CN102875537A - Novel preparation method of antithrombosis medicine - Google Patents
Novel preparation method of antithrombosis medicine Download PDFInfo
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- CN102875537A CN102875537A CN2012103312665A CN201210331266A CN102875537A CN 102875537 A CN102875537 A CN 102875537A CN 2012103312665 A CN2012103312665 A CN 2012103312665A CN 201210331266 A CN201210331266 A CN 201210331266A CN 102875537 A CN102875537 A CN 102875537A
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- 0 CC1(C)O[C@]([C@](C[C@]2N)OCC(O*)=O)[C@@]2O1 Chemical compound CC1(C)O[C@]([C@](C[C@]2N)OCC(O*)=O)[C@@]2O1 0.000 description 10
- DDEDQHVHVPJFAC-UHFFFAOYSA-N CCCSc(nc1Cl)nc(Cl)c1[N+]([O-])=O Chemical compound CCCSc(nc1Cl)nc(Cl)c1[N+]([O-])=O DDEDQHVHVPJFAC-UHFFFAOYSA-N 0.000 description 1
- LTDJMKYALYUWBG-SNINTGQOSA-N CCCSc1nc(N[C@H](C)[C@@H](C)c(cc2)cc(F)c2F)c2NNN([C@H](C3)[C@@H]4OC(C)(C)O[C@@H]4[C@H]3OCCO)c2n1 Chemical compound CCCSc1nc(N[C@H](C)[C@@H](C)c(cc2)cc(F)c2F)c2NNN([C@H](C3)[C@@H]4OC(C)(C)O[C@@H]4[C@H]3OCCO)c2n1 LTDJMKYALYUWBG-SNINTGQOSA-N 0.000 description 1
- WLEOHEIRUFTYCF-FYEBJQQMSA-N CCCSc1nc(N[C@H](C2)[C@@H]2c(cc2)cc(F)c2F)c2nn[n]([C@H](C3)[C@@H]4OC(C)(C)O[C@@H]4[C@H]3OCCO)c2n1 Chemical compound CCCSc1nc(N[C@H](C2)[C@@H]2c(cc2)cc(F)c2F)c2nn[n]([C@H](C3)[C@@H]4OC(C)(C)O[C@@H]4[C@H]3OCCO)c2n1 WLEOHEIRUFTYCF-FYEBJQQMSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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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Abstract
The invention provides a novel preparation method which is easily industrially achieved and is simple and convenient to carry out and is established under a new intermediate. The invention relates to a novel preparation method of micromolecule anticoagulant Ticagrelor, and synchronously relates to an intermediate body for synthesizing the Ticagrelor and a preparation method of the intermediate. With the adoption of the synthesis method provided by the invention, the side reaction in the reaction process can be effectively reduced, the purity of the intermediate is improved, and the purifying way of the intermediate is simplified.
Description
Technical field:
The present invention relates to the new preparation method of a kind of ADZ6140, in addition, the invention still further relates to the new intermediate that uses in the method.
Background technology:
ADZ6140 be Astrazeneca AB research and development a kind of novel, have optionally small molecules anticoagulant, be the oral P2Y12 adenosine diphosphate receptor antagonists of first reversible mating type.Purine 2 receptor subtype P2Y12 on the ADZ6140 energy reversibility ground vasoactive smooth muscle cell (VSMC), the platelet aggregation that ADP is caused has obvious restraining effect, and it is rapid to orally use rear onset, therefore can effectively improve acute coronary patient's symptom.Because the antiplatelet effects of ADZ6140 is reversible, it needs the patient who carries out in advance performing the operation again behind the anticoagulant therapy particularly applicable for those.
Result of study shows that ADZ6140 is compared with clopidogrel, can obviously reduce the primary terminal point event such as patient's heart stalk, palsy or cardiovascular death, and the severe haemorrhage complication does not increase.Subordinate phase test for be coronary bypass patient's medication, the result shows that ADZ6140 is effective; It is higher with the irrelevant main bleeding episode incidence of bypass operation of coronary artery that ADZ6140 causes, and comprised some fatal intracranialing hemorrhage.But in all bleeding episodes, ADZ6140 group patient's mortality ratio is obviously low.
ADZ6140, i.e. (1S, 2S, 3R shown in the formula 1,5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] amino]-5-(propyl group sulfydryl)-3H-1,2,3-triazole [4,5-d] pyrimidine-3 base]-5-(2-hydroxyl-oxethyl)-1,2-encircles pentanediol.Patent WO 00/34283 has openly reported a kind of synthetic method of ADZ6140, and concrete synthetic route is as follows:
Patent WO 00/34283 adopts compound F 17-hydroxy-corticosterone ormula-2 and Formula-3 to carry out condensation; condensation product is through reduction; form the triazole ring structure with the Isopentyl nitrite reaction again; continue amination and obtain intermediate Formula-7; intermediate Formula-7 obtains intermediate Formula-8 with the reaction of trifyl methyl acetate in the presence of butyllithium; by with Isopentyl nitrite and bromoform reaction amino being converted into bromine group; again with fragment Formula-10 condensation; and the ester reduction group, take off at last the acetonylidene protection and obtain ADZ6140.
The disadvantage of this route is; in the raw material Formula-3 structure owing to be subject to the impact of strong electron-withdrawing group group nitro; two cl radical activity on the ortho position are very high; and contain simultaneously amino and two active groups of hydroxyl in the Formula-2 structure; side reaction very easily occurs in the reaction; the by product that produces in the reaction brings very large difficulty for the purifying of follow-up intermediate; intermediate Formula-7 prepares and has adopted expensive reagent trifyl methyl acetate in the Formula-8 process; and there are simultaneously hydroxyl and amino in the reaction materil structure; side reaction is more in the reaction; purification difficult; the route reaction step of this patent report is many; side reaction is many, and each goes on foot intermediate and all need adopt column chromatography purification to be unfavorable for the enforcement of industrialization.
US Patent No. 2003/0148888 has openly been reported a kind of synthetic route of ADZ6140, and this synthetic method is improved the synthetic method of patent WO00/34283 report, and synthetic route is as follows:
At first that the raw material Formula-2 that uses among the patent WO 00/34283 is amino by upper CBZ protection; with the ethyl bromoacetate reaction hydroxyl is converted into ethoxyacetic acid ethyl ester group under the strong alkaline condition; the ester reduction group; at last reduction is taken off the common four-step reaction of CBZ protection and is converted into raw material Formula-a; simultaneously first the raw material Formula-3 in the above-mentioned patent is carried out nitroreduction and obtain raw material Formula-b; it is that raw material carries out condensation that patent US2003/0148888 adopts Formula-a and Formula-b; form the triazole structure with the Sodium Nitrite reaction again; continue and compound F 17-hydroxy-corticosterone ormula-10 condensation; hydrolysis removes the acetonylidene protection and obtains ADZ6140 under the last acidic conditions; this route weak point is that structural two the cl radical activity of raw material Formula-b are little; need 100 ℃ of high temperature to react for a long time during with raw material Formula-a condensation; and except amino, also has hydroxyl on the raw material Formula-a structure; high temperature reacts for a long time side reaction can occur; simultaneously owing to all contain amino in the raw material; unstable under the high temperature; these factors cause in the condensation reaction side reaction many; color is very dark; for the purifying of follow-up intermediate brings difficulty, yield is difficult to guarantee.
Patent WO2011/017108 has reported another synthetic route, and synthetic route is as follows:
It is raw material and compound F 17-hydroxy-corticosterone ormula-a condensation that difference is to adopt the raw material Formula-3 that the cl radical activity is higher in the structure, restore and obtain intermediate Formula-c, the later reaction step is consistent with the method for patent US2003/0148888 report, this route exists raw material Formula-a to have simultaneously amino and hydroxyl equally, the problem of side reaction occurs during with the Formula-3 condensation easily, brings difficulty for the purifying of follow-up intermediate.
Summary of the invention
The invention provides a kind of new, industrial easy realization, easy and be based upon economic means on the new intermediate, the method prepares (1S, 2S by following reaction scheme, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] amino]-5-(propyl group sulfydryl)-3H-1,2,3-triazole [4,5-d] pyrimidine-3 base]-5-(2-hydroxyl-oxethyl)-1,2-encircles pentanediol (ADZ6140):
An object of the present invention is to provide the preparation method for the synthesis of new intermediate and this intermediate of ADZ6140.
Another object of the present invention provides a kind of new synthesis route for preparing ADZ6140.This synthetic method can effectively reduce the side reaction in the reaction process, improves the purity of intermediate, simplifies the purifying mode of intermediate, can economical, the high-quality ADZ6140 product that obtains by this synthetic method.
For realizing first purpose, a kind of intermediate of synthetic ADZ6140, suc as formula Formula-E:
Wherein R is C1～C6 low alkyl group, preferred ethyl.
A kind of intermediate of synthetic ADZ6140 is suc as formula Formula-F
Wherein the definition of R is the same.
A kind of synthetic ADZ6140 intermediate is suc as formula Formula-G
Wherein the definition of R is the same.
The method of described synthetic ADZ6140 intermediate Formula-E compound is that formula Formula-D compound and formula Formula-3 compound are taken off condensation one one's share of expenses for a joint undertaking HCl reaction production Formula-E compound under alkaline environment.
The reaction medium that carries out chemical reaction in the intermediate formula Formula-E compou nd synthesis method of the present invention is inert organic solvents, and described inert solvent is C1～C4 halogenated aryl hydrocarbon, the ether of C2～C6, and the nitrile of C2～C6 is preferably tetrahydrofuran (THF).
Carry out the organic bases that chemical reaction adopts in the intermediate formula Formula-E compou nd synthesis method of the present invention and can be diisopropylethylamine, triethylamine or pyridine are preferably diisopropylethylamine.
In the above-mentioned reaction system add formula Formula-D compound (preparation method sees US2003/0148888), the mol ratio of formula Formula-3 compound and organic bases is 1: 1: 1～1: 3: 6, is preferably 1: 1.6: 3.
The temperature of the chemical reaction in the intermediate formula Formula-E synthetic method of the present invention is-10～50 degrees centigrade in addition, is preferably 0～10 degree centigrade.
The intermediate formula Formula-E compou nd synthesis method reaction times of the present invention is 2～3 hours
It is the compound and the reaction of formula Formula-3 compound of Formula-D that synthetic method of the present invention adopts general formula, and ester group produces side reaction with respect to more stable being difficult to of the hydroxyl that contains reactive hydrogen in the reaction of docking with halogen.The synthetic route of the ADZ6140 that patent WO 00/34283, US2003/0148888 and WO2011/017108 openly report adopts respectively the compound F 17-hydroxy-corticosterone ormula-2 and the Formula-a that contain active hydroxyl and amino to react with formula Formula-3 and Formula-b compound respectively, be difficult to avoid producing the condensation side reaction of hydroxyl and cl radical under the alkaline condition, the intermediate purification difficult, the purity of very difficult control product.
The inventor has carried out careful research to the crucial condensation reaction of reporting in above-mentioned three patents, a lot of improvement have been carried out simultaneously, comprise temperature control, molar ratio control, the selection of organic bases, the change of reaction feeding sequence all is difficult to suppress the generation of side reaction, can not solve purity difference, the problem that yield is low, we adopt compound F 17-hydroxy-corticosterone ormula-D and the formula Formula-3 condensation that only contains a reactive group amino in the structure at surprised discovery in the experiment, after Isopentyl nitrite becomes the triazole structure, again ester group in the structure is reduced into hydroxyl, can greatly reduce the by product in the reaction, effectively simplify the purge process of intermediate, the finished product ADZ6140 quality improves greatly.
The method of described synthetic ADZ6140 intermediate Formula-F compound is: adopting formula Formula-E compound is raw material, is that amino obtains compound F 17-hydroxy-corticosterone ormula-F by reduction reaction with nitroreduction in the structure.
The reaction medium that carries out chemical reaction in the intermediate Formula-F compou nd synthesis method of the present invention is preferably methyl alcohol, ethanol for being selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methyl tertiary butyl ether and mixed solvent thereof.
Carrying out the catalyzer that chemical reaction adopts in the medium spacing body Formula-F compou nd synthesis method of the present invention is palladium-carbon catalyst, is preferably the palladium carbon that contains palladium 10%.
In the above-mentioned reaction system add formula Formula-E compound, the mass ratio that contains the palladium carbon of palladium 10% is 1:: 0.01～1: 1, be preferably 1: 0.1～1: 0.15.
The temperature of the chemical reaction in the intermediate formula Formula-F synthetic method of the present invention is 0～50 degree centigrade in addition, is preferably 20～30 degrees centigrade.
The intermediate formula Formula-F compou nd synthesis method reaction times of the present invention is 15～20 hours
Above-mentioned reaction can be adopted the method for iron powder or zinc powder reduction, but the comparatively violent easily punching of iron powder and zinc powder reduction acid adding elicitation procedure material, the aftertreatment three wastes are many, and yield is undesirable.
The synthetic method of synthetic ADZ6140 intermediate formula Formula-G of the present invention is: formula Formula-F compound forms the triazole ring and obtains formula Formula-G compound in inert organic solvents with in the Isopentyl nitrite reaction structure,
The reaction medium that carries out chemical reaction in the medium spacing Formula-G compou nd synthesis method of the present invention is inert organic solvents, is preferably acetonitrile.
The mol ratio that adds formula Formula-F compound and Isopentyl nitrite in the above-mentioned reaction system is 1: 1～1: 5, is preferably 1: 2.
The temperature of the chemical reaction in the intermediate formula Formula-G synthetic method of the present invention is 30～80 degrees centigrade in addition, is preferably 65～75 degrees centigrade.
The intermediate formula Formula-G compou nd synthesis method reaction times of the present invention is 0.5～8 hour, preferred 1～2 hour.
In order to realize another object of the present invention, utilize above-mentioned intermediate to synthesize ADZ6140, comprise the steps:
1. the synthesis type Formula-G compound of formula Formula-H compound is sloughed a part hydrogenchloride with formula Formula-10 compound (preparation method sees patent WO 00/34283) at alkaline condition and is obtained formula Formula-H compound in inert organic solvents
The reaction medium that carries out chemical reaction in the step of the present invention is inert organic solvents, and described inert solvent is preferably methylene dichloride.
Carry out the organic bases that chemical reaction adopts in the step of the present invention and can be diisopropylethylamine, triethylamine or pyridine are preferably diisopropylethylamine.
In the above-mentioned reaction system add formula Formula-G compound, the mol ratio of formula Formula-10 compound and organic bases is 1: 1: 1～1: 3: 6, is preferably 1: 2: 3.
The temperature of the chemical reaction in the step of the present invention is-10～50 degrees centigrade in addition, is preferably 20～30 degrees centigrade.
The step reaction time of the present invention is 15～20 hours
2. the synthesis type Formula-H compound of formula Formula-e compound obtains formula Formula-e compound by reduction reaction in inert organic solvents.
The reaction medium that carries out chemical reaction in the step of the present invention is inert organic solvents, is preferably tetrahydrofuran (THF).
Carry out the reductive agent that chemical reaction adopts in the step of the present invention and be preferably sodium borohydride.
Carry out the reducing catalyst that chemical reaction adopts in the step of the present invention and be preferably lithiumbromide.
In the above-mentioned reaction system add formula Formmula-H compound, the mol ratio of sodium borohydride and lithiumbromide is 1: 1: 1～1: 5: 5, is preferably 1: 2.5: 2.5.
The temperature of the chemical reaction in the step of the present invention is 0～80 degree centigrade in addition, is preferably 40～50 degrees centigrade.
The step reaction time of the present invention is 1～5 hour, preferred 1～2 hour.
Reported among the patent WO 00/34283 by the DIBAL-H reduction ester group has been converted into hydroxyl, because dangerous high in the DIBAL-H use procedure, simultaneously the complicated three wastes of last handling process are many, obtain formula Formula-e compound and efficiently solve these problems and adopt lithiumbromide catalysis sodium borohydride to reduce ester group.
3. take off the acetonylidene protection by acid-catalyzed hydrolysis in the synthesis type Formula-e compound inert organic solvents of formula 1 compound (ADZ6140) and obtain compound L
Crystallization in the recrystallisation solvent that is selected from Virahol, isopropanol-water, ether, methyl tertbutyl, ethyl acetate, acetone, acetone-ether, acetone-methyl tertiary butyl ether, acetone-normal hexane, acetone-sherwood oil, ethyl acetate-ether, ethyl acetate-normal hexane, ethyl acetate-normal heptane, ethyl acetate-sherwood oil and composition thereof obtains the formula 1 (ADZ6140) of crystal form to the ADZ6140 crude product in the step of the present invention.
In a word, the present invention adopts be economical, efficient, environmental pollution is little, production operation is simple, suitable industrial synthesis technique.
Further illustrate content of the present invention below in conjunction with embodiment, describe but content of the present invention is not limited to the condition of embodiment.
Embodiment:
Embodiment 1
Synthetic (R is ethyl in the structural formula) of formula Formula-E compound:
With 60g (0.23mol, 1.0eq) formula Formula-D compound (R is ethyl in the structural formula, and the preparation method sees US2003/0148888), 140mL (0.74mol, 3.0eq) DIPEA adds among the 900mL THF, and stirring at room 0.5 hour is stand-by.99.2g (0.37mol, 1.6eq) formula Formula-3 compound is added among the 180mLTHF, be chilled to 0-5 ℃, nitrogen protection drips above-mentioned stand-by solution, and about one hour, the control temperature was at 0-5 ℃.After dripping, keep reaction system to stir two hours at 0-5 ℃, TLC detects and remains without raw material.Add 250mL ethyl acetate diluting soln, wash (300mL) organic phase with water, saturated aqueous common salt (300mL) is washed once, anhydrous sodium sulfate drying, the concentrated faint yellow oily thing of 150g that obtains, add 300g silica gel after adding 500ml methylene dichloride stirring and dissolving in the oily matter, stir, concentrating under reduced pressure eliminates methylene dichloride, add the 500ml normal hexane, stirring to pulp 30 minutes, suction filtration, mother liquor concentrating under reduced pressure reclaim unreacted raw material Formula-3 and a small amount of product F ormula-E, the filter cake silica-gel mixture is used 1000ml ethyl acetate stirring to pulp 30 minutes, suction filtration, mother liquor are evaporated to dried 85.7g oily matter Formula-E, yield 76.1%.
NMR?δH(CDCl
3)8.56(1H，d，J＝7.6Hz)，4.70(1H，t，J＝6.8Hz)，4.66(1H，dd，J＝5.6Hz，J＝1.6Hz)，4.55(1H，dd，J＝5.6Hz，J＝1.2Hz)，4.25～4.20(4H，m)，4.06(1H，d，J＝4.0Hz)，3.19～3.03(2H，m)，2.36～2.30(1H，m)，2.03(1H，d，J＝14.8Hz)，1.81～1.74(2H，m)，1.42(3H，s)，1.29(3H，t，J＝7.2Hz)，1.26(3H，s)，1.04(3H，t，J＝7.2Hz).
Embodiment 2
Synthetic (R is ethyl in the structural formula) of formula Formula-F compound:
65g (132mmol) formula F compound is dissolved in the 70mL methyl alcohol, and adding 6.5g content is 10% palladium carbon under the nitrogen protection, replacing hydrogen.Synthesis under normal pressure is 20 hours under the room temperature, and TLC detects and remains without raw material.Filter palladium carbon, filter cake 50mL methanol wash, concentrated filtrate obtains 57g oily matter, need not purifying and is directly used in the next step, yield 93.4%.
NMR?δH(CDCl
3)6.32(1H，d，J＝7.6Hz)，4.64(1H，t，J＝7.2Hz)，4.57～4.54(2H，m)，4.33～4.20(3H，m)，4.12～4.07(1H，m)，3.98(1H，d，J＝4.0Hz)，3.76(2H，br?s)，3.16～3.09(1H，m)，3.03～2.96(1H，m)，2.32～2.25(1H，m)，1.88(1H，d，J＝14.8Hz)，1.77～1.71(2H，m)，1.41(3H，s)，1.29(3H，t，J＝7.2Hz)，1.24(3H，s)，1.01(3H，t，J＝7.2Hz).
Embodiment 3
Synthetic (R is ethyl in the structural formula) of formula Formula-G compound:
52g (113mmol, 1.0eq) formula G compound is dissolved in the 150mL acetonitrile.Add 30.4mL (226mmol, 2.0eq) Isopentyl nitrite, be heated to 70 ℃ of reactions 1 hour, TLC detects and remains without raw material.To react concentrated behind the cool to room temperature and obtain the 51.1g brown oil, yield 96.0% need not to be further purified, and is directly used in the next step.
NMR?δH(CDCl
3)5.52(1H，q，J＝3.5Hz)，5.18(1H，dt，J＝10.0Hz，J＝3.5Hz)，4.85(1H，dd，J＝6.5Hz，J＝2.0Hz)，4.20～4.11(3H，m)，4.08(2H，d，J＝4.0Hz)，3.24～3.18(2H，m)，2.79～2.73(2H，m)，1.87～1.80(2H，m)，1.55(3H，s)，1.36(3H，s)，1.26(3H，t，J＝7.5Hz)，1.09(3H，J＝7.5Hz).
Embodiment 4
Synthetic (R is ethyl in the structural formula) of formula Formula-H compound:
With 36g (76.3mmol, 1.0eq) formula Formula-G compound is dissolved among the 360mL DCM, add 12.9g (76.3mmol, 1.0eq) formula Formula-10 compound (preparation method sees patent WO 00/34283) and 40.0mL (228.9mmol, 30eq) DIPEA.Stirred overnight at room temperature, TLC detects and remains without raw material.Reaction solution is respectively washed once with 300mL water and 300mL saturated aqueous common salt, minute gets organic phase, and anhydrous sodium sulfate drying filters, and is evaporated to dried 45.1g oily matter, and yield 97.8% is directly used in the next step.
ESI-MS：605(M+H
+)
Embodiment 5
Synthesizing of formula Formula-e compound:
With 0.26g (6.87mmol, 2.5eq) sodium borohydride, 0.6g (6.9mmol, 2.5eq) lithiumbromide adds among the 5mL THF under nitrogen protection.Above-mentioned reaction solution control temperature stirred 45 minutes at 50 ℃.Drip 30g (49.6mmol, 1.0eq) formula Formula-H compound dissolution at the solution of 100mL THF, the control temperature drips 30 minutes at 50 ℃, and dropping is dripped 2mL methyl alcohol after finishing again.Drip 180mL water, a large amount of gases generate, and the control rate of addition prevents the punching material, drip rear 40 ℃ of reactions one hour, and TLC detects and remains without raw material.Reaction adds 500mL ethyl acetate extraction product, and organic phase is respectively washed once with 300mL water and 300mL saturated aqueous common salt, anhydrous sodium sulfate drying, and concentrated organic phase obtains 24.4g oily matter, and yield 87.4% is directly used in the next step.
ESI-MS：563(M+H
+)
Embodiment 6
Synthesizing of formula 1 compound (ADZ6140):
24g (42.7mmol) formula Formula-e compound is dissolved in the 120mL toluene, and the 5-10 ℃ of lower 50mL/50mL concentrated hydrochloric acid/methyl alcohol that drips maintains the temperature at after dripping about 5 ℃ and reacted 30 minutes.Add 50mL water, standing demix minute is got the water that contains the product hydrochloride and methyl alcohol mutually, water/methanol system is regulated water PH to 6-7 with saturated sodium bicarbonate solution, adds 200mL ethyl acetate extraction product, divides and gets organic phase, water layer extracts once with the 200ml ethyl acetate again, merge organic phase, organic phase with 100ml water and the washing of 100ml saturated common salt, is got organic phase respectively, use anhydrous sodium sulfate drying, activated carbon decolorizing filters, the concentrated 19.1g oily matter that obtains.
The 152.8ml acetonitrile will be added in the above-mentioned oily matter, heating for dissolving, under stirring, slowly cool to 30～40 ℃, add 0.1g ADZ6140 crystal seed and induce, slowly there are a large amount of solids to separate out, stirring is cooled to 0～5 ℃, stirring and crystallizing 3 hours, suction filtration, filtration cakes torrefaction, get off-white color solid 14.4g, the crude product that obtains is dissolved fully with the heating of 144ml ethyl acetate, slowly drip the 115.2ml normal hexane, slowly there are a large amount of white solids to separate out, stirring is cooled to 0～5 ℃, stirring and crystallizing 3 hours, suction filtration, filter cake washs with the mixed solvent of 20ml ethyl acetate/normal hexane=10/8, drain, 40 ℃ of lower vacuum-dryings of filter cake get white solid 12.9g, HPLC purity＞99%, yield: 57.8%.
ESI-MS：523(M+H
+)
NMR?δH(DMSO)9.35(1H，d，J＝4.0Hz)，7.35～7.28(2H，m)，7.08(1H，m)，5.10(1H，d，J＝6.4Hz)，5.03(1H，d，J＝4.0Hz)，4.96(1H，q，J＝9.2Hz)，4.60～4.50(2H，m)，3.95(1H，br?s)，3.76(1H，m)，3.52～3.47(4H，m)，3.16～3.09(1H，m)，2.97～2.92(1H，m)，2.88～2.83(1H，m)2.63(1H，dt，J＝13.6Hz，J＝8.4Hz)，2.30～2.22and?2.16～2.08(1H，m)，2.07～2.00(1H，m)，1.70～1.35(4H，m)，0.99and?0.82(3H，t，J＝7.2).
Claims (31)
1. the intermediate of a synthetic ADZ6140 is formula Formula-E compound:
Wherein R is C1～C6 low alkyl group in the said structure formula.
2. the method for preparing the described compound of claim 1, the method is: formula Formula-D compound and formula Formula-3 compound are taken off condensation one one's share of expenses for a joint undertaking HCl reaction production Formula-E compound doing under the alkaline environment.
3. described method according to claim 2 is characterized in that selected inert organic solvents is C1～C4 halogenated aryl hydrocarbon, the ether of C2～C6, the nitrile of C2～C6.
4. described method is characterized in that described inert organic solvents is tetrahydrofuran (THF) according to claim 3.
5. described method according to claim 2 is characterized in that described organic bases is diisopropylethylamine (DIPEA), triethylamine or pyridine.
6. described method according to claim 5 is characterized in that described organic bases is diisopropylethylamine.
7. described method according to claim 2 is characterized in that, formula Formula-D compound, and the mol ratio of formula Formula-3 compound and organic bases is 1: 1: 1～1: 3: 6.
8. described method according to claim 2 is characterized in that described temperature of reaction is-10～50 degrees centigrade.
9. the intermediate of a synthetic ADZ6140 is formula Formula-F compound:
Wherein R is C1～C6 low alkyl group in the said structure formula.
10. the method for preparing the described compound of claim 9, the method is: formula Formula-E compound mode by catalyst hydrogenation in organic solvent is amino with nitroreduction.
11. described method is characterized in that according to claim 10, the organic solvent of institute is for being selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), methyl tertiary butyl ether and mixed solvent thereof.
12. described method is characterized in that according to claim 10, described catalyzer is palladium-carbon catalyst.
13. described method is characterized in that according to claim 10, described adding formula Formula-E compound is 1 with the mass ratio that contains the palladium carbon of palladium 10%:: 0.01～1: 1.
14. described method is characterized in that according to claim 10, the temperature of described chemical reaction is 0～50 degree centigrade.
15. the intermediate of a synthetic ADZ6140 is formula Formula-G compound
Wherein R is C1～C6 low alkyl group in the said structure formula.
16. prepare the method for the described compound of claim 15, the method is: formula Formula-F compound forms the formula Formula-G compound of triazole ring structure with the Isopentyl nitrite reaction in organic solvent.
17. described method is characterized in that according to claim 16, described organic solvent is acetonitrile.
18. described method is characterized in that according to claim 16, the described mol ratio that adds formula Formula-F compound and Isopentyl nitrite is 1: 1～1: 5.
19. described method is characterized in that according to claim 16, the temperature of described chemical reaction is 0～80 degree centigrade.
20. the method for a synthetic ADZ6140 comprises the steps:
(a) formula Formula-G compound is sloughed the condensation of a part hydrogenchloride with formula Formula-10 compound at alkaline condition and is obtained formula Formula-H compound in inert organic solvents
Wherein R is C1～C6 low alkyl group in the said structure formula
(b) formula Formula-H compound by reduction reaction, goes back that ester group obtains formula Formula-e compound in the primary structure in inert organic solvents.
(c) formula Formula-e compound takes off acetonylidene protection by acid-catalyzed hydrolysis and obtains formula 1 compound (ADZ6140) crude product in organic solvent, and crude product obtains high-quality ADZ6140 product through solvent treatment.
21. described method is characterized in that according to claim 20, the selected reaction medium of described step a is methylene dichloride.
22. described method is characterized in that according to claim 20, the organic bases that described step a adopts can be diisopropylethylamine, triethylamine or pyridine.
23. described method is characterized in that according to claim 22, described organic bases is diisopropylethylamine.
24. described method is characterized in that according to claim 20, adds formula Formula-G compound among the described step a, the mol ratio of formula Formula-10 compound and organic bases is 1: 1: 1～1: 3: 6.
25. described method is characterized in that according to claim 20, the temperature of described step a reaction is-10～50 degrees centigrade.
26. described method is characterized in that according to claim 20, the described inert organic solvents of described step b is tetrahydrofuran (THF).
27. described method is characterized in that according to claim 20, the reductive agent that described step b adopts is preferably sodium borohydride.
28. described method is characterized in that according to claim 20, the reducing catalyst that described step b adopts is lithiumbromide.
29. described method is characterized in that according to claim 20, described step b adds formula Formula-H compound, and the mol ratio of sodium borohydride and lithiumbromide is 1: 1: 1～1: 5: 5.
30. described method is characterized in that according to claim 20, the temperature of described step b reaction is 0～80 degree centigrade.
31. described method according to claim 20, it is characterized in that refining solvent is selected from the formula 1 (ADZ6140) that crystallization in the recrystallisation solvent of Virahol, isopropanol-water, ether, methyl tertbutyl, ethyl acetate, acetone, acetone-ether, acetone-methyl tertiary butyl ether, acetone-normal hexane, acetone-sherwood oil, ethyl acetate-ether, ethyl acetate-normal hexane, ethyl acetate-normal heptane, ethyl acetate-sherwood oil and composition thereof obtains crystal form among the described step c.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360396A (en) * | 2013-06-27 | 2013-10-23 | 苏州明锐医药科技有限公司 | Method for preparing ticagrelor |
| CN103524429A (en) * | 2013-09-28 | 2014-01-22 | 银杏树药业(苏州)有限公司 | Preparation method of ticagrelor and novel intermediates of ticagrelor |
| WO2014036823A1 (en) * | 2012-09-10 | 2014-03-13 | 常州制药厂有限公司 | Novel preparation method of antithrombosis medicine |
| CN103992323A (en) * | 2014-04-18 | 2014-08-20 | 南通常佑药业科技有限公司 | Ticagrelor preparation method |
| WO2014155389A2 (en) * | 2013-03-25 | 2014-10-02 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of ticagrelor |
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| WO2014166337A1 (en) * | 2013-04-07 | 2014-10-16 | 杭州领业医药科技有限公司 | Crystalline form of ticagrelor and manufacturing method and usage thereof |
| CN104193748A (en) * | 2014-08-14 | 2014-12-10 | 严白双 | Method for synthesizing ticagrelor |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1334816A (en) * | 1998-12-04 | 2002-02-06 | 阿斯特拉曾尼卡有限公司 | Triazolo (4,5-D) pyrimidine compounds |
| US20030148888A1 (en) * | 2000-06-02 | 2003-08-07 | Ulf Larsson | Novel triazolo pyrimidine compounds |
| CN101235024A (en) * | 2008-02-01 | 2008-08-06 | 中国科学院上海有机化学研究所 | Benzodihydropyrane compounds, synthesizing method and use thereof |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| WO2012138981A2 (en) * | 2011-04-06 | 2012-10-11 | Teva Pharmaceutical Industries Ltd. | New intermediates and processes for preparing ticagrelor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875537A (en) * | 2012-09-10 | 2013-01-16 | 常州制药厂有限公司 | Novel preparation method of antithrombosis medicine |
-
2012
- 2012-09-10 CN CN2012103312665A patent/CN102875537A/en active Pending
-
2013
- 2013-03-22 WO PCT/CN2013/073061 patent/WO2014036823A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1334816A (en) * | 1998-12-04 | 2002-02-06 | 阿斯特拉曾尼卡有限公司 | Triazolo (4,5-D) pyrimidine compounds |
| US20030148888A1 (en) * | 2000-06-02 | 2003-08-07 | Ulf Larsson | Novel triazolo pyrimidine compounds |
| CN101235024A (en) * | 2008-02-01 | 2008-08-06 | 中国科学院上海有机化学研究所 | Benzodihydropyrane compounds, synthesizing method and use thereof |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| WO2012138981A2 (en) * | 2011-04-06 | 2012-10-11 | Teva Pharmaceutical Industries Ltd. | New intermediates and processes for preparing ticagrelor |
Cited By (19)
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|---|---|---|---|---|
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| WO2014155389A2 (en) * | 2013-03-25 | 2014-10-02 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of ticagrelor |
| WO2014155389A3 (en) * | 2013-03-25 | 2015-01-15 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of ticagrelor |
| CN104284897B (en) * | 2013-04-07 | 2016-06-01 | 杭州领业医药科技有限公司 | Brilliant type of ADZ6140 and its production and use |
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| CN104284897A (en) * | 2013-04-07 | 2015-01-14 | 杭州领业医药科技有限公司 | Crystalline form of ticagrelor and manufacturing method and usage thereof |
| US9359366B2 (en) | 2013-04-10 | 2016-06-07 | Jiangsu Hengrui Medicine Co., Ltd. | Intermediate of Ticagrelor and preparation method therefor, and preparation method for Ticagrelor |
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