CN102731467B - The intermediate of ADZ6140 and prepare the method for ADZ6140 - Google Patents
The intermediate of ADZ6140 and prepare the method for ADZ6140 Download PDFInfo
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- 0 CC1(C)O[C@@](*)(CC[C@@]2O)[C@]2O1 Chemical compound CC1(C)O[C@@](*)(CC[C@@]2O)[C@]2O1 0.000 description 2
- AXPYGRDXRLICKY-JRTVQGFMSA-N CC1(C)O[C@H]([C@H](C[C@H]2N)O)[C@H]2O1 Chemical compound CC1(C)O[C@H]([C@H](C[C@H]2N)O)[C@H]2O1 AXPYGRDXRLICKY-JRTVQGFMSA-N 0.000 description 1
- YESFOLYRVUODAF-DNMUOXJYSA-N CCCSc1nc(Cl)c2nn[n]([C@H](C3)[C@@H]4OC(C)(C)O[C@@H]4[C@H]3OCC[Tm])c2n1 Chemical compound CCCSc1nc(Cl)c2nn[n]([C@H](C3)[C@@H]4OC(C)(C)O[C@@H]4[C@H]3OCC[Tm])c2n1 YESFOLYRVUODAF-DNMUOXJYSA-N 0.000 description 1
- IUCHRJJXIZKLTA-UHFFFAOYSA-N OCCOC(c1ccccc1)(c1ccccc1)c1ccccc1 Chemical compound OCCOC(c1ccccc1)(c1ccccc1)c1ccccc1 IUCHRJJXIZKLTA-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides the new ticagrelor midbody shown in formula 5 or its salt, wherein P1 is hydroxy-protective group, and the preparation method of these intermediates; The invention still further relates to the method utilizing the compound shown in formula 5 to prepare ADZ6140.Utilize the method for the Intermediate Preparation ADZ6140 shown in formula 5 to have the advantage that technique is simple, yield is high, " three wastes " are few, the needs of suitability for industrialized production can be met.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to the intermediate of small molecules anticoagulant ticagrelor, Intermediate Preparation method and utilize the method for these Intermediate Preparation ADZ6140s.
Background technology
ADZ6140 (Ticagrelor; Once code name was used: ADZ6140, ARC126532), belong to cyclopentyl triazolopyrimidines, chemistry (1S by name, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1,2-glycol, be by U.S.'s AstraZeneca (AstraZeneca) company research and develop a kind of novel, there is optionally small molecules anticoagulant.This medicine can purine 2 acceptor (Purinoceptor2 reversibly on vasoactive smooth muscle cell (VSMC), P2) hypotype P2Y12, obvious restraining effect is had to the platelet aggregation that ADP causes, and it is rapid to orally use rear onset, therefore effectively can improve the symptom of acute coronary patient.And because of the antiplatelet effects of ADZ6140 be reversible, its for those need after carrying out anticoagulant therapy in advance again row operation patient particularly applicable.The molecular formula of ADZ6140: C
23h
28f
2n
6o
4s, No. CAS: 274693-27-5, there is the chemical structure shown in following formula:
Astra Pharmaceuticals Ltd discloses chemical structure and the pharmaceutical use of ADZ6140 in patent CN1270590, CN1334816, also discloses the method preparing ADZ6140 simultaneously, and the synthetic route of the method is for shown in following formula:
In this preparation method, yield lower than 30%, and needs in reaction process to use severe toxicity and expensive perosmic anhydride (osmium acid anhydride) catalyzed alkene cis-oxidation to become glycol, and these unfavorable factors limit the application of the method in actual production.Therefore, the intermediate developing superior performance is still very necessary with the preparation method meeting needs of production.
Summary of the invention
The object of this invention is to provide the key intermediate in synthesis ADZ6140 process, and the synthetic method of these intermediates.Another object of the present invention is to provide the method utilizing above-mentioned Intermediate Preparation ADZ6140.
For achieving the above object, the present invention adopts following technical scheme:
The present invention provide firstly intermediate or its salt of the ADZ6140 shown in formula 5:
Wherein, P
1for hydroxy-protective group.
Preferably, P
1for allyl group or the carbalkoxy of the benzyl of the trityl of silylation, trityl or replacement, benzyl or replacement, alkoxy methyl or alkoxyl group substituent methyl, acyl group, allyl group or replacement.
Further preferably, P
1for t-butyldimethylsilyi, tert-butyldiphenylsilanyl, trityl, benzyl, to methoxy-benzyl, 2-THP trtrahydropyranyl, methoxymethyl, 2-ethoxyethyl group, ethanoyl, benzoyl, pivaloyl group, allyl group, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), tablet held before the breast by officials methoxycarbonyl or allyloxycarbonyl.
Present invention also offers the method for preparation formula 5 compound, the method comprises the steps:
A () protects to obtain the compound shown in formula 2 to the amino on the compound shown in formula 1;
B () formula 2 compound and formula 3 compound react to obtain the compound shown in formula 4;
C () sloughs the amido protecting group P on formula 4 compound
2obtain formula 5 compound;
Wherein
P
1hydroxyl protecting group, P
2for amino protecting group, L is leavings group.
Preferably, P
1for THP trtrahydropyranyl, the carbalkoxy of the allyl group of the benzyl of the trityl of silylation, trityl or replacement, benzyl or replacement, alkoxy methyl or alkoxyl group substituent methyl, acyl group, allyl group or replacement, THP trtrahydropyranyl or replacement.
Preferably, P
2for carbobenzoxy-(Cbz), tertbutyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl group, ortho-nitrophenyl alkylsulfonyl, p-nitrophenyl alkylsulfonyl, pivaloyl group, benzoyl, trityl, 2,4-dimethoxy-benzyls, to methoxy-benzyl or benzyl.
Preferably, L is the leavings group of p-toluenesulfonyl, methylsulfonyl, trifluoroacetyl group or halogen.Halogen refers to chlorine, bromine or iodine.
The those of ordinary skill of medicinal chemistry arts should know structure and the english abbreviation of these common chemical groups, such as: p-toluenesulfonyl (-Ts), methylsulfonyl (-Ms), trifluoroacetyl group (-Tfs), carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), trityl (Trt), 2-THP trtrahydropyranyl (THP), phthaloyl (Pht), trifluoroacetyl group (Tfa), benzoyl (Bz), benzyl (Bn) etc.
The present invention also provides the method utilizing formula 5 compound to prepare ADZ6140 further, the method comprises the steps: 4 shown in (a) formula 5 compound and formula 6, the chloro-2-of 6-bis-(rosickyite alkyl)-5-pyrimidinamine compounds reacts, obtained formula 7 compound;
B () formula 7 compound and alkali-metal nitrite react, obtained compound shown in formula 8;
C the compound shown in the compound shown in () formula 8 with formula 9 is coupled and obtains the compound shown in formula 10;
D compound shown in formula 10 is sloughed hydroxy-protective group and is namely obtained Ticagrelor by ();
Wherein, P
1for THP trtrahydropyranyl, the carbalkoxy of the allyl group of the benzyl of the trityl of silylation, trityl or replacement, benzyl or replacement, alkoxy methyl or alkoxyl group substituent methyl, acyl group, allyl group or replacement, THP trtrahydropyranyl or replacement.
Further, the alkali-metal nitrite in step (b) is Sodium Nitrite or potassium nitrite, preferred Sodium Nitrite.
The compound that the present invention program provides is the important intermediate of synthesis ADZ6140, and utilize the technique of these Intermediate Preparation ADZ6140s simple, yield is higher, can meet the needs of suitability for industrialized production.
Embodiment
In order to make technical problem solved by the invention, technical scheme and beneficial effect clearly understand, below in conjunction with specific embodiment, the present invention is further illustrated.
one end of ethylene glycol is connected blocking group by embodiment 1, the other end connects leavings group
(1) one end of ethylene glycol is first connected blocking group by step a
By step a1:
100g ethylene glycol is dissolved in 150mlDMF; add 219.4g imidazoles (2.0eq; 3.22mol); cryosel bath is cooled to about 0 DEG C, slowly adds 362.8g (1.5eq, 2.42mol) TBDMSCl in batches; stirring at room temperature 1h after reinforced; reaction generation two products, namely only protect a hydroxyl and two hydroxyl full guard, wherein compound 3-TS accounts for 40%.Reaction solution is extracted with ethyl acetate three times, organic phase washed with water, and saturated nacl aqueous solution washes three times, anhydrous sodium sulfate drying, and concentrated post obtains 110g compound 3-TS, yield 39%.
Or step a2:
Under nitrogen protection, 100g ethylene glycol is dissolved in 250ml pyridine, ice bath is cooled to less than 0 DEG C; then 281ml Benzoyl chloride (1.5eq, 2.42mo1) is dripped, after dropwising; stirring reaction 1h; slowly poured into by reaction solution in the cold aqueous solution, gained solution with ethyl acetate extracts three times, merges organic phase; gained organic phase uses water and saturated common salt water washing three times respectively; anhydrous sodium sulphate T is dry, and concentrated post obtains 124.8g compound 3-Bz, yield 43%.
Or step a3:
Under nitrogen protection; 100g ethylene glycol is dissolved in 200ml tetrahydrofuran (THF); ice bath is cooled to about 0 DEG C; then 674.6g trityl chloride (1.5eq is added; 2.42mol); 465.5ml triethylamine (2.0eq is added again after stirring; 3.22mol), after reflux 2h, be cooled to room temperature; concentrated except desolventizing; residue 300ml acetic acid ethyl dissolution, gained organic phase washed with water and saturated aqueous common salt respectively wash three times, anhydrous sodium sulfate drying; concentrated post obtains 220.5g compound 3-Trt, yield 45%.(2) again the other end is connected leavings group
By step b1:
Under nitrogen protection; by 189.2g triphenyl phosphorus (1.2eq; 0.72mol) be dissolved in 300ml methylene dichloride, add 81.6g imidazoles (2.0eq, 1.2mol); then after being cooled to-5 DEG C; add 91.4g iodine (1.2eq, 0.72mol), after stirring reaction is about 1h; drip 100g compound 3-Bz (being dissolved in 200ml methylene dichloride), dropwise rear stirring reaction 1h.By in reaction solution impouring 500ml water, stir layering, water layer uses dichloromethane extraction twice again, and merge organic layer, organic layer washes twice with saturated aqueous common salt again, and the concentrated post of anhydrous sodium sulfate drying obtains 140.8g compound 3-1, yield 85%.
Or step b2:
Under nitrogen protection, 100g compound 3-Bz is dissolved in 250ml pyridine, and ice bath is cooled to 0 DEG C; slowly add 171.6g (1.5eq, 0.9mol) Tosyl chloride, stirring at room temperature reaction 1.5h after reinforced in batches; reaction solution is poured in 300ml water; aqueous phase is extracted with ethyl acetate three times, and merge organic phase, organic phase 1N hydrochloric acid is washed till neutrality; then water and saturated common salt water washing three times is used; anhydrous sodium sulfate drying, concentrated post obtains 147.8g compound 3-2, yield 76.9%.
Or step b3:
Under nitrogen protection; by 102.3g triphenyl phosphorus (1.2eq; 0.39mol) be dissolved in 300ml methylene dichloride, add 44.7g imidazoles (2.0eq, 0.66mol); then after being cooled to-5 DEG C; add 91.4g iodine (1.2eq, 0.39mol), after stirring reaction is about 1h; drip 100g compound 3-Trt (being dissolved in 200ml methylene dichloride), dropwise rear stirring reaction 1h.By in reaction solution impouring 500ml water, stir layering, water layer uses dichloromethane extraction twice again, and merge organic layer, organic layer washes twice with saturated aqueous common salt again, and the concentrated post of anhydrous sodium sulfate drying obtains the compound 3-3 of 115.7g, yield 85%.
the synthesis of embodiment 2 formula 5-1 compound
Step (a):
Under nitrogen protection, by 138g compound 1 (1.0eq, 0.8mol) (according to the preparation of CN1432017A disclosure method) to be dissolved in 250ml tetrahydrofuran (THF) and 67g sodium bicarbonate (1.0eq, in mixing solutions 0.80mol), ice bath is cooled to less than 0 DEG C, drip 128ml third alkenyloxycarbonyl chlorine (1.5eq, 1.2mol), dropwise rear room temperature reaction 12h, reaction solution is poured in 600ml water, separate organic layer, concentrate to obtain residue 300ml acetic acid ethyl dissolution, water layer is extracted with ethyl acetate twice again, combined ethyl acetate layer, organic layer 1N hydrochloric acid is washed till neutrality, saturated common salt is washed, anhydrous sodium sulfate drying obtains 168.1g compound 2-1, yield 82.0%.
Step (b):
Under nitrogen protection, by 50g compound 2-1 (1eq, 0.19mol) be dissolved in 150ml anhydrous tetrahydro furan, cryosel bath is cooled to less than 0 DEG C, slowly add 9.3gNaH (1.2eq in batches, 0.23mol), stirring reaction 0.5h, drip 95.3g compound 3-3 (1.2eq, tetrahydrofuran solution 100ml 0.23mol), dropwise rear stirring reaction 1h, reaction solution is poured into cancellation in 300ml saturated ammonium chloride solution, stir layering, organic layer concentrates, residue with Ethyl acetate dissolves, water layer is extracted with ethyl acetate twice again, merge organic phase, and with saturated common salt water washing three times, anhydrous sodium sulfate drying, concentrate to obtain 81.0g compound 4-1, yield 78.4%.
Step (c):
Be dissolved in 500ml methylene dichloride by 70g (1eq, 0.13mol) compound 4-1, ice bath is cooled to about 0 DEG C, then adds 5ml water under nitrogen protection, 5.5gPdCl
2(PPh
3)
2(0.06eq, 0.078mol) and 170.3gBu
3snH (4.5eq, 0.585mol), after reinforced, 0 DEG C is kept to react 20min, then reaction solution is poured into water, stirring separates organic layer, and water layer dichloromethane extraction twice, after concentrating under reduced pressure goes out most of solvent, precipitation is had to produce, elimination insolubles, the concentrated post of filtrate obtains 45.4g compound 5-1, yield 76%.
the synthesis of embodiment 3 formula 5-2 compound
Under nitrogen protection, by 138g compound 1 (1.0eq, 0.78mol) (according to CN1432017A disclosure method preparation) be dissolved in 400ml tetrahydrofuran (THF), ice bath is cooled to about 0 DEG C, add 228ml triethylamine (2.0eq, 1.44mol), after stirring 0.5h, add 204gCbzCl (1.5eq in batches, 1.2mol), after room temperature reaction 2h, reaction solution is poured in 600ml water, separate organic layer, concentrate to obtain residue 300ml acetic acid ethyl dissolution, water layer is extracted with ethyl acetate twice again, combined ethyl acetate layer, organic layers with water is washed till neutrality, saturated common salt is washed, anhydrous sodium sulfate drying obtains 225g compound 2-2, yield 92%.
Step (b):
Under nitrogen protection; by 50g compound 2-2 (1eq; 0.16mol) be dissolved in 150ml anhydrous tetrahydro furan; cryosel bath is cooled to less than 0 DEG C; slowly add 7.7gNaH (1.2eq, 0.19mol), stirring reaction 0.5h in batches; the 3-4 dripping 48.6g (1.2eq, 0.19mol) (can according to being similar to
embodiment 1method synthesis) tetrahydrofuran solution 100ml, dropwise rear stirring reaction 1h, reaction solution is poured into cancellation in 300ml saturated ammonium chloride solution, stir layering, organic layer concentrates, residue with Ethyl acetate dissolves, and water layer is extracted with ethyl acetate twice again, merges organic phase, and with saturated common salt water washing three times, anhydrous sodium sulfate drying, concentrates to obtain 56.5g compound 4-2, yield 80.1%.
Step (c):
140g compound 4-2 (1eq, 0.32mol) is dissolved in 300ml ethanol, then adds 10g10% and obtain Pd-C, keep hydrogen pressure 2atm, stirring at room temperature reaction 2h, raw material reaction is complete, elimination Pd-C, the concentrated post of filtrate obtains 87.3g compound 5-2, yield 90.3%.
the synthesis of embodiment 4 ADZ6140
Step (a):
Get 42.7g formula 6 compound (1.1eq, 0.18mol) 4,6-bis-chloro-2-(rosickyite alkyl)-5-PYRIMITHAMINE is dissolved in 200ml ethanol, adds 75g compound 5-1 (1eq under stirring, 0.16mol), then add 125ml triethylamine, reactor seals between keeping 20 ~ 25 DEG C by temperature, temperature is elevated to 120 ~ 125 DEG C, reaction mixture to remain within this temperature range 30 hours, is then cooled to 75 DEG C, relief pressure.Mixed solution is obtained temperature and be adjusted to 50 DEG C, pressure reducing and steaming solvent at 30 ~ 40 DEG C, add ethyl acetate 200ml and water 300ml, with the hydrochloric acid soln of 3M, the pH value of mixed solution is adjusted to 5, be separated two-phase, organic phase with 15% brine It, organic phase concentrating under reduced pressure obtains compound 7-1.
Step (b):
Previous step gained compound 7-1 is dissolved in the mixing solutions of 350ml acetic acid and 50ml water, and is cooled to 2 DEG C, add water (65ml) solution of Sodium Nitrite (15g), the temperature of mixture is remained on less than 7 DEG C.Then mixed solution is warmed to 7 DEG C, adds 500ml ethyl acetate, then add the wet chemical of 200ml37%, layering, organic phase removes acetic acid with the solution of potassium carbonate washing of 21% again, and aqueous phase discarded, organic phase concentrating under reduced pressure obtains compound 8-1.
Step (c):
The compound 8-1 that previous step is obtained is dissolved in 200ml acetonitrile, then add shown in 50g formula 9 trans-(1R, 2S)-2-(3,4-difluorophenyl)-cyclopropylamine (2R)-2-hydroxyl-2-phenyl acetate salt, after stirring, in mixing solutions, slowly add 63ml triethylamine, keep temperature of reaction between 20 ~ 25 DEG C, reaction mixture is stirred 10 hours, then concentrating under reduced pressure at 30 DEG C.In residue, add 500ml ethyl acetate and 250ml water, then the pH value in mixing solutions is adjusted to about 4, layering with the hydrochloric acid of 3M, the organic phase common salt aqueous solution of 15% washs, and concentrating under reduced pressure obtains compound 10-1.
Step (d):
Compound 10-1 is dissolved in trifluoroacetic acid (TFA) aqueous solution of 90% of 200ml, stirred at ambient temperature reaction 10h, then adds the sodium bicarbonate of 200g, reaction solution is neutralized, then in aqueous phase, add 500ml ethyl acetate, under stirring, mixed solution is heated to 45 DEG C, point water-yielding stratum.Ethyl acetate solution is heated to 47 DEG C, then 125ml octane-iso is added, mixing solutions is stirred 20 minutes, and then add 125ml octane-iso, mixing solutions is heated to 47 DEG C, heated and stirred 0.5h, normal temperature Slow cooling, filter, with the mixing solutions washing of octane-iso and ethyl acetate, dry 62g ADZ6140 (Ticagrelor).Ms：523[M+H]
+
It should be noted that and the foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. the intermediate of the ADZ6140 shown in formula 5 or its salt:
Wherein, P
1for silylation, trityl, benzyl, to methoxy-benzyl, 2-THP trtrahydropyranyl, acyl group or allyl group.
2. ticagrelor midbody according to claim 1 or its salt, is characterized in that, P
1for t-butyldimethylsilyi, tert-butyldiphenylsilanyl, trityl, benzyl, to methoxy-benzyl, 2-THP trtrahydropyranyl, ethanoyl, benzoyl, pivaloyl group or allyl group.
3. prepare the method for formula 5 compound according to claim 1, it is characterized in that, the method comprises the steps:
A () protects to obtain the compound shown in formula 2 to the amino on the compound shown in formula 1;
B () formula 2 compound and formula 3 compound react to obtain the compound shown in formula 4;
C () sloughs the amido protecting group P on formula 4 compound
2obtain formula 5 compound;
Wherein, P
1for silylation, trityl, benzyl, to methoxy-benzyl, 2-THP trtrahydropyranyl, acyl group or allyl group, P
2for amino protecting group, L is leavings group.
4. the method preparing ticagrelor midbody according to claim 3, is characterized in that, P
2for carbobenzoxy-(Cbz), tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl group, ortho-nitrophenyl alkylsulfonyl, p-nitrophenyl alkylsulfonyl, pivaloyl group, benzoyl, trityl, 2,4-dimethoxy-benzyls, to methoxy-benzyl or benzyl.
5. the method preparing ticagrelor midbody according to claim 3, is characterized in that, L is the leavings group of p-toluenesulfonyl, methylsulfonyl, trifluoroacetyl group or halogen.
6. utilize the method for the Intermediate Preparation ADZ6140 described in claim 1, it is characterized in that, the method comprises the steps:
A 4,6-bis-chloro-2-(rosickyite the alkyl)-5-pyrimidinamine compounds shown in () formula 5 compound and formula 6 reacts, obtained formula 7 compound;
B () formula 7 compound and alkali-metal nitrite react, obtained compound shown in formula 8;
C the compound shown in the compound shown in () formula 8 with formula 9 is coupled and obtains the compound shown in formula 10;
D compound shown in formula 10 is sloughed P by ()
1obtain Ticagrelor;
Wherein, P
1for silylation, trityl, benzyl, to methoxy-benzyl, acyl group, allyl group or 2-THP trtrahydropyranyl.
7. the method preparing ADZ6140 according to claim 6, is characterized by, and the alkali-metal nitrite described in step (b) is Sodium Nitrite or potassium nitrite.
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| CN201110094639.7A CN102731467B (en) | 2011-04-15 | 2011-04-15 | The intermediate of ADZ6140 and prepare the method for ADZ6140 |
| PCT/CN2012/072775 WO2012139455A1 (en) | 2011-04-15 | 2012-03-22 | Intermediates of ticagrelor and method for preparing ticagrelor |
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| CA2859580A1 (en) * | 2011-12-23 | 2013-06-27 | Lek Pharmaceuticals D.D. | Synthesis of triazolopyrimidine compounds |
| WO2013163892A1 (en) * | 2012-05-02 | 2013-11-07 | Sunshine Lake Pharma Co., Ltd. | Novel triazolo pyrimidine compounds and a process of preparation thereof |
| CN103626743B (en) * | 2012-08-23 | 2018-06-08 | 广东东阳光药业有限公司 | New intermediate of Ticagrelor and preparation method thereof |
| CN103772393B (en) * | 2012-10-18 | 2017-08-04 | 博瑞生物医药（苏州）股份有限公司 | Crystal formation of Ticagrelor and preparation method thereof |
| CN103848834B (en) * | 2012-12-06 | 2017-09-22 | 博瑞生物医药（苏州）股份有限公司 | A kind of method and its intermediate for preparing Ticagrelor |
| CN104341402B (en) * | 2013-07-23 | 2018-04-27 | 博瑞生物医药（苏州）股份有限公司 | A kind of method for preparing ticagrelor midbody |
| CN104045620B (en) * | 2013-03-12 | 2017-05-10 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of intermediate of ticagrelor |
| WO2014155389A2 (en) * | 2013-03-25 | 2014-10-02 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of ticagrelor |
| ITMI20130487A1 (en) * | 2013-03-29 | 2014-09-30 | Chemo Res S L | SELECTIVE ALCHILATION OF CYCLOPENTILALCULES |
| CN103288836B (en) * | 2013-06-27 | 2015-03-11 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor |
| WO2014206187A1 (en) | 2013-06-24 | 2014-12-31 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor and intermediates thereof |
| 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 |
| CN103304567B (en) * | 2013-06-27 | 2015-05-20 | 苏州明锐医药科技有限公司 | Preparation method of ticagrelor |
| CN104744424B (en) * | 2013-12-27 | 2018-12-25 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of ticagrelor midbody |
| CN104650160A (en) * | 2015-01-13 | 2015-05-27 | 济南大学 | Novel synthesis method of capecitabine key intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose |
| CN105968113B (en) * | 2015-03-12 | 2019-06-07 | 四川海思科制药有限公司 | A kind of triazolopyrimidine derivative and its application |
| CN107141298A (en) * | 2017-07-24 | 2017-09-08 | 苏州信恩医药科技有限公司 | A kind of synthetic method of ticagrelor |
| CN107513070B (en) * | 2017-09-28 | 2019-09-20 | 淮阴工学院 | A kind of synthetic method of compound ticagrelor and its intermediate of synthesis |
| CN111978327B (en) * | 2019-05-24 | 2022-06-10 | 南京一心和医药科技有限公司 | Preparation method of ticagrelor |
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| CN1432017A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Triazolo pyrimidine compounds |
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| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
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| CN1432017A (en) * | 2000-06-02 | 2003-07-23 | 阿斯特拉曾尼卡有限公司 | Triazolo pyrimidine compounds |
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| From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis;Brian Springthorpe, et.al.;《Bioorganic & Medicinal Chemistry Letters》;20070819;第17卷;第6013-6018页 * |
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