CN105940003A - A production method and a new crystalline form of an intermediate of synthesis of ticagrelor - Google Patents
A production method and a new crystalline form of an intermediate of synthesis of ticagrelor Download PDFInfo
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- CN105940003A CN105940003A CN201480061207.8A CN201480061207A CN105940003A CN 105940003 A CN105940003 A CN 105940003A CN 201480061207 A CN201480061207 A CN 201480061207A CN 105940003 A CN105940003 A CN 105940003A
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- 0 CCCSc(c(CC)c1Cl)nc2c1nn[n]2[C@](C[C@@](CCCCO)[C@@]1*)[C@@]1O Chemical compound CCCSc(c(CC)c1Cl)nc2c1nn[n]2[C@](C[C@@](CCCCO)[C@@]1*)[C@@]1O 0.000 description 2
- VCKIETNGSCUQQC-NLQMIUDCSA-N C[C@H](C1)[C@@H]1C(/C=C(\C(\F)=C/C)/F)=C Chemical compound C[C@H](C1)[C@@H]1C(/C=C(\C(\F)=C/C)/F)=C VCKIETNGSCUQQC-NLQMIUDCSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to preparation of ticagrelor of formula I and comprises a reaction of a compound of formula IV with a deprotection agent in a solvent to a compound of formula V, which is advantageously isolated by crystallization and subsequently used for the preparation of ticagrelor. The substituent R in formulae IV and V is CH2CH2OH, CH2COOH, or CH2COOR1; R1 is a branched or unbranched R1-C4 alkyl; and X is NH2, NO2f or NHCHO.
Description
Technical field
The present invention relates to the preparation method of the improvement of ticagrelor (ticagrelor) (I), described auspicious for lattice
Lip river (I) is for be had chemical name (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluoro by what Formulas I represented
Phenyl) cyclopropyl]-amino]-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl
Ethyoxyl) compound of-1,2-ring pentanediol
Background technology
There is chemical name (1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl]-ammonia
Base]-5-(rosickyite base)-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl)-1,2-ring penta
Glycol and the ticagrelor of formula (I)
It is the active drug substance of product B RILIQUE, described product B RILIQUE and aspirin
(ASA) using together, it is indicated for prevention and suffers from acute coronary syndrome (instability
Angina pectoris, the myocardial infarction [NSTEMI] raised without ST or have the myocardial infarction [STEMI] that ST raises)
Adult patients (include through treatment patient or with percutaneous coronary get involved (PCI) patient for the treatment of or
Patient after coronary bypass grafting (CABG)) atherothrombosis event.
WO0034283 is expressly recited ticagrelor, has further related to preparation and use the side of ticagrelor
Method.Patent application WO 2001092262 subsequently describes single polymorphic forms I-IV, amorphous
Type form, the preparation of these forms and their purposes in pharmaceutical composition.But, drawn
Application in preferably crystal form be used for preparing pharmaceutical composition, since it is known that armorphous shape
Formula does not has crystal form stable, and armorphous form typically presents the impurity of higher amount.
Application WO2011067571 describes have various altogether formation such as glycolic, salicylic acid,
The eutectic of succinic acid, malonic acid or vanillic acid.
Application WO2008024044 and WO2008024045 describes the drug regimen of ticagrelor
Thing.Embodiment is mentioned there is crystalline Formula II and III and at least one filler, at least one glues
Compound, at least one fluidizer and the preparation of disintegrating agent.Described compositions contains more than 50%
Active component and being prepared by wet granulation.Application WO2011076749 discusses to have and determines greatly
The pharmaceutical preparation of little ticagrelor granule.
Patent application WO0034283 and WO0192262 (scheme 1) and WO0192263 (scheme
2) synthesis of ticagrelor is had been described in.
It is real that patent application WO2012138981 contains the program similar with the program mentioned in priority patent
Executing example, it utilizes Aminocyclopentane-1, and (X is NH with pyrimidine 2 for 2-glycol 1a, 1b, 1c, 1d2、
NO2, NHCHO) condensation, and conversion subsequently produces ticagrelor.
Summary of the invention
It is an object of the invention to the preparation method of ticagrelor I
Its synthesis order based on display in scheme 3,
Wherein R is CH2CH2OH、CH2COOH or CH2COOR1；R1For side chain or unbranched
C1-C4 alkyl；And X is NH2、NO2Or NHCHO.
The primary response of whole synthesis is that Aminocyclopentane glycol II and pyrimidines i II is condensed, and produces middle
Thing IV, it can be separated or can not be separated.All a key character of synthesis is compound
The deprotection subsequently of IV produces compound V.
Synthesis early stage, still just remove protection group eliminate in synthesis step subsequently molecule remove-insurance
The necessity protected, is likely to be formed the impurity being difficult to remove in synthesis step subsequently so that product produces
Rate and quality are worse.
Compound V can be from different selected from methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetic acid
Propyl ester etc. or they and crystallization or recrystallization in the various solvents of the group of the mixture of water.
It is proved favourable with the purity of the reaction of pyrimidines i II and speed for Aminocyclopentane glycol II
It is to use 60 DEG C to 150 DEG C, the preferably 80 DEG C reaction temperatures to 140 DEG C of scopes, uses relative to change
Compound II is at the tertiary amine of 1 to 30 molar equivalents ranges, preferably at the three of 2 to 12 molar equivalents ranges
Ethamine is as alkali, and uses alcohol or the mixture of alcohol and water, preferred methanol, ethanol, propanol, different
Propanol or ethylene glycol are as solvent.
One of specific embodiment carrying out this synthesis order (scheme 4) preferably 2-[[(3aR, 4S, 6R, 6aS)-
6-amino tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-base] epoxide]-second
The chloro-2-of alcohol IIa Yu 4,6-bis-(rosickyite base)-pyrimidine-5-amine IIIa in the presence of triethylamine at methanol, ethanol
Or 90-130 DEG C of condensation in their mixture, producing intermedium IVa, IVa is permissible for this intermedium
Precipitate by adding various anti-solvent such as heptane and/or water and separated with appropriateness purification.But,
This separation is not necessarily.
The key feature of this program is in the next stage to compound IVa deprotection, produces compound
Va.Compound Va is solid matter, and can be by solvent (such as, the first different from many
Alcohol, ethanol, acetonitrile, isopropanol, ethyl acetate, isopropyl acetate etc.) in crystallization and be purified.
It is proved solvent and the mixture of water particularly convenient, because suitably for the purification effect of crystallization
Under the conditions of, compound Va can have characteristic diffraction patterns be the most not yet described
(Fig. 1) purified crystals form crystallizes from aqueous solvent.This crystal form is corresponding to a hydration
Thing, because its study plot contains the water of 4.0% to 5.2% and (uses karr Fischer (Karl Fischer)
Titration measuring).On the other hand, anhydrous solvent only obtains amorphous products, then crystallization is just
Not there is any significant purification effect.But, diffraction pattern armorphous form shown in Figure 2 has
Hygroscopicity, and it absorbs atmospheric moisture when being allowed to stand for, thus the water content in intermedium is not enough to
Gained form for authenticating compound Va.By using CuK α radiometric compound Va to exist
Characteristic reflection in X-ray coatings: 5.8 ° ± 0.2 °；7.2°±0.2°；9.1°±
0.2°；11.7°±0.2°；18.3°±0.2°；22.6°±0.2°；23.5°±0.2°
With 28.7 ° ± 0.2 ° 2 θ.
Can use subsequently amyl nitrite or sodium nitrite selected from acetonitrile, oxolane, water or
The solvent of the group of their mixture carries out the diazotising of compound Va, produces compound VIa.For
Accelerating reaction, the catalyst adding acid form is favourable, and this allows to the response time from 5
Hour shorten to 1.5 hours.Already tested with acetic acid, hydrochloric acid or sulphuric acid.Compound VIa is also solid
Body material, it is also possible to can be by being preferably purified from MTBE recrystallization.But, separate this
One intermedium is not necessarily.
Then, in the next step, compound VIa and (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine
(preferably with the form with the salt of R-MA) (preferably is selected from triethylamine, two different at tertiary amine or inorganic base
Propylethylamine, sodium carbonate, the group of potassium carbonate) in the presence of react, produce ticagrelor I.
Accompanying drawing explanation
Fig. 1-penetrate according to the X-of the hydrate crystallization form of the compound Va of embodiment 1 and 2 preparation
Line coatings.
Fig. 2-according to the X-ray powder of the most armorphous form of the compound Va of embodiment 3 preparation
End figure.
Fig. 3-from the efficiency of crystallization of embodiment 4 is for the gained dependency of the water yield added in crystallization
(data according in table 2).Letter " C " highlights wherein crystallization condition and results in compound
The experiment of the especially convenient crystal form of Va.
Detailed description of the invention
Embodiment uses changes embodiment in detail below, illustrates the present invention in more detailed manner.These are real
Execute example and the improvement of the program according to the present invention is described, only there is characterisation and limit the most in any way
The scope of the present invention.
Embodiment 1:(1S, 2S, 3R, 5S)-3-[(the chloro-2-of 5-amino-6-(rosickyite base)-pyrimidine-4-yl) amino]-
The preparation of 5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol (Va).
By 2-[[(3aS, 4R, 6S, 6aR)-4-amino-2,2-dimethyl-4,5,6,6a-of L-TARTARIC ACID salt form
Tetrahydrochysene-3aH-cyclopenta [d] [1,3]-dioxole-6-base] epoxide]-ethanol (32.6g, 89
Mmol) it is dissolved in the chloro-2-of 4,6-bis-(rosickyite base)-pyrimidine-5-amine (20.5g, 86mmol, compound IIIa)
In methanol (80ml).By triethylamine (60ml；430mmol) add in solution.Then, at pressure
Reactant mixture is heated approximately at 99 to 105 DEG C by container and stirs 22 hours.Hereafter, make
The reactant mixture cooled down with ethyl acetate (90ml) dilution, and by under reduced pressure evaporating major part
Solvent and concentrate described mixture.Use the mixing that 90ml ethyl acetate and the dilution of 180ml water concentrate
Thing, and extract.Top organic facies is separated and by under reduced pressure evaporation major part solvent
And concentrate.Heptane (140ml) is used to dilute the dense of agitation at the temperature (60-70 DEG C) raised
Contracting mixture, then places crystallization by the mixture of agitation.After being cooled to 0 DEG C, by filtering
Remove light brown product and use a small amount of heptane wash.After vacuum drying, it is thus achieved that 30g has and is higher than
The intermedium IVa of the HPLC purity of 98.5%.Then using HR MS checking MW is 418.94
(C17H27ClN4O4S)。
Compound IVa (the 28.5g obtained is stirred in the mixture of 90ml methanol and 15ml water；
68mmol).Then in suspension, add 36% hydrochloric acid (20ml, about 240mmol).Then will
The solution obtained stirs 3.5 hours at about 35 DEG C.Then, by distilling major part in vaporizer
More volatile solvent and concentrate described mixture.Use the mixture that the dilution of 130ml water concentrates, so
Rear stirring, is neutralized by being added dropwise over the NaOH aqueous solution (about 150ml) of 5%.Will be mixed
Compound stirs overnight.Within second day, it is cooled to 0 DEG C, grayish crystallized product is leached and uses few
The water washing of amount.After vacuum drying, it is thus achieved that 25.5g has the chemical combination of the HPLC purity of 99.5%
Thing Va (being 80% relative to IIIa).Then using HR MS checking MW is 378.87
(C14H23ClN4O4S).The water content using karl fischer method to measure is 4.8%.Described crystallization is produced
The X-ray coatings of thing are shown in Fig. 1.The position summarizing diffraction maximum in table 1 is strong with theirs
Degree.Characteristic peak is: 5.8 °；7.2°；11.7°；18.3°；22.6 ° and 28.7 ° of 2 θ.
Table 1.
1H NMR (250MHz, dmso-d6,25 DEG C): δ 7.00 (d, J=6.9Hz, 1H)；4.85(brs,
2H)；4.79 (d, J=4.3Hz, 1H)；4.72 (d, J=6.1Hz, 1H)；4.54(m,1H)；4.19 (quintet,
J=7.4Hz, 1H)；3.89(m,1H)；3.80(m,1H)；3.64(m,1H)；3.38-3.53(m,4H)；2.94
(m,2H)；2.53(m,1H)；1.63 (sextet, J=7.4Hz, 2H)；1.25(m,1H)；0.95(t,
J=7.6Hz, 3H).
Embodiment 2:(1S, 2S, 3R, 5S)-3-[(the chloro-2-of 5-amino-6-(rosickyite base)-pyrimidine-4-yl) amino]-
The preparation of 5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol (Va).
By 2-[[(3aS, 4R, 6S, 6aR)-4-amino-2,2-dimethyl-4,5,6,6a-of L-TARTARIC ACID salt form
Tetrahydrochysene-3aH-cyclopenta [d] [1,3]-dioxole-6-base] epoxide]-ethanol (65g, 177
Mmol) it is dissolved in the chloro-2-of 4,6-bis-(rosickyite base)-pyrimidine-5-amine (41g, 172mmol, compound IIIa)
In methanol (120ml).By triethylamine (120ml；0.86mmol) add in solution.Then, in pressure
Reactant mixture is heated approximately at 105 DEG C by force container and stirs about 20 hours.Hereafter, second is used
The reactant mixture of acetoacetic ester (180ml) dilution cooling, and by under reduced pressure evaporation major part solvent
And enriched mixture.Use the mixture that 2-methyl-tetrahydro furan (180ml) dilution concentrates, and
Add HCl/water solution (25ml dense HCl+330ml water), and extract.Top is had
Machine is separated and is concentrated by under reduced pressure evaporation major part solvent.Then at 200ml ethanol and
The mixture of 30ml water stirs the mixture of concentration.36% hydrochloric acid (40ml) is added in suspension.
Then the solution obtained is stirred 4 hours at a temperature of 35 DEG C.Then, by distillation in vaporizer
Fall the more volatile solvent of major part and concentrate described mixture.Use the mixed of 260ml water dilution concentration
Compound, then stirs, by being added dropwise over the NaOH aqueous solution (about 140ml) of 10% and by it
Neutralize.Mixture is stirred overnight.Within second day, it is cooled to 0 DEG C, reddish brown crystallized product is leached
And wash with water.
Then the wet product of stirring and pumping and being dissolved in acetonitrile (400ml), and stir,
And it is gradually cooling to 0 DEG C, solution is placed crystallization.By product suction and wash with 35ml ice acetonitrile.
After vacuum drying, it is thus achieved that 48g have the HPLC purity of 98.5% compound Va (relative to
IIIa is 77%).Then using HR MS checking MW is 378.87 (C14H23ClN4O4S).Make
The water content measured with karl fischer method is 5.0%, and the diffraction pattern of described crystallized product is corresponding
In Fig. 1.
1H NMR (250MHz, dmso-d6,25 DEG C): δ 7.00 (d, J=6.9Hz, 1H)；4.85(brs,
2H)；4.79 (d, J=4.3Hz, 1H)；4.72 (d, J=6.1Hz, 1H)；4.54(m,1H)；4.19 (quintet,
J=7.4Hz, 1H)；3.89(m,1H)；3.80(m,1H)；3.64(m,1H)；3.38-3.53(m,4H)；2.94
(m,2H)；2.53(m,1H)；1.63 (sextet, J=7.4Hz, 2H)；1.25(m,1H)；0.95(t,
J=7.6Hz, 3H).
Embodiment 3: make (1S, 2S, 3R, 5S)-3-[(the chloro-2-of 5-amino-6-(rosickyite base)-pyrimidine-4-yl) ammonia
Base]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol (Va) crystallizes from anhydrous acetonitrile.
As a comparison, make to utilize crystallization one water of the compound Va that the program described in embodiment 1 obtains
Compound is tied from anhydrous acetonitrile (using water content=0.03% that Carl Fischer titration method measures) again
The mixture of compound Va (12.0g) and acetonitrile (90ml) is heated to 42 DEG C, lazy by crystalline substance
Property atmosphere in stir, wherein there is being completely dissolved of solid matter.By obtained solution at indifferent gas
Atmosphere stirs, then in 3 hours, is cooled to 1 to 2 DEG C, observe that reddish brown is solid simultaneously when 32 DEG C
Occurring mutually, it is the most thickening.After cooling completes 1 hour, quickly suction reddish brown product was also in supply
It is vacuum dried in the case of noble gas.Obtain 11.0g and there is the light brown powder of 1.8% water content
End, its diffraction pattern being shown in Fig. 2 is corresponding to the most armorphous form.
Embodiment 4: in various solvents and depend on the water yield and make (1S, 2S, 3R, 5S)-3-[(5-amino-6-chlorine
-2-(rosickyite base)-pyrimidine-4-yl) amino]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol (Va) crystallization.
Make the crude intermediate Va with different purity according to embodiment 1 or 2 preparation from various solvents
Or recrystallization in solvent mixture, and observe the water yield process for crystallization of solvent and interpolation, product
Rate and purification effect and for the quality of products therefrom and the impact of form.Use ultra high efficiency liquid phase color
Spectrum (UPLC), the compound that ratio (the passing through normalization) assessment of peak area loads from chromatogram
The purity of the intermedium Va of Va and purification.Then the Carl Fischer titration method using standard is monitored
Water content in the intermedium of purification.Then the shape of X-ray powder diffraction detection repurity product is used
Formula (crystallization/armorphous) (about characteristic result, see Fig. 1 and Fig. 2).
Crystallize in inert nitrogen atmosphere as follows: make to weigh has known purity
In the mixture of the water that compound Va is dissolved in selected anhydrous solvent or solvent and particular measurement amount,
It is heated to 40 to 50 DEG C (amounting to the dissolved compound Va of 9 to 16ml/g).Dissolve this in nitrogen
The device of gas inerting is carried out.The solution of the compound Va obtained is stirred vigorously 2 through mechanical agitator
To 3 hours, gradually it is cooled to 0 to 5 DEG C until crystallization occurs.It is stirred for 45-60 at the temperature disclosed above
After minute, solid product is quickly aspirated on the filter and subsequently at reduced pressure at room temperature (about 100
Millibar) it is dried.Solvent, the water yield of interpolation, initial substance and the purity of purifying substance of use, institute
The productivity of product, water content and the crystal form or the armorphous form that measure are summarized in table 2 below
In.In view of crystallization, there are two basic functions and separate the chemical combination of preparation with possible maximum output
The fact that thing and from contained admixture (impurity) prepared by purification as much as possible compound,
The result of crystallization can be assessed in the way of different from least the above two kinds of viewpoints.In order to apparent, I
In last hurdle of table 2, introduce its energy of crystalline rate that a combined value is referred to as
Enough it is defined as taking advantage of of the weight yield of separated compound and the percentage ratio of the impurity removed by crystallization
Long-pending.Therefore, the material of the input that crystalline rate is mentioned in being previous hurdle and the intermedium Va of separation
Weight yield and the combination of purity, and therefore, it highlights the purification of carried out crystallization with numeral
Effect.
FIG. 3 below summarizes the result in table 2 with the clear diagrammatic form simplified, is tied by display
Brilliant efficiency is for adding the dependency of the water yield, and Fig. 3 clearly demonstrates and from anhydrous solvent (0ml/g
Water) in crystallization compare, add the notable actively impact of water, and illustrate wherein crystallization condition simultaneously
Cause occurring compound Va crystal form (marking with letter " C " in Fig. 3) situation compared to
The special benefit of the situation of armorphous form occurs.
Table 2
Embodiment 5:(1S, 2S, 3R, 5S) (the chloro-5-of 7-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] is phonetic for-3-
Pyridine-3-base] preparation of-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol (VIa)
At 45 DEG C, compound Va (12.5g, 33.3mmol) is dissolved in acetonitrile (60ml).Then exist
45 DEG C are added dropwise over amyl nitrite (6.4ml, 47mmol) and at 45 DEG C by reactant mixture
Stir 5 hours.In vaporizer, under reduced pressure evaporate solvent, produce the solid matter of baby pink.
Obtaining 12.5g (97%) compound VIa, it is the most i.e. used for described in embodiment 7
Following reaction.
Or, can make compound VIa such as from isopropyl acetate, t-butyl methyl ether, toluene or
Recrystallization in their mixture.
Then using HR MS checking MW is 389.86 (C14H20ClN5O4S)。
1H NMR (250MHz, dmso-d6,25 DEG C): δ 5.13 (quartet, J=8.9Hz, 1H)；
4.62 (dd, J=8.6Hz, J=4.8Hz, 1H)；3.97 (dd, J=4.7Hz, J=1.6Hz, 1H)；3.79(m,1H)；
3.51(m,4H)；3.21 (dt, J=7.0Hz, J=1.8Hz, 2H)；2.72(m,1H)；2.14(m,1H)；1.75
(sextet, J=7.3Hz, 2H)；1.02 (t, J=7.3Hz, 3H).
Embodiment 6:(1S, 2S, 3R, 5S) (the chloro-5-of 7-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] is phonetic for-3-
Pyridine-3-base] preparation of-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol (VIa)
At 45 DEG C, compound Va (20g, 50mmol) is dissolved in acetonitrile (160ml).By acetic acid
(0.9ml) add in solution as catalyst.Then, nitrous acid is added at 45 DEG C by instiling
Isopentyl ester (9.0ml, 67mmol), then stirs reactant mixture 1.5 hours at 45 DEG C.Steaming
Send out and device under reduced pressure evaporates solvent, produce the solid matter of baby pink.Obtain 20g (about 100%)
The compound VIa of amount, its most i.e. following reaction described in the embodiment 8.
Then using HR MS checking MW is 389.86 (C14H20ClN5O4S)。
1H NMR (250MHz, dmso-d6,25 DEG C): δ 5.13 (quartet, J=8.9Hz, 1H)；4.62
(dd, J=8.6Hz, J=4.8Hz, 1H)；3.97 (dd, J=4.7Hz, J=1.6Hz, 1H)；3.79(m,1H)；
3.51(m,4H)；3.21 (dt, J=7.0Hz, J=1.8Hz, 2H)；2.72(m,1H)；2.14(m,1H)；1.75
(sextet, J=7.3Hz, 2H)；1.02 (t, J=7.3Hz, 3H).
Embodiment 7:(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] amino]-
5-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-
The preparation of glycol (ticagrelor)
By 2-methyl-tetrahydro furan (80ml) and (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine R-almond
Hydrochlorate (8.3g, 25mmol) adds in compound VIa (10.0g, about 25mmol).At 20-
30 DEG C are added dropwise over triethylamine (10ml；75mmol).At 20 to 30 DEG C, mixture is stirred 3 little
Time.Then, add water (80ml) and be added dropwise over 36% hydrochloric acid (2.0ml).After stirring 10 minutes
Separate phase.Top organic facies is evaporated in evaporator for decompression, produces the wet solid matter of 13g.Make this
One raw product crystallizes from acetonitrile (100ml).Obtain 11.3g (86%) to have higher than 99.5%
The compound I (ticagrelor) of HPLC purity.
It is 522.57 (C with HR MS checking MW23H28F2N6O4S)。
1H NMR(500MHz,dmso-d6,100℃):δ8.84(b,1H)；7.27(m,2H)；7.07
(m,1H)；4.98 (quartet, J=8.7Hz, 1H)；4.73(m,1H)；4.62(m,2H)；4.16(m,1H)；
4.01(m,1H)；3.84(m,1H)；3.55(m,4H)；2.97-3.10(m,2H)；2.96(m,1H)；2.64
(m,1H)；2.23(m,1H)；2.10(m,1H)；1.64(m,2H)；1.53(m,1H)；1.36(m,1H)；
0.93 (t, J=7.1Hz, 3H).
Embodiment 8:(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] amino]-
5-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-
The preparation of glycol (ticagrelor)
By flat for 2-methyl-tetrahydro furan (160ml) and (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine R-
Fructus Persicae hydrochlorate (16.5g, 51mmol) adds in compound VIa (20g, 50mmol).At 20 to 30 DEG C
It is added dropwise over N, N-di-isopropyl-ethyl amine (26ml；150mmol).Will mixing at 20 to 30 DEG C
Thing stirs 3 hours.Then, add water (160ml) and be added dropwise over 36% hydrochloric acid (3.8ml).Stir
Phase is separated after mixing 10 minutes.Top organic facies is evaporated in evaporator for decompression, produces 28g wet solid
Body material.Make this raw product recrystallization from acetonitrile (200ml).Obtain 23g (87%) and there is height
The compound I (ticagrelor) of the HPLC purity in 99.5%.
It is 522.57 (C with HR MS checking MW23H28F2N6O4S)。
1H NMR(500MHz,dmso-d6,100℃):δ8.84(b,1H)；7.27(m,2H)；7.07
(m,1H)；4.98 (quartet, J=8.7Hz, 1H)；4.73(m,1H)；4.62(m,2H)；4.16(m,1H)；
4.01(m,1H)；3.84(m,1H)；3.55(m,4H)；2.97-3.10(m,2H)；2.96(m,1H)；2.64
(m,1H)；2.23(m,1H)；2.10(m,1H)；1.64(m,2H)；1.53(m,1H)；1.36(m,1H)；
0.93 (t, J=7.1Hz, 3H).
Embodiment 9:(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] amino]-
5-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-
The preparation of glycol (ticagrelor)
At 45 DEG C, compound Va (20g, 50mmol) is dissolved in acetonitrile (160ml).By 36%
Hydrochloric acid (0.3ml) adds in solution as catalyst.Then, it is added dropwise over Asia at 40 to 45 DEG C
Isoamyl nitrate (9.0ml, 67mmol) and 35 to 40 DEG C of stirring reactant mixtures 1 hour.
In vaporizer by evaporation about 1/2 solvent and concentrating under reduced pressure reactant mixture.By described solution
Dilute with toluene (60ml), then again subtracted by the solvent of evaporation about 1/2 in vaporizer
Pressure concentrates.
Hereafter, it is added dropwise to be dissolved in 2-first through stir by described enriched mixture at 20 to 30 DEG C
(1R, 2S)-2-(3,4-difluorophenyl) the cyclopropylamine R-MA salt (16.5 of base-oxolane (140ml)
G, 51mmol) and triethylamine (22ml；In mixture 158mmol).20 to 30 DEG C of agitations
Mixture 2.5 hours.Then, add water (150ml) and be added dropwise over 36% hydrochloric acid (4.0ml).
Phase is separated after stirring 10 minutes.Top organic facies is evaporated in evaporator for decompression, produces 29g wet
Solid matter.Then this rugosity product of recrystallization from acetonitrile (200ml).With more than 99.0%
HPLC purity obtains 22.7g (86%) compound I (ticagrelor).
It is 522.57 (C with HR MS checking MW23H28F2N6O4S)。
1H NMR(500MHz,dmso-d6,100℃):δ8.84(b,1H)；7.27(m,2H)；7.07
(m,1H)；4.98 (quartet, J=8.7Hz, 1H)；4.73(m,1H)；4.62(m,2H)；4.16(m,1H)；
4.01(m,1H)；3.84(m,1H)；3.55(m,4H)；2.97-3.10(m,2H)；2.96(m,1H)；2.64
(m,1H)；2.23(m,1H)；2.10(m,1H)；1.64(m,2H)；1.53(m,1H)；1.36(m,1H)；
0.93 (t, J=7.1Hz, 3H).
Embodiment 10:(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] ammonia
Base]-5-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-
The preparation of 1,2-glycol (ticagrelor)
At 45 DEG C, compound Va (20g, 50mmol) is dissolved in acetonitrile (100ml) and toluene
(60ml) in mixture.96% sulphuric acid (0.25ml) is added in solution as catalyst.
Then, it is added dropwise over amyl nitrite (9.0ml, 67mmol) at 40 to 45 DEG C, then exists
Reactant mixture is stirred 2 hours by 40 DEG C.Vaporizer is being subtracted by the solvent of evaporation about 2/3
Pressure concentrated reaction mixture.
Hereafter, 20 to 30 DEG C by concentrate mixture with ethyl acetate (160ml) dilution and by
Drip and add (1R, 2S)-2-(3,4-difluorophenyl) the cyclopropylamine R-MA salt being dissolved in 200ml water to
(16.5g, 51mmol) and potassium carbonate (K2CO3；18g, 130mmol) stirring mixture in.?
Mixture is stirred 2.5 hours by 20 to 30 DEG C.Phase is separated after reaction.By top organic facies at vaporizer
Middle reduction vaporization, produces the wet solid matter of 29g.Then make this raw product from acetonitrile (200ml)
Middle recrystallization.The compound I of 22.4g (86%) is obtained (for lattice with the HPLC purity higher than 99.0%
Rui Luo).
It is 522.57 (C with HR MS checking MW23H28F2N6O4S)。
1H NMR(500MHz,dmso-d6,100℃):δ8.84(b,1H)；7.27(m,2H)；7.07
(m,1H)；4.98 (quartet, J=8.7Hz, 1H)；4.73(m,1H)；4.62(m,2H)；4.16(m,1H)；
4.01(m,1H)；3.84(m,1H)；3.55(m,4H)；2.97-3.10(m,2H)；2.96(m,1H)；2.64
(m,1H)；2.23(m,1H)；2.10(m,1H)；1.64(m,2H)；1.53(m,1H)；1.36(m,1H)；
0.93 (t, J=7.1Hz, 3H).
Embodiment 11:(1S, 2S, 3R, 5S)-3-[7-[[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl] amino]-
5-(rosickyite base)-3H-[1,2,3] triazol [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-
The preparation of glycol (ticagrelor)
At 45 DEG C, compound Va (40g, 100mmol) is dissolved in acetonitrile (320ml).Will
Acetic acid (1.8ml) adds in solution as catalyst.Then, nitrous acid is added at 40 to 45 DEG C
Isopentyl ester (17ml, 127mmol), then stirs reactant mixture 1.5 hours at 45 to 40 DEG C.
By the solvent under reduced pressure concentrated reaction mixture of evaporation about 1/2 in vaporizer.By described molten
Liquid toluene (100ml) dilutes, then in vaporizer by the solvent of evaporation about 1/2 again
Concentrating under reduced pressure.
Hereafter, it is added slowly to be dissolved in 2-methyl-tetrahydro furan by the mixture of concentration at 20 to 30 DEG C
(260ml) (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine R-MA salt (33g, 100mmol) in
With in the agitation mixture of triethylamine (44ml, 316mmol).At 20 to 30 DEG C, mixture is stirred
2 hours.Then, add water (280ml) and be added dropwise over 36% hydrochloric acid (8.0ml).Stirring 15
Phase is separated after minute.Top organic facies is evaporated in evaporator for decompression, produces the wet solid matter of 59g.
Then this raw product recrystallization from acetonitrile (360ml) is made.With the HPLC purity higher than 99.5%
Obtain the compound I (ticagrelor) of 46g (87%).
It is 522.57 (C with HR MS checking MW23H28F2N6O4S)。
1H NMR(500MHz,dmso-d6,100℃):δ8.84(b,1H)；7.27(m,2H)；7.07
(m,1H)；4.98 (quartet, J=8.7Hz, 1H)；4.73(m,1H)；4.62(m,2H)；4.16(m,1H)；
4.01(m,1H)；3.84(m,1H)；3.55(m,4H)；2.97-3.10(m,2H)；2.96(m,1H)；2.64
(m,1H)；2.23(m,1H)；2.10(m,1H)；1.64(m,2H)；1.53(m,1H)；1.36(m,1H)；
0.93 (t, J=7.1Hz, 3H).
Experimental section
X-ray powder diffraction
Use X ' PERT PRO MPD PANalytical powder diffractometer to obtain diffraction pattern, use spoke
PenetrateExcitation voltage: 45kV, anode current: 40mA, measurement scope:
2-40 ° of 2 θ, the increment under 0.5 second reflection time of staying: 0.01 ° of 2 θ, use has
10/0.5mm the flat sample of area/thickness measures.0.02 radian (rad) rope is drawn slit
(Soller slit), 10mm mask and 1/4 ° of fixing antiscatter slits are used for revising primary array.Sample
The raying area of product is 10mm, uses program-controlled divergent slit.0.02 radian rope is drawn slit
It is used for revising secondary array with 5.0 antiscatter slits.
Claims (14)
1. the method for formula I ticagrelor
It is characterized in that, make formula IV compound
Wherein R is CH2CH2OH、CH2COOH or CH2COOR1；R1For side chain or unbranched
R1-C4 alkyl；And X is NH2、NO2Or NHCHO,
React in a solvent with deprotection agent, with production V compound
Wherein R is CH2CH2OH、CH2COOH or CH2COOR1；R1For side chain or unbranched
R1-C4 alkyl；And X is NH2、NO2Or NHCHO,
After carrying out optional separation by crystallization, described Formula V compound is used for preparing ticagrelor.
Method the most according to claim 1, it is characterised in that it originates in formula IV aization
Compound
And by the Formula V a compound that described formula IV a compound deprotection is obtained
By crystallization with monohydrate form by isolated or purified.
3. the intermedium of Formula V a, it represents as used CuK α radiometric X-ray powder
Following characteristic reflection in figure: 5.8 ± 0,2 °；7.2±0,2°；9.1±0,2°；11.7±
0,2°；18.3±0,2°；22.6±0,2°；23.5 ± 0,2 ° and 28.7 ° ± 0,2 ° of 2 θ,
And the water of the amount containing 4.5 ± 1.0 weight %.
4. the purposes of the intermedium Va prepared by the method for claim 1, it is used for preparing
Ticagrelor.
Method the most according to claim 1, it is characterised in that use hydrochloric acid or sulphuric acid to make
For described deprotection agent.
Method the most according to claim 1, it is characterised in that use organic solvent and water
Mixture as making the described solvent that described compound Va crystallizes.
Method the most according to claim 6, it is characterised in that be used for making described compound
Described organic solvent choosing free methanol, ethanol, ethyl acetate, isopropyl acetate, the acetonitrile of Va crystallization
The group formed with their mixture.
Method the most according to claim 6, it is characterised in that be used for making described compound
The mixture that described solvent is acetonitrile and water of Va crystallization, it contains the water of amount of 0.1-0.9ml/g.
Method the most according to claim 7, it is characterised in that by the mixing of first alcohol and water
Thing is used for making described compound Va crystallize.
Method the most according to claim 1, it is characterised in that the institute in deprotection steps
State solvent and select free methanol, ethanol, propanol, isopropanol, ethylene glycol, water and their mixture group
The group become.
11. methods according to claim 2, it is characterised in that it farther includes described
Compound Va with amyl nitrite in a solvent, reacts the most in the presence of a catalyst,
Produce compound VIa
Described compound VIa with (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine, preferably with
The salt form of the mandelic acid of (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine, in a solvent and in the presence of a base
After reaction, it is provided that Formulas I ticagrelor.
12. methods according to claim 11, it is characterised in that be used for preparing described chemical combination
The described solvent of thing VIa is acetonitrile.
13. methods according to claim 11, it is characterised in that described catalyst is for being selected from
The acid of the group being made up of hydrochloric acid, sulphuric acid and acetic acid.
14. methods according to claim 11, it is characterised in that for described compound
VIa is 2-methyl-four with the described solvent of the described reaction of (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine
Hydrogen furan, and described alkali is triethylamine or N, N-di-isopropyl-ethyl amine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ2013-866A CZ2013866A3 (en) | 2013-11-08 | 2013-11-08 | Novel crystalline form of ticagrelor synthesis intermediate and process for preparing thereof |
| CZPV2013-866 | 2013-11-08 | ||
| PCT/CZ2014/000131 WO2015067230A1 (en) | 2013-11-08 | 2014-11-07 | A production method and a new crystalline form of an intermediate of synthesis of ticagrelor |
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Country Status (4)
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| CN (1) | CN105940003A (en) |
| CZ (1) | CZ2013866A3 (en) |
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| WO (1) | WO2015067230A1 (en) |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012138981A2 (en) * | 2011-04-06 | 2012-10-11 | Teva Pharmaceutical Industries Ltd. | New intermediates and processes for preparing ticagrelor |
| WO2013092900A1 (en) * | 2011-12-23 | 2013-06-27 | Lek Pharmaceuticals D.D. | Synthesis of triazolopyrimidine compounds |
| WO2014102830A1 (en) * | 2012-12-31 | 2014-07-03 | Megafine Pharma (P) Ltd. | A process for preparation of ticagrelor and intermediates thereof |
| WO2014139489A1 (en) * | 2013-03-14 | 2014-09-18 | Zentiva K.S. | Method for the preparation of ticagrelor and intermediates suitable therefore |
| CN104098553A (en) * | 2013-04-10 | 2014-10-15 | 江苏恒瑞医药股份有限公司 | Ticagrelor intermediate and preparation method thereof and ticagrelor preparation method |
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| TWI229674B (en) | 1998-12-04 | 2005-03-21 | Astra Pharma Prod | Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses |
| GB0013407D0 (en) | 2000-06-02 | 2000-07-26 | Astrazeneca Ab | Forms of a chemical compound |
| GB0013488D0 (en) | 2000-06-02 | 2000-07-26 | Astrazeneca Ab | Chemical compound |
| TWI482772B (en) | 2006-08-21 | 2015-05-01 | Astrazeneca Ab | Compositions, suitable for oral administration, comprising a triazolo(4,5-d)pyrimidin derivate |
| US20080045548A1 (en) | 2006-08-21 | 2008-02-21 | Astrazeneca Ab | Pharmaceutical Compositions |
| WO2011067571A1 (en) | 2009-12-03 | 2011-06-09 | Astrazeneca Ab | Co - crystals of a triazolo [4,5 - d] pyrimidine platelet aggregation inhibitor |
| WO2011076749A2 (en) | 2009-12-23 | 2011-06-30 | Ratiopharm Gmbh | Solid pharmaceutical dosage form |
-
2013
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2014
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012138981A2 (en) * | 2011-04-06 | 2012-10-11 | Teva Pharmaceutical Industries Ltd. | New intermediates and processes for preparing ticagrelor |
| WO2013092900A1 (en) * | 2011-12-23 | 2013-06-27 | Lek Pharmaceuticals D.D. | Synthesis of triazolopyrimidine compounds |
| WO2014102830A1 (en) * | 2012-12-31 | 2014-07-03 | Megafine Pharma (P) Ltd. | A process for preparation of ticagrelor and intermediates thereof |
| WO2014139489A1 (en) * | 2013-03-14 | 2014-09-18 | Zentiva K.S. | Method for the preparation of ticagrelor and intermediates suitable therefore |
| CN104098553A (en) * | 2013-04-10 | 2014-10-15 | 江苏恒瑞医药股份有限公司 | Ticagrelor intermediate and preparation method thereof and ticagrelor preparation method |
Non-Patent Citations (1)
| Title |
|---|
| DISCLOSED ANONYMOUSLY: "Crystalline Intermediates of (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluoro phenyl) cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5,d] pyrimidine-3-yl]-5-(2-hydroxyethoxy)- 1,2-cyclopentanediol", 《IP.COM》 * |
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| HUP1600376A2 (en) | 2016-08-29 |
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