CN102659815B - Method for preparing selective anticoagulant ticagrelor and intermediates thereof - Google Patents

Method for preparing selective anticoagulant ticagrelor and intermediates thereof Download PDF

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CN102659815B
CN102659815B CN 201210138562 CN201210138562A CN102659815B CN 102659815 B CN102659815 B CN 102659815B CN 201210138562 CN201210138562 CN 201210138562 CN 201210138562 A CN201210138562 A CN 201210138562A CN 102659815 B CN102659815 B CN 102659815B
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card gray
carbon atom
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CN102659815A (en
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安荣昌
董学军
王伟华
庄大浪
徐全文
彭少平
陈平
陈星�
蔡振伟
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Aifon Zhiyuan (Kaiyuan) Pharmaceutical Co. Ltd.
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PHARMARESOURCES (SHANGHAI) CO Ltd
KAIYUAN HENGTAI PHARMA CO Ltd
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

The invention discloses a method for preparing selective anticoagulant ticagrelor and intermediates thereof. According to the method, the ticagrelor is synthesized by multi-step reaction, and brand-new intermediates I, II and III are involved in the reaction. The method is novel in technical route, easy and convenient to operate and suitable for industrialized mass production.

Description

A kind of selectivity anticoagulant for preparing is for the method for card Gray and intermediate thereof
Technical field
The present invention relates to have optionally, the anticoagulant compound belongs to technical field of medicine synthesis for the brand-new synthetic method of card Gray and pharmacy acceptable salt thereof.
Background technology
For card Gray, English name: Ticagrelor; Once used code name: ADZ6140, AR-C126532 belongs to the cyclopentyl triazolopyrimidines, chemistry (1S by name, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3, the 4-dichlorophenyl) cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1, the 2-glycol.This medicine be by U.S.'s AstraZeneca (AstraZeneca) company research and development a kind of novel, have an optionally small molecules anticoagulant.Purine 2 acceptor (purinoceptor2 on this medicine energy reversibility ground vasoactive smooth muscle cell (VSMC), P2) hypotype P2Y12, the platelet aggregation that ADP is caused has the obvious suppression effect, and it is rapid to orally use the back onset, therefore can effectively improve acute coronary patient's symptom.And because the antiplatelet effects for card Gray is reversible, it is for those need the patient of row operation be particularly suitable again after carrying out anticoagulant therapy in advance.Comparing the most attractive advantage of its rival's clopidogrel for card Gray is significantly to reduce the death that cardiovascular source property and all reasons cause.It is a kind of anticoagulant that has a extensive future.
Comprise US6525060 about the relevant patent documentation of synthetic method for card Gray in the prior art, US20030148888 and WO2011017108 etc., they disclose a plurality of synthetic methods.Wherein patent US20030148888 discloses the synthetic route (seeing synthetic route 1) with the synthetic target product of thiobarbituricacid (I-5).I-5 is through alkylation, make I-7 with the condensation of para-totuidine diazotization, phosphorus oxychloride chlorination and catalytic hydrogenolytic cleavage; compound I-7 gets I-8 with intermediate compound I-4 condensation under the triethylamine effect; compound I-8 makes 8-azapurine analog derivative I-9 through Sodium Nitrite/acetic acid cyclization, and compound I-9 removes the acetonylidene protecting group with I-10 through cyclization, acidolysis and makes for card Gray.
Figure BDA00001604543000021
Synthetic route 1
Patent US6525060 (seeing synthetic route 2) discloses via 2-rosickyite base-4, the synthetic route of the synthetic target product of 6-two chloro-, 5 nitro-pyrimidines (II-1).Compound I I-1 and II-2 are at N; condensation under the effect of N-diisopropylethylamine; the II-3 of gained gets 8-azaadenine analog derivative II-6 through iron powder/acetic acid reduction, amyl nitrite (i-AmONO) cyclization, ammonification; compound I I-6 under the butyllithium effect with 2-trifluoro-methanesulfonyl oxy methyl acetate II-7 reaction after; again through bromo, with chiral intermediate II-10 condensation, remove the isopropylidene protection finally by diisobutyl aluminium hydride (DIBAL-H) reduction ester group, acidolysis and obtain for card Gray.
Figure BDA00001604543000031
Synthetic route 2
Summary of the invention
At above-mentioned defective of the prior art, the invention discloses a kind of novel preparation method (seeing synthetic route 3) for card Gray.In this method, be that raw material makes through polystep reaction and has complicated chipal compounds A with natural D-ribose.Simultaneously, in synthetic process for card Gray, relate to a plurality of brand-new intermediates, the technological line novelty, easy and simple to handle, be fit to industrialized production.
Figure BDA00001604543000032
Synthetic route 3
This shows that the present invention at first relates to for card Gray key intermediate I, it has the structure shown in the formula I,
Wherein R1, R2 are selected from hydrogen, alkyl, cycloalkyl, aryl separately or in the same manner; R4 is halogen, hydroxyl or trifluoromethanesulfonic acid base; R5 is nitro, nitroso-group, azanol or substituted-amino.
The invention still further relates to the above-mentioned method for card Gray key intermediate I of preparation, comprising: compd A and B
Figure BDA00001604543000042
Reaction obtains intermediate compound I.
Wherein the preparation of compd A can be with reference to (J.Org.Chem. 70, 6885,2005; J.Org.Chem. 55, 3853,1990) and method in the document, it is raw material with D-ribose, the acetonylidene protection, through azanol reaction, reactions such as cyclization make (seeing synthetic route 4), wherein remove the method that protecting group also can adopt benzyl to transform various carbamates on the N and carry out.
Figure BDA00001604543000043
Synthetic route 4
The preparation of compd B can be with reference to the method in the WO2011017108A2 document, and it is with 4,6-dihydroxyl-2-mercaptopyrimidine, and is nitrated through alkylation, and chlorination makes (seeing synthetic route 5).
Figure BDA00001604543000051
Synthetic route 5
Secondly, the present invention relates to for card Gray key intermediate II, it has the structure shown in the formula II,
Figure BDA00001604543000052
Wherein R1, R2 are selected from hydrogen, alkyl, cycloalkyl, aryl separately or in the same manner; R5 is nitro, nitroso-group, azanol or substituted-amino; R6 is (replacement) aryloxy, (replacement) heterocycle aryloxy or triazole.
The invention still further relates to the above-mentioned method for card Gray key intermediate II of preparation, comprising: intermediate compound I and R 6H or R 6Anion salt reaction obtain intermediate II.
Be reflected under the alkaline condition and carry out, selected alkali comprises triethylamine, Trimethylamine 99, and diisopropyl ethyl amine etc., solvent can be selected methylene dichloride, chloroform, 1,2-ethylene dichloride etc., the post-reaction treatment process can adopt column chromatography or crystallization in alcohol.
Again, the present invention relates to for card Gray key intermediate III, it has the structure shown in the formula III,
Figure BDA00001604543000053
Wherein R1, R2 are selected from hydrogen, alkyl, cycloalkyl, aryl separately or in the same manner; R6 is (replacement) aryloxy, (replacement) heterocycle aryloxy or triazole.
The invention still further relates to the above-mentioned method for card Gray key intermediate III of preparation, comprising: intermediate II obtains intermediate III through reduction, diazotization cyclization.
The reduction reaction of intermediate II can be chosen in zinc powder, and the palladium charcoal carries out under the multiple reduction reagent conditions such as Ranny Ni, at acetic acid, and methyl alcohol, ethanol carries out in the tetrahydrofuran (THF) equal solvent, and reaction can be directly used in next step reaction after conventional treating processes.
The process of diazotization cyclization can be selected reagent such as Sodium Nitrite, potassium nitrite, carries out to room temperature condition at 0 ° of C, and reaction solvent can be chosen in acetic acid or the water, and the post-reaction treatment process can adopt washing.
At last, the present invention relates to a kind of preparation for the method for card Gray and salt thereof, comprise; Intermediate III and Compound C
Figure BDA00001604543000061
Reaction obtains Compound D
Figure BDA00001604543000062
Compound D and compd E reaction,
Figure BDA00001604543000063
Again through carboxylicesters reduction, take off the acetonylidene protecting group, salify obtains for card Gray and salt thereof,
Figure BDA00001604543000064
Wherein R7 is hydrogen, silicon alkoxyl group, alkyl oxide or alkoxyl group; R8 is halogen or (replacement) sulphonate; But R7 and R8 cyclization are ring texture; " C=R9 " is " C=O " or " CH2 ".
Be reflected under the organic bases condition and carry out, selected alkali comprises Trimethylamine 99, triethylamine, and diisopropyl ethyl amine, solvent can be selected acetonitrile etc., and the post-reaction treatment process can adopt column chromatography.
In the method for the present invention's preparation for card Gray key intermediate I, R1, R2 are preferably methyl, and R3, R4 are preferably halogen, R5 is preferably nitro.
In the method for the present invention's preparation for card Gray key intermediate II, R6 is preferably (replacement) aryloxy, and the substituting group on the phenyl ring can be but be not limited to (single or polysubstituted) methyl or methoxy etc.
In the method for the present invention's preparation for card Gray and salt thereof, R7 is preferably methoxyl group, oxyethyl group or tert.-butoxy, and R8 is preferably bromine or iodine, and " C=R9 " is preferably ketone group.
In the patent application of the present invention, unless otherwise mentioned:
" alkyl " comprises straight chain and the side chain of 1-8 carbon atom, is good with 1-3 carbon atom.Alkyl can comprise for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group etc.
The saturated mono ring structure of 3-8 carbon atom of " cycloalkyl " expression, cyclopropyl for example, cyclobutyl, cyclopentyl, cyclohexyl etc.
Description of drawings
Accompanying drawing 1: the 1H-NMR collection of illustrative plates of intermediate 2;
Accompanying drawing 2: the 1H-NMR collection of illustrative plates of intermediate 4;
Accompanying drawing 3: the 1H-NMR collection of illustrative plates of intermediate 6;
Accompanying drawing 4: the 1H-NMR collection of illustrative plates of intermediate 7;
Accompanying drawing 5: the 1H-NMR collection of illustrative plates of intermediate 8;
Accompanying drawing 6: the 1H-NMR collection of illustrative plates of intermediate 9;
Accompanying drawing 7: the 1H-NMR collection of illustrative plates of intermediate 10;
Accompanying drawing 8: the 1H-NMR collection of illustrative plates of intermediate 11;
Accompanying drawing 9: the 1H-NMR collection of illustrative plates of intermediate 12;
Accompanying drawing 10: for card Gray's 1H-NMR collection of illustrative plates.
Embodiment
The present invention is described in further detail below by embodiment, the purpose of embodiment be the explanation and non-limiting.
Embodiment 1
(3aR, 4S, 7R, 7aS)-and 6-phenmethyl-2,2-dimethyl tetrahydro-3aH-4,7-methylene radical [1,3] dioxy cyclopentenes [4, the 5-d] [preparation of 1,2] oxazine (2)
With raw material 1(7.45g, 47.8mmol) be dissolved in 95% ethanol (52mL) with the benzyl oxammonium hydrochloride, add Na 2CO 3(11.30g, 106.2mmol), stirring reaction is 1 hour under the room temperature.TLC filters after detecting (sherwood oil: ethyl acetate=3:1, raw material Rf=0.6 and product Rf=0.3) reaction end, and filtrate concentrates.
In above-mentioned enriched material, add dimethylbenzene (40mL), be warming up to 150 ℃, continue after backflow 1-2 hour, TLC detects (sherwood oil: ethyl acetate=10:1, raw material Rf=0.1 and product Rf=0.4) after reaction finishes, decompression adds ethyl acetate (100mL) and water (200mL) except removal xylene, separates organic phase.(sherwood oil: ethyl acetate=30:1 → 20:1) obtains product 2 output: 9.04g, yield: 72% to cross column purification.
1H?NMR(400MHz,CDCl 3)δ7.37–7.24(m,5H),4.45(s,1H),4.39–4.10(m,2H),4.01(d,J=12.7Hz,1H),3.70(d,J=12.7Hz,1H),3.54(s,1H),2.05(t,J=14.7Hz,2H),1.43(s,3H),1.26(d,J=7.2Hz,3H)。
Embodiment 2
(3aR, 4S, 7R, 7aS)-2,2-dimethyl tetrahydro-3aH-4,7-methylene radical [1,3] dioxy cyclopentenes [4, the 5-d] [preparation of 1,2] oxazine (4)
Figure BDA00001604543000091
With compound 2(5g, 19.15mmol) be dissolved in 1, the 2-ethylene dichloride (30mL), add lithium iodide (3.85g; 285.7mmol), this system is down to 0 ℃, under the nitrogen protection; slowly drip 1-chloroethyl chloro-formic ester (22g, 10mL 1 191.5mmol), 2-dichloroethane solution.This reaction system is risen to room temperature, stirred 20 hours, TLC detects (sherwood oil: ethyl acetate=10:1, intermediate Rf=0.35).It is standby that this reaction solution is concentrated evaporate to dryness.
Add 20mL methyl alcohol in the above-mentioned concentrated solution, be warming up to 50 ℃, after stirring after half an hour TLC and detecting (sherwood oil: ethyl acetate=1:1, intermediate Rf=0.2) reaction and finish, the pressure reducing and steaming solvent.(methylene dichloride: methyl alcohol=20:1) obtains product 4 to cross column purification.
Output: 2.05g, yield: 55%.
1H?NMR(400MHz,CDCl 3)δ4.95(s,1H),4.60(d,J=5.6Hz,1H),4.49(s,1H),4.26(d,J=5.6Hz,1H),2.22(d,J=12.4Hz,1H),1.91(d,J=12.4Hz,1H),1.39(s,3H),1.25(s,3H)。
Embodiment 3
(3aR, 4S, 7R, 7aS)-and 6-(6-chloro-5-nitro-2 (rosickyite base) pyrimidine-4-yl)-2,2-dimethyl tetrahydro-3aH-4,7-methylene radical [1,3] dioxy cyclopentenes [4, the 5-d] [preparation of 1,2] oxazine (6)
Figure BDA00001604543000101
With compound 5(3.97g, 15mmol) be dissolved in the 35mL methylene dichloride, the adding triethylamine (2.63g, 26mmol).This system is cooled to 0 ℃, under the nitrogen protection, adds compound 4(2.20g, 13mmol) in batches.This reaction system is risen to room temperature, and after stirring 1 hour, add the water of 20mL, separate organic phase, concentrated column purification (sherwood oil: ethyl acetate=20:1), obtain product 6.
Output: 3.98g, yield: 80%.
1H?NMR(400MHz,CDCl 3)δ5.13(s,1H),4.69(s,1H),4.35(m,1H),4.40(m,1H),2.28(d,J=8.4Hz,1H),1.96(m,1H),1.46(s,3H),1.30(s,3H),1.05(t,J=7.2Hz,3H)。
Embodiment 4
(3aR, 4S, 7R, 7aS)-2,2-dimethyl-6-(5-nitro-6-phenoxy group-2-(rosickyite base) pyrimidine-4-yl) tetrahydrochysene-3aH-4,7-methylene radical [1,3] dioxy cyclopentenes [4, the 5-d] [preparation of 1,2] oxazine (7)
Figure BDA00001604543000102
Phenol (1.40g, 15mmol) and cesium carbonate (6.56g 20mmol) is added in the 20mL acetonitrile and stirs, following compound 6(4g of ice-water bath, 10mmol) drips of solution that is dissolved in the 10mL acetonitrile is added.This reaction solution is risen to room temperature, and stir 1 detection reaction end as a child (TLC shows that reaction finishes sherwood oil: ethyl acetate=10: 1, raw material Rf=0.4, product Rf=0.35).After boiling off solvent, add the ethyl acetate of 20mL and the water of 20mL, separate organic phase, dry concentrating adds the making beating of 5mL absolute ethyl alcohol and stirring in the resistates, filter, and obtains compound 7.
Output: 4g, yield: 90%.
LC-MS:M+H +=461
1H?NMR(400MHz,d6-DMSO)δ7.22-7.48(m,5H),5.03(s,1H),4.88(s,1H),4.43(d,J=5.2Hz,1H),4.27(d,J=5.2Hz,1H),2.28(m,2H),2.16(d,J=11.2Hz,1H),1.85(d,J=11.2Hz,1H),1.48(m,2H),1.40(s,3H),1.26(s,3H),0.78(t,J=7.2Hz,3H)。
Embodiment 5
(3aR, 4S, 6R, 6aS)-and 6-(5-amino-6-phenoxy group-2-(rosickyite base) pyrimidine-4-base is amino)-2, the preparation of 2-dimethyl-tetrahydrochysene-3aH-cyclopentyl [d] [1,3] dioxy cyclopentenes-4-alcohol (8).
Figure BDA00001604543000111
With compound 7(2g, 4.3mmol) be dissolved in the methyl alcohol, (2.8g is 43mmol) with two acetic acid to add zinc powder.This system is warming up to backflow, continue to stir half an hour after detection reaction finish.(TLC shows that reaction finishes sherwood oil: ethyl acetate=20: 1).Cross column purification (sherwood oil: ethyl acetate=3: 1) obtain compound 8.
Output: 1.5g, yield: 80%.
LC-MS:M+H +433
1H?NMR(400MHz,d6-DMSO)δ7.05-7.39(m,5H),6.33(d,J=7.6Hz,1H),5.35(d,J=3.2Hz,1H),4.50(d,J=6.0Hz,1H),4.43(d,J=6.0Hz),4.35(t,J=6.0Hz,1H),4.08(s,3H),2.79(dd,J 1=6.4Hz,J 2=8.0Hz,2H),2.22(m,1H),1.70(d,13.6H),1.52(m,2H),1.36(s,3H),1.21(s,,3H),0.82(t,J=7.2Hz,3H)。
Embodiment 6
(3aR, 4S, 6R, 6aS)-2, the preparation of 2-dimethyl-6-(7-phenoxy group-5-(rosickyite base)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl)-tetrahydrochysene-3aH-cyclopentyl [d] [1,3] dioxy cyclopentenes-4-alcohol (9)
Figure BDA00001604543000121
(1g 2.3mmol) is dissolved in the mixed solvent of the acetic acid of 10mL and water (9:1) with compound 8.This system is cooled to 0-10 ℃, slowly drips NaNO 2(800mg, aqueous solution 5mL 11.5mmol).After dropwising, stirred 1 hour down at 0-10 ℃.Reaction system is slowly poured in the mixed system of the ethyl acetate of ice and water, separated organic phase, and use NaHCO respectively 3The aqueous solution, the saturated common salt water washing.Drying concentrates.Obtain compound 9.
Output: 1g, yield: 95%.
1H?NMR(400MHz,CDCl 3)δ7.38-7.55(m,5H),5.35(dd,J 1=4.0Hz,J 2=3.2Hz,1H),5.28(d,J=4.4Hz,1H),5.12(m,1H),5.35(dd,J 1=4.0Hz,J 2=3.2Hz,1H),4.18(m,1H),2.93(t,J=7.6Hz,2H),2.61(m,1H),1.56(m,2H),1.48(s,3H),1.28(s,9H),0.84(t,J=7.62Hz,3H)。
Embodiment 7
2-(the preparation of (3aR, 4S, 6R, 6aS)-2,2-dimethyl-6-(7-phenoxy group-5-(rosickyite base)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl)-tetrahydrochysene-3aH-cyclopentyl [d] [1,3] dioxy cyclopentenes-4-oxygen base) tert.-butyl acetate (10)
With compound 9(1g, 2.2mmol) be dissolved in the dry DMF of 15mL, and the displacement nitrogen protection.This system is cooled to-20 ℃.Add in batches NaH (132mg, 60%, 3.3mmol).After finishing, after stirring 20min under this temperature, the THF solution of dripping bromine tert.-butyl acetate (862mgin 1 mL THF, 4.4mmol), reaction rises to room temperature, continues to stir after 1 hour, reaction solution is slowly poured in the aqueous solution of the ethyl acetate of ice and potassium primary phosphate, separate organic phase, dry concentrating.Cross column purification (sherwood oil: ethyl acetate=5:1), obtain compound 10.
Output: 660mg, yield: 50%.
1H?NMR(400MHz,CDCl 3)δ7.28(m,5H),5.55(dd,J 1=3.6Hz,J 2=7.2Hz,1H),5.21(m,1H),4.86(dd,J 1=2.4Hz,J 2=6.8Hz,1H),4.14(m,1H),4.03(d,J=2.4Hz,2H),2.91(dd,J 1=6.4Hz,J 2=8.0Hz,2H),2.75(t,J=7.2Hz,2H),1.61(m,2H),1.57(s,3H),1.48(s,9H),1.37(s,3H),0.89(t,J=7.2Hz,3H)。
Embodiment 8
2-((3aR, 4S, 6R, 6aS)-6-(7-((1R, 2S)-2-(3, the 4-difluorophenyl) cyclopropylamino)-5-(rosickyite base)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl)-2,2-dimethyl-tetrahydrochysene-3aH-cyclopentyl [d] [1,3] dioxy cyclopentenes-4-oxygen base) preparation of tert.-butyl acetate (11)
Figure BDA00001604543000132
With compound 10(100mg, 0.17mmol) be dissolved in the 2mL acetonitrile, add DIPEA(43mg, 0.34mmol) and (1R, 2S)-(43mg, 0.26mmol), being warming up to refluxes spends the night 2-(3,4-difluorophenyl) cyclopropylamine.This reaction solution is directly mixed silica gel cross column purification (sherwood oil: ethyl acetate=5: 1) obtain compound 11.
Output: 65mg, yield: 60%.
1H?NMR(400MHz,CDCl 3)δ7.08(m,3H),5.42(dd,J 1=4.0Hz,J 2=6.0Hz,1H),5.10(m,1H),4.78(dd,J 1=2.8Hz,J 2=6.8Hz,1H),4.10(m,1H),4.01(d,J=7.2Hz,2H),3.07(m,3H),2.70(m,2H),2.17(m,1H),1.90(m,1H),1.69(m,2H),1.54(s,3H),1.45(s,9H),1.32(s,3H),0.99(t,J=7.2Hz,3H)。
Embodiment 9
2-((3aR, 4S, 6R, 6aS)-6-(7-((1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamino)-5-(rosickyite base)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl)-2,2-dimethyl-tetrahydrochysene-3aH-cyclopentyl [d] [1,3] dioxy cyclopentenes-4-oxygen base) preparation of ethanol (12)
Figure BDA00001604543000141
With compound 11(64mg, 0.10mmol) be dissolved among the anhydrous THF, add under the ice bath 10mg LAH (lithium aluminum hydride, 2.5eq), rise to room temperature after, (PE/EA=3:1 Rf=0.3) detects raw material reaction and finishes, and the product generation is arranged to stir LC-MS after 1 hour.The Prep-TLC purifying obtains compound 12.
Output: 48mg, yield: 77%.
1H?NMR(400MHz,CDCl 3)δ6.95-7.16(m,3H),5.52(dd,J 1=2.0Hz,J 2=6.0Hz,1H),5.17(m,1H),4.88(d,J=6.4Hz,1H),4.04(m,1H),3.51–3.68(m,4H),3.04–3.13(m,3H),2.67(m,2H),2.48(m,1H),1.98(br,1H),1.72(dd,J 1=6.0Hz,J 2=14.0Hz,2H),1.55(s,3H),1.37(s,3H),0.98(t,J=7.2Hz,3H)。
Embodiment 10
(1S, 2S, 3R, 5S)-3-(7-((1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamino)-5-(rosickyite base)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl)-5-(2-hydroxy ethoxy) pentamethylene-1, and the 2-glycol (13, preparation Ticagrelor)
Figure BDA00001604543000151
With compound 12(60mg, 0.1mmol) be dissolved in the methyl alcohol of 2mL, under the room temperature, add the hydrochloric acid (3N) of 5mL, continue to stir 1 hour, the HPLC detection reaction finishes.Prep-HPLC prepares end product 13.
Output: 40mg, yield: 73%
LC-MS:M+H +523
1H?NMR(400MHz,CD 3OD)δ7.28-7.13(m,2H),7.07(s,1H),5.13(q,1H),4.77(m,1H),4.19(m,1H),3.93(m,1H),3.77-3.60(m,4H),3.09(m,2H),3.00-2.85(m,1H),2.84–2.71(m,1H),2.23(m,2H),1.79-1.54(m,2H),1.54-1.32(m,2H),0.93(t,J=7.3Hz,3H)。

Claims (8)

1. for card Gray key intermediate I, it has the structure shown in the formula I,
Figure FDA00003133949800011
R wherein 1, R 2Straight or branched alkyl for 1-3 carbon atom; R 4Be halogen or hydroxyl; R 5Be nitro, nitroso-group or azanol.
2. prepare the described method for card Gray key intermediate I of claim 1, comprising: compd A and B
Figure FDA00003133949800012
Reaction obtains intermediate compound I
Figure FDA00003133949800013
R wherein 1, R 2Straight or branched alkyl for 1-3 carbon atom; R 3, R 4Be halogen or hydroxyl; R 5Be nitro, nitroso-group or azanol.
3. method according to claim 2, wherein R 1And R 2Be methyl, R 4Be halogen, R 5Be nitro.
4. for card Gray key intermediate II, it has the structure shown in the formula II,
R wherein 1, R 2Straight or branched alkyl for 1-3 carbon atom; R 5Be nitro, nitroso-group or azanol; R 6Be aryloxy.
5. prepare the described method for card Gray key intermediate II of claim 4, comprising: intermediate compound I and R 6H or R 6Anion salt reaction obtain intermediate II,
Figure FDA00003133949800022
Described intermediate compound I is shown below,
Figure FDA00003133949800023
R wherein 1, R 2Straight or branched alkyl for 1-3 carbon atom; R 4Be halogen or hydroxyl; R 5Be nitro, nitroso-group or azanol; R 6Be aryloxy.
6. for card Gray key intermediate III, it has the structure shown in the formula III,
Figure FDA00003133949800024
R wherein 1, R 2Straight or branched alkyl for 1-3 carbon atom; R 6Be aryloxy.
7. prepare the described method for card Gray key intermediate III of claim 6, comprising: intermediate II obtains intermediate III through reduction, diazotization cyclization,
Figure FDA00003133949800031
Described intermediate II is shown below,
Figure FDA00003133949800032
R wherein 1, R 2Straight or branched alkyl for 1-3 carbon atom; R 5Be nitro, nitroso-group or azanol; R 6Be aryloxy.
8. a method for preparing for card Gray and salt thereof comprises; Intermediate III and Compound C
Figure FDA00003133949800033
Reaction obtains Compound D
Compound D and compd E reaction,
Again through carboxylicesters reduction, take off the acetonylidene protecting group, salify obtains for card Gray and salt thereof,
Figure FDA00003133949800041
Described intermediate III is shown below,
Figure FDA00003133949800042
R wherein 1, R 2Straight or branched alkyl for 1-3 carbon atom; R 6Be aryloxy; R 7Be methoxyl group, oxyethyl group or tert.-butoxy; R 8Be bromine or iodine; " C=R 9" be ketone group.
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Publication number Priority date Publication date Assignee Title
CN102659815B (en) * 2012-05-04 2013-07-17 开原亨泰制药股份有限公司 Method for preparing selective anticoagulant ticagrelor and intermediates thereof
CN103664958B (en) * 2012-09-26 2017-06-27 四川海思科制药有限公司 A kind of crystal formation of Ticagrelor and preparation method thereof
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CN104098553B (en) 2013-04-10 2017-11-28 江苏恒瑞医药股份有限公司 The preparation method of intermediate of ticagrelor and preparation method thereof and ticagrelor
CN103304545B (en) * 2013-06-26 2015-05-20 苏州明锐医药科技有限公司 5-amino-1,4-disubstituent-1,2,3-triazole and preparation method thereof
CN103304567B (en) * 2013-06-27 2015-05-20 苏州明锐医药科技有限公司 Preparation method of ticagrelor
CN103288837B (en) * 2013-06-27 2015-08-05 苏州明锐医药科技有限公司 The preparation method of ticagrelor
CN103360396B (en) * 2013-06-27 2015-07-01 苏州明锐医药科技有限公司 Method for preparing ticagrelor
CN103588751B (en) * 2013-11-07 2014-12-17 苏州明锐医药科技有限公司 Method for preparing ticagrelor intermediate
CN103588750B (en) * 2013-11-07 2014-11-26 苏州明锐医药科技有限公司 Method for preparing ticagrelor intermediate
CN103992323B (en) * 2014-04-18 2017-03-29 南通常佑药业科技有限公司 A kind of preparation method of ticagrelor
CN105669674A (en) * 2014-11-21 2016-06-15 重庆圣华曦药业股份有限公司 Ticagrelor new crystal form, and application thereof in medicine preparation
CN106496180A (en) * 2016-10-19 2017-03-15 青岛云天生物技术有限公司 A kind of preparation method of ticagrelor intermediate
CN106496179A (en) * 2016-10-19 2017-03-15 青岛云天生物技术有限公司 A kind of synthesis technique of ticagrelor intermediate
CN106496247A (en) * 2016-10-19 2017-03-15 青岛云天生物技术有限公司 A kind of preparation method of ticagrelor midbody

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525060B1 (en) * 1998-12-04 2003-02-25 Astrazeneca Uk Limited Triazolo(4,5-d)pyrimidine compounds

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0013488D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Chemical compound
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
CN102659815B (en) * 2012-05-04 2013-07-17 开原亨泰制药股份有限公司 Method for preparing selective anticoagulant ticagrelor and intermediates thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525060B1 (en) * 1998-12-04 2003-02-25 Astrazeneca Uk Limited Triazolo(4,5-d)pyrimidine compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"替卡格雷合成路线图解";陈莉莉 等;《中国医药工业杂志》;20111231;第42卷(第2期);第146-150页 *
陈莉莉 等."替卡格雷合成路线图解".《中国医药工业杂志》.2011,第42卷(第2期),第146-150页.

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