CN110194771A - A kind of preparation method of the medicinal II crystal form of ticagrelor - Google Patents
A kind of preparation method of the medicinal II crystal form of ticagrelor Download PDFInfo
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- CN110194771A CN110194771A CN201910379354.4A CN201910379354A CN110194771A CN 110194771 A CN110194771 A CN 110194771A CN 201910379354 A CN201910379354 A CN 201910379354A CN 110194771 A CN110194771 A CN 110194771A
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- ticagrelor
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- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 37
- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 37
- 239000013078 crystal Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 23
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 230000000087 stabilizing effect Effects 0.000 abstract description 2
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000002245 particle Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 238000005119 centrifugation Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000126 substance Chemical group 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000007689 inspection Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to the preparation methods of ticagrelor, and in particular to a kind of preparation method of the medicinal II crystal form of ticagrelor；This method provides a kind of by 2- (3AR; 4S; 6R; 6AS) -6- (the chloro- 2- rosickyite base -4- pyrimidine radicals of 5- amido -6-) amino tetrahydro -2; 2- dimethyl -4H- cyclopenta -1; 3- dioxolane -4- base] oxygen]-ethyl alcohol prepares the new method of the medicinal II crystal form of ticagrelor, and this method process stabilizing, crystal form purity are high, partial size is small and uniform, are easy to large-scale production.
Description
Technical field
The present invention relates to the preparation methods of ticagrelor, and in particular to a kind of preparation side of the medicinal II crystal form of ticagrelor
Method, specifically, high-purity prepares ticagrelor different crystal forms, the technique the present invention relates to the selection by crystallization condition
Stablize, yield is relatively high, useless in technique to arrive special installation and reagent.
Background of invention
Ticagrelor (Ticagrelor, chemical structure are shown in formula I) belongs to cyclopenta triazolopyrimidines, is
One kind of AstraZeneca company research and development is novel to have the small molecule for selectively treating acute coronary syndrome (ACS)
Anticoagulation medicine, 2 receptor of purine (P2) hypotype P2Y12 that can reversibly on vasoactive smooth muscle cell, without metabolism
Activation, has apparent inhibiting effect to platelet aggregation caused by adenosine diphosphate (ADP), has and works rapidly, and curative effect is strong, significant to drop
The features such as low patient's bleeding event risk, reduction cardiovascular mortality.
The patent CN1247583C of Astrazeneca AB discloses four crystal forms (crystal form I, crystal form II, the crystalline substance of ticagrelor
Type III, crystal form IV) and amorphous state and preparation method thereof.In above-mentioned crystal form, II type crystalline stability is best, while
Unit marketed products are ground with crystal form by original, but the recrystallisation solvent chloroform of II type crystallization is more toxic, and is not suitable for scale metaplasia
It produces；And crystalline particle is uneven, there are bulky grain (40-60um) need to first be crushed when carrying out preparation preparation, preparation at
This height.
To sum up, it is still necessary to further being studied ticagrelor crystallization processes, find that crystal form purity is high, partial size is small and
It uniformly, while can industrialized production, the lower ticagrelor crystallization processes of production cost.
Summary of the invention
Goal of the invention
The purpose of the present invention is to provide a kind of new method for preparing ticagrelor different crystal forms, this method process stabilizing,
Crystal form purity is high, partial size is small and uniform, is easy to large-scale production.
Technical solution
That the present invention provides a kind of crystal form purities is high, partial size is small and uniform, the suitable preparation method for being easy to industrialization production,
It mainly comprises the steps that
One kind passing through 2- (3AR, 4S, 6R, 6AS) -6- (the chloro- 2- rosickyite base -4- pyrimidine radicals of 5- amido -6-) amino tetrahydro -
2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- bases] oxygen]-ethyl alcohol prepares the new method of ticagrelor, and it should
Method is characterized in:
Step (1): 2- (3AR, 4S, 6R, 6AS) -6- (the chloro- 2- rosickyite base -4- pyrimidine radicals of 5- amido -6-) amino tetrahydro -
2,2- dimethyl
- 4H- cyclopenta -1,3- dioxolane -4- base] oxygen]-ethyl alcohol under sodium nitrite, acetic acid existence condition,
Certain
At a temperature of reaction generate 2- [[(3aR, 4S, 6R, 6aS) -6- [chloro- 5- rosickyite base -3H-1,2,3- triazole [4,5- of 7-
D] pyrimidin-3-yl] four
Hydrogen -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- base] oxygen]-ethyl alcohol (intermediate 2)；
Step (2): intermediate 2 generates ticagrelor crude product under methanol hydrochloride solution effect；
Step (3): after the concentration of ticagrelor crude product, atent solvent is added, generates ticagrelor finished product.
40~70 DEG C of temperature of residue when atent solvent being added in the step (3), wherein preferably 60~70 DEG C.
Residual volume/intermediate 2=0-20V/W, preferably 6-8V/W after concentration in the step (3).
Atent solvent is normal heptane, hexamethylene and isooctane in step (3), wherein it is preferred that normal heptane.
Crystallization temperature -10~10 DEG C of the step (3), wherein preferably 0~10 DEG C.
Its preparation route are as follows:
The invention has the advantages that being prepared by simple technique, the acquisition partial size of high yield is small and uniformly replaces lattice
Rui Luo, and it is suitable for large-scale production without chloroform.Because crystallization item is different, i.e. different solvents or crystallization solvent ratio are to obtaining
Crystal form have an impact, display has plenty of crystal form I in embodiment in the present invention, has plenty of crystal form II, and it is mixed to have plenty of crystal form I and II
Crystalline substance, subtle condition change its crystal form and also change therewith, the time being specifically concentrated in crystallization and concentration journey
Different solvents etc. are added dropwise in degree, and result is different, thus the present invention provide a kind of optimum optimization condition obtain purity is high, high income,
Its partial size small (being lower than 40 μm) and orientation obtain the ticagrelor product of crystal form II.
Detailed description of the invention
Fig. 1 ticagrelor II crystalline substance DSC figure
Fig. 2 ticagrelor I crystalline substance DSC figure
Fig. 3 ticagrelor I and II mixed crystal DSC figure
Fig. 4 ticagrelor II crystalline substance XRD diagram
Fig. 5 ticagrelor I and II mixed crystal XRD diagram
Specific embodiment
For a better understanding of the present invention, carry out the technical solution that the present invention will be described in detail below with reference to specific example, still
The present invention is not limited thereto.
Embodiment 1
In 1L reaction flask, toluene (300ml), 2- (3AR, 4S, 6R, 6AS) -6- (chloro- 2- of 5- amido -6- are sequentially added
Rosickyite base -4- pyrimidine radicals) amino tetrahydro -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- base] oxygen]-second
Alcohol (intermediate 1) (62.6g, 149mmol), acetic acid (50.0g, 834mmol), stirring are cooled to 0-10 DEG C, and sodium nitrite is added dropwise
Aqueous solution (10.8g sodium nitrite/25ml water).Drop is warming up to 20-30 DEG C after finishing, stir 10min, and wet chemical is added dropwise
(61.8g potassium carbonate/125ml water) adjusts pH=7-8, and system stands liquid separation, and organic phase is spare (intermediate 2).
In 3L reaction flask, organic phase is walked in addition, stirring is cooled to 0-10 DEG C, and the concentrated hydrochloric acid and methanol of pre-cooling is added dropwise
Mixed liquor (271.9g concentrated hydrochloric acid/250ml methanol) is stirred to react 5min, stands liquid separation.Into water phase be added 1L purified water and
0.5L ethyl acetate, is cooled to 0-10 DEG C, and 125g sodium bicarbonate is added into reaction system, adjusts pH=7-8, stands liquid separation.Water
The extraction of Xiang Zaiyong 0.5L ethyl acetate, merges organic phase, then washed twice with the purified water of 1.2L, stands liquid separation, and organic phase is used
Active carbon decoloring and the dry 30min of anhydrous sodium sulfate, are filtered spare (ticagrelor organic phase)；
Organic phase is concentrated into residue about 0.5L for 40-45 DEG C in 2L reaction flask, and residue is warming up to 60-70 DEG C, temperature control drop
Add normal heptane, after drop finishes, be down to 0-10 DEG C, stir 3h, centrifugation, 40-45 DEG C of filter cake is dried under vacuum to constant weight (difference is less than again
0.5%) off-white powder, is obtained, yield spectra: 80-90%.
It is detected through HPLC, product purity 99.5%；DSC and XRD detection, sample are II crystal form；Malvern ParticleSizer inspection
It surveys particle size range and is less than 30um.
Embodiment 2
The preparation method is the same as that of Example 1 for ticagrelor organic phase solution.
Normal heptane is added dropwise in organic phase in 2L reaction flask, after drop finishes, is down to 0-10 DEG C, stirs 48h, centrifugation, filter cake 40-45
It DEG C is dried under vacuum to constant weight (difference is again less than 0.5%), obtains off-white powder, yield spectra: 60-65%.
It is detected through HPLC, product purity 99.2%；DSC and XRD detection, sample are II crystal form；Malvern ParticleSizer inspection
It surveys particle size range and is less than 20um.
Embodiment 3
The preparation method is the same as that of Example 1 for ticagrelor organic phase solution.
Organic phase is concentrated into residue about 0.5L for 40-45 DEG C in 2L reaction flask, and residue is warming up to 60-70 DEG C, temperature control drop
Add hexamethylene, after drop finishes, be down to 0-10 DEG C, stir 3h, centrifugation, 40-45 DEG C of filter cake is dried under vacuum to constant weight (difference is less than again
0.5%) off-white powder, is obtained, yield spectra: 75-80%.
It is detected through HPLC, product purity 99.5%；DSC and XRD detection, sample are II crystal form；Malvern ParticleSizer inspection
Survey particle size range 30-40um.
Embodiment 4
The preparation method is the same as that of Example 1 for ticagrelor organic phase solution.
Organic phase is concentrated into residue about 0.5L for 40-45 DEG C in 2L reaction flask, and residue is warming up to 60-70 DEG C, temperature control drop
Add isooctane, after drop finishes, be down to 0-10 DEG C, stir 3h, centrifugation, 40-45 DEG C of filter cake is dried under vacuum to constant weight (difference is less than again
0.5%) off-white powder, is obtained, yield spectra: 70-80%.
It is detected through HPLC, product purity 99.3%；DSC and XRD detection, sample are II crystal form；Malvern ParticleSizer inspection
Survey particle size range 30-40um.
Embodiment 5
The preparation method is the same as that of Example 1 for ticagrelor organic phase solution.
Organic phase is concentrated into residue about 0.5L for 40-45 DEG C in 2L reaction flask, and residue is warming up to 60-70 DEG C, temperature control drop
Add normal heptane, after drop finishes, be down to -10-0 DEG C, stir 2h, centrifugation, 40-45 DEG C of filter cake is dried under vacuum to constant weight (difference is less than again
0.5%) off-white powder, is obtained, yield spectra: 80-90%.
It is detected through HPLC, product purity 95.6%；DSC and XRD detection, sample are II crystal form；Malvern ParticleSizer inspection
Survey particle size range 30-40um.
Reference examples 1
The preparation method is the same as that of Example 1 for ticagrelor organic phase solution.
Organic phase is concentrated to dryness for 40-45 DEG C in 2L reaction flask, and residue is warming up to 60-70 DEG C, and normal heptane is added dropwise in temperature control,
After drop finishes, it is down to 0-10 DEG C, stirs 3h, centrifugation, 40-45 DEG C of filter cake is dried under vacuum to constant weight (difference is again less than 0.5%), obtains class
White solid, yield spectra: 80-90%.
It is detected through HPLC, product purity 99.5%；DSC and XRD detection, sample are I and II mixed crystal；Malvern ParticleSizer
Detect particle size range 40-50um.
The preparation method is the same as that of Example 1 for 2 ticagrelor organic phase solution of reference examples.
Organic phase is concentrated into residue about 0.5L for 40-45 DEG C in 2L reaction flask, and temperature control is added dropwise normal heptane and is down to after drop finishes
To 0-10 DEG C, 3h is stirred, centrifugation, 40-45 DEG C of filter cake is dried under vacuum to constant weight (difference is again less than 0.5%), off-white powder is obtained,
Yield spectra: 80-90%.
It is detected through HPLC, product purity 97.2%；DSC and XRD detection, sample are I and II mixed crystal；Malvern ParticleSizer
Detect particle size range 40-50um.
Reference examples 3
Embodiment 2 in patent CN1247583C is ground according to original to repeat.
Chloroform (150ml) is added in 45g ticagrelor, is heated to dissolving, acquired solution is placed into crystallised overnight, and
40-50 DEG C of drying obtains off-white powder, yield spectra: 75-85% to constant weight (difference is again less than 0.5%) under flowing nitrogen.
It is detected through HPLC, product purity 98.2%；DSC and XRD detection, sample II crystal；Malvern ParticleSizer detects particle size range
40-60um, and have bulky grain.
Claims (9)
1. a kind of preparation method of the medicinal II crystal form of ticagrelor, it is characterised in that: realize as follows
Step 1:2- (3AR, 4S, 6R, 6AS) -6- (the chloro- 2- rosickyite base -4- pyrimidine radicals of 5- amido -6-) amino tetrahydro -2,2- two
Methyl -4H- cyclopenta -1,3- dioxolane -4- base] oxygen]-ethyl alcohol 1 under sodium nitrite, acetic acid existence condition,
Controlling thermotonus generation 2-, [[[the chloro- 5- rosickyite base -3H-1,2,3- triazole [4,5-d] of 7- is phonetic by (3aR, 4S, 6R, 6aS) -6-
Pyridine -3- base] tetrahydro -2,2- dimethyl -4H- cyclopenta -1,3- dioxolane -4- base] oxygen]-ethyl alcohol 2 i.e. intermediate 2；
Step 2: intermediate 2 generates ticagrelor crude product Ticagrelor under methanol hydrochloride solution effect；
Step 3: after the concentration of ticagrelor crude product, atent solvent is added, generates ticagrelor crystal form II；
2. the method according to claim 1, wherein residue temperature 40 when atent solvent being added in step 3~
70℃。
3. the method according to claim 1, wherein in step 3 be added atent solvent when residue temperature be 60~
70℃。
4. the method according to claim 1, wherein 2 mass of residual volume/intermediate after being concentrated in step 3
For 0-20V/W.
5. the method according to claim 1, wherein 2 mass of residual volume/intermediate after being concentrated in step 3
For 6-8V/W.
6. the method according to claim 1, wherein atent solvent is normal heptane, hexamethylene or different pungent in step 3
Alkane.
7. the method according to claim 1, wherein atent solvent is normal heptane in step 3.
8. the method according to claim 1, wherein crystallization temperature -10~10 DEG C of step 3.
9. the method according to claim 1, wherein the crystallization temperature of step 3 is 0~10 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112898304A (en) * | 2019-11-19 | 2021-06-04 | 北京四环制药有限公司 | Preparation method of high-purity ticagrelor crystal form II |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1817883A (en) * | 2000-06-02 | 2006-08-16 | 阿斯特拉曾尼卡有限公司 | New crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound |
| CN105801583A (en) * | 2014-12-31 | 2016-07-27 | 徐州万邦金桥制药有限公司 | Purification method of ticagrelor |
-
2019
- 2019-05-08 CN CN201910379354.4A patent/CN110194771A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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