CN104250251B - Preparation method for ticagrelor - Google Patents

Preparation method for ticagrelor Download PDF

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CN104250251B
CN104250251B CN201310256646.1A CN201310256646A CN104250251B CN 104250251 B CN104250251 B CN 104250251B CN 201310256646 A CN201310256646 A CN 201310256646A CN 104250251 B CN104250251 B CN 104250251B
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compound
formula
acid
reaction
ticagrelor
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CN104250251A (en
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黄悦
张涛
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Shanghai Jingxin Biological Medical Co ltd
Shaoxing Jingxin Pharmaceutical Co.,Ltd.
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Shangyu Jingxin Pharmaceutical Co Ltd
SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd
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    • 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

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The invention provides a preparation method for ticagrelor. The method comprises the reaction steps shown in the specification, and concretely comprises the following steps: (1) in the presence of an alkali, coupling a formula II compound with a formula III compound to generate a formula IV compound; (2) under an acidic condition, performing reduction and deprotection on the formula IV compound, so as to obtain a formula V compound; (3) performing diazotization and ring closure on the formula V compound, so as to generate a formula VI compound; and (4) under an alkali condition, coupling the formula VI compound with a formula VII compound, so as to obtain ticagrelor shown as a formula I. The method is mild in reaction conditions and simple in post-treatment, is capable of effectively controlling impurities and improving the optical purity of the product, is suitable for industrialized production and has relatively large application value.

Description

A kind of preparation method of ticagrelor
Technical field
The present invention relates to the preparation of medicine, and in particular to a kind of preparation method of small molecule anti-coagulants ticagrelor.
Background technology
(1S, 2S, 3R, 5S) -3- [7- [(1R, 2S) -2- (3,4- difluorophenyls) cyclopropyl amino] -5- (rosickyite base) -3H- [1,2,3] triazole [4,5-d] and pyrimidin-3-yl] -5- (2- hydroxy ethoxies) cyclopenta -1,2- glycol（Ticagrelor, ticagrelor）, No. CAS is 274693-27-5, with shown in following structural：
Ticagrelor is a kind of new, selective of U.S.'s AstraZeneca (AstraZeneca) company research and development Small molecule anticoagulant.The medicine receptor subtype P2Y12 of purine 2 reversibly on vasoactive smooth muscle cell (VSMC), Ticagrelor is not prodrug, therefore does not need metabolic activation, to adenosine diphosphate (ADP)（ADP）The platelet aggregation for causing has significantly Inhibitory action, and it is rapid to work after orally using, and can be effectively improved the symptom of acute coronary patient.With Thienopyridines medicine Thing（Clopidogrel, prasugrel etc.）Difference, ticagrelor is reversible antagonist to P2Y12ADP acceptors, so for those are needed Again the patient of row operation is especially suitable after anticoagulant therapy is carried out in advance.
Patent WO0034283 of Astrazeneca AB of the U.S. discloses a kind of preparation method of ticagrelor, the method Reaction equation sees below：
The method reaction scheme is longer, and part steps conversion ratio is low, separates difficulty, and portion of reagent is not commercialized or valency Lattice are expensive, in addition, last propylidene protection group is easily caused the part racemization of cyclopropylamine fragment when removing, and isomers is post-processed It is difficult to remove, is unsuitable for industrialized production.
Astrazeneca AB of the U.S. discloses a kind of side of the shorter synthesis ticagrelor of respective routes in WO0192263 again Method：
Because the method is when five-membered ring fragment and pyrimidine fragment are docked, nitro-pyrimidine is changed to into aminopyrimidine, causes ammonia The activity of chlorine atom is substantially reduced on base substituted pyrimidines, needs higher temperature and long period to obtain acceptable conversion Rate, and violent due to reaction condition so that it is more polymictic produce it is inevitable.In addition, the method is finally still needed Removing propylidene base protection under strong acid condition, therefore overcome the defect of WO0034283 methods presence.
Auspex Pharmaceuticals Inc.（Auspex Pharmaceuticals Inc）Patent WO2011017108 In view of defect of the WO0192263 patents when five-membered ring fragment and pyrimidine fragment are docked, again nitro is introduced into pyrimidine ring.Though So reactivity increases,
But reactions steps increase, overall yield of reaction declines.Meanwhile, this method does not still solve asking for strong acid deprotection Topic.
In addition, Chinese patent CN102311437 is disclosed and prolonged using light（Mitsunobu）Reaction, by pyrimido triazole with Five-membered ring hydroxylate is docked, and has effectively been evaded cyclopropylamine and has been docked later strong acid deprotection steps,
But, reagent diethylazodicarboxylate needed for Mitsunobu reactions（DEAD）, triphenylphosphine and thus introduce Triphen phosphine oxide and hydrazine diester compound be difficult to be removed in easy method, therefore, the method is not suitable for industrial production yet.
The content of the invention
The technical problem to be solved is to overcome above-mentioned weak point, and research and design reaction condition is gentle, step Rapid shorter, post processing is simple, can effectively evade product racemization caused by the de- propylidene protection of strong acid, improves optical purity, so as to To impurity effective control, the preparation method of high-optical-purity ticagrelor.
The invention provides a kind of preparation method of ticagrelor.
The inventive method is comprised the following steps：
（1）Formula II compound with formula III compound in the presence of a base, is coupled and generates formula IV compound；
（2）Formula IV compound is reduced in acid condition and deprotection, obtains Formula V compound；
（3）Formula V compound generates Formula IV compound through diazotising and cyclization；
（4）Formula IV compound is coupled in the basic conditions with Formula VII compound, obtains ticagrelor compound of formula I.
In the inventive method, the alkali described in step (1) is selected from one or more of inorganic base or organic base；Alkali and formula III The mol ratio of compound is 1-10:1；Reaction temperature is -20 DEG C -20 DEG C, preferably -10 DEG C -10 DEG C；Solvent is selected from dichloromethane One or more of alkane, tetrahydrofuran or ethanol, preferably dichloromethane；Inorganic base adds reactant in the way of the aqueous solution System, inorganic base is selected from one or several of sodium carbonate, potassium carbonate, NaOH or potassium hydroxide, preferably potassium carbonate；It is organic Alkali is selected from diisopropyl ethyl amine（DIPEA）, triethylamine or 1,8- diazabicylos-bicyclic (5,4,0) -7- hendecenes（DBU） One or more, preferably diisopropyl ethyl amine（DIPEA）, triethylamine.
Step（2）Described acid condition is that the pH value of reaction system is adjusted to into 1-3 with strong acid；Described reduction can be Electronation, may also be catalytic hydrogen reduction；Described strong acid is selected from one or several of hydrochloric acid, sulfuric acid or trifluoroacetic acid, Preferably hydrochloric acid；Described electronation, reducing agent is one or more of iron powder, stannous chloride, zinc powder；Reducing agent and formula IV The mol ratio of compound is 1-10:1；The catalytic hydrogen reduction, using palladium carbon, platinum carbon or Raney Ni as catalyst, catalysis The mass ratio of agent and IV compounds is 5%-10%：1；Reaction temperature is 0 DEG C -100 DEG C；Reaction dissolvent is water or alcohol, described alcohol One or several for methyl alcohol, ethanol or isopropanol.
Step（3）Described diazo-reaction uses inorganic nitroso compound or organic sub-nitrate compound conduct Diazo reagent；Described inorganic nitroso compound selected from natrium nitrosum, potassium nitrite one or more, it is described organic Nitrites compound is selected from one or more of Isopropyl Nitrite or isoamyl nitrite；It is with inorganic nitroso compound During diazo reagent, acid need to be added, add the mole of acid for 1-10 times of Formula V compound, preferably 2-5 times, described acid For acetic acid, nitroso compound is 1-10 with the mol ratio of Formula V compound:1；Reaction temperature is -10 DEG C -20 DEG C；Reaction dissolvent Selected from dichloromethane, toluene, acetonitrile or ethanol one or more, preferably dichloromethane.
During with organic sub-nitrate compound as diazo reagent, the mol ratio of nitrites compound and Formula V compound For 1-10:1；Reaction temperature is 0 DEG C -100 DEG C；Reaction dissolvent is one or more of tetrahydrofuran, dioxane or acetonitrile, excellent Elect as acetonitrile or dioxane one or more.
Step（4）The alkali for using in the basic conditions is organic base or inorganic base；Described organic base is different selected from two Ethylamine（DIPEA）, triethylamine or 1,8- diazabicylos-bicyclic (5,4,0) -7- hendecenes (DBU) one kind or several Kind；Described inorganic base is selected from one or several of sodium carbonate, potassium carbonate, NaOH or potassium hydroxide；Reaction temperature is 0 DEG C -100 DEG C, preferably 0 DEG C -30 DEG C；Reaction dissolvent is selected from the one of toluene, dichloromethane, acetonitrile, tetrahydrofuran or dioxane Plant or several, preferably dichloromethane；The mol ratio of Formula IV and Formula VII compound is 1：1.0-5.0, preferably 1:1.0-2.0； The mol ratio of alkali and Formula VII compound is 1.0-5.0：1.
The effect of the present invention：
（1）Compared with prior art, realize by formula IV compound reduction process while sloughing propylidene blocking group Two steps and a step, diazotising cyclization is then carried out in the presence of nitroso compound, so that reactions steps contract significantly Short, cost is greatly reduced, and is conducive to industrialized realization.
（2）It has surprisingly been found that nitro is reduced in acid condition amino when the present inventor realizes this design, and And, under this acid condition, while slough propylidene protection group, although product Formula V compound is containing more hydrogen bond donor and receives Body, but it is fat-soluble due to itself, and do not occur that inventor worried originally is water-soluble excessive, it is difficult to extraction separation purification Problem.
（3）In diazo process, two adjacent hydroxyls exposed due to deprotection on the pentamethylene base of Formula V compound Base is not only subject to diazotizing impact, and increases solubility of the raw material in water phase so that diazotising and cyclization step Easily occur, yield is higher.In last handling process, due to the removal and exposed, the fat-soluble decline of hydroxyl of protection group, So that Formula IV compound is easily crystallized separating out.
（4）Due to Formula IV compound and (1R, 2S) -2-（3,4- difluorophenyls）Cyclopropylamine（Formula VII）Docking and rear place Reason need not use strong acid, by simple post processing, it is possible to obtain the ticagrelor of high-optical-purity（Specific rotatory power is -61.5 °）.
The inventive method reaction condition is gentle, and post processing is simple, energy effective control impurity, improves the optical purity of product, It is suitable for industrialized production, there is larger using value.
Specific embodiment
First, 2- [((3aR, 4S, 6R, 6aS) -6- { [chloro- 2- of 5- nitro -6-（Rosickyite alkyl）- 4- pyrimidine radicals] amino }- 3aH- tetrahydro cyclopentyls dialkylene simultaneously amyl- 4- yls of [d] [1,3] dioxane) epoxide] -1- ethanol（Formula IV compound）Synthesis
Embodiment 1
Formula II compound is added in 100 milliliters of there-necked flasks（The chloro- 2- of 4,6- bis-（Propyl dithiocarbamate）Pyrimidine -5- amine）（2.68 gram, 20 mMs）, dichloromethane（25 milliliters）, 0 DEG C is cooled to, add formula III compound（[3αR-（3aα,4α,6α,6aα）]-6- Amino-amyl- 4- the alcohol of the dimethyl -4H- cyclopenta -1,3- dioxanes of tetrahydrochysene -2,2）Tartrate（3.65 grams, 10 millis Mole）, potassium carbonate is added dropwise（4.2 grams, 30 mMs）10 milliliters of the aqueous solution.After dripping, 0 DEG C of insulation, stirring 30 minutes, so After be warming up to room temperature（25℃）, continue to stir 2 hours.Dichloromethane layer is separated, 10 milliliters of water layer dichloromethane is washed, dichloromethane Alkane is laminated simultaneously, with anhydrous sodium sulfate drying, filters, and rotary evaporation desolventizing, residue is used column chromatography（Eluent is：Second Acetoacetic ester：Methylene chloride volume ratio=0-20%：1 gradient elution）, 1.25 grams of product formula IV compounds are obtained, with compound III's Feed intake gauge, yield 28%.
Product obtained in the present embodiment is confirmed after testing as formula IV compound：
HPLC purity（Purity）:99.0%;
Chiral purity（Purity）:99.0%;
MS(ESI):m/z=450.99[M+H+];
1HNMR(400MHz,DMSO):δ=12.71(s,1H),9.75(m,1H),4.67–4.56(m,3H),4.10–3.90 (m,1H),3.87–3.74(m,2H),3.57(s,2H),3.27–3.03(m,2H),2.21(m,1H),1.94(m,1H),1.80– 1.59(m,2H),1.44–1.33(m,3H),1.26–1.17(m,3H),0.98(t,J=7.3Hz,3H);
13C NMR(400MHz,CDCl3):δ=165.34,155.72,113.29,110.14,85.54,84.83,82.90, 71.26,69.58,60.45,57.80,32.89,32.45,26.50,24.21,23.20,13.63;
Embodiment 2
Compound II is added in 150 milliliters of there-necked flasks（5.4 grams, 20 mMs）, the tartrate (7.2 of compound III Gram, 20 mMs), dichloromethane（50 milliliters）, -20 DEG C are cooled to, instill potassium carbonate（8.2 grams, 30 mMs）The aqueous solution 30 milliliters.Completion of dropping, is warming up to 0 DEG C and stirs 2 hours.Separate dichloromethane layer, dichloromethane layer anhydrous sodium sulfate drying, Filter, rotary evaporation desolventizing, residue is used column chromatography（Eluent is：Ethyl acetate：Methylene chloride volume ratio=0- 20%：1 gradient elution）, 2.5 grams of product formula IV compounds are obtained, with the gauge that feeds intake of compound III, yield 28%.
Product obtained in the present embodiment is confirmed after testing as formula IV compound
Embodiment 3
Compound II is added in 150 milliliters of there-necked flasks（5.4 grams, 20 mMs）, dichloromethane（50 milliliters）, it is cooled to 0 DEG C, add 4.1 grams of potassium carbonate.By the tartrate (3.65 grams, 10 mMs) of compound III, 20 milliliters of dichloromethane are added, Instill potassium carbonate（4.1 grams, 15 mMs）20 milliliters of the aqueous solution prepare educt, by the dichloromethane layer containing educt point From.It is slowly added dropwise into the reaction bulb of compound II and potassium carbonate, completion of dropping, is incubated 0 DEG C and stirs 2 hours.Separate dichloromethane Alkane layer, dichloromethane layer anhydrous sodium sulfate drying is filtered, and rotary evaporation desolventizing, residue is used column chromatography（Eluent For：Ethyl acetate：Methylene chloride volume ratio=0-20%：1 gradient elution）, 3.5 grams of product formula IV compounds are obtained, with compound The gauge that feeds intake of III, yield 78%.
Product obtained in the present embodiment is confirmed after testing as formula IV compound
Embodiment 4
Compound II is added in 150 milliliters of there-necked flasks（8.0 grams, 30 mMs）, dichloromethane（50 milliliters）, it is cooled to 0 ℃.By the tartrate (3.65 grams, 10 mMs) of compound III, 30 milliliters of dichloromethane are added, add diisopropyl ethyl Amine（DIPEA, 6.5 grams, 50 mMs）The educt of prepare compound III, this dichloromethane solution for containing educt is delayed Slowly in dropping to the reaction bulb of compound II, completion of dropping is incubated 0 DEG C and stirs 5 hours.20 milliliters of system water is washed three times, is used Saturated common salt is washed 1 time, dichloromethane layer anhydrous sodium sulfate drying, is filtered, rotary evaporation desolventizing, residue column chromatography Separate（Eluent is：Ethyl acetate：Methylene chloride volume ratio=0-20%：1 gradient elution）, obtain 3.5 grams of product formula IV chemical combination Thing, with the gauge that feeds intake of compound III, yield 78%.
Product obtained in the present embodiment is confirmed after testing as formula IV compound
2nd, 2- [((3aR, 4S, 6R, 6aS) -6- { [chloro- 2- of 5- amino -6-（Rosickyite alkyl）- 4- pyrimidine radicals] amino } 5- （2- hydroxyl-oxethyls）- 1,2- pentamethylene glycol（Formula V compound）Synthesis
Embodiment 5
Formula IV compound (0.9 gram, 2 mMs), iron powder are added in 100 milliliters of there-necked flasks（0.9 gram, 16 mMs）, first Alcohol（10 milliliters）, after being heated to 60 DEG C concentrated hydrochloric acid is instilled（4 milliliters）Methyl alcohol（4 milliliters）Solution, completion of dropping reacts 2 at 60 DEG C Hour.It is cooled to room temperature（25℃）, pH=8-9 is adjusted with saturated sodium bicarbonate aqueous solution, and saturated aqueous common salt is added, system is used Dichloromethane（30 milliliters, 3 times）Extraction, dichloromethane layer merges, anhydrous sodium sulfate drying, rotary evaporation desolventizing, residue Use column chromatography（Eluent is：Ethyl acetate：Methylene chloride volume ratio=0-10%：1 gradient elution）, obtain product Formula V 0.57 gram of compound, yield：75%.
Product obtained in the present embodiment is confirmed after testing as Formula V compound
HPLC purity（Purity）:99.0%;
Chiral purity（Purity）:99.0%;
MS(ESI):m/z=379[M+H+];
1HNMR(400MHz,CDCl3):δ=6.97(d,J=6.8Hz,1H),4.84(m,3H),4.74(d,J=5.4Hz, 1H),4.57(s,1H),4.20(q,J=7.7Hz,1H),3.89(m,J=6.2Hz,1H),3.81(s,1H),3.64(m,1H), 3.53–3.40(m,4H),3.04–2.86(m,2H),2.55(m,1H),1.64(m,J=7.3Hz,2H),1.25(m,1H),0.96 (t,J=7.3Hz,3H);
13C NMR(400MHz,CDCl3):δ=155.51,152.97,137.85,120.41,83.06,75.62,74.76, 71.21,60.81,55.20,35.21,32.61,23.26,13.79;。
Embodiment 6
The water thing of stannous chloride two is added in 25 milliliters of there-necked flasks（3.6 grams, 16 mMs）, add 4 milliliters of concentrated hydrochloric acids, heating To 60 DEG C to clarifying, insulation, slow portion-wise adds formula IV compound（1.8 gram, 4 mMs）, finish and reacted 2 hours at 60 DEG C. Room temperature is cooled to, with 1N sodium hydrate aqueous solutions pH=8-9, system dichloromethane are adjusted（30 milliliters, 3 times）Extraction, organic layer Merge, anhydrous sodium sulfate drying, filter, rotary evaporation desolventizing, residue is used column chromatography（Eluent is：Ethyl acetate： Methylene chloride volume ratio=0-10%：1 gradient elution）, obtain 1.06 grams of product Formula V compound, yield：70%.
Product obtained in the present embodiment is confirmed after testing as Formula V compound
Embodiment 7
Formula IV compound is added in 100 milliliters of single port bottles（1.8 grams, 4 mMs）, 50 milliliters of methyl alcohol is added, add 4 milliliters Concentrated hydrochloric acid, adds 10% 0.2 gram of palladium carbon, hydrogen exchange 3 times, room temperature to reduce overnight.Hydrogen is removed, it is water-soluble with 1N NaOH Liquid adjusts pH=8-9, system dichloromethane（10 milliliters, 3 times）Extraction, organic layer merges, anhydrous sodium sulfate drying, filters, rotation Turn evaporation desolventizing, residue is used column chromatography（Eluent is：Ethyl acetate：Methylene chloride volume ratio=0-10%：1 gradient Wash-out）, obtain 1.2 grams of product Formula V compound, yield：80%.
Product obtained in the present embodiment is confirmed after testing as Formula V compound
3rd,（1S,2S,3R,5S）-5-（Rosickyite alkyl）- 3H- [1,2,3] triazol [4,5-d] pyrimidin-3-yl] -5-（2- Hydroxyl-oxethyl）- 1,2- pentamethylene glycol（Formula IV compound）Synthesis
Embodiment 8
Formula V compound (0.5 gram, 1.32 mMs), acetone are added in 100 milliliters of there-necked flasks（10 milliliters）, acetic acid（3 millis Rise）, 20 DEG C are maintained the temperature at, instill natrium nitrosum（0.11 milligram, 1.59 mMs）Water（0.5 milliliter）Solution.Drip Stir 2 hours after finishing, with sodium acid carbonate pH=8-9 is adjusted, be extracted with ethyl acetate（30 milliliters, 3 times）, ethyl acetate layer merging, Anhydrous sodium sulfate drying, rotary evaporation desolventizing, residue is used column chromatography（Eluent is：Ethyl acetate）, obtain colourless Solid, 0.46 gram, yield 89%.
Product obtained in the present embodiment is confirmed after testing as Formula IV compound
HPLC purity（Purity）:99.0%;
Chiral purity（Purity）:99.0%;
MS(ESI):m/z=390[M+H+];
1HNMR(400MHz,DMSO)δ5.13(q,J=9.1Hz,1H),4.81(m,2H),4.62(dd,J=8.8,4.8Hz, 1H),3.98(d,J=3.4Hz,1H),3.79(m,1H),3.46-3.53(m,4H),3.22(m,2H),2.73(m,1H),2.14 (m,1H),1.76(m,2H),1.01(t,J=8.0Hz,3H);
13C NMR(100MHz,DMSO)δ170.09,152.26,151.21,132.33,82.12,75.04,74.08, 71.33,62.47,60.75,33.52,33.34,22.20,13.62.;
Embodiment 9
In 100 milliliters of there-necked flasks, Formula V compound is added（3.8 grams, 10 mMs）, isoamyl nitrite（2 milliliters, 15 millis Mole）, acetonitrile（50 milliliters), it is heated to 70 DEG C and reacts 2 hours, rotary evaporation desolventizing, residue with ethyl acetate：N-hexane Volume ratio is 1:15 milliliters of 1 mixed solvent, is recrystallized to give product Formula IV compound, colorless solid, 3.0 grams, yield 77%.
Product obtained in the present embodiment is confirmed after testing as Formula IV compound
4th, the synthesis of ticagrelor (Ticagrelor)
Embodiment 10
Formula IV compound is added in 25 milliliters of there-necked flasks（0.39 gram, 1 mM）, potassium carbonate（0.41 gram, 3 mMs）, Formula VII compound（Trans-（1R,2S）- 2- (3,4- difluorophenyls)-cyclopropylamine）Mandelate（0.35 gram, 1.1 mmoles You）, water（3 milliliters）, dichloromethane（20 milliliters）, it is stirred at room temperature 4 hours.Separate dichloromethane layer, anhydrous sodium sulfate drying, mistake Filter, rotary evaporation desolventizing, column chromatography for separation（Eluent is：Ethyl acetate：Methylene chloride volume ratio=0-10%：1 gradient is washed It is de-）, obtain 450 milligrams of colorless solid ticagrelor, yield：86.2%.
Product obtained in the present embodiment is confirmed after testing as Formula VII compound ticagrelor.
HPLC purity（Purity）:99.0%;
Chiral purity（Purity）:99.0%;
MS(ESI):m/z=523[M+H+];
1HNMR(400MHz,DMSO)δ9.38(d,J=4.1Hz,1H),7.32(m,2H),7.08(1H),5.13(d,J= 6.4Hz,1H),5.07(d,J=4.1Hz,1H),4.96(t,J=9.1Hz,1H),4.62(m,1H),4.56(m,1H),3.95(s, 1H),3.76(m,1H),3.55–3.46(m,4H),3.16(m,1H),2.95(m,1H),2.90–2.85(m,1H),2.64(m, 1H),2.13(m,1H),2.09–1.97(m,1H),1.52(m,3H),1.38(m,1H),0.82(t,J=7.3Hz,3H).;
13C NMR(100MHz,DMSO)δ169.63,154.42,149.89,139.65,123.63,123.30,117.59, 117.42,115.37,115.20,82.25,74.81,74.15,71.31,60.98,60.76,34.56,33.71,32.80, 24.50,22.75,15.49,13.43。
Specific rotatory power is -61.5 °,（The measuring condition of optically-active：Measuring condition -- wavelength：589nm, sample concentration：200 millis Gram/100 milliliters, temperature：20 DEG C, solvent:Methyl alcohol（Analysis is pure））.
Comparative example：
With the optical value obtained with deprotection method after concentrated acid of the patents such as WO0192263（Such as above-mentioned document report）Respectively Such as following table：
Hydrochloric acid（Mol/L） The de- propylidene time（Hour） Optical value
4 3 -47°
6 3 -51°
12 3 -49°
It is high that the above results illustrate that the inventive method is obtained product purity.

Claims (8)

1. a kind of preparation method of ticagrelor, it is characterised in that the method is comprised the following steps：
(1) Formula II compound with formula III compound in the presence of a base, is coupled and generates formula IV compound；
(2) formula IV compound is reduced in acid condition and deprotection, obtains Formula V compound；
(3) Formula V compound generates Formula IV compound through diazotising and cyclization；
(4) Formula IV compound is coupled in the basic conditions with Formula VII compound, obtains ticagrelor compound of formula I；
Wherein, the acid condition described in step (2) is that the pH value of reaction system is adjusted to into 1-3 with strong acid；It is described to be reduced to urge Change hydro-reduction；Described strong acid is selected from one or several of hydrochloric acid, sulfuric acid or trifluoroacetic acid；The catalytic hydrogen reduction, Using palladium carbon, platinum carbon or Raney Ni as catalyst, catalyst and IV compounds mass ratio be 5%-10%:1；Reaction temperature For 0 DEG C -100 DEG C；Reaction dissolvent is water or alcohol, and described alcohol is one or several in methyl alcohol, ethanol or isopropanol.
2. a kind of preparation method of ticagrelor according to claim 1, it is characterised in that the alkali choosing described in step (1) From inorganic base or organic base one or more；Alkali is 1-10 with the mol ratio of formula III compound:1；Reaction temperature be -20 DEG C - 20℃；Solvent is selected from one or more of dichloromethane, tetrahydrofuran or ethanol；Inorganic base adds reaction in the way of the aqueous solution System, the concentration of inorganic base aqueous solution is 1-5 mol/Ls, and inorganic base is selected from sodium carbonate, potassium carbonate, NaOH or hydroxide Potassium one or several；Organic base selected from diisopropyl ethyl amine, triethylamine or 1,8- diazabicylos-bicyclic (5,4,0)- One or more of 7- hendecenes.
3. a kind of preparation method of ticagrelor according to claim 2, it is characterised in that step (1) the reaction temperature Spend for -10 DEG C -10 DEG C；Inorganic base is potassium carbonate, and the concentration of inorganic base aqueous solution is 1-3 mol/Ls, and organic base is diisopropyl Ethylamine or triethylamine；Solvent is dichloromethane.
4. the preparation method of a kind of ticagrelor according to claim 1, it is characterised in that strong used by described reduction Acid is hydrochloric acid.
5. a kind of preparation method of ticagrelor according to claim 1, it is characterised in that the diazonium described in step (3) Change reaction and use inorganic nitroso compound or organic sub-nitrate compound as diazo reagent；Described inorganic nitrous Based compound is selected from one or more of natrium nitrosum, potassium nitrite；Described organic sub-nitrate compound is selected from nitrous acid One or more of isopropyl ester or isoamyl nitrite；During with inorganic nitroso compound as diazo reagent, acid need to be added, plus The mole for entering acid is 1-10 times of Formula V compound, and described acid is acetic acid；Inorganic nitroso compound and Formula V compound Mol ratio is 1-10:1；Reaction temperature is -10 DEG C -20 DEG C；Reaction dissolvent is selected from the one of dichloromethane, toluene, acetonitrile or ethanol Plant or several；Or
During with organic sub-nitrate compound as diazo reagent, the mol ratio of organic sub-nitrate compound and Formula V compound For 1-10:1；Reaction temperature is 0 DEG C -100 DEG C；Reaction dissolvent is selected from one or more of tetrahydrofuran, dioxane or acetonitrile.
6. preparation method according to claim 5, it is characterised in that step (3) is with inorganic nitroso compound as diazonium When changing reagent, the mole for adding acid is 2-5 times of Formula V compound；Reaction dissolvent is selected from dichloromethane；Or
During with organic sub-nitrate compound as diazo reagent, reaction dissolvent is selected from acetonitrile or one kind or several of dioxane Kind.
7. the preparation method of a kind of ticagrelor according to claim 1 and 2, it is characterised in that step (4) is described in alkali Property under the conditions of the alkali that uses be organic base or inorganic base；Described organic base is selected from diisopropyl ethyl amine, triethylamine or 1,8- One or more of diazabicylo-bicyclic (5,4,0) -7- hendecenes；Described inorganic base is selected from sodium carbonate, potassium carbonate, hydrogen Sodium oxide molybdena or potassium hydroxide one or several；Reaction temperature is 0 DEG C -100 DEG C；Reaction dissolvent selected from toluene, dichloromethane, One or more of acetonitrile, tetrahydrofuran, dioxane；The mol ratio of Formula IV and Formula VII compound is 1：1.0-5.0；Alkali and The mol ratio of Formula VII compound is 1.0-5.0：1.
8. preparation method according to claim 7, it is characterised in that step (4) reaction temperature is 0 DEG C -30 DEG C；Reaction is molten Agent is dichloromethane；The mol ratio of Formula IV and Formula VII compound is 1:1.0-2.0.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (en) * 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
WO2011017108A2 (en) * 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Cyclopropyl modulators of p2y12 receptor
CN102311437A (en) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 Preparation method of platelet-aggregation-resisting medicament Ticagrelor
WO2012138981A2 (en) * 2011-04-06 2012-10-11 Teva Pharmaceutical Industries Ltd. New intermediates and processes for preparing ticagrelor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (en) * 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
WO2011017108A2 (en) * 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Cyclopropyl modulators of p2y12 receptor
CN102311437A (en) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 Preparation method of platelet-aggregation-resisting medicament Ticagrelor
WO2012138981A2 (en) * 2011-04-06 2012-10-11 Teva Pharmaceutical Industries Ltd. New intermediates and processes for preparing ticagrelor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
替卡格雷合成路线图解;陈莉莉;《中国医药工业杂志》;20111231;第42卷(第2期);第146-150页 *

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