CN107141298A - A kind of synthetic method of ticagrelor - Google Patents
A kind of synthetic method of ticagrelor Download PDFInfo
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- CN107141298A CN107141298A CN201710603920.6A CN201710603920A CN107141298A CN 107141298 A CN107141298 A CN 107141298A CN 201710603920 A CN201710603920 A CN 201710603920A CN 107141298 A CN107141298 A CN 107141298A
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- 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
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Abstract
The invention provides a kind of ticagrelor（1）Synthetic method：First by compound（2）And compound（3）It is substituted reaction and compound is made（4）；The compound（4）Compound is made in substitution reaction through mercaptan（5）；Compound（5）And compound（6）Compound is made in via palladium-catalyzed asymmetric allylic substitution reaction（7）；Compound（7）Compound is made through asymmetric dihydroxylation（8）；Compound（8）Compound is made through the reaction of double hydroxyl protections（9）；Compound（9）Compound is made through hydroxyl substitution reaction（10）；Final compound（10）Ticagrelor is obtained through hydroxyl deprotection reaction（1）.The method that the present invention is provided 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 bulk drug.
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's research finds that said synthesis route provides new process route prepared by a kind of ticagrelor.This method
Simple and easy to apply, cost is relatively low, and yield is higher, and product quality preferably, 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 ticagrelor midbody compound（4）, compound（5）, compound（7）, chemical combination
Thing（8）, compound（9）, compound（10）Synthetic method and ticagrelor new synthesis process.
The purpose of the present invention can be realized by following measures：
A kind of synthetic method of ticagrelor：First by compound（2）And compound（3）It is substituted reaction and compound is made（4）；Institute
State compound（4）Compound is made in substitution reaction through mercaptan（5）；Compound（5）And compound（6）Via palladium-catalyzed asymmetric alkene
Compound is made in third substitution reaction（7）；Compound（7）Compound is made through asymmetric dihydroxylation（8）；Compound
（8）Compound is made through the reaction of double hydroxyl protections（9）；Compound（9）Compound is made through hydroxyl substitution reaction（10）；Finally change
Compound（10）Ticagrelor is obtained through hydroxyl deprotection reaction（1）, its reaction equation is as follows：
。
A kind of midbody compound of ticagrelor（4）Preparation method, comprise the following steps：By compound（2）And change
Compound（3）It is substituted reaction and compound is made（4）, reaction equation is as follows：
。
A kind of ticagrelor midbody compound（5）Preparation method, it is characterised in that：Compound（4）Substitution through mercaptan is anti-
Compound should be made（5）, it is as follows the step of reaction：
。
A kind of ticagrelor midbody compound（7）Preparation method, it is characterised in that：Compound（5）And compound（6）Through palladium
It is catalyzed asymmetric allylic substitution reaction and compound is made（7）, it is as follows the step of reaction：
。
The reaction dissolvent of shown preparation method is selected from anhydrous THF, absolute ether, dry toluene, anhydrous dimethyl benzene, anhydrous
Dichloromethane is anhydrous, the one or more in 2- methyltetrahydrofurans, anhydrous DMSO, anhydrous DMA, dry DMF and anhydrous TBME,
Wherein preferred solvent is dry DMF；Reaction temperature is selected from 0 DEG C~100 DEG C, and wherein preferable temperature is 60 DEG C~80 DEG C；Reaction is urged
Agent is selected from Pd (PPh3)4, Pd2(dba)3, [Pd(allyl)Cl]2, Pd(OAc)2And PdCl2In one or more, its
Middle preferred catalyst is Pd2(dba)3；Part is selected from PPh3, dba, P(OEt)3, P (cyclohexyl)3, P (tert-butyl group)3, P
(p-methylphenyl)3, P (3,5- xylyl)3, P (to fluoroform phenyl)3With P (OMe)3In one or more, wherein it is preferred that P
(OMe)3；The ratio of catalyst and part is 1:2.
A kind of ticagrelor midbody compound（8）Preparation method, it is characterised in that：Compound（7）Through asymmetric double
Compound is made in hydroxylating（8）, it is as follows the step of reaction：
。
The reaction dissolvent of shown preparation method is selected from THF, ether, toluene, dimethylbenzene, dichloromethane, 2- methyl tetrahydrochysenes
One or more in furans, DMSO, DMA, DMF, acetone, the tert-butyl alcohol and TBME, wherein preferred solvent are acetone；Reaction temperature
Selected from -20 DEG C~60 DEG C, wherein preferable temperature is 0 DEG C~20 DEG C.
A kind of ticagrelor midbody compound（9）Preparation method, it is characterised in that：Compound（8）Protected through double hydroxyls
Compound is made in shield reaction（9）, it is as follows the step of reaction：
。
A kind of ticagrelor midbody compound（10）Preparation method, it is characterised in that：Compound（9）Replace through hydroxyl
Compound is made in reaction（10）, it is as follows the step of reaction：
。
A kind of ticagrelor（1）Preparation method, it is characterised in that：Final compound（10）Obtained through hydroxyl deprotection reaction
To ticagrelor（1）, it is as follows the step of reaction：
The invention provides a kind of new method of synthesis ticagrelor, compared with prior art, its remarkable advantage is：Should
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 4
Under nitrogen protection, under the conditions of 0 DEG C, 178g is added into 5L four round flask（1.05 mol）Compound（3）
With 123g (1.1mol) potassium tert-butoxides in the anhydrous DMA of 2L, control temperature is no more than 5 DEG C, stirs and delays after 1 hour after adding
It is slow to add 190g compounds（2）, 50 DEG C or so are warming up to, TLC monitoring reactions, reaction terminates after 5 hours, is down to room temperature, slowly
Add 2L water, stirring and crystallizing, filtering, filter cake washs with 1L TBME, through dry intermediate（4）317g.
Mass yield is 167%, HPLC detection purity：99.02%.
1H NMR (500 MHz, DMSO-d6) δ 13.62 (s, 1H), 7.59 (s, 1H), 7.50 – 6.92
(m, 3H), 3.55 – 3.45 (m, 1H), 2.06 – 1.95 (m, 1H), 0.77 – 0.55 (m, 2H).
ESI+ [M+H]+=323.
Embodiment 2
The preparation of compound 5
Under a nitrogen atmosphere, under the conditions of 0 DEG C, reaction dissolvent anhydrous DMA 1L and 81 g are added into 2L four round flask
N-propyl mercaptan（1.07 mol）, the g of potassium tert-butoxide 132 (1.2 mol) is slowly added to, compound is slowly added dropwise after stirring half an hour
（4）315 g (0.98 mol), are warming up to 50 DEG C or so, TLC monitoring reactions, reaction terminates after 2 hours, is down to room temperature after adding,
1L water is slowly added to, stirring and crystallizing, filtering, filter cake is washed with 500 mL TBME, through dry intermediate（5）337.9g.
Mass yield is 107%, HPLC detection purity：99.21%.
1H NMR (500 MHz, DMSO-d6) δ 13.58 (s, 1H), 7.59 (s, 1H), 7.33 – 6.83
(m, 3H), 3.47 – 3.36 (m, 1H), 2.99 (q, J = 13.2 Hz, 2H), 1.96 – 1.89 (m, 1H),
1.30 (t, J = 13.2 Hz, 3H), 0.77 – 0.55 (m, 2H).
ESI+ [M+H]+=363.
Embodiment 3
The preparation of compound 7
Under a nitrogen atmosphere, at ambient temperature, toward addition reaction dissolvent dry DMF 1L and 335 in 2L four round flask
G compounds（5）（0.96 mol）With 164g compounds（6）（1.15mol）, it is slowly added to the g of palladium catalyst 8.8 (9.6 mmol)
With the g of part 2.4 (19.2 mmol), compound is slowly added dropwise after stirring half an hour（4）315 g (0.98 mol), rise after adding
Warm to 60 DEG C or so, TLC monitoring reactions, reaction terminates after 8 hours, is down to room temperature, is slowly added to 1L water, and stirring and crystallizing is filtered,
Filter cake is washed with 1L TBME, through dry intermediate（7）392.1g.
Mass yield is 117%, HPLC detection purity：99.37%.
1H NMR (500 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.37 – 6.90 (m, 3H), 6.23
(dd, J = 21.5, 12.4 Hz, 1H), 5.81 – 5.44 (m, 2H), 4.92 (dd, J = 26.1, 13.6
Hz, 1H), 4.39 (s, 1H), 3.43 (m, 1H), 2.99 (q, J = 13.2 Hz, 2H), 2.38 (m, 1H),
2.02 – 1.79 (m, 1H), 1.79 – 1.59 (m, 1H), 1.30 (t, J = 13.2 Hz, 3H), 0.57 (m,
2H).
ESI+ [M+H]+=445.
Embodiment 4
The preparation of compound 8
Under the conditions of 0 DEG C, reaction dissolvent acetone 1L, the ML of water 500 and 390 g compounds are added into 5L four round flask
（7）（0.91 mol）, it is slowly added to OsO42.3g（9.1 mmol）,NMO 213g（1.82 mol）With（DHQD）2PHAL
35.4g（45.5 mmol）, stir and 25 DEG C or so be warming up to after half an hour, TLC monitoring reactions, reaction terminates after 18 hours, is down to
Room temperature, uses n-butyl acetate extraction（3*1 L）, merge organic phase, through the compound that is concentrated under reduced pressure to obtain（8）Crude product, crude product is through methanol/water
Recrystallize to obtain intermediate（8）388.9g.
Mass yield is 99.7%, HPLC detection purity：99.58%.
1H NMR (500 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.34 – 6.72 (m, 3H), 5.91
(s, 1H), 4.51 – 3.69 (m, 5H), 3.55 (td, J = 18.9, 14.9 Hz, 1H), 2.99 (q, J =
13.2 Hz, 2H), 2.18 – 1.70 (m, 2H), 1.57 (ddd, J = 24.7, 12.8, 10.6 Hz, 1H),
1.30 (t, J = 13.2 Hz, 3H), 1.07 (b, 1H), 0.67 (m, 2H).
ESI+ [M+H]+=479.
Embodiment 5
The preparation of compound 9
At ambient temperature, toward addition reaction dissolvent ethanol 1L and 385 g compounds in 2L four round flask（8）（0.83
mol）, the g of 2,2- di ethyl propyl ethers 132 (1 mol) and the g of p-methyl benzenesulfonic acid 8 is slowly added to, is warming up to after stirring half an hour
Backflow, TLC monitoring reactions, reaction terminates after 12 hours, is down to room temperature, is washed with saturated aqueous sodium carbonate 500mL, point liquid,
Aqueous phase n-butyl acetate extraction（3*1 L）, merge organic phase, through the compound that is concentrated under reduced pressure to obtain（9）Crude product, crude product is through ethanol/water
Recrystallize to obtain intermediate（9）412.3g.
Mass yield is 107%, HPLC detection purity：99.46%.
1H NMR (500 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.36 – 6.89 (m, 3H), 5.20
(s, 1H), 4.66 (d, J = 35.0 Hz, 2H), 4.07 (s, 1H), 3.54 (s, 1H), 2.99 (s, 2H),
2.48 – 1.50 (m, 3H), 1.30 (s, 3H), 1.21 (s, 6H), 1.07 (b, 1H), 0.76 (m, 2H).
ESI+ [M+H]+=519.
Embodiment 6
The preparation of compound 10
Under nitrogen protection, under the conditions of 0 DEG C, 410g is added into 5L four round flask（0.81 mol）Compound（9）
With 95g (0.85mol) potassium tert-butoxides in 2L dry DMFs, control temperature is no more than 5 DEG C, stirs and delays after 1 hour after adding
It is slow to add 231g iodide（0.85 mol）, 50 DEG C or so are warming up to, TLC monitoring reactions, reaction terminates after 2 hours, is down to room
Temperature, is slowly added to 2L water, stirring and crystallizing, and filtering, filter cake is washed with 1L TBME, through dry intermediate（10）504.4g.
Mass yield is 123%, HPLC detection purity：99.77%.
1H NMR (500 MHz, DMSO ) δ 7.59 (s, 1H), 7.29 – 6.95 (m, 3H), 5.12
(td, J = 17.4, 3.1 Hz, 1H), 4.77 – 4.41 (m, 2H), 4.41 – 4.20 (m, 3H), 3.66
(t, J = 14.4 Hz, 2H), 3.26 (q, J = 19.2 Hz, 1H), 2.99 (q, J = 13.2 Hz, 2H),
2.24 – 1.62 (m, 3H), 1.42 (s, 9H), 1.30 (t, J = 13.2 Hz, 3H), 1.21 (s, 6H),
0.73 – 0.47 (m, 2H).
ESI+ [M+H]+=663.
Embodiment 1
The preparation of ticagrelor 1
Under nitrogen protection, under the conditions of 0 DEG C, 500g is added into 5L four round flask（0.77 mol）Compound（10）
With 2 L methanol, aqueous hydrochloric acid solution is slowly added to（2M）200mL, control temperature is no more than 5 DEG C, is warmed to room temperature after adding, TLC prisons
Control reaction, reaction terminates after 2 hours, and be concentrated under reduced pressure to obtain ticagrelor（1）Crude product, crude product recrystallizes smart through TBME/ n-hexanes
Product 391.1g.
Mass yield is 78.2%, HPLC detection purity：99.96%.
NMRδH (d6-DMSO): 8.95 (d, 1H), 7.39-7.21 (m, 2H), 7.10-7.00 (m, 1H),
5.12 (d, 1H), 5.05 (d, 1H), 4.96 (q, 1H), 4.62-4.54 (m, 2H), 3.95 (brs, 1H),
3.79-3.73 (m, 1H), 3.55-3.47 (m, 4H), 3.20-3.13 (m, 1H), 2.98-2.81 (m, 2H),
2.63 (d, 1H), 2.29-2.21 and 2.16-2.09 (m, 1H), 2.07-2.00 (m, 1H), 1.73-1.33
(m, 4H), 0.99 (t, 3H).
ESI+ [M+H]+=523.
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
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 (10)
1. a kind of synthesis type（1）The method of compound ticagrelor intermediate, it is characterised in that：First by compound（2）And chemical combination
Thing（3）It is substituted reaction and compound is made（4）；The compound（4）Compound is made in substitution reaction through mercaptan（5）；Chemical combination
Thing（5）And compound（6）Compound is made in via palladium-catalyzed asymmetric allylic substitution reaction（7）；Compound（7）Through asymmetric
Compound is made in dihydroxylation（8）；Compound（8）Compound is made through the reaction of double hydroxyl protections（9）；Compound（9）Through
Compound is made in hydroxyl substitution reaction（10）；Final compound（10）Ticagrelor is obtained through hydroxyl deprotection reaction（1）, its is anti-
Answer formula as follows：
。
2. a kind of midbody compound of ticagrelor（4）Preparation method, comprise the following steps：By compound（2）And chemical combination
Thing（3）It is substituted reaction and compound is made（4）, reaction equation is as follows：
；
Preferably, compound（2）The solvent of reaction is selected from anhydrous THF, absolute ether, dry toluene, anhydrous dimethyl benzene, anhydrous two
Chloromethanes is anhydrous, the one or more in 2- methyltetrahydrofurans, anhydrous DMSO, anhydrous DMA, dry DMF and anhydrous TBME, its
Middle preferred solvent is anhydrous DMA.
3. a kind of ticagrelor midbody compound（5）Preparation method, it is characterised in that：Compound（4）Substitution through mercaptan
Compound is made in reaction（5）, it is as follows the step of reaction：
；
Preferably, reaction dissolvent be selected from anhydrous THF, absolute ether, dry toluene, anhydrous dimethyl benzene, anhydrous methylene chloride it is anhydrous,
One or more in 2- methyltetrahydrofurans, anhydrous DMSO, anhydrous DMA, dry DMF and anhydrous TBME, wherein preferred solvent
For anhydrous DMA.
4. a kind of ticagrelor midbody compound（7）Preparation method, it is characterised in that：Compound（5）And compound（6）Through
Compound is made in the asymmetric allylic substitution reaction of palladium chtalyst（7）, it is as follows the step of reaction：
。
5. the preparation method as shown in claim 4, it is characterised in that:Reaction dissolvent is selected from anhydrous THF, absolute ether, anhydrous
Toluene, anhydrous dimethyl benzene, anhydrous methylene chloride are anhydrous, 2- methyltetrahydrofurans, anhydrous DMSO, anhydrous DMA, dry DMF and nothing
One or more in water TBME, wherein preferred solvent are dry DMF；Reaction temperature is selected from 0 DEG C~100 DEG C, wherein it is preferred that temperature
Spend for 60 DEG C~80 DEG C；Catalysts are selected from Pd (PPh3)4, Pd2(dba)3, [Pd(allyl)Cl]2, Pd(OAc)2With
PdCl2In one or more, wherein preferred catalyst be Pd2(dba)3；Part is selected from PPh3, dba, P(OEt)3, P (rings
Hexyl)3, P (tert-butyl group)3, P (p-methylphenyl)3, P (3,5- xylyl)3, P (to fluoroform phenyl)3With P (OMe)3In
One or more, wherein it is preferred that P (OMe)3；The ratio of catalyst and part is 1:2.
6. a kind of ticagrelor midbody compound（8）Preparation method, it is characterised in that：Compound（7）Through asymmetric pair of hydroxyl
Compound is made in glycosylation reaction（8）, it is as follows the step of reaction：
。
7. the preparation method as shown in claim 6, it is characterised in that:Reaction dissolvent be selected from THF, ether, toluene, dimethylbenzene,
One or more in dichloromethane, 2- methyltetrahydrofurans, DMSO, DMA, DMF, acetone, the tert-butyl alcohol and TBME, wherein it is preferred that
Solvent is acetone；Reaction temperature is selected from -20 DEG C~60 DEG C, and wherein preferable temperature is 0 DEG C~20 DEG C.
8. a kind of ticagrelor midbody compound（9）Preparation method, it is characterised in that：Compound（8）Through double hydroxyl protections
Compound is made in reaction（9）, it is as follows the step of reaction：
。
9. a kind of ticagrelor midbody compound（10）Preparation method, it is characterised in that：Compound（9）It is anti-through hydroxyl substitution
Compound should be made（10）, it is as follows the step of reaction：
。
10. a kind of ticagrelor（1）Preparation method, it is characterised in that：Final compound（10）Obtained through hydroxyl deprotection reaction
To ticagrelor（1）, it is as follows the step of reaction：
。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107513070A (en) * | 2017-09-28 | 2017-12-26 | 淮阴工学院 | A kind of synthetic method of compound ticagrelor and its intermediate of synthesis |
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| CN103288836A (en) * | 2013-06-27 | 2013-09-11 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor |
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| CN1270590A (en) * | 1997-07-22 | 2000-10-18 | 英国阿斯特拉药品有限公司 | Novel compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107513070A (en) * | 2017-09-28 | 2017-12-26 | 淮阴工学院 | A kind of synthetic method of compound ticagrelor and its intermediate of synthesis |
| CN107513070B (en) * | 2017-09-28 | 2019-09-20 | 淮阴工学院 | A kind of synthetic method of compound ticagrelor and its intermediate of synthesis |
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