CN104003943A - Preparation method for ticagrelor intermediate - Google Patents
Preparation method for ticagrelor intermediate Download PDFInfo
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- CN104003943A CN104003943A CN201410187498.7A CN201410187498A CN104003943A CN 104003943 A CN104003943 A CN 104003943A CN 201410187498 A CN201410187498 A CN 201410187498A CN 104003943 A CN104003943 A CN 104003943A
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- YWQHBNWCKUPZOT-MTBQWSTDSA-N CCCSc(nc1N[C@H](C2)[C@@H]2c(cc2F)ccc2F)nc(C)c1/N=N\N[C@H](C[C@H](CCCO)[C@H]1O)[C@@H]1O Chemical compound CCCSc(nc1N[C@H](C2)[C@@H]2c(cc2F)ccc2F)nc(C)c1/N=N\N[C@H](C[C@H](CCCO)[C@H]1O)[C@@H]1O YWQHBNWCKUPZOT-MTBQWSTDSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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Abstract
A disclosed preparation method for a ticagrelor intermediate comprises the following steps: (1) preparation of an intermediate I; (2) preparation of an intermediate II; and (3) preparation of the ticagrelor intermediate 4,6-dichloro-5-nitro-2-propylthiopyrimidine. The beneficial effects comprise that the technological method is short in route, easy and practicable in operation, small in environment pollution and applicable to large-scale industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of ticagrelor intermediate.
Background technology
Ticagrelor (Ticagrelor) Shi You U.S.'s AstraZeneca (AstraZeneca) company research and development a kind of novel, there is optionally small molecules anticoagulant.On December 31st, 2010, the Initial Public Offering of ticagrelor Pian Britain; After this in European countries' listings such as Germany, Denmark, trade(brand)name is Brilique.On July 20th, 2011, U.S. FDA approval listing.Its chemical name is: (1
s,2
s,3
r, 5S)-3-[7-[(1
r,2
s)-2-(3,4-difluorophenyl) cyclopropylamino]-5-(thiopropyl)-3
h-[1,2,3] triazoles [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1,2-glycol.Structure is as follows:
Ticagrelor, as novel platelet aggregation inhibitor, is the active medicine that does not need liver to activate, and acts on initial fast; And the combination of itself and platelet receptor is reversible, this reduction for Acute Coronary Syndrome Patients hemorrhage risk is very useful; In to the patient of clopidogrel low reaction, ticagrelor has validity; In the bleeding problems of following in antithrombotic therapy process, comparing with clopidogrel, there is not the increase of profuse bleeding in ticagrelor treatment, has just caused some non-CABG hemorrhage and fatal increase of intracranialing hemorrhage of being correlated with; Although the generation of other untoward reactions (comprising the increase of expiratory dyspnea, ventricle intermittence and serum uric acid and creatinine level etc.) has also been followed in ticagrelor treatment, but the generation major part of these untoward reactions is of short duration, patient can tolerate, and can stop by therapy discontinued.Obviously, ticagrelor is a very promising medicine, has good Clinical efficacy and reasonably security, to the Antiplatelet therapy of ACS, will have a huge impact.Percutaneous coronary intervention (pci) (PCI) guide of China in 2012 is the recommendation medicine using ticagrelor as ACS patient's Antiplatelet therapy, 4,6-bis-chloro-5-nitro-2-rosickyite yl pyrimidines (as follows)
It is the synthetic important intermediate of ticagrelor.Patent WO97/03084 has openly reported 4 first, the synthetic route of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines, this patent report 4,6-dihydroxyl-2-mercaptopyrimidine is raw material, dock with halogenopropane is 4,6-dihydroxyl-2-rosickyite yl pyrimidines, then obtain the chloro-5-nitro-2-of 4,6-bis-rosickyite yl pyrimidines through nitric acid nitrating and hydroxy chloride generation.Subsequently, also to have carried out with 4,6-dihydroxyl-2-mercaptopyrimidine be that raw material carries out synthetic route report for patent WO98/28300, WO90/05142 and WO2011017108.In this synthetic route, need to use strong acid and strong acylating reagent, the industrial effluent producing is many, and environmental pollution is large, is unfavorable for large-scale commercial production.And in patent WO2011101740, reported that take diethyl malonate and thiocarbamide is raw material, cyclization is after 4,6-dihydroxyl-2-mercaptopyrimidine to be 4,6-dihydroxyl-2-rosickyite yl pyrimidines with docking with halogenopropane, through nitric acid nitrating and hydroxy chloride generation, obtain 4 again, the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines, but this route is longer, also produces more industrial effluent, environmental pollution is large, is also unfavorable for large-scale commercial production.Therefore, need a kind of new technical scheme to address the above problem.
Summary of the invention
The invention provides a kind of preparation method who operates easy row, pollutes little ticagrelor intermediate.
The technical solution used in the present invention: a kind of preparation method of ticagrelor intermediate comprises the following steps:
(1) preparation of intermediate I: raw material 2-nitro diethyl malonate and thiocarbamide are added in solvent, solvent is methyl alcohol, ethanol or tetrahydrofuran (THF), add again highly basic, highly basic is sodium methylate, sodium ethylate, sodium tert-butoxide or potassium tert.-butoxide, it is intermediate I that raw material cyclization under highly basic effect becomes pyrimidine ring product, and the structure of intermediate I is as follows:
。
(2) preparation of intermediate II: intermediate I is added in solvent, solvent is water, methyl alcohol, ethanol or tetrahydrofuran (THF), add again highly basic and halogenopropane, highly basic is sodium hydroxide, potassium hydroxide or sodium tert-butoxide, halogenopropane is iodopropane or N-PROPYLE BROMIDE, and under highly basic effect, intermediate I is docked with halogenopropane, obtains 4,6-dihydroxyl-2-rosickyite yl pyrimidines is intermediate II, and the structure of described intermediate II is as follows:
。
(3) ticagrelor intermediate is 4; the preparation of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines: will add in solvent in intermediate II; solvent is methylene dichloride or toluene; add again alkali and acylating reagent; alkali is salt of wormwood, triethylamine, DIPEA or pyridine; acylating reagent is thionyl chloride, oxalyl chloride or phosphorus oxychloride; intermediate II is reacted and is obtained 4 with acylating reagent under alkali effect; the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines; described 4, the structure of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines is as follows:
。
Said process can summarize and be:
。
Beneficial effect of the present invention: this processing method route is brief, operation is easily gone, and environmental pollution is little, is suitable for large-scale industrial production.
Embodiment
Embodiment 1
The preparation of intermediate I: add 31.1g thiocarbamide (0.41mol in reaction flask, 1.2eq), 70.0g 2-nitro diethyl malonate (0.34mol, 1.0eq) with 500mL methyl alcohol, be heated with stirring to back flow reaction, slowly drip 300mL sodium methylate (36.7g, 0.68mol, 2.0eq) methanol solution; Drip and finish, keep back flow reaction, TLC detection reaction; React complete, be cooled to room temperature, with hydrochloric acid, adjust pH value closely acid, suction filtration, uses water rinse filter cake, dries, and obtains 55.5g off-white color solid, yield: 86%.
The preparation of intermediate II: add successively sodium hydroxide solution and the 80mL methyl alcohol of 40g intermediate I (0.21mol, 1.0eq) and 130g 10% in reaction flask, stir, drip 54.4g iodopropane (0.32mol, 1.5eq); Dropwise at room temperature reaction, TLC detection reaction; React complete, with hydrochloric acid, adjust pH value to acid, have solid to separate out, suction filtration, uses water rinse filter cake, dries, and obtains 36.6g off-white color solid phase prod, yield: 75%.
4, the preparation of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines: add 34g intermediate II (0.15mol in reaction flask, 1.0eq) with 109.4g phosphorus oxychloride (0.72mol, 4.5eq), stir the lower 58.1g of dropping DIPEA(0.45mol, 3.0eq), dropwise, be heated with stirring to back flow reaction, TLC monitors reaction; React complete, reaction solution is poured in 500mL mixture of ice and water, toluene for reaction solution (100mL * 3) extracts, merge organic phase, organic phase is respectively with 150mL water, 150mL sodium hydrogen carbonate solution and the washing of 150mL saturated common salt, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure solvent, obtains 34.4g oily matter product, yield: 88%.
Embodiment 2
The preparation of intermediate I: add 26.7g thiocarbamide (0.35mol in reaction flask, 1.2eq), 60.0g 2-nitro diethyl malonate (0.29mol, 1.0eq) with 400mL dehydrated alcohol, be heated with stirring to back flow reaction, slowly drip 200mL sodium ethylate (39.4g, 0.58mol, 2.0eq) methanol solution; Drip and finish, keep back flow reaction, TLC detection reaction; React complete, be cooled to room temperature, with hydrochloric acid, adjust pH value to acid, suction filtration, uses water rinse filter cake, dries, and obtains 47.0g off-white color solid, yield: 85%.
The preparation of intermediate II: add successively sodium hydroxide solution and the 60mL ethanol of 30g intermediate I (0.16mol, 1.0eq) and 95g 10% in reaction flask, stir, drip 29.0g N-PROPYLE BROMIDE (0.24mol, 1.5eq); Dropwise, be warming up to 45 ℃ of reactions, TLC detection reaction; React complete, with hydrochloric acid, adjust pH value to acid, have solid to separate out, suction filtration, uses water rinse filter cake, dries, and obtains 26.0g off-white color solid phase prod, yield: 71%.
4, the preparation of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines: add 20g intermediate II (0.09mol, 1.0eq), 30.9g thionyl chloride (0.26mol, 3.0eq) and 300mL toluene in reaction flask, stir the lower 27.8g triethylamine (0.26mol, 3.0eq) that drips; Dropwise, be heated with stirring to 85-90 ℃ of reaction, TLC monitors reaction; React complete, reaction solution is poured in 600mL mixture of ice and water, stirred standing separatory, toluene for water layer (200mL * 3) extracts, merge organic phase, organic phase is with using respectively 200mL water, 200mL sodium hydrogen carbonate solution and the washing of 300mL saturated common salt, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure solvent, obtains 19.2g oily matter product, yield: 83%.
Embodiment 3
The preparation of intermediate I: add 21.4g thiocarbamide (0.28mol in reaction flask, 1.2eq), 48g 2-nitro diethyl malonate (0.23mol, 1.0eq) with 300mL tetrahydrofuran (THF), be heated with stirring to back flow reaction, slowly drip 200mL sodium tert-butoxide (44.2g, 0.46mol, 2.0eq) methanol solution; Drip and finish, keep back flow reaction, TLC detection reaction; React complete, be cooled to room temperature, with hydrochloric acid, adjust pH value to acid, suction filtration, uses water rinse filter cake, dries, and obtains 38.9g off-white color solid, yield: 88%.
The preparation of intermediate II: add successively sodium hydroxide solution and the 100mL methyl alcohol of 45g intermediate I (0.23mol, 1.0eq) and 140g 10% in reaction flask, stir, drip 61.8g iodopropane (0.37mol, 1.6eq); Dropwise at room temperature reaction, TLC detection reaction; React complete, with hydrochloric acid, adjust pH value to acid, have solid to separate out, suction filtration, uses water rinse filter cake, dries, and obtains 41.3g off-white color solid phase prod, yield: 77%.
4, the preparation of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines: add 36g intermediate II (0.15mol, 1.0eq), 71.4g sulfur oxychloride (0.6mol, 4.0eq) and 500mL methylene dichloride in reaction flask, stir the lower 35.6g pyridine (0.45mol, 3.0eq) that drips; Dropwise, be heated with stirring to 85-90 ℃ of reaction, TLC monitors reaction; React complete, reaction solution is poured in 600mL mixture of ice and water, stirred standing separatory, toluene for water layer (300mL * 3) extracts, merge organic phase, organic phase is with using respectively 300mL water, 300mL sodium hydrogen carbonate solution and the washing of 300mL saturated common salt, anhydrous sodium sulfate drying, suction filtration, evaporated under reduced pressure solvent, obtains 35g oily matter product, yield: 84%.
Beneficial effect: this processing method route is brief, operation is easily gone, and environmental pollution is little, is suitable for large-scale industrial production.
Claims (9)
1. a preparation method for ticagrelor intermediate, is characterized in that this preparation method comprises the following steps:
(1) preparation of intermediate I: raw material 2-nitro diethyl malonate and thiocarbamide are added in solvent, then add highly basic, to become pyrimidine ring product be intermediate I in cyclization under highly basic effect, and the structure of described intermediate I is as follows:
(2) preparation of intermediate II: intermediate I is added in solvent, add highly basic and halogenopropane, under highly basic effect, intermediate I is docked with halogenopropane, obtains 4 again, 6-dihydroxyl-2-rosickyite yl pyrimidines is intermediate II, and the structure of described intermediate II is as follows:
(3) ticagrelor intermediate is 4; the preparation of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines: intermediate II is added in solvent; add again alkali and acylating reagent; intermediate II is reacted and is obtained 4 with acylating reagent under alkali effect; the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines; described 4, the structure of the chloro-5-nitro-2-of 6-bis-rosickyite yl pyrimidines is as follows:
。
2. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the solvent described in step (1) is methyl alcohol, ethanol or tetrahydrofuran (THF).
3. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the highly basic described in step (1) is sodium methylate, sodium ethylate, sodium tert-butoxide or potassium tert.-butoxide.
4. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the solvent described in step (2) is water, methyl alcohol, ethanol or tetrahydrofuran (THF).
5. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the highly basic described in step (2) is sodium hydroxide, potassium hydroxide or sodium tert-butoxide.
6. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the halogenopropane described in step (2) is iodopropane or N-PROPYLE BROMIDE.
7. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the solvent described in step (3) is methylene dichloride or toluene.
8. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the alkali described in step (3) is salt of wormwood, triethylamine, DIPEA or pyridine.
9. the preparation method of a kind of ticagrelor intermediate according to claim 1, is characterized in that: the acylating reagent described in step (3) is thionyl chloride, oxalyl chloride or phosphorus oxychloride.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089984A (en) * | 2017-04-11 | 2017-08-25 | 荆楚理工学院 | A kind of synthetic method of Ticagrelor |
| CN110256360A (en) * | 2019-06-19 | 2019-09-20 | 浙江科技学院 | A kind of preparation method of chloro- 5- nitro -2- (the third sulfydryl)-pyrimidine of 4,6- bis- |
| CN111205232A (en) * | 2020-02-26 | 2020-05-29 | 浙江天宇药业股份有限公司 | Synthesis method of ticagrelor intermediate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068574A (en) * | 1991-04-06 | 1993-02-03 | 菲索斯有限公司 | The preparation method of adenosine triphosphate acid-like substance |
| CN101679426A (en) * | 2007-05-04 | 2010-03-24 | 阿斯利康(瑞典)有限公司 | 9-(pyrazol-3-yl)-9h-purine-2-amine and 3-(pyraz0l-3-yl)-3h-imidaz0[4,5-b]pyridin-5-amine derivatives and their use for the treatment of cancer |
| WO2011101740A1 (en) * | 2010-02-16 | 2011-08-25 | Actavis Group Ptc Ehf | Improved processes for preparing ticagrelor intermediate, 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine |
| CN102659691A (en) * | 2012-05-23 | 2012-09-12 | 山东诚创医药技术开发有限公司 | Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine |
| CN102952084A (en) * | 2012-11-15 | 2013-03-06 | 大连九信生物化工科技有限公司 | Synthesis method of 4, 6-dichloro-2-methylthio-5-nitro pyrimidine |
| CN103288748A (en) * | 2013-06-21 | 2013-09-11 | 四川铂瑞生物医药有限公司 | Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine |
| CN103429576A (en) * | 2010-12-20 | 2013-12-04 | 阿特维斯集团公司 | Novel processes for preparing triazolo[4,5-d]pyrimidine derivatives and intermediates thereof |
| CN103787984A (en) * | 2014-01-26 | 2014-05-14 | 苏州特瑞药业有限公司 | Preparation method of Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine |
-
2014
- 2014-05-06 CN CN201410187498.7A patent/CN104003943A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068574A (en) * | 1991-04-06 | 1993-02-03 | 菲索斯有限公司 | The preparation method of adenosine triphosphate acid-like substance |
| CN101679426A (en) * | 2007-05-04 | 2010-03-24 | 阿斯利康(瑞典)有限公司 | 9-(pyrazol-3-yl)-9h-purine-2-amine and 3-(pyraz0l-3-yl)-3h-imidaz0[4,5-b]pyridin-5-amine derivatives and their use for the treatment of cancer |
| WO2011101740A1 (en) * | 2010-02-16 | 2011-08-25 | Actavis Group Ptc Ehf | Improved processes for preparing ticagrelor intermediate, 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine |
| CN103429576A (en) * | 2010-12-20 | 2013-12-04 | 阿特维斯集团公司 | Novel processes for preparing triazolo[4,5-d]pyrimidine derivatives and intermediates thereof |
| CN102659691A (en) * | 2012-05-23 | 2012-09-12 | 山东诚创医药技术开发有限公司 | Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine |
| CN102952084A (en) * | 2012-11-15 | 2013-03-06 | 大连九信生物化工科技有限公司 | Synthesis method of 4, 6-dichloro-2-methylthio-5-nitro pyrimidine |
| CN103288748A (en) * | 2013-06-21 | 2013-09-11 | 四川铂瑞生物医药有限公司 | Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine |
| CN103787984A (en) * | 2014-01-26 | 2014-05-14 | 苏州特瑞药业有限公司 | Preparation method of Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine |
Non-Patent Citations (1)
| Title |
|---|
| 吴倩倩，等: "2-丙硫基-4,6-二氯-5-氨基嘧啶的合成", 《中国医药工业杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089984A (en) * | 2017-04-11 | 2017-08-25 | 荆楚理工学院 | A kind of synthetic method of Ticagrelor |
| CN110256360A (en) * | 2019-06-19 | 2019-09-20 | 浙江科技学院 | A kind of preparation method of chloro- 5- nitro -2- (the third sulfydryl)-pyrimidine of 4,6- bis- |
| CN110256360B (en) * | 2019-06-19 | 2020-09-15 | 浙江科技学院 | Preparation method of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine |
| CN111205232A (en) * | 2020-02-26 | 2020-05-29 | 浙江天宇药业股份有限公司 | Synthesis method of ticagrelor intermediate |
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Application publication date: 20140827 |