CN105859720A - Method for preparing ticagrelor solution - Google Patents
Method for preparing ticagrelor solution Download PDFInfo
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- CN105859720A CN105859720A CN201510028151.2A CN201510028151A CN105859720A CN 105859720 A CN105859720 A CN 105859720A CN 201510028151 A CN201510028151 A CN 201510028151A CN 105859720 A CN105859720 A CN 105859720A
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- 0 CCCSc1nc(N[C@](C2)[C@@]2c(cc2F)ccc2F)c2nn[n]([C@](C3)[C@@](*)C[C@]3OCC*)c2n1 Chemical compound CCCSc1nc(N[C@](C2)[C@@]2c(cc2F)ccc2F)c2nn[n]([C@](C3)[C@@](*)C[C@]3OCC*)c2n1 0.000 description 1
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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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- 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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Abstract
The invention discloses a method for preparing a ticagrelor solution. According to the invention, hydroxy of a ticagrelor I crude product is protected by a protective group, then a crude product of a compound II is separated and purified to obtain the high purity compound II; the hydroxy protective group of the high purity compound II is removed under proper reaction conditions, a reaction mixture is post-processed and then the by-product is removed to obtain the high purity ticagrelor I, the ticagrelor I, a solvent or/and pharmaceutic adjuvant form a solution, after the solvent is removed, ticagrelor or a mixture containing ticagrelor and accessory with medicinal requirement can be obtained. The method has the advantages of mild reaction condition, simple operation, low cost, and environmental protection, and is suitable for industrial production.
Description
Technical field
The present invention relates to the purification process of anticoagulation medicine, more particularly to the preparation method of a kind of ticagrelor solution.
Background technology
Ticagrelor (Ticagrelor), trade name Belling reaches (Brilinta), and chemical name is:
(1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3,4-difluorobenzene) cyclopropyl] amino } (propylthio oxygen is phonetic for-5-
Pyridine)-3H-[1,2,3]-triazophos [4,5-d] pyrimidin-3-yl]-5-(2-ethoxy) Pentamethylene .-1,2-glycol, its structure such as formula (I)
Shown in:
Ticagrelor (Ticagrelor) is a kind of novel anticoagulant researched and developed by Astrazeneca AB of Britain
Agent, for acute coronary syndrome, (unstable angina pectoris, non-ST elevation acute myocardial infraction or ST section raise cardiac muscle
Infarction) patient, gets involved patient that (PCI) treat to reduce thrombosis including accepting Drug therapy and percutaneous coronary
The incidence rate of property cardiovascular event, obtained in U.S. food pharmaceuticals Supervision Bureau (FDA) license in July, 2011
City.Ticagrelor is a kind of novel cyclopenta triazolo pyrimidine class (CPTP) oral anti-diabetic agent thing, ATC generation
Code is B01AC24.Ticagrelor is non-precursor medicine, need not activate through liver metabolism and get final product direct onset, with P2Y12
Adp receptor reversibility combines.PLATO result of study shows, ticagrelor treatment is not increasing mainly to go out for 12 months
In the case of blood, relatively clopidogrel significantly reduces the cardiovascular death/myocardial infarction/apoplexy of ACS patient further and is combined
Endpoints risk reaches 16%, significantly reduces cardiovascular death simultaneously and reaches 21%.Treat to ACS based on ticagrelor
The benefit that patient brings, associated guideline both domestic and external all recommends, and ticagrelor is controlled for the antiplatelet of ACS patient
Treat.And heart of Europe disease association two authoritative guides (ESC NSTE-ACS guides in 2011 and 2012
STEMI guide) in point out especially, can not accept ticagrelor treatment patient in could use clopidogrel, also
Fully show the accreditation of reduction mortality rate further for new drug.In recent years, pushing away along with ticagrelor clinical practice
Extensively, the demand of its crude drug is increased the most year by year.
It is initial that Chinese patent CN1128801C discloses one with (1S-is cis)-4-acetate-2-cyclopentenes-1-alcohol
The route of ticagrelor prepared by raw material, and reactions steps is as follows:
In this route except minority intermediate is the most purified be directly used in next step in addition to, remaining intermediate and ticagrelor
It is purified by the method for column chromatography.Isolated and purified means used by this route are difficult to industrialization, obtained
The purity of ticagrelor is also difficult to meet medicinal requirement, in addition it is also necessary to recrystallization purifying further.
Chinese patent CN1200940C discloses one with [3 α R-(3a α, 4 α, 6 α, 6a α)]-6-amino-tetrahydrochysene-2,2-
Dimethyl-4H-cyclopenta-1,3-dioxane amyl-4-alcohol is the route of initiation material, and reactions steps is as follows:
Several key intermediate compound (V), compound (IV) and compound (III) in this route are
Rufous sticky oil thing, and the most purified it is directly used in next step.Final step, after processing in the completed, through second
Acetoacetic ester/isobutyltrimethylmethane. is recrystallized to give ticagrelor crude product.This crude product also needs to be further purified, such as: ethyl acetate/
The making beating of isobutyltrimethylmethane. recrystallization, n-butyl acetate and isopropanol making beating, can be only achieved purity (the HPLC analytical pure of 98%
Degree).But the HPLC purity assay of 98% can not meet medicinal, if to prepare replacing as active constituents of medicine
Ge Ruiluo, in addition it is also necessary to be further purified.
In industrialized production, the most frequently used and maximally effective means of purification is exactly recrystallization.Due to compound (V),
Compound (IV) and the character of compound (III) itself, it is difficult to form solid, be the most just difficult to pass through recrystallization
Method carry out purification.Compound (I) is although being prone to recrystallization, but owing to existing recrystallization system is specific miscellaneous to some
The removal effect of matter is the most bad, so needing repeatedly purification.Purge process repeatedly, makes to add answering of preparation technology
Miscellaneous degree, the most therefore yield is substantially reduced.Therefore the production year cost of this technique and cost of material also can be greatly improved.
To sum up, develop easy and simple to handle a, purification process for ticagrelor that purity is high, advantageously reduce this product
Cost, has been allowed to more preferable market prospect.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of ticagrelor solution, chemical reaction condition temperature in the method
With, easy and simple to handle, it is to avoid using column chromatography, operation is routine operation, the product purity obtained is high；Cost
Cheap, environmentally friendly, the three wastes of generation are easily controllable and process, and are suitable for industrialized production.
In order to achieve the above object, the present invention provides following technical scheme:
The preparation method of a kind of ticagrelor solution, it is characterised in that including:
1) content is not less than ticagrelor I crude product and the hydroxyl protecting group reagent reacting of 83wt%, in ticagrelor I structure
In at least one hydroxyl on introduce protection group, obtain compound II crude product；
2) compound II crude product is through recrystallization, obtains the compound II highly finished product of correspondence；
3) compound II highly finished product react eliminating hydroxide protection group through deprotection base, remove byproduct of reaction, prepare and replace
The ticagrelor solution that Ge Ruiluo I highly finished product are formed with solvent, in this solution, the content of solute is not higher than 80wt.%；
Reaction equation is as follows:
Wherein, hydroxyl protecting group P, P1And P2Three is identical or different, but is asynchronously hydrogen；
P is selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,-C (O) SR1,
-C(O)NR4R5,-C (S) NR4R5Or-C (O) NHSO2R1；
P1And P2Selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,
-C(O)SR1,-C (O) NR4R5、-C(S)NR4R5,-C (O) NHSO2R1,-CR4R5,-BR1Or-BOR1；
Wherein, R1、R2And R3Separately selected from the alkyl containing 1～8 carbon atom, substituted contain 1～8 carbon atom
Alkyl, aryl or substituted aryl；
R4And R5Separately selected from hydrogen, alkyl containing 1～8 carbon atom, substituted contain 1～8 carbon atom alkyl,
Aryl or substituted aryl；
P1、P2Mutually independent, or together with the two oxygen atom being connected with them and the carbon atom that is connected with oxygen atom
Form formula such as5～8 yuan of heterocycles；
P3For by P1And P2The group formed so that chemical bond is connected.Wherein, when forming 5 ring, P3For-CR4R5,
-BR1Or-BOR1。
Further, step 1) in introduce the temperature of protection group reaction be 0～90 DEG C, preferably 20～70 DEG C.
Further, step 2) recrystallization solvent selected from containing less than 8 carbon atoms alcohol, ether, ester, amide,
One or more in nitrile, ketone, alkane, unsaturated hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, sulfone, sulfoxide and water.
Further, step 3) in the temperature of deprotection base reaction be 0～90 DEG C, preferably 20～70 DEG C, solvent selects
The alcohol of self-contained less than 8 carbon atoms, ether, ester, amide, nitrile, ketone, alkane, aromatic hydrocarbons, halogenated hydrocarbons, sulfone, sulfoxide
With one or more in water.
Further, by step 3) ticagrelor solution carry out recrystallization or be dried, be met replacing of medicinal requirements
Ge Ruiluo solid, the solvent of recrystallization is selected from the alcohol containing less than 8 carbon atoms, ether, ester, amide, nitrile, ketone, alkane
One or more in hydrocarbon, unsaturated hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, sulfone, sulfoxide and water.
Also, after the ticagrelor solution that obtains adds pharmaceutic adjuvant recrystallization or be dried again, be met medicinal requirements
The solid mixture of ticagrelor and adjuvant.
The present invention also provides for a kind of compound as shown in formula II:
Wherein, in formula II, hydroxyl protecting group P, P1And P2Three is identical or different, but is asynchronously hydrogen；
P is selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,-C (O) SR1,
-C(O)NR4R5,-C (S) NR4R5Or-C (O) NHSO2R1；
P1And P2Selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,
-C(O)SR1,-C (O) NR4R5、-C(S)NR4R5,-C (O) NHSO2R1,-CR4R5,-BR1Or-BOR1；
Wherein, R1、R2And R3Separately selected from the alkyl containing 1～8 carbon atom, substituted contain 1～8 carbon atom
Alkyl, aryl or substituted aryl, R4And R5Separately selected from hydrogen, the alkyl containing 1～8 carbon atom, replacement
The alkyl containing 1～8 carbon atom, aryl or substituted aryl；
P1、P2Mutually independent, or together with the two oxygen atom being connected with them and the carbon atom that is connected with oxygen atom
Form 5～8 yuan of heterocycles；
Wherein, when P is hydrogen, P1And P2It is asynchronously alkyl, and the oxygen atom that is connected with them and and oxygen atom
The carbon atom being connected is formed without 5 yuan of heterocycles containing alkylidene together.
Preferably, P1And P25 yuan are formed together with the oxygen atom being connected with them and the carbon atom being connected with oxygen atom
Heterocycle, structure represented by a formula X:
P3For-BR1Or-BOR1。
In the method for the present invention, the solvent in the ticagrelor solution prepared can be reaction dissolvent during deprotection, anti-
Extractant after should terminating or other solvents of the needs displacement according to subsequent handling.
The method using the present invention, the raw material that HPLC purity assay is 85%～90% after introducing hydroxyl protecting group,
The purity of the compound II crude product obtained is generally 80%～90% (HPLC purity assay), and this crude product is the most molten
The compound II that purity is more than 99.7%, individual event impurity is less than 0.1% is i.e. can get after carrying out a recrystallization under agent system,
Dried purification yield is up to more than 85%, then deprotection base obtains ticagrelor solution.
In the chemical constitution of ticagrelor, containing two adjacent secondary hydroxyl groups and a primary OH, this polyhydroxy
The structure of base has certain similarity with the structure of five yuan of sugared rings, although molecular weight is relatively big, but fusing point ratio relatively low (100
About DEG C).Especially when after the methylene protection that two adjacent secondary hydroxyl groups are replaced, form the class of compound III
Like thing, fusing point will be lower, is unfavorable for crystallization or solidification.Such as, the synthesis road that patent CN1200940C is reported
Intermediate III, IV and V in line are difficult to crystallization purifying because fusing point is relatively low, can only obtain the crude product of finished product
After be purified again.
Currently, the quality control of medicine is had higher requirement by Drug Administration department of various countries, in the technique of crude drug
Exploitation being wished, more rate-determining steps is in order to control the quality of crude drug.If according to technique of the prior art,
The most it is not purified obtaining the continuous 3 step midbody products before finished product, then just cannot progressively control each step
The impurity of middle generation, these Impurity Potentials must run up in finished product, increases the difficulty of purification further.
In the building-up process of ticagrelor, create some physical propertys (such as dissolubility, polarity etc.) and produce with target
The impurity that thing is close, it is difficult to remove.The way of purification provided by patent CN1200940C, the crude product of its finished product exists
After purification twice, being still difficult to remove those impurity close with target product physical property, product purity is 98%, still
So can not meet medicinal requirements (HPLC purity assay more than 99%, any unknown individual event impurity is not higher than 0.1%).
Therefore, the present invention introduces suitable blocking group in the structure of ticagrelor, to change its physicochemical property, so
Being purified the ticagrelor introducing blocking group afterwards, deprotection base obtains highly purified ticagrelor the most again
Reach purification purpose.
Although in the chemical constitution of ticagrelor, in addition to the secondary hydroxyl groups adjacent containing two and a primary OH,
Possibly together with a secondary amine, but this amido is connected with pyrimidine ring, and reactivity is relatively low.Therefore, the present invention is to for lattice
Suitable blocking group is introduced, to change its physical property, as improved compound on the part or all of hydroxyl of auspicious Lip river
Fusing point and crystal property, the difference of the physical property between increase target product and impurity, it is allowed to be more favorable for purification.
Beneficial effects of the present invention:
1), in the present invention, the content of ticagrelor I crude product is not less than 83% (mass fraction), generally 83～90%,
Three hydroxyls of ticagrelor I are completely or partially by after suitable radical protection, and the compound II of formation has good
Physical property, can form solid, and be prone to crystallization.
2) present invention is when deprotection base, chooses different conditions according to different protection groups, but these conditions are equal
The gentleest, reaction temperature, between 0～90 DEG C, is not related to very exothermic and produces the reaction of a large amount of gases, and,
The by-product introduced because of deprotection base can be removed, in addition, no by the simple mode such as extraction, washing
Can introduce new impurity, the ticagrelor solution purity obtained is more than 99.7%, and individual event impurity is less than 0.1%.
3) chemical reaction condition that the present invention relates to is gentle, and the reaction temperature introducing and removing protection group is 0～90 DEG C,
Pressure is routine operation at below 0.35MPa, operation, it is to avoid use column chromatography, it is easy to accomplish industry metaplasia
Producing, raw materials used and reagent is business-like, cheap raw material, and the three wastes of generation are easily controllable and process.
Therefore, the purification process reaction condition of the present invention is gentle, easy and simple to handle, with low cost, environmental friendliness, is suitable for industry
Metaplasia is produced.
Detailed description of the invention
In order to further appreciate that the present invention, below in conjunction with embodiment, the preferred embodiment of the invention is described, but
Should be appreciated that these describe simply for further illustrating the features and advantages of the present invention rather than wanting right of the present invention
The restriction asked.
Embodiment 1 P=trityl, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analytical pure
Degree), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triphenylchloromethane (3.62g, 13.0mmol) and dichloromethane (60ml), the lower mix homogeneously of stirring.It is warming up to
25～30 DEG C, dropping triethylamine (1.32g, 13.0mmol), and stir reaction at this temperature.React 3～4 hours
After, after HPLC follows the tracks of reaction completely, add saturated ammonium chloride solution (50ml) cancellation reaction.Separate organic facies,
Aqueous phase dichloromethane (50ml) extracts once.Merge organic facies, and washed once with water (50ml), anhydrous sulfur
Acid sodium is dried, and reduced under vacuum removes dichloromethane.In residue, add methanol (60ml), be heated to refluxing also
It is incubated 30 minutes, filtered while hot.Collect filtrate, continue to be heated to backflow, with after be cooled to 20～25 through 1～2 hour
DEG C, and it is incubated 1 hour.Filter, collect filter cake, be dried under vacuum, obtain white solid 6.81g and be compound
(II A) highly finished product, yield 89.0%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR (400MHz, d6-DMSO): 9.33 (d, J=4.0Hz, 1H), 7.45-7.20 (m, 17H), 7.05-7.00 (m,
1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m,
1H),3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,1H),
2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,
2H), 1.37-1.31 (m, 2H), 0.75 (s, J=7.8Hz, 3H) .LC-MS (ESI): m/z765.
To 100ml three neck round bottom fill in add above-claimed cpd (II A) highly finished product (6.50g, 8.5mmol),
Methanol (65ml), the concentrated hydrochloric acid (3.3ml) of 35% and normal heptane (22ml), stir 2～3 little at 20～25 DEG C
Time.After HPLC follows the tracks of reaction completely, separatory removes normal heptane layer, and methanol water layer extracts with normal heptane (22ml) again
Take 2 times.Add water (130ml) to methanol water layer, and regulate pH to 7.0～7.5 with saturated sodium carbonate solution.
Said mixture is extracted 3 times with dichloromethane (50ml), combined dichloromethane layer, washs with water (50ml), nothing
Aqueous sodium persulfate is dried, and is filtrated to get the dichloromethane solution of ticagrelor.Record in solution containing for lattice by content analysis method
Auspicious Lip river 4.4g, yield 99.1%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).LC-MS
(ESI): m/z523.
Embodiment 2 P=tert-butyl diphenyl is silica-based, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Tert-butyl diphenyl chlorosilane (3.30g, 12.0mmol) and dichloromethane (60ml), the lower mix homogeneously of stirring.Rise
Temperature, to 25～30 DEG C, drips triethylamine (1.21g, 12.0mmol), and stirs reaction at this temperature.Reaction 2～3
After hour, after HPLC follows the tracks of reaction completely, add saturated ammonium chloride solution (50ml) cancellation reaction.Separate organic
Phase, aqueous phase dichloromethane (50ml) extracts once.Merge organic facies, and washed once with water (50ml), nothing
Aqueous sodium persulfate is dried, and reduced under vacuum removes dichloromethane.In residue, add toluene (50ml), be heated to
55～60 DEG C and be incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and be incubated 1 hour.Filter, filter
Cake normal heptane (50ml) is pulled an oar, and again filters, and is dried, obtains white solid 6.62g, be under filter cake vacuum
Compound (II B) highly finished product, yield 87.0%, (HPLC purity assay, individual event impurity is less than purity 99.8%
0.1%).1H NMR (400MHz, d6-DMSO): 9.31 (d, J=4.0Hz, 1H), 7.45-7.20 (m, 12H),
7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H),
3.98-3.95(m,1H),3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,
1H),2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),
1.46-1.38 (m, 2H), 1.37-1.31 (m, 2H), 0.98 (s, 9H), 0.76 (d, J=7.8Hz, 3H) .LC-MS (ESI):
m/z761。
To 100ml three neck round bottom fill in add above-claimed cpd (II B) highly finished product (6.46g, 8.5mmol),
Tetrabutyl ammonium fluoride (3.35g, 12.8mmol) and oxolane (65ml), stir 2～3 little at 20～25 DEG C
Time.After HPLC follows the tracks of reaction completely, adding water (130ml) and normal heptane (30ml), separatory removes normal heptane layer,
Oxolane water layer extracts 2 times with normal heptane again.Extract said mixture 3 times with dichloromethane (50ml), close
And dichloromethane layer, washing 2 times with water (50ml), anhydrous sodium sulfate is dried, and filters, obtains the two of ticagrelor
Chloromethanes solution.The 4.4g Han ticagrelor in solution, yield 99.1%, purity 99.8% (HPLC is recorded by content analysis method
Purity assay, individual event impurity is less than 0.1%).LC-MS (ESI): m/z523.
Embodiment 3 P=4-Phenylbenzoyl, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triethylamine (1.21g, 12.0mmol), 4-(N, N-dimethylamino) pyridine (0.05g) and dichloromethane (50ml),
The lower mix homogeneously of stirring.It is warming up to 25～30 DEG C, the dichloro of dropping 4-Phenylbenzoyl chloride (2.60g, 12.0mmol)
Dichloromethane, and stir reaction at this temperature.After reacting 4 hours, after HPLC follows the tracks of reaction completely, add full
React with ammonium chloride solution (50ml) cancellation.Separating organic facies, aqueous phase dichloromethane (50ml) extracts once.
Merging organic facies, and respectively washed once with saturated sodium carbonate solution (50ml) water (50ml), anhydrous sodium sulfate is dried,
Reduced under vacuum removes dichloromethane.The mixing of ethyl acetate/normal heptane (1:1, volume ratio) is added in residue
Solvent (50ml), is heated to 55～60 DEG C and is incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and
It is incubated 1 hour.Filter, be dried under filter cake vacuum, obtain white solid 6.07g and be compound (II C) highly finished product,
Yield 86.4%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,
D6-DMSO): 9.33 (d, J=4.0Hz, 1H), 7.70-7.20 (m, 11H), 7.05-7.00 (m, 1H), 5.13 (d,
J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H), 3.82-3.76
(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,1H),2.82-2.74(m,1H),
2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,2H),1.37-1.31(m,
2H), 0.76 (d, J=7.8Hz, 3H) .LC-MS (ESI): m/z703.
To 100ml three neck round bottom fill in add above-claimed cpd (II C) highly finished product (5.62g, 8.0mmol),
Potassium carbonate (3.31g, 24.0mmol) and methanol (56ml), stir 5～6 hours at 20～25 DEG C.HPLC with
After track reaction completely, add water (130ml).With dichloromethane (50ml) extractive reaction mixture 3 times, merge
Dichloromethane layer, washs with water (50ml), and anhydrous sodium sulfate is dried, and filters, obtains the dichloromethane of ticagrelor
Solution.The 4.1g Han ticagrelor in solution, yield 98.1%, purity 99.8% (HPLC is recorded by content analysis method
Purity assay, individual event impurity is less than 0.1%).LC-MS (ESI): m/z523.
Embodiment 4 P=4-nitrobenzenesulfonyl, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triethylamine (1.21g, 12.0mmol), 4-(N, N-dimethylamino) pyridine (0.05g) and pyridine (50ml), stirring
Lower mix homogeneously.Being warming up to 25～30 DEG C, the dichloromethane of dropping 4-nitrosulfonyl chloride (2.66g, 12.0mmol) is molten
Liquid, and stir reaction at this temperature.After reacting 4 hours, after HPLC follows the tracks of reaction completely, add saturated chlorination
Ammonium salt solution (50ml) cancellation is reacted.Reactant mixture dichloromethane (50ml) extracts 3 times.Merge organic facies,
And respectively wash 2 times with saturated ammonium chloride solution (50ml) water (50ml), anhydrous sodium sulfate is dried, reduced under vacuum
Remove dichloromethane.The mixed solvent (50ml) of ethyl acetate/normal heptane (1:1, volume ratio) is added in residue,
Be heated to 55～60 DEG C and be incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and be incubated 1 hour.Cross
Filter, is dried under filter cake vacuum, obtains white solid 6.16g and is compound (II D) highly finished product, yield 87.0%,
Purity 99.7% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,d6-DMSO):
9.32 (d, J=4.0Hz, 1H), 8.42 (d, J=7.2Hz, 2H), 8.04 (d, J=7.2Hz, 2H), 7.40-7.20 (m, 2H),
7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H),
3.98-3.95(m,1H),3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,
1H),2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),
1.46-1.38 (m, 2H), 1.37-1.31 (m, 2H), 0.76 (d, J=7.8Hz, 3H) .LC-MS (ESI): m/z708.
To 100ml three neck round bottom fill in add above-claimed cpd (II D) highly finished product (6.01g, 8.5mmol),
1,8-diazabicylo 11 carbon-7-alkene (0.91g, 6.0mmol) and acetonitrile (60ml), stir at 20～25 DEG C
5～6 hours.After HPLC follows the tracks of reaction completely, less than 35 DEG C concentrate removing major part acetonitrile, add dichloromethane
(60ml).Dichloromethane layer respectively washs 2 times with hydrochloric acid solution (50ml) and the water (50ml) of 3%, anhydrous sulfur
Acid sodium is dried, and filters, obtains the dichloromethane solution of ticagrelor.Record in solution containing auspicious for lattice by content analysis method
Lip river 4.4g, yield 99.0%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).LC-MS
(ESI): m/z523.
Embodiment 5 P=terf-butylsulfinyl, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
The ticagrelor crude product (5.94g, 10.0mmol) that content is 88% is added in the three neck round bottom of 100ml
With pyridine (60ml), the lower mix homogeneously of stirring.At 25～30 DEG C, dropping butylsulfinyl chloride (1.69g,
Dichloromethane solution 12.0mmol).Drip and finish, be heated to backflow and stir reaction at this temperature.Reaction 4～5 is little
After Shi Hou, HPLC follow the tracks of reaction completely, add saturated ammonium chloride solution (50ml) cancellation reaction.Reactant mixture
3 times are extracted with dichloromethane (50ml).Merge organic facies, and with saturated citric acid solution (50ml) water (50ml)
Each washing 2 times, anhydrous sodium sulfate is dried, and reduced under vacuum removes dichloromethane.Acetonitrile/acetone is added in residue
The mixed solvent (40ml) of (10:1, volume ratio), is heated to 55～60 DEG C and is incubated 30 minutes, with after through 1～2
Hour it is cooled to 20～25 DEG C, and is incubated 1 hour.Filter, be dried under filter cake vacuum, obtain white solid 5.14g
Being compound (II E) highly finished product, yield 82.0%, (HPLC purity assay, individual event impurity is or not purity 99.8%
More than 0.1%).1H NMR (400MHz, d6-DMSO): 9.33 (d, J=4.0Hz, 1H), 7.40-7.20 (m, 2H),
7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H),
3.98-3.95(m,1H),3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,
1H),2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),
1.46-1.38 (m, 2H), 1.37-1.31 (m, 2H), 1.29 (s, 9H), 0.76 (d, J=7.8Hz, 3H) .LC-MS (ESI):
m/z627.
To 100ml three neck round bottom fill in add above-claimed cpd (II E) highly finished product (5.02g, 8.0mmol),
Methanol (50ml) and the concentrated hydrochloric acid (5.0ml) of 35%, stir 2～3 hours at 20～25 DEG C.HPLC follows the tracks of anti-
Should completely after, in reactant mixture add water (100ml), and with saturated sodium carbonate solution regulate pH to 7.0～7.5.
Said mixture is extracted 3 times with dichloromethane (50ml), combined dichloromethane layer, washs with water (50ml), nothing
Aqueous sodium persulfate is dried, and filters, obtains the dichloromethane solution of ticagrelor.Record in solution containing replacing by content analysis method
Ge Ruiluo 4.1g, yield 98.1%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).
LC-MS (ESI): m/z523.
Embodiment 6 P=2,4-dinitrophenyl sulfenyl, P1=hydrogen, P2During=hydrogen, the preparation of ticagrelor solution
Method
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triethylamine (1.21g, 12.0mmol), 4-(N, N-dimethylamino) pyridine (0.05g) and dichloromethane (60ml),
The lower mix homogeneously of stirring.It is warming up to 25～30 DEG C, drips 2,4-dinitrophenyl time sulfonic acid chloride (2.82g, 12.0mmol)
Dichloromethane solution, and stir reaction at this temperature.After reacting 3 hours, after HPLC follows the tracks of reaction completely,
Add saturated ammonium chloride solution (50ml) cancellation reaction.Reactant mixture dichloromethane (50ml) extracts 3 times.
Merging organic facies, and respectively wash 2 times with saturated ammonium chloride solution (50ml) and water (50ml), anhydrous sodium sulfate is done
Dry, reduced under vacuum removes dichloromethane.Dichloromethane/normal heptane (1:2, volume ratio) is added in residue
Mixed solvent (50ml), is heated to 55～60 DEG C and is incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour,
And it is incubated 1 hour.Filter, under filter cake vacuum be dried, obtain white solid 6.17g be compound (II F) refine
Product, yield 85.6%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,
D6-DMSO): 9.34 (d, J=4.0Hz, 1H), 8.81 (s, 1H), 8.34 (d, J=7.2Hz, 1H), 7.88 (d, J=7.2Hz,
1H), 7.40-7.20 (m, 2H), 7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H),
4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H), 3.82-3.76 (m, 1H), 3.68-3.54 (m, 1H), 3.16-3.02
(m,4H),2.94-2.86(m,1H),2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),
1.56-1.50 (m, 1H), 1.46-1.38 (m, 2H), 1.37-1.31 (m, 2H), 0.76 (d, J=7.8Hz, 3H) .LC-MS
(ESI): m/z721.
To 100ml three neck round bottom fill in add above-claimed cpd (II F) highly finished product (6.0g, 8.3mmol),
Methanol (60ml) and the concentrated hydrochloric acid (6.0ml) of 35%, stir 5～6 hours at 20～25 DEG C.HPLC follows the tracks of anti-
Should completely after, regulate pH to 7.0～7.5 with saturated aqueous sodium carbonate, less than 35 DEG C concentrate and remove most of second methanol,
Add dichloromethane (60ml).Dichloromethane layer use water (50ml) washs, and anhydrous sodium sulfate is dried, and filters,
Dichloromethane solution to ticagrelor.The 4.3g Han ticagrelor in solution is recorded by content analysis method, yield 99.1%,
Purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).LC-MS (ESI): m/z523.
Embodiment 7 P=4-nitrobenzyloxycarbonyl base, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triethylamine (1.21g, 12.0mmol), 4-(N, N-dimethylamino) pyridine (0.05g) and dichloromethane (50ml),
The lower mix homogeneously of stirring.It is warming up to 25～30 DEG C, the two of dropping chloro-carbonic acid-4-p-Nitrobenzyl (2.82g, 12.0mmol)
Chloromethanes solution, and stir reaction at this temperature.After reacting 3～4 hours, after HPLC follows the tracks of reaction completely, add
Enter saturated ammonium chloride solution (50ml) cancellation reaction.Reactant mixture dichloromethane (50ml) extracts 3 times.Close
And organic facies, and respectively wash 2 times with saturated ammonium chloride solution (50ml) and water (50ml), anhydrous sodium sulfate is dried,
Reduced under vacuum removes dichloromethane.The mixing of ethyl acetate/normal heptane (1:1, volume ratio) is added in residue
Solvent (60ml), is heated to 55～60 DEG C and is incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and
It is incubated 1 hour.Filter, under filter cake vacuum be dried, obtain white solid 5.63g be compound (II G) refine
Product, yield 80.2%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,
D6-DMSO): 9.33 (d, J=4.0Hz, 1H), 8.12 (d, J=7.2Hz, 2H), 7.58 (d, J=7.2Hz, 2H),
7.40-7.20 (m, 2H), 7.05-7.00 (m, 1H), 5.21 (s, 2H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d,
J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H), 3.82-3.76 (m, 1H), 3.68-3.54 (m,
1H),3.16-3.02(m,4H),2.94-2.86(m,1H),2.82-2.74(m,1H),2.72-2.62(m,1H),
2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,2H),1.37-1.31(m,2H),0.76
(d, J=7.8Hz, 3H) .LC-MS (ESI): m/z702.
In the stainless steel autoclave of 100ml add above-claimed cpd (II G) highly finished product (5.47g, 7.8mmol),
Methanol (60ml) and palladium carbon (5%, w/w) (0.5g).After nitrogen displacement and hydrogen exchange, it is passed through hydrogen,
It is forced into 0.2～0.3MPa, stirs 3～4 hours at 20～25 DEG C.After HPLC follows the tracks of reaction completely, discharge hydrogen,
After nitrogen displacement, Filtration of catalyst, filtrate extracts 3 times with normal heptane (20ml).Methanol layer adds activated carbon
(0.5g), it is heated to backflow, filtered while hot, obtains the methanol solution of ticagrelor.Record molten by content analysis method
The 4.0g Han ticagrelor in liquid, yield 98.1%, (HPLC purity assay, individual event impurity is less than purity 99.8%
0.1%).LC-MS (ESI): m/z523.
Embodiment 8 P=benzyl thiocarbonyl group, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triethylamine (1.21g, 12.0mmol), 4-(N, N-dimethylamino) pyridine (0.05g) and dichloromethane (60ml),
The lower mix homogeneously of stirring.It is warming up to 25～30 DEG C, the two of dropping benzyl chloride thiocarboxylic (2.24g, 12.0mmol)
Chloromethanes solution, and stir reaction at this temperature.After reacting 3 hours, after HPLC follows the tracks of reaction completely, add
Saturated ammonium chloride solution (50ml) cancellation is reacted.Reactant mixture dichloromethane (50ml) extracts 3 times.Merge
Organic facies, and respectively wash 2 times with saturated ammonium chloride solution (50ml) and water (50ml), anhydrous sodium sulfate is dried,
Reduced under vacuum removes dichloromethane.Sulfolane/methyl tertiary butyl ether(MTBE) (1:1, volume ratio) is added in residue
Mixed solvent (60ml), is heated to 55～60 DEG C and is incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour,
And it is incubated 1 hour.Filter, be dried under filter cake vacuum, obtain white solid 5.54g and be compound (II H) essence
Goods, yield 82.4%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H
NMR (400MHz, d6-DMSO): 9.33 (d, J=4.0Hz, 1H), 7.45-7.20 (m, 7H), 7.05-7.00 (m, 1H),
5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 4.61 (s, 2H),
3.98-3.95(m,1H),3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,
1H),2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),
1.46-1.38 (m, 2H), 1.37-1.31 (m, 2H), 0.76 (d, J=7.8Hz, 3H) .LC-MS (ESI): m/z673.
In the three neck round bottom of 100ml add above-claimed cpd (II H) highly finished product (5.38g, 8.0mmol),
Tetrabutyl ammonium fluoride (4.2g, 16.0mmol) and dimethyl sulfoxide (50ml).Stir 1 hour at 20～25 DEG C.
After HPLC follows the tracks of reaction completely, add water (100ml).Reactant mixture ethyl acetate (50ml) extracts 3
Secondary.Merge organic layer, wash 2 times respectively with saturated aqueous sodium carbonate (50ml) and water (50ml).Ethyl acetate
Layer adds activated carbon (0.5g), is heated to backflow, filtered while hot, obtains the ethyl acetate solution of ticagrelor.With
Content analysis method records the 4.1g Han ticagrelor in solution, yield 98.1%, purity 99.8% (HPLC purity assay,
Individual event impurity is less than 0.1%).LC-MS (ESI): m/z523.
Embodiment 9 P=phenyl formamide base, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 85% (HPLC analysis
Purity), content 83% (mass fraction).
In the three neck round bottom of 100ml add content be 83% ticagrelor crude product (6.30g, 10.0mmol),
Carbanil (1.43g, 12.0mmol) and pyridine (60ml), the lower mix homogeneously of stirring.It is warming up to 55～60 DEG C,
And stir reaction at this temperature.After reacting 3～4 hours, after HPLC follows the tracks of reaction completely, add saturated ammonium chloride
Solution (120ml) cancellation is reacted.Reactant mixture dichloromethane (50ml) extracts 3 times.Merge organic facies,
And respectively wash 2 times with saturated ammonium chloride solution (50ml), water (50ml), anhydrous sodium sulfate is dried, dense under vacuum
Contracting removes dichloromethane.The mixing adding acetonitrile/DMF (4:1, volume ratio) in residue is molten
Agent (60ml), is heated to 55～60 DEG C and is incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and protect
Temperature 1 hour.Filter, be dried under filter cake vacuum, obtain white solid 5.45g and be compound (II I) highly finished product,
Yield 84.9%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,
D6-DMSO): 9.88 (s, 1H), 9.33 (d, J=4.0Hz, 1H), 7.55-7.20 (m, 7H), 7.05-7.00 (m, 1H), 5.13
(d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H),
3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,1H),2.82-2.74(m,
1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,2H),
1.37-1.31 (m, 2H), 0.76 (d, J=7.8Hz, 3H) .LC-MS (ESI): m/z642.
In the three neck round bottom of 100ml add above-claimed cpd (II I) highly finished product (5.13g, 8.0mmol),
Sodium hydroxide (3.20g, 24.0mmol) and methanol (50ml).Stir 8 hours at 20～25 DEG C.HPLC with
After track reaction completely, the hydrochloric acid with 5% regulates pH=6.5～7.0.Below 35 DEG C, concentrate and remove major part methanol,
Add water (100ml).Reactant mixture ethyl acetate (50ml) extracts 3 times.Merge organic layer, with 3%
Hydrochloric acid (50ml) washs 2 times, then washes 1 time respectively with water (50ml) and saturated sodium bicarbonate aqueous solution (50ml).
Ethyl acetate layer is dried with anhydrous sodium sulfate, filters, obtains the ethyl acetate solution of ticagrelor.Use content analysis
Method records the 4.1g Han ticagrelor in solution, yield 98.1%, and (HPLC purity assay, individual event is miscellaneous for purity 99.8%
Matter is less than 0.1%).LC-MS (ESI): m/z523.
Embodiment 10 P=N, N-dimethyl thio formamido, P1=hydrogen, P2During=hydrogen, the preparation of ticagrelor solution
Method
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 85% (HPLC analysis
Purity), content 83% (mass fraction).
In the three neck round bottom of 100ml add content be 83% ticagrelor crude product (6.30g, 10.0mmol),
Isosorbide-5-Nitrae-diaza-dicyclo [2,2,2] octane (1.35g, 12.0mmol) and DMF (60ml), stirring
Lower mix homogeneously.The solution of dropping dimethylamino sulfur acute pyogenic infection of nails acyl chlorides (1.48g, 12.0mmol), is heated to 60～70 DEG C
And stir reaction at this temperature.After reacting 2～3 hours, after HPLC follows the tracks of reaction completely, add saturated ammonium chloride
Solution (120ml) cancellation is reacted.Reactant mixture dichloromethane (50ml) extracts 3 times.Merge organic facies,
And respectively wash 2 times with saturated ammonium chloride solution (50ml) water (50ml), anhydrous sodium sulfate is dried, reduced under vacuum
Remove dichloromethane.The mixed solvent (60ml) of acetonitrile/dimethyl sulfoxide (5:1, volume ratio) is added in residue,
Be heated to 55～60 DEG C and be incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and be incubated 1 hour.Cross
Filter, is dried under filter cake vacuum, obtains white solid 5.1g and is compound (II J) highly finished product, and yield 84% is pure
Degree 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,d6-DMSO):9.33
(d, J=4.0Hz, 1H), 7.40-7.20 (m, 2H), 7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d,
J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H), 3.82-3.76 (m, 1H), 3.68-3.54 (m,
1H),3.16-3.02(m,4H),2.98(s,6H),2.94-2.86(m,1H),2.82-2.74(m,1H),2.72-2.62(m,
1H),2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,2H),1.37-1.31(m,2H),0.76
(d, J=7.8Hz, 3H) .LC-MS (ESI): m/z610.
In the stainless steel autoclave of 100ml add above-claimed cpd (II J) highly finished product (4.9g, 8.0mmol) and
The methanol solution (7mol/L) (50ml) of ammonia.Stir 3～4 hours at 20～25 DEG C.HPLC follows the tracks of and has reacted
Quan Hou, adds water (100ml).Reactant mixture isopropyl acetate (50ml) extracts 3 times.Merge organic layer,
2 times are washed respectively with saturated aqueous citric acid solution (50ml) and water (50ml).Ethyl acetate layer adds activated carbon (0.5g),
It is heated to backflow, filtered while hot, obtains the isopropyl acetate solution of ticagrelor.Record in solution by content analysis method
Containing ticagrelor 4.0g, yield 95.7%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).
LC-MS (ESI): m/z523.
Embodiment 11 P=4-sulfonyloxy methyl amido carbonyl, P1=hydrogen, P2During=hydrogen, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 85% (HPLC analysis
Purity), content 83% (mass fraction).
In the three neck round bottom of 100ml add content be 83% ticagrelor crude product (6.30g, 10.0mmol),
Tolysulfonyl based isocyanate (2.37g, 12.0mmol) and oxolane (60ml), the lower mix homogeneously of stirring.
It is warming up to 55～60 DEG C, and stirs reaction at this temperature.After reacting 3～4 hours, after HPLC follows the tracks of reaction completely,
Add saturated ammonium chloride solution (120ml) cancellation reaction.Reactant mixture dichloromethane (50ml) extracts 3 times.
Merging organic facies, and respectively wash 2 times with saturated ammonium chloride solution (50ml) water (50ml), anhydrous sodium sulfate is dried,
Reduced under vacuum removes dichloromethane.The mixed solvent (60ml) of acetonitrile/water (4:1, volume ratio) is added in residue,
Be heated to 55～60 DEG C and be incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and be incubated 1 hour.Cross
Filter, is dried under filter cake vacuum, obtains white solid 6.14g and is compound (II K) highly finished product, yield 85.4%,
Purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,
D6-DMSO): 11.92 (s, 1H), 9.33 (d, J=4.0Hz, 1H), 7.60-7.20 (m, 6H), 7.05-7.00 (m, 1H),
5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H),
3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,4H),2.94-2.86(m,1H),2.82-2.74(m,
1H),2.72-2.62(m,1H),2.43(s,3H),2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,
2H), 1.37-1.31 (m, 2H), 0.76 (d, J=7.8Hz, 3H) .LC-MS (ESI): m/z720.
In the three neck round bottom of 100ml add above-claimed cpd (II K) highly finished product (5.75g, 8.0mmol),
Pyridine (10ml) and methanol (50ml).Stir 2～3 hours at 20～25 DEG C.After HPLC follows the tracks of reaction completely,
Add water (100ml).Reactant mixture ethyl acetate (50ml) extracts 3 times.Merge organic layer, with saturated
Aqueous citric acid solution (50ml) and water (50ml) wash 2 times respectively.Ethyl acetate layer adds activated carbon (0.5g),
It is heated to backflow, filtered while hot, obtains the ethyl acetate solution of ticagrelor.Record in solution by content analysis method and contain
Ticagrelor 4.1g, yield 98.1%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).
LC-MS (ESI): m/z523.
Embodiment 12 P=acetyl group, P1=acetyl group, P2During=acetyl group, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triethylamine (3.64g, 36.0mmol), 4-(N, N-dimethylamino) pyridine (0.05g) and dichloromethane (60ml),
The lower mix homogeneously of stirring.It is warming up to 25～30 DEG C, dropping chloroacetic chloride (2.83g, 12.0mmol), and at this temperature
Stirring reaction.After reacting 3～4 hours, after HPLC follows the tracks of reaction completely, add saturated ammonium chloride solution (120ml)
Cancellation is reacted.Reactant mixture dichloromethane (50ml) extracts 2 times.Merge organic facies, and use saturated ammonium chloride
Solution (50ml) water (50ml) respectively washing 2 times, anhydrous sodium sulfate is dried, and reduced under vacuum removes dichloromethane.
In residue, add the mixed solvent (40ml) of toluene/acetone (3:1, volume ratio), be heated to 55～60 DEG C and protect
Temperature 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour, and be incubated 1 hour.Filter, be dried under filter cake vacuum,
Obtaining white solid 5.73g and be compound (II L) highly finished product, yield 88.4%, (HPLC divides purity 99.8%
Analysis purity, individual event impurity is less than 0.1%).1H NMR (400MHz, d6-DMSO): 9.33 (d, J=4.0Hz, 1H),
7.40-7.20 (m, 2H), 7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98
(q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H), 3.82-3.76 (m, 1H), 3.68-3.54 (m, 1H), 3.16-3.02 (m,
2H),2.94-2.86(m,1H),2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),2.01(s,
9H), 1.56-1.50 (m, 1H), 1.46-1.38 (m, 2H), 1.37-1.31 (m, 2H), 0.76 (d, J=7.8Hz, 3H).
LC-MS (ESI): m/z649.
In the three neck round bottom of 100ml add above-claimed cpd (II L) highly finished product (5.51g, 8.5mmol),
Lithium hydrate (0.61g, 25.5mmol), methanol (40ml) and water (10ml).2～3 are stirred at 20～25 DEG C
Hour.After HPLC follows the tracks of reaction completely, add water (100ml).Reactant mixture ethyl acetate (50ml) extracts
Take 3 times.Merging organic layer, hydrochloric acid solution (50ml) and water (50ml) with 3% wash 2 times respectively.Acetic acid second
Ester layer adds activated carbon (0.5g), is heated to backflow, filtered while hot, obtains the ethyl acetate solution of ticagrelor.
The 4.4g Han ticagrelor in solution, yield 99.1%, purity 99.8% (HPLC analytical pure is recorded by content analysis method
Degree, individual event impurity is less than 0.1%).LC-MS (ESI): m/z523.
Embodiment 13 P=trimethyl is silica-based, P1=trimethyl is silica-based, P2When=trimethyl is silica-based, ticagrelor solution
Preparation method
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analysis
Purity), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Double (trimethyl silyl) acetamide (8.59g, 42.0mmol) of N, O-and dichloromethane (60ml), stirring is lower mixed
Close uniformly.It is warming up to backflow, and stirs reaction at this temperature.After reacting 1～2 hour, HPLC follows the tracks of and has reacted
Quan Hou, reactant mixture is concentrated to dryness.The mixed of ethyl acetate/normal heptane (4:1, volume ratio) is added in residue
Bonding solvent (50ml), is heated to 55～60 DEG C and is incubated 30 minutes, with after be cooled to 20～25 DEG C through 1～2 hour,
And it is incubated 1 hour.Filter, be dried under filter cake vacuum, obtain white solid 6.53g and be compound (II M) essence
Goods, yield 88.3%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H
NMR (400MHz, d6-DMSO): 9.30 (d, J=4.0Hz, 1H), 7.40-7.20 (m, 2H), 7.05-7.00 (m, 1H),
5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H),
3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,2H),2.94-2.86(m,1H),2.82-2.74(m,
1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,2H),
1.37-1.31 (m, 2H), 0.75 (d, J=7.8Hz, 3H), 0.20 (s, 27H) .LC-MS (ESI): m/z740.
In the three neck round bottom of 100ml add above-claimed cpd (II M) highly finished product (6.28g, 8.5mmol),
Glacial acetic acid (10ml), methanol (40ml) and water (10ml).Stir 2～3 hours at 20～25 DEG C.HPLC
After following the tracks of reaction completely, add water (100ml).Reactant mixture ethyl acetate (50ml) extracts 3 times.Close
And organic layer, to wash respectively 2 times with saturated sodium bicarbonate solution (50ml) and water (50ml), anhydrous sodium sulfate is dried,
Filter, obtain the ethyl acetate solution of ticagrelor.Record the 4.4g Han ticagrelor in solution by content analysis method, receive
Rate 99.1%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%), LC-MS (ESI):
m/z523。
Embodiment 14 P=trityl, P1And P2It is same methylmethylene altogether, the preparation side of ticagrelor solution
Method
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analytical pure
Degree), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Trimethyl orthoacetate (1.56g, 13.0mmol), anhydrous p-methyl benzenesulfonic acid (0.5g) and oxolane (60ml).Reaction
Mixture is heated to backflow, reacts 5～6 hours, and after HPLC follows the tracks of reaction completely, less than 35 DEG C concentrations remove big portion
Divide oxolane, dilute with dichloromethane (60ml), and add triphenylchloromethane (3.34g, 12.0mmol),
It is warming up to 25～30 DEG C, dropping triethylamine (1.21g, 12.0mmol), and stir reaction at this temperature.Reaction 3～4
After hour, after HPLC follows the tracks of reaction completely, add saturated ammonium chloride solution (50ml) cancellation reaction.Separate organic
Phase, aqueous phase dichloromethane (50ml) extracts once.Merge organic facies, and washed once with water (50ml), nothing
Aqueous sodium persulfate is dried, and reduced under vacuum removes dichloromethane.In residue, add methanol (60ml), be heated to back
Flow and be incubated 30 minutes, filtered while hot.Collect filtrate, continue to be heated to backflow, with after be cooled to through 1～2 hour
20～25 DEG C, and it is incubated 1 hour.Filter, collect filter cake, be dried under vacuum, obtain white solid being of 7.10g
Compound (II N) highly finished product, yield 89.7%, purity 99.8% (HPLC purity assay, individual event impurity is less than 0.1%).1H NMR (400MHz, d6-DMSO): 9.33 (d, J=4.0Hz, 1H), 7.40-7.20 (m, 17H), 7.05-7.00 (m,
1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m,
1H),3.82-3.76(m,1H),3.68-3.54(m,1H),3.16-3.02(m,3H),2.94-2.86(m,1H),
2.82-2.74(m,1H),2.72-2.62(m,1H),2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38
(m, 5H), 1.37-1.31 (m, 2H), 0.75 (d, J=7.8Hz, 3H) .LC-MS (ESI): m/z791.
To 100ml three neck round bottom fill in add above-claimed cpd (II N) highly finished product (6.72g, 8.5mmol),
The acetic acid aqueous solution (70ml) of 80%, the hydrochloric acid (2ml) of 35% and normal heptane (20ml), stir at 40～45 DEG C
Mix 3～4 hours.After HPLC follows the tracks of reaction completely, separatory removes normal heptane layer, and acetic acid water layer uses normal heptane again
(22ml) 2 times are extracted.Add water (140ml) to acetic acid water layer, extract above-mentioned with dichloromethane (50ml)
Mixture 3 times, combined dichloromethane layer, with water (50ml), saturated sodium bicarbonate solution (50ml) and saturated food
Saline (50ml) respectively washing 2 times, anhydrous sodium sulfate is dried, and is filtrated to get the dichloromethane solution of ticagrelor.With
Content analysis method records the 4.4g Han ticagrelor in solution, yield 99.1%, purity 99.8% (HPLC purity assay,
Individual event impurity is less than 0.1%).LC-MS (ESI): m/z523.
Embodiment 15 P=trityl, P3In R1=phenyl, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analytical pure
Degree), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Phenylboric acid (1.59g, 13.0mmol), anhydrous magnesium sulfate (5.0g) and oxolane (60ml).Reactant mixture heats
To 25～30 DEG C, react 5～6 hours, after HPLC follows the tracks of reaction completely, be filtered to remove magnesium sulfate, add in filtrate
Enter triphenylchloromethane (3.34g, 12.0mmol), be warming up to 25～30 DEG C, dropping triethylamine (1.21g, 12.0mmol),
And stir reaction at this temperature.After reacting 3～4 hours, after HPLC follows the tracks of reaction completely, add saturated ammonium chloride
Solution (50ml) cancellation is reacted.Separating organic facies, aqueous phase dichloromethane (50ml) extracts once.Merge organic
Phase, and washed once with water (50ml), anhydrous sodium sulfate is dried, and reduced under vacuum removes dichloromethane.To remnants
Thing adds ethanol (60ml), is heated to 55～60 DEG C and is incubated 30 minutes, filtered while hot.Collect filtrate, continue
Be heated to backflow, with after be cooled to 20～25 DEG C through 1～2 hour, and be incubated 1 hour.Filter, collect filter cake, very
Empty lower dry, obtain white solid 7.50g and be compound (X A) highly finished product, yield 88.3%, purity 99.8%
(HPLC purity assay, individual event impurity is less than 0.1%).1H NMR(400MHz,d6-DMSO):9.30(d,
J=4.0Hz, 1H), 7.40-7.20 (m, 22H), 7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d,
J=4.0Hz, 1H), 4.98 (q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H), 3.82-3.76 (m, 1H), 3.68-3.54 (m,
1H),3.16-3.02(m,2H),2.94-2.86(m,1H),2.82-2.74(m,1H),2.72-2.62(m,1H),
2.14-2.02(m,1H),1.56-1.50(m,1H),1.46-1.38(m,2H),1.37-1.31(m,2H),0.75
(d, J=7.8Hz, 3H) .LC-MS (ESI): m/z851.
To 100ml three neck round bottom fill in add above-claimed cpd (X A) highly finished product (7.23g, 8.5mmol),
Aqueous hydrochloric acid solution (7ml), methanol (70ml) and the normal heptane (20ml) of 35%, stirs 3～4 at 40～45 DEG C
Hour.After HPLC follows the tracks of reaction completely, separatory removes normal heptane layer, and methanol water layer is again with normal heptane (22ml)
Extract 2 times.Add water (140ml) to methanol water layer, extract said mixture 3 with dichloromethane (50ml)
Secondary, combined dichloromethane layer, with water (50ml), saturated sodium carbonate solution (50ml) and saturated aqueous common salt (50ml)
Each washing 2 times, anhydrous sodium sulfate is dried, and is filtrated to get the dichloromethane solution of ticagrelor.Survey by content analysis method
Obtaining the 4.4g Han ticagrelor in solution, yield 99.1%, (HPLC purity assay, individual event impurity is or not purity 99.8%
More than 0.1%).LC-MS (ESI): m/z523.
Embodiment 16 P=trityl, P3In R1=cyclohexyl epoxide, the preparation method of ticagrelor solution
Reaction scheme is as follows:
Ticagrelor crude product is prepared according to the method for Chinese patent CN1200940C, and purity is 90% (HPLC analytical pure
Degree), content 88% (mass fraction).
In the three neck round bottom of 100ml add content be 88% ticagrelor crude product (5.94g, 10.0mmol),
Triphenylchloromethane (3.34g, 12.0mmol) and dichloromethane (60ml).It is warming up to 25～30 DEG C, drips three
Ethamine (1.21g, 12.0mmol), and stir reaction at this temperature.After reacting 3～4 hours, HPLC follows the tracks of anti-
Should completely after, add saturated ammonium chloride solution (50ml) cancellation reaction.Separating organic facies, aqueous phase is with dichloromethane (50ml)
Extraction is once.Merging organic facies, and washed once with water (50ml), anhydrous sodium sulfate is dried, and reduced under vacuum removes
Remove dichloromethane.Residue oxolane (60ml) dilutes, and adds boric acid (0.68g, 11.0mmol), hexamethylene
Alcohol (1.20g, 12.0mmol), anhydrous magnesium sulfate (5.0g) and oxolane (60ml).React 7～8 hours, HPLC
After following the tracks of reaction completely, it is filtered to remove magnesium sulfate, adds saturated ammonium chloride solution (50ml) cancellation reaction.Separate
Machine phase, aqueous phase dichloromethane (50ml) extracts once.Merge organic facies, and washed once with water (50ml),
Anhydrous sodium sulfate is dried, and reduced under vacuum removes dichloromethane.Toluene/n-heptane (1:1, body is added in residue
Long-pending ratio) (60ml), it is heated to 55～60 DEG C and is incubated 30 minutes, filtered while hot.Collect filtrate, continue to be heated to
Backflow, with after be cooled to 20～25 DEG C through 1～2 hour, and be incubated 1 hour.Filter, collect filter cake, dry under vacuum
Dry, obtain white solid 7.60g and be compound (X B) highly finished product, yield 87.0%, purity 99.7% (HPLC
Purity assay, individual event impurity is less than 0.1%).1H NMR (400MHz, d6-DMSO): 9.35 (d, J=4.0Hz, 1H),
7.40-7.20 (m, 17H), 7.05-7.00 (m, 1H), 5.13 (d, J=6.4Hz, 1H), 5.07 (d, J=4.0Hz, 1H), 4.98
(q, J=8.8Hz, 2H), 3.98-3.95 (m, 1H), 3.82-3.76 (m, 1H), 3.68-3.54 (m, 1H), 3.50-3.44 (m,
1H),3.16-3.02(m,2H),2.94-2.86(m,1H),2.82-2.74(m,1H),2.72-2.62(m,1H),
2.14-2.02 (m, 1H), 1.75-1.31 (m, 15H), 0.75 (d, J=7.8Hz, 3H) .LC-MS (ESI): m/z873.
To 100ml three neck round bottom fill in add above-claimed cpd (X B) highly finished product (7.42g, 8.5mmol),
Aqueous hydrochloric acid solution (7ml), methanol (70ml) and the normal heptane (20ml) of 35%, stirs 3～4 at 40～45 DEG C
Hour.After HPLC follows the tracks of reaction completely, separatory removes normal heptane layer, adds water (140ml) in methanol water layer,
Again with toluene (22ml) extracts 2 times.Extract above-mentioned methanol water layer 3 times with dichloromethane (50ml), merge two
Chloromethanes layer, respectively washs 2 with water (50ml), saturated sodium carbonate solution (50ml) and saturated aqueous common salt (50ml)
Secondary, anhydrous sodium sulfate is dried, and is filtrated to get the dichloromethane solution of ticagrelor.Record in solution by content analysis method
Containing ticagrelor 4.4g, yield 99.1%, purity 99.7% (HPLC purity assay, individual event impurity is less than 0.1%).
LC-MS (ESI): m/z523.
Claims (10)
1. the preparation method of a ticagrelor solution, it is characterised in that including:
1) take content and be not less than ticagrelor I crude product and the hydroxyl protecting group reagent reacting of 83wt.%, at ticagrelor I
Introduce protection group at least one hydroxyl in structure, obtain compound II crude product；
2) compound II crude product is through recrystallization, obtains the compound II highly finished product of correspondence；
3) compound II highly finished product react eliminating hydroxide protection group through deprotection base, remove by-product, prepare for lattice auspicious
The ticagrelor solution that Lip river I highly finished product are formed with solvent, in this solution, the content of solute is not higher than 80wt.%；
Reaction equation is as follows:
Wherein, hydroxyl protecting group P, P1And P2Three is identical or different, but is asynchronously hydrogen；
P is selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,-C (O) SR1,
-C(O)NR4R5,-C (S) NR4R5Or-C (O) NHSO2R1；
P1And P2Selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,
-C(O)SR1,-C (O) NR4R5、-C(S)NR4R5,-C (O) NHSO2R1,-CR4R5,-BR1Or-BOR1；
Wherein, R1、R2And R3Separately selected from the alkyl containing 1～8 carbon atom, substituted contain 1～8 carbon
The alkyl of atom, aryl or substituted aryl；
R4And R5Separately selected from hydrogen, alkyl containing 1～8 carbon atom, substituted contain 1～8 carbon atom
Alkyl, aryl or substituted aryl；
P1、P2Independence, or the two oxygen atom being connected with them mutually and the carbon atom being connected with oxygen atom
Form formula together such as5～8 yuan of heterocycles；
P3For by P1And P2The group formed so that chemical bond is connected.
The preparation method of ticagrelor solution the most according to claim 1, it is characterised in that described step 1)
When middle introducing protection group forms 5 yuan of heterocycles, P3For-CR4R5,-BR1Or-BOR1。
The preparation method of ticagrelor solution the most according to claim 1, it is characterised in that step 1) middle introducing guarantor
The temperature protecting base reaction is 0～90 DEG C, preferably 20～70 DEG C.
The preparation method of ticagrelor solution the most according to claim 1, it is characterised in that step 3) middle removing guarantor
The temperature protecting base reaction is 0～90 DEG C, preferably 20～70 DEG C.
The preparation method of ticagrelor solution the most according to claim 1, it is characterised in that step 3) in solvent
Selected from the alcohol containing less than 8 carbon atoms, ether, ester, amide, nitrile, ketone, alkane, unsaturated hydrocarbons, aromatic hydrocarbons, halogen
For one or more in hydrocarbon, sulfone, sulfoxide and water.
6. according to the preparation method of the ticagrelor solution described in any one of Claims 1 to 5, it is characterised in that step 2)
The solvent of middle recrystallization is selected from the alcohol containing less than 8 carbon atoms, ether, ester, amide, nitrile, ketone, alkane, insatiable hunger
With one or more in hydrocarbon, aromatic hydrocarbons, halogenated hydrocarbons, sulfone, sulfoxide and water.
7. according to the preparation method of the ticagrelor solution described in any one of Claims 1 to 5, it is characterised in that by step 3)
Ticagrelor solution carry out recrystallization or be dried, be met the ticagrelor solid of medicinal requirements；Wherein,
The solvent of recrystallization is selected from the alcohol containing less than 8 carbon atoms, ether, ester, amide, nitrile, ketone, alkane, unsaturation
One or more in hydrocarbon, aromatic hydrocarbons, halogenated hydrocarbons, sulfone, sulfoxide and water.
The preparation method of ticagrelor solution the most according to claim 7, it is characterised in that step 4) in obtaining
Ticagrelor solution add after pharmaceutic adjuvant again recrystallization or be dried, be met the ticagrelor of medicinal requirements
Solid mixture with adjuvant.
9. the compound as shown in formula II:
Wherein, hydroxyl protecting group P, P1And P2Three is identical or different, but is asynchronously hydrogen；
P is selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,-C (O) SR1,
-C(O)NR4R5,-C (S) NR4R5Or-C (O) NHSO2R1；
P1And P2Selected from hydrogen ,-R1,-SiR1R2R3,-C (O) R1,-SO2R1,-SOR1,-SR1,-C (O) OR1,
-C(O)SR1,-C (O) NR4R5、-C(S)NR4R5,-C (O) NHSO2R1,-CR4R5,-BR1Or-BOR1；
Wherein, R1、R2And R3Separately selected from the alkyl containing 1～8 carbon atom, substituted contain 1～8 carbon
The alkyl of atom, aryl or substituted aryl, R4And R5Separately selected from hydrogen, alkyl containing 1～8 carbon atom,
Substituted contain the alkyl of 1～8 carbon atom, aryl or substituted aryl；
P1、P2Independence, or the two oxygen atom being connected with them mutually and the carbon atom one being connected with oxygen atom
Rise and form 5～8 yuan of heterocycles；
Wherein, when P is hydrogen, P1And P2It is asynchronously alkyl, and the oxygen atom that is connected with them and former with oxygen
The carbon atom that son is connected is formed without 5 yuan of heterocycles containing alkylidene together.
Compound the most according to claim 9, it is characterised in that P1And P2The oxygen atom that is connected with them and with
Oxygen atom be connected carbon atom form 5 yuan of heterocycles together, structure represented by a formula X:
P3For-BR1Or-BOR1。
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| CN106243108A (en) * | 2015-06-03 | 2016-12-21 | 四川海思科制药有限公司 | A kind of highly purified ticagrelor and preparation method thereof |
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