CN104788458A - Preparation method of ticagrelor - Google Patents
Preparation method of ticagrelor Download PDFInfo
- Publication number
- CN104788458A CN104788458A CN201510125844.3A CN201510125844A CN104788458A CN 104788458 A CN104788458 A CN 104788458A CN 201510125844 A CN201510125844 A CN 201510125844A CN 104788458 A CN104788458 A CN 104788458A
- Authority
- CN
- China
- Prior art keywords
- ethyl acetate
- compound
- ticagrelor
- solvent
- mixed solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of ticagrelor, and belongs to the technical field of ticagrelor. The preparation method comprises the following steps: using 2-[(3aR,4S,6R,6aS)-6-[5-amino-6-chloro-2-(propysulfenyl)pyrimidin-4-amino]-2,2-methyltetrahydro-3aH-cyclopentyl[d][1,3]benzodioxo-4-oxy]ethanol (I), and adopting a one-pot method to prepare a (1S,2S,3R,5S)-3-[7-chloro-5-(propylthiooxypyridine)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol compound (II), and then preparing ticagrelor (III) from the compound (II). The preparation method of ticagrelor disclosed by the invention is simple in synthetic operation, high in yield, low in cost, good in stability of the intermediate, and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of ticagrelor, particularly relate to from 2-[(3aR, 4S, 6R, 6aS)-6-[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-ammonia]-2, 2-methyl tetrahydrochysene-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol (I) adopt " one kettle way " preparation (1S, 2S, 3R, 5S)-3-[the chloro-5-of 7-(propylthiouracil)-3H-[1, 2, 3]-triazole [4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1, 2-glycol (II), again from (1S, 2S, 3R, 5S)-3-[the chloro-5-of 7-(propylthiouracil)-3H-[1, 2, 3]-triazole [4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1, 2-glycol (II) prepares the method for ticagrelor (III), belong to ticagrelor technical field.
Background technology
Ticagrelor (Ticagrelor) be researched and developed by AstraZeneca (AstraZeneca) company a kind of novel there is optionally small molecules anticoagulant.This medicine can purinoceptor 2 (purinoceptor 2 reversibly on vasoactive smooth muscle cell (VSMC), P2) hypotype P2Y12, obvious restraining effect is had to the platelet aggregation that adenosine diphosphate (ADP) causes, and it is rapid to orally use rear onset, effectively can improve the symptom of acute coronary patient.Ticagrelor is reversible inhibitor to P2Y12 acceptor, so for those need the patient of row operation be particularly applicable again after carrying out anticoagulant therapy in advance.
Ticagrelor, chemistry (1S, 2S, 3R by name, 5S)-3-[7-{ [(1R, 2S)-2-(3,4-difluorobenzene) cyclopropyl] amino-5-(propylthiouracil)-3H-[1,2,3]-triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1,2-glycol, its structural formula is:
The synthetic route of ticagrelor and the existing a lot of report of preparation method, find after analyzing published synthetic route and preparation method, although route is different, its process is reacted by the different chemical of following three intermediate A, B and C mostly, differential responses order and different linking mode prepare ticagrelor.
The synthetic route of patent WO97/03084, WO99/05142, WO2000/34283 and WO2012/138981 is:
The synthetic method of patent WO2001/36421, WO2001/36438WO2001/92263 and WO2011/017108 is the introducing of the 2-ethanol functional group first completed in five-ring, condensation reaction is there is again with dichloro substituted pyrimidines amine (intermediate A), after diazotization ring closure reaction, with intermediate B generation substitution reaction, finally obtain ticagrelor.Patent WO2012/139455 and CN102675321 considers the side reaction that 2-ethanol functional group may exist in subsequent reactions in addition, is thus first protected by its hydroxyl, then carries out amine substitution reaction, finally generate ticagrelor by deprotection again.
Patent WO2012/172426 then considers the side reaction that 2-ethanol functional group may exist in subsequent reactions, selects first on five-ring, to retain methyl acetate functional group, after the link completing three intermediates, finally ester group is reduced into alcohol.
Patent WO2013/037942, WO2012/085665 and EP2570405 then have adjusted the response hierarchy of three intermediates; first there is condensation reaction in intermediate A and B; with intermediate C, condensation reaction occurs again, after eventually passing ring closure reaction, Deprotection obtains ticagrelor again.
Patent CN102311437 proposes another kind of synthesis thinking, under the effect of triphenylphosphine and diethylazodicarboxylate, coupling is realized by the hydroxyl on five-ring and the nitrogen-atoms on triazole, but due to the directivity of triazole ring, make the more difficult control of coupling position.
In sum; the document of preparing of published ticagrelor all carries out around the preparation of three important intermediate (A, B and C), protection, link and reaction up to now; but which no matter is taked-all there is the intermediate of oily in kind of synthetic route; poor stability; apt to deteriorate; be unfavorable for the shortcomings such as long-time storage, the unstable of intermediate brings drawback to large-scale industrial production ticagrelor.Therefore, seek new preparation method can prepare ticagrelor more simple and conveniently, the development for the economic technology of this bulk drug is most important.
Summary of the invention
The technical problem to be solved in the present invention overcomes the deficiencies in the prior art, and provide a kind of synthesis step simple, processing ease, productive rate is high, and cost is low, is applicable to the preparation method of industrial ticagrelor.
The technical scheme that the technical problem to be solved in the present invention adopts is, a kind of preparation method of ticagrelor, specifically by 2-[(3aR, 4S, 6R, 6aS)-6-amino-2, 2-dimethyl tetrahydro-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol succinate, 2-rosickyite base-4, 6-bis-chlorine-5-amido pyrimidine and (1R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine hydrochloride prepares ticagrelor, wherein have employed " one kettle way " and synthesize important intermediate (1S, 2S, 3R, 5S)-3-[the chloro-5-of 7-(propylthiouracil)-3H-[1, 2, 3]-triazole [4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1, 2-diol intermediates (II), good stability, be conducive to long-time storage, again by the direct synthetic compound (1S of intermediate II, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3, 4-difluorobenzene) cyclopropyl] amino-5-(propylthiouracil)-3H-[1, 2, 3]-triazole [4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1, 2-glycol (III), i.e. ticagrelor, simple to operate, productive rate is high.Comprise the following steps:
(1) at the temperature of 90 DEG C-110 DEG C, with 2-[(3aR, 4S, 6R, 6aS)-6-amino-2, 2-dimethyl tetrahydro-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol succinate and 2-rosickyite base-4, 6-bis-chlorine-5-amido pyrimidine is raw material, with N, N-diisopropylethylamine, triethylamine or N, N-dimethylcyclohexylamine is organic bases, react in a solvent, described solvent is 1, 4-dioxane, or toluene, or Virahol and 1, 4-dioxane mixed solvent, or Virahol and toluene Mixed Solvent, acetonitrile and 1, 4-dioxane mixed solvent, or the mixed solvent of acetonitrile and toluene, reaction times is 16-20 hour, then recrystallization, the mixed solution that the solvent that recrystallization uses is ethyl acetate and normal heptane, or the mixed solution of ethyl acetate and sherwood oil, or the mixed solution of ethyl acetate and normal hexane, or the mixed solution of tetrahydrofuran (THF) and normal heptane, or the mixed solution of tetrahydrofuran (THF) and normal hexane, or the mixed solution of tetrahydrofuran (THF) and sherwood oil, obtain compound (I) compound 2-[(3aR, 4S, 6R, 6aS)-6-[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-ammonia]-2, 2-methyl tetrahydrochysene-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol,
The structural formula of Compound I is:
Described recrystallization method is: preferably use ethyl acetate and normal hexane.
(2) under 0 DEG C to room temperature, by compound 2-[(3aR, 4S, 6R, 6aS)-6-[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-ammonia]-2, 2-methyl tetrahydrochysene-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol and compound (I) and strong acid with amount of substance than 1:(20-40) mix, wherein be added dropwise to the aqueous solution being equivalent to 6-20 equivalent Sodium Nitrite mutually, add methyl alcohol, ethanol, acetonitrile, methanol aqueous solution, aqueous ethanolic solution or acetonitrile solution are as reaction solvent, " one kettle way " is adopted to react 1-2 hour, adjust pH=6-7, then recrystallization, recrystallization uses methanol aqueous solution, aqueous ethanolic solution, acetonitrile solution, the mixing solutions of ethyl acetate and normal heptane, the mixing solutions of ethyl acetate and sherwood oil, the mixing solutions of ethyl acetate and normal hexane, the mixing solutions of tetrahydrofuran (THF) and normal heptane, the mixing solutions of the mixing solutions of tetrahydrofuran (THF) and normal hexane or tetrahydrofuran (THF) and sherwood oil, obtain Compound II per,
The structural formula of Compound II per is:
Described strong acid is concentrated hydrochloric acid, and its molar equivalent is equivalent to 20-40 times of equivalent of compound (I).
Described diazo reagent is Sodium Nitrite, and its molar equivalent is equivalent to 6-20 times of equivalent of compound (I).
Described reaction solvent particular methanol.
Described temperature of reaction be 0 DEG C to room temperature, preferably 0 DEG C.
Described recrystallization ethyl acetate and normal hexane.
(3) at the temperature of room temperature to 40 DEG C, by compound (II) and (1R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine hydrochloride, with amount of substance than 1:(1.1-1.5) mixing, add the triethylamine being equivalent to 2-3 equivalent, N, N-diisopropylethylamine or N, N-dimethylcyclohexylamine is as organic bases, with Virahol, 1, 4-dioxane or Virahol and 1, the mixed solvent of 4-dioxane is as reaction solvent, reaction 1-2 hour, use the aqueous solution cancellation reaction of ammonium chloride, and adjust pH to be neutral, use the mixed solution of ethyl acetate and sherwood oil, the mixed solution recrystallization of the mixed solution of ethyl acetate and normal hexane or ethyl acetate and normal heptane, filter to obtain compound III, i.e. ticagrelor,
The structural formula of compound III is:
Described organic bases is triethylamine or DIPEA or N, N-dimethylcyclohexylamine, and its equivalent is 2-3 equivalent.
Described temperature of reaction is room temperature to 40 DEG C, preferably 25 DEG C-30 DEG C.
Described solvent is the mixed solvent of Virahol or Isosorbide-5-Nitrae-dioxane or Virahol and Isosorbide-5-Nitrae-dioxane, preferred Virahol.
Described recrystallization method is ethyl acetate and sherwood oil or ethyl acetate and normal hexane or ethyl acetate and normal heptane recrystallization, ethyl acetate and normal hexane.
The synthetic route chemical equation of the present invention is as follows:
In the synthetic route of the present invention, have employed " one kettle way " and synthesized Compound II per, simplify synthesis step, reaction conditions is simple, and easy to operate, the reaction times is short, and aftertreatment is easy, can the high product of the acquisition purity of high yield; And Compound II per is compound as white solid, good stability, is conducive to long preservation.The synthesis of compound III (ticagrelor), reaction conditions is simple, and processing ease, transformation efficiency is high, is convenient to obtain highly purified product.
The synthetic method of the ticagrelor of the present invention, synthesis step is simple, and processing ease, productive rate is high, and cost is low, and intermediate good stability, is suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific examples, the present invention is described in further detail, but the present invention is not limited to following examples.
Embodiment 1
Compound 2-[(3aR, 4S, 6R, 6aS)-6-[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-ammonia]-2,2-methyl tetrahydrochysene-3aH-cyclopentyl [d] [1,3] dioxy-4-oxygen] preparation of ethanol (I)
By 2-[(3aR, 4S, 6R, 6aS)-6-amino-2, 2-dimethyl tetrahydro-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol succinate (100.0g, 0.30mol) join 500ml 1, in 4-dioxane, then N is added, N-diisopropylethylamine (193.0g, 1.5mol), add 4 again, the chloro-5-amino of 6-bis--2-rosickyite yl pyrimidines (71.4g, 0.30mol), be heated to 100 DEG C stir 20 hours, TLC monitoring reaction is until 4, the chloro-5-amino of 6-bis--2-rosickyite yl pyrimidines reacts completely, then saturated ammonium chloride solution cancellation reaction is added, then extraction into ethyl acetate separatory is added 2 times, saturated common salt washing organic phase, anhydrous sodium sulfate drying, filter, by organic phase concentrating under reduced pressure, then ethyl acetate and normal hexane recrystallization is used, 40 DEG C of dry white solid 110.2g, yield 89%.
1h NMR (DMSO-d
6, 400MHz): δ (ppm)=0.97 (t, 3H), 1.23 (s, 3H), 1.38 (s, 3H), 1.64-1.66 (m, 2H), 1.88 (d, 1H), 2.21-2.23 (m, 1H), 2.98-3.00 (m, 2H), 3.47-3.49 (m, 1H), 3.51-3.53 (m, 1H), 3.54-3.57 (m, 2H), 3.89 (s, 1H), 4.34 (d, 1H), 4.49 (d, 1H), 4.54 (m, 1H), 4.71 (s, 2H), 4.97 (t, 1H), (6.56 d, 1H).
13c NMR (DMSO-d
6, 100MHz): δ (ppm)=13.21,22.85,23.98,26.31,32.09,32.86,56.55,60.31,70.31,83.16,83.66,84.08,109.98,119.71,138.46,151.91,155.72.HRMS-ESI (m/z) [M+H]
+[C
17h
28clN
4o
4s]
+calculated value 419.1519, detected value 419.1508.
Compound (1S, 2S, 3R, 5S)-3-[the chloro-5-of 7-(propylthiouracil)-3H-[1,2,3]-triazole [4,5-d] pyrimidin-3-yl] preparation of-5-(2-hydroxyethyl) pentamethylene-1,2-glycol (II)
By 2-[(3aR, 4S, 6R, 6aS)-6-[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-ammonia]-2,2-methyl tetrahydrochysene-3aH-cyclopentyl [d] [1,3] and dioxy-4-oxygen] alcohol cpd (I) (78g, 0.19mol) is dissolved in 600ml methyl alcohol, stir under being then placed in 0 DEG C of environment, when to system, temperature reaches 0 DEG C, then be added dropwise to concentrated hydrochloric acid 396ml, dropwise, be then added dropwise to NaNO
2(196.6g) the aqueous solution, dropwises reaction 1 hour, then slowly drips saturated K
2cO
3solution, adjust pH to neutral, then concentrating under reduced pressure, adds extraction into ethyl acetate separatory 2 times, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, filters, removes solvent under reduced pressure, ethyl acetate and normal hexane recrystallization, filter, 40 DEG C of dry white solid 63.7g, yield 86%.
1h NMR (DMSO-d
6, 400MHz): δ (ppm)=1.01 (t, 3H), 1.72-1.77 (m, 2H), 2.11-2.14 (m, 1H), 2.69-2.74 (m, 1H), 3.17-3.34 (m, 2H), 3.47-3.52 (m, 4H), 3.77-3.78 (m, 1H), 3.97-4.16 (m, 1H), 4.59-4.64 (m, 2H), 5.12-5.22 (m, 3H).
13c NMR (DMSO-d
6, 100MHz): δ (ppm)=13.67,22.66,33.34,33.59,55.43,62.47,71.32,75.03,82.18,119.71,132.31,151.20,152.25,170.09.HRMS-ESI (m/z) [M+H]
+[C
14h
21clN
5o
4s]
+calculated value 390.1003, detected value 390.1001.
Compound (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3,4-difluorobenzene) cyclopropyl] amino-5-(propylthiouracil)-3H-[1,2,3]-triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1,2-glycol (III), the i.e. preparation of ticagrelor
By (1S, 2S, 3R, 5S)-3-[the chloro-5-of 7-(propylthiouracil)-3H-[1, 2, 3]-triazole [4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1, 2-glycol (51.0g, 0.13mol) be dissolved in 300ml Virahol, stirring at room temperature, then triethylamine is added, and then add (the 1R of Virahol dissolving, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine hydrochloride (32.1g, 0.156mol), 25 DEG C of stirrings, TLC monitoring reaction is until compound reacts completely, then adding saturated ammonium chloride solution adjusts pH for neutral, concentrating under reduced pressure, then extraction into ethyl acetate separatory is added 2 times, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, ethyl acetate and normal hexane recrystallization, filter, dry white solid 61.9g, yield 91%.
1h NMR (DMSO-d
6, 400MHz): δ (ppm)=0.82 (t, 3H), 1.37-1.39 (m, 1H), 1.50-1.53 (m, 2H), 1.54-1.57 (m, 1H), 2.02-2.05 (m, 1H), 2.12-2.14 (m, 1H), 2.63-2.65 (m, 1H), 2.84-2.86 (m, 1H), 2.95-2.96 (m, 1H), 3.14-3.17 (m, 1H), 3.46-3.49 (m, 2H), 3.50-3.53 (m, 2H), 3.75-3.77 (m, 1H), 3.96 (brs, 1H), 4.55-4.58 (m, 1H), 4.63 (t, 1H), 4.93-4.97 (m, 1H), 5.07 (d, 1H), 5.14 (d, 1H), 7.05-7.08 (m, 1H), 7.33 (brs, 1H), 7.34-7.37 (m, 1H), 9.38 (s, 1H).
13c NMR (DMSO-d
6, 100MHz): δ (ppm)=13.40,15.45,22.72,24.47,32.77,33.67,34.54,60.94,61.02,71.24,74.12,74.79,82.22,115.25,117.46,123.24,123.60,139.76,148.21,149.83,149.86,154.38,169.60.HRMS-ESI (m/z) [M+H]
+[C
23h
29f
2n
6o
4s]
+calculated value 523.1939, detected value 523.1934.
Claims (4)
1. the preparation method of a ticagrelor, it is characterized in that, by 2-[(3aR, 4S, 6R, 6aS)-6-amino-2, 2-dimethyl tetrahydro-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol succinate, 2-rosickyite base-4, 6-bis-chlorine-5-amido pyrimidine and (1R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine hydrochloride prepares ticagrelor, wherein have employed " one kettle way " and synthesize important intermediate (1S, 2S, 3R, 5S)-3-[the chloro-5-of 7-(propylthiouracil)-3H-[1, 2, 3]-triazole [4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1, 2-diol compound (II), again by midbody compound (II) directly synthetic compound (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3, 4-difluorobenzene) cyclopropyl] amino-5-(propylthiouracil)-3H-[1, 2, 3]-triazole [4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyethyl) pentamethylene-1, 2-glycol (III), i.e. ticagrelor, comprise the following steps:
(1) at the temperature of 90 DEG C-110 DEG C, with 2-[(3aR, 4S, 6R, 6aS)-6-amino-2, 2-dimethyl tetrahydro-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol succinate and 2-rosickyite base-4, 6-bis-chlorine-5-amido pyrimidine is raw material, with N, N-diisopropylethylamine, triethylamine or N, N-dimethylcyclohexylamine is organic bases, react in a solvent, described solvent is 1, 4-dioxane, or toluene, or Virahol and 1, 4-dioxane mixed solvent, or Virahol and toluene Mixed Solvent, acetonitrile and 1, 4-dioxane mixed solvent, or the mixed solvent of acetonitrile and toluene, reaction times is 16-20 hour, then recrystallization, the mixed solution that the solvent that recrystallization uses is ethyl acetate and normal heptane, or the mixed solution of ethyl acetate and sherwood oil, or the mixed solution of ethyl acetate and normal hexane, or the mixed solution of tetrahydrofuran (THF) and normal heptane, or the mixed solution of tetrahydrofuran (THF) and normal hexane, or the mixed solution of tetrahydrofuran (THF) and sherwood oil, obtain compound (I) compound 2-[(3aR, 4S, 6R, 6aS)-6-[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-ammonia]-2, 2-methyl tetrahydrochysene-3aH-cyclopentyl [d] [1, 3] and dioxy-4-oxygen] ethanol,
The structural formula of compound (I) is:
(2) under 0 DEG C to room temperature, by compound 2-[(3aR, 4S, 6R, 6aS)-6-[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-ammonia]-2,2-methyl tetrahydrochysene-3aH-cyclopentyl [d] [1,3] dioxy-4-oxygen] ethanol and compound (I) and strong acid with amount of substance than 1:(20-40) mix, be added dropwise to the aqueous solution being equivalent to 6-20 equivalent Sodium Nitrite wherein, then add methyl alcohol, ethanol, acetonitrile, methanol aqueous solution, aqueous ethanolic solution or acetonitrile solution are as reaction solvent, and adopt " one kettle way " to react 1-2 hour, adjust pH=6-7, then recrystallization, recrystallization uses methanol aqueous solution, aqueous ethanolic solution, acetonitrile solution, the mixing solutions of ethyl acetate and normal heptane, the mixing solutions of ethyl acetate and sherwood oil, the mixing solutions of ethyl acetate and normal hexane, the mixing solutions of tetrahydrofuran (THF) and normal heptane, the mixing solutions of the mixing solutions of tetrahydrofuran (THF) and normal hexane or tetrahydrofuran (THF) and sherwood oil, obtains compound (II),
The structural formula of compound (II) is:
(3) at the temperature of room temperature to 40 DEG C, by compound (II) and (1R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine hydrochloride, with amount of substance than 1:(1.1-1.5) mixing, add the triethylamine being equivalent to 2-3 equivalent, N, N-diisopropylethylamine or N, N-dimethylcyclohexylamine is as organic bases, with Virahol, 1, 4-dioxane or Virahol and 1, the mixed solvent of 4-dioxane is as reaction solvent, reaction 1-2 hour, use the aqueous solution cancellation reaction of ammonium chloride, and adjust pH to be neutral, use the mixed solution of ethyl acetate and sherwood oil, the mixed solution recrystallization of the mixed solution of ethyl acetate and normal hexane or ethyl acetate and normal heptane, filter to obtain compound III, i.e. ticagrelor,
The structural formula of compound III is:
2. according to the preparation method of a kind of ticagrelor of claim 1, it is characterized in that, the described recrystallization of step (1) uses ethyl acetate and normal hexane.
3. according to the preparation method of a kind of ticagrelor of claim 1, it is characterized in that, step (2) described strong acid is concentrated hydrochloric acid; Described reaction solvent particular methanol;
Described reaction preferably 0 DEG C; Recrystallization selects the mixed solution of ethyl acetate and normal hexane.
4. according to the preparation method of a kind of ticagrelor of claim 1, it is characterized in that, step (3) described temperature of reaction is 25 DEG C-30 DEG C;
Described solvent Virahol; Recrystallization selects the mixed solution of ethyl acetate and normal hexane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510125844.3A CN104788458A (en) | 2015-03-21 | 2015-03-21 | Preparation method of ticagrelor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510125844.3A CN104788458A (en) | 2015-03-21 | 2015-03-21 | Preparation method of ticagrelor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104788458A true CN104788458A (en) | 2015-07-22 |
Family
ID=53553692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510125844.3A Pending CN104788458A (en) | 2015-03-21 | 2015-03-21 | Preparation method of ticagrelor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104788458A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311560A (en) * | 2014-09-16 | 2015-01-28 | 北京红太阳药业有限公司 | Ticagrelor preparation method |
| CN105669681A (en) * | 2016-04-11 | 2016-06-15 | 成都华宇制药有限公司 | Synthesis method for ticagrelor |
| CN108892670A (en) * | 2018-07-12 | 2018-11-27 | 江西国药有限责任公司 | A kind of preparation method of high-purity ticagrelor |
| CN111848632A (en) * | 2020-09-07 | 2020-10-30 | 河南师范大学 | Preparation method of platelet aggregation inhibitor ticagrelor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| WO2013150495A2 (en) * | 2012-04-05 | 2013-10-10 | Dr. Reddy's Laboratories Limited | Preparation of ticagrelor |
| CN104250251A (en) * | 2013-06-25 | 2014-12-31 | 上海京新生物医药有限公司 | Preparation method for ticagrelor |
-
2015
- 2015-03-21 CN CN201510125844.3A patent/CN104788458A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| WO2013150495A2 (en) * | 2012-04-05 | 2013-10-10 | Dr. Reddy's Laboratories Limited | Preparation of ticagrelor |
| CN104250251A (en) * | 2013-06-25 | 2014-12-31 | 上海京新生物医药有限公司 | Preparation method for ticagrelor |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311560A (en) * | 2014-09-16 | 2015-01-28 | 北京红太阳药业有限公司 | Ticagrelor preparation method |
| CN104311560B (en) * | 2014-09-16 | 2017-04-26 | 北京红太阳药业有限公司 | Ticagrelor preparation method |
| CN105669681A (en) * | 2016-04-11 | 2016-06-15 | 成都华宇制药有限公司 | Synthesis method for ticagrelor |
| CN108892670A (en) * | 2018-07-12 | 2018-11-27 | 江西国药有限责任公司 | A kind of preparation method of high-purity ticagrelor |
| CN111848632A (en) * | 2020-09-07 | 2020-10-30 | 河南师范大学 | Preparation method of platelet aggregation inhibitor ticagrelor |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2882118T3 (en) | Ruxolitinib Synthesis Procedure | |
| CN104788458A (en) | Preparation method of ticagrelor | |
| CN103360396B (en) | Method for preparing ticagrelor | |
| CN103288837B (en) | The preparation method of ticagrelor | |
| CN103992323B (en) | A kind of preparation method of ticagrelor | |
| CN107573333A (en) | The preparation method of intermediate of ticagrelor and preparation method thereof and ticagrelor | |
| CN103539773A (en) | Method for preparing ticagrelor key intermediate | |
| CN1321975C (en) | Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use | |
| CN104250251B (en) | Preparation method for ticagrelor | |
| CN102250016B (en) | Method for preparing 4,5,6-trichloropyrimidine | |
| CN105669681A (en) | Synthesis method for ticagrelor | |
| CN104311560B (en) | Ticagrelor preparation method | |
| CN103304567A (en) | Preparation method of ticagrelor | |
| CN103275056B (en) | Preparation method of ticagrelor midbody | |
| CN103923086B (en) | A kind of preparation method of 5-alkoxyl-1,2,4-triazole [4,3-c] pyrimidine-3 (2H)-thioketone | |
| CN103951669B (en) | Synthesis method of Anagliptin key intermediate | |
| CN100376546C (en) | Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use | |
| CN106279171A (en) | A kind of preparation method of Idelalisib | |
| CN107674079B (en) | Synthesis method of ibrutinib | |
| CN105153167A (en) | Ticagrelor crystal and medicinal composition comprising same | |
| CN110218192A (en) | preparation method of 2-amino-4, 6-dimethoxypyrimidine | |
| CN104844598A (en) | Synthesis method of 8-methoxy ethyl formate imidazole and [1,2a]pyridine-3-ethyl formate | |
| CN102850356B (en) | The preparation method of pyrazolo [3,4-d] pyrimidinamine compound | |
| CN103992319A (en) | Pyridine carboxylic acid compounds and preparation method thereof | |
| CN104311567B (en) | One prepares the method for 4-amino-3-(4-amino-benzene) furo [2,3-d] pyrimidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150722 |
|
| RJ01 | Rejection of invention patent application after publication |