- A kind of 1. synthesis type（1）The method of compound ticagrelor intermediate, it is characterised in that：Compound（2）Through rhodium catalysis not Symmetrical three-membered ring reaction（New catalyst system and catalyzing）Ticagrelor midbody compound is made（1）, its reaction equation is as follows：。
- 2. the preparation method as shown in claim 1, it is characterised in that:Reaction dissolvent be anhydrous tetrahydro furan, absolute ether, Anhydrous methyl tertbutyl ether, anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofurans, without water beetle One or more in alcohol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous propanone and anhydrous acetonitrile, wherein preferred solvent are anhydrous two Chloromethanes;Reaction temperature is -80 DEG C~20 DEG C, and wherein preferable temperature is -30 DEG C~-25 DEG C;Rhodium catalyst is selected from Rh2 (pfb)4、Rh2(OAc)4、RhCl3、Rh2(OCOt-Bu)4, mandelic acid rhodium, trifluoroacetic acid rhodium and [Rh (cod)2]BF4, wherein it is preferred that Catalyst is Rh2(OAc)4；Part is：；Catalyst and The ratio of part is 1:1.
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| CN201710603936.7A CN107382735A (en) | 2017-07-24 | 2017-07-24 | A kind of synthetic method of ticagrelor intermediate |
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| CN201710603936.7A CN107382735A (en) | 2017-07-24 | 2017-07-24 | A kind of synthetic method of ticagrelor intermediate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102381988A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Method for preparing intermediate compound of Rivastigmine and intermediate compound |
| CN103508899A (en) * | 2013-10-23 | 2014-01-15 | 开原亨泰制药股份有限公司 | Method for preparing ticagrelor key intermediate and racemate thereof and special intermediate for implementing method |
| CN104326922A (en) * | 2014-11-03 | 2015-02-04 | 成都百裕科技制药有限公司 | Method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine |
| CN104744266A (en) * | 2013-12-31 | 2015-07-01 | 上虞京新药业有限公司 | Preparation method of ticagrelor intermediate |
-
2017
- 2017-07-24 CN CN201710603936.7A patent/CN107382735A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102381988A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Method for preparing intermediate compound of Rivastigmine and intermediate compound |
| CN103508899A (en) * | 2013-10-23 | 2014-01-15 | 开原亨泰制药股份有限公司 | Method for preparing ticagrelor key intermediate and racemate thereof and special intermediate for implementing method |
| CN104744266A (en) * | 2013-12-31 | 2015-07-01 | 上虞京新药业有限公司 | Preparation method of ticagrelor intermediate |
| CN104326922A (en) * | 2014-11-03 | 2015-02-04 | 成都百裕科技制药有限公司 | Method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine |
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