CN110467619A - A kind of preparation method of ticagrelor - Google Patents
A kind of preparation method of ticagrelor Download PDFInfo
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- 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
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Abstract
The invention belongs to chemicals technical fields, and in particular to a kind of preparation method of ticagrelor, using not steaming toluene process in the preparation method, it is low that this method obtains impurity P content in ticagrelor, and the step of steaming toluene is omitted, shortens the production cycle, improves production efficiency；Toluene can all separate recycling in subsequent phase process, reduce the loss of toluene during reduced pressure, and pollution of the toluene gas to air during reduced pressure；Since finished product is relatively unstable during concentration, temperature height can generate the impurity for being difficult to remove, and temperature-controlled precision requires high.The step of steaming toluene is omitted, the purity of product can be improved；The drying steps of organic phase are omitted, the use of anhydrous sodium sulfate is omitted, reduces operating procedure, improves production efficiency, reduce the generation of dangerous waste.
Description
Technical field
The invention belongs to chemicals technical fields, and in particular to a kind of preparation method of ticagrelor.
Background technique
Acute coronary syndrome (acute coronary syndromes, ACS) is with coronary atherosclerosis
Plaque rupture or erosion, secondary complete or incomplete occluding thrombus are formed as one group of clinical syndrome of pathologic basis, are one
A kind of serious types of kind common serious cardiovascular disease and coronary heart disease.ACS includes Acute ST-segment Elevation cardiac muscle stalk
Extremely (STEMI), patients with acute non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UA).Antithrombotic drug exists
It is played an important role in ACS treatment.The antithrombotic drug of clinical use can be divided into anticoagulant, anti-blood by its mechanism of action
Platelet medicine and Thrombolytic Drugs.Antiplatelet drug therein can be divided into again cox-2 inhibitors, ADP (P2Y12) receptor antagonist,
GPIIb/IIIa receptor antagonist etc..In today of acute coronary syndrome (ACS) sustainable growth, Antiplatelet therapy is still to work as
One of critical treatment measure of preceding ACS.It is small that ticagrelor is that a kind of novel cyclopenta triazolo pyrimidine class (CPTP) takes orally anti-blood
Plate drug, ATC code are B01AC24.Ticagrelor is non-precursor medicine, can directly be worked without liver metabolism activation, with
P2Y12ADP receptor invertibity combines.PLATO result of study shows that ticagrelor, which is treated 12 months, is not increasing main bleeding
In the case of, cardiovascular death/myocardial infarction/stroke composite end points event of ACS patient is further significantly reduced compared with clopidogrel
Risk significantly reduces cardiovascular death up to 21% up to 16%.It is treated based on ticagrelor and is benefited to ACS patient's bring,
Associated guideline both domestic and external is recommended, and ticagrelor is used for the Antiplatelet therapy of ACS patient.And in heart of Europe disease association
It is even more to point out in two authoritative guides (ESC NSTE-ACS guides in 2011 and STEMI guide in 2012), cannot receiving
Clopidogrel could be used in the patient of ticagrelor treatment, also sufficiently shows and recognizing for the death rate is further decreased for new drug
It can.
Although the synthesis for ticagrelor has had more research, however, currently used synthetic method walks
It is rapid complex, and yield is lower, and this price for also resulting in ticagrelor is higher, increases the medication burden of patient.Cause
This, researchs and develops a kind of preparation method of new ticagrelor, for patient's important in inhibiting.
Summary of the invention
For these reasons, in order to solve the deficiencies in the prior art, applicant obtains a kind of new ticagrelor for preparing
Method, for this method using toluene process is not steamed, it is low that this method obtains impurity P content in ticagrelor, and steaming is omitted
The step of toluene, shortens the production cycle, improves production efficiency；Toluene can all separate recycling in subsequent phase process, subtract
The loss of toluene during reduced pressure, and pollution of the toluene gas to air during reduced pressure are lacked；By
Relatively unstable during concentration in finished product, temperature height can generate the impurity for being difficult to remove, and temperature-controlled precision requires high.It omits
The step of steaming toluene, it can be improved the purity of product；The drying steps of organic phase are omitted, making for anhydrous sodium sulfate is omitted
With reducing operating procedure, improve production efficiency, reduce the generation of dangerous waste.
To achieve the above object, technical scheme is as follows:
A kind of preparation method of ticagrelor:
(1) (C is prepared17H24CIN5O4S) toluene solution: raw material (C is taken17H27CIN4O4S), toluene, acetic acid, nitrous acid is added
The aqueous solution of sodium, until (C in reaction system17H27CIN4O4S) less than 0.5%, wet chemical is added, adds water extraction,
Retain organic phase are as follows: (C17H24CIN5O4S) toluene solution；
(2) (C is prepared26H32F2N6O4S) toluene solution: taking potassium carbonate and water to be made into clarified solution, is cooled to room temperature in advance, spare；
Negate formula-(1R, 2S) -2- (3,4- difluorophenyl)-cyclopropylamine hydrochloride (C9H10CIF2N) it is added to the water, it is spare；Step
(1) (C in17H24CIN5O4S) toluene solution adds spare wet chemical, adds spare trans--(1R, 2S) -2- (3,4- difluoros
Phenyl)-cyclopropylamine hydrochloric acid (C9H10CIF2N) aqueous solution, reaction terminate；Liquid separation is stood, lower layer's water phase discards；Organic phase with by
The mixed liquor extraction that glacial acetic acid, sodium chloride and water are made into；Organic phase is extracted with saturated sodium chloride solution primary again；Gained upper layer has
Machine is mutually (C26H32F2N6O4S) toluene solution；
(3) it prepares ticagrelor: taking step (2) (C26H32F2N6O4S) in toluene solution, methanol is added, stirs evenly；Drop
Enriching hydrochloric acid；Drop finishes, and it is anti-to continue stirring；Methanol is added, is stirred, stirring is stopped, being stood, upper toluene is recycled, removed by liquid separation
Layer methanol-water phase, is added ethyl acetate, stirs evenly, and the rear aqueous solution that potassium carbonate is added dropwise, drop finishes, continues to stir；It stands, point
Liquid, lower layer's water phase discard；Organic phase washed once with saturated sodium chloride solution again, stand split-phase；Lower layer's water phase discards, and filtrate is simultaneously
It is transferred in enrichment facility；After organic phase to a large amount of solids precipitation is concentrated under reduced pressure, ethyl acetate scale to before being concentrated is added, is added dropwise
N-hexane, drop is complete, continues to stir, and is centrifuged, and filter cake is rinsed once with ethyl acetate/n-hexane, then is rinsed once with n-hexane；Filter
Cake is dried under reduced pressure, and obtains ticagrelor (C23H28F2N6O4S)。
Wherein prepare (C17H24CIN5O4S) the method for toluene solution are as follows:
Toluene, (C are added into reaction kettle17H27CIN4O4S), stir, after be added at one time acetic acid, sufficiently stir
It mixes to system and clarifies, rear system cooling；The aqueous solution of sodium nitrite is added dropwise at -10 DEG C ± 20 DEG C in temperature in control system；Drop finishes,
Temperature continues to be stirred to react at -10 DEG C ± 10 DEG C in control system；Reaction is until (C17H27CIN4O4S) less than 0.5%, as instead
Answer terminal；The solution prepared in advance by potassium carbonate and water is added dropwise in Xiang Shangshu system in control system Nei Wen -10 ± 10 DEG C；Drop finishes,
5 ± 15 DEG C of temperature continues to stir 30min in holding system, and rear water supplement is extracted, and upper organic phase is (C17H24CIN5O4S) first
Benzole soln.
Wherein prepare (C26H32F2N6O4S) the method for toluene solution are as follows:
Potassium carbonate and water are made into clarified solution, are cooled to room temperature in advance, it is spare；At 100 ± 10 DEG C, by trans--(1R, 2S) -2-
(3,4- difluorophenyl)-cyclopropylamine hydrochloride (C9H10CIF2N) it is added to the water, yellow clarified solution is spare；It takes
(C17H24CIN5O4S spare wet chemical is added dropwise in) toluene solution, 25 ± 15 DEG C of temperature in control system, and drop finishes, stirring
10min；25 ± 15 DEG C of temperature in control system, is added dropwise spare trans--(1R, 2S) -2- (3,4- difluorophenyl)-cyclopropylamine hydrochloric acid
Salt (C9H10CIF2N) aqueous solution, drop finish, 25 ± 15 DEG C of control system temperature, continue that reaction is sufficiently stirred, reaction terminates；It stands
30min, liquid separation, lower layer's water phase discard；Organic phase is extracted with the mixed liquor being made by glacial acetic acid, sodium chloride and water；Organic phase is again
It is primary with saturated sodium chloride solution extraction；Gained upper organic phase (C26H32F2N6O4S) toluene solution.
Wherein ticagrelor the preparation method comprises the following steps:
Take (C26H32F2N6O4S) toluene solution is added methanol, stirs；Reaction kettle cools down, temperature in control system
10 ± 10 DEG C, concentrated hydrochloric acid is added dropwise；Drop finishes, and 10 ± 10 DEG C of temperature, continues to be stirred to react 6h~12h in control system；Reaction terminates control
10 ± 10 DEG C of temperature in system processed, adds methanol, stirs 10min-30min, stops stirring, stands 30min, liquid separation, by upper layer first
Benzene recycling, takes lower layer's methanol-water phase, and control system Nei Wen -10 ± 10 DEG C are added ethyl acetate, stir evenly, carbonic acid is added dropwise afterwards
The aqueous solution of potassium, drop finish, and continue to stir 30min；It stands, liquid separation, lower layer's water phase discards；Organic phase uses saturated sodium chloride solution again
It washed once, stand split-phase；Lower layer's water phase discards, and filtrate is simultaneously transferred in enrichment facility；Reduced pressure organic phase (45 ± 5 DEG C,
Vacuum degree≤- 0.07MPa) be precipitated to a large amount of solids after, add ethyl acetate scale to before being concentrated, temperature 50 ± 5 in control system
DEG C system is clarified, n-hexane is added dropwise, drop finishes, 25 ± 5 DEG C of temperature in control system, continues to stir 12h, centrifugation, filter cake acetic acid
Ethyl ester/n-hexane rinsing is primary, then is rinsed once with n-hexane；Filter cake be dried under reduced pressure 8h (50 ± 5 DEG C, vacuum degree≤-
0.07Mpa), ticagrelor raw material is obtained.
The ticagrelor raw material that the present invention obtains, through HPLC checked for impurities P be 0.02%~0.08% (standard be less than
0.15%).(since product is relatively unstable during concentration, temperature height can generate the impurity for being difficult to remove, temperature-controlled precision
It is required that high.The step of steaming toluene is omitted, the purity of product can be improved.)
This hair has following beneficial technical effects:
1, the step of steaming toluene is omitted, shortens the production cycle, improves production efficiency.
2, toluene can all separate recycling in subsequent phase process, reduce toluene during reduced pressure
Loss, and pollution of the toluene gas to air during reduced pressure.
3, since finished product is relatively unstable during concentration, temperature height can generate the impurity for being difficult to remove, temperature control essence
Degree requires high.The step of steaming toluene is omitted, the purity of product can be improved.
4, the drying steps of organic phase are omitted, the use of anhydrous sodium sulfate is omitted, reduces operating procedure, improves
Production efficiency reduces the generation of dangerous waste.
5, the obtained ticagrelor raw material of the present invention, through HPLC checked for impurities P be 0.02%~0.08% (standard for less than
0.15%).
Material name of the present invention is shown in Table 1.
The raw material chemical name of the present invention of table 1
Specific embodiment
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.Prepare embodiment
Embodiment 1
At room temperature, toluene (101kg), III C of intermediate are added into reaction kettle17H27CIN4O4S (21.00kg), is sufficiently stirred
Mix uniformly, after be added at one time acetic acid (18.06kg), be stirred well to system clarification, the cooling of rear system；It is warm in control system
At -10 ± 20 DEG C, water (10.50kg) solution of sodium nitrite (4.15kg) is added dropwise；Drop finish, in control system temperature at -10 DEG C, after
It is continuous to be stirred to react；After reacting 1h, start to control in sampling, it is primary at interval of one hour sample detection, until intermediate III
C17H27CIN4O4S is less than 0.5%, as reaction end；It Nei Wen -10 DEG C of control system, is added dropwise in advance by carbon in Xiang Shangshu system
The solution that sour potassium (21.15kg) and water (42.00kg) prepare；Drop finish, in holding system temperature 5 DEG C continue stir 30min, after add
Water is extracted, upper organic phase C17H24CIN5O4S toluene solution；
At room temperature, potassium carbonate (13.86kg) and water (21.0kg) are made into clarified solution, are cooled to room temperature in advance, for use；100℃
Under, II c (10.3kg) is added in water (63.00kg), yellow clarified solution, for use；Intermediate IV obtained in reaction kettle
C17H24CIN5O4Wet chemical is added dropwise in S toluene solution, 25 DEG C of temperature in control system, and drop finishes, and stirs 10min；Control system
C is added dropwise in 25 DEG C of interior temperature9H10CIF2N aqueous solution, drop finish, 25 ± 15 DEG C of control system temperature, continue that reaction is sufficiently stirred, and react
Terminate；30min, liquid separation are stood, lower layer's water phase discards；Organic phase is with by glacial acetic acid (2.03kg), sodium chloride (6.3kg) and water
The mixed liquor extraction that (56.7kg) is made into；Organic phase is extracted with saturated sodium chloride solution primary again；Gained upper organic phase
(C26H32F2N6O4S) toluene solution；
At room temperature, resulting intermediate V C is walked upwards26H32F2N6O4In S toluene solution, it is added methanol (70kg), sufficiently
It stirs evenly；Reaction kettle cools down, and concentrated hydrochloric acid 91.77L is added dropwise in 10 DEG C of temperature in control system；Drop finishes, 10 DEG C of temperature in control system,
Continue to be stirred to react 9h；10 DEG C of temperature in finishing control system is reacted, is added methanol (70kg), 20min is stirred, stops stirring, it is quiet
30min is set, upper toluene is recycled (88kg) by liquid separation, takes lower layer's methanol-water phase, Nei Wen -10 DEG C of control system, acetic acid is added
Ethyl ester (200kg), stirs evenly, and water (300kg) solution of potassium carbonate (69.3kg) is added dropwise afterwards, drop finishes, and continues to stir 30min；
It stands, liquid separation, lower layer's water phase discards；Organic phase washed once with 567kg saturated sodium chloride solution again, stand split-phase；Lower water
It mutually discards, filtrate is simultaneously transferred in enrichment facility；Organic phase (45 DEG C of interior temperature, vacuum degree≤- 0.07MPa) is concentrated under reduced pressure to a large amount of
After solid is precipitated, ethyl acetate scale to before being concentrated is added, 50 DEG C of temperature clarifies system in control system, and n-hexane is added dropwise
(179kg), drop finish, 25 DEG C of temperature in control system, continue to stir 12h, centrifugation, filter cake ethyl acetate/n-hexane (18.00kg/
22.00kg) rinsing is primary, then is rinsed once with n-hexane (40.00kg)；Filter cake be dried under reduced pressure 8h (50 ± 5 DEG C, vacuum degree≤-
0.07Mpa), ticagrelor C is obtained23H28F2N6O4S (yield: 75%-85%).
Through HPLC checked for impurities P (molecular formula C26H35F2N5O4It S) is 0.04% (standard is less than 0.15%).(due to product
Relatively unstable during concentration, temperature height can generate the impurity for being difficult to remove, and temperature-controlled precision requires high.Steaming first is omitted
The purity of product can be improved in the step of benzene.)
Impurity P detection method:
It is protected from light operation.Take this product appropriate, accurately weighed, solubilizer [water-acetonitrile (65:35)] dissolution, which is made in every 1ml, to be contained
The solution of 1mg, shakes up, as test solution；Precision measures appropriate, quantitatively dilute to be made in every 1ml with solvent and contains the molten of 1 μ g
Liquid, as contrast solution.Take impurity P and ticagrelor reference substance each appropriate, dissolved with solvent and dilute be made it is about miscellaneous in every 1ml
The solution of matter 10 μ g and ticagrelor 1mg, as system suitability solution.According to high performance liquid chromatography (Chinese Pharmacopoeia 2015 editions
General rule 0512) measurement, with octadecylsilane chemically bonded silica be filler [Agilent Zorbax SB-C18 column (150mm ×
4.6mm, 1.8 μm)], with phosphate buffer 1.-acetonitrile (90:10) for mobile phase A, with 2 zero-acetonitrile of phosphate buffer
(30:70) is Mobile phase B；According to the form below carries out linear gradient elution；Column temperature is 55 DEG C, Detection wavelength 242nm.System is taken to be applicable in
Property 5 μ l of solution, inject liquid chromatograph, record chromatogram, peak sequence is followed successively by impurity P, ticagrelor, ticagrelor with it is miscellaneous
Separating degree should meet the requirements between mass peak；Precision measures 5 μ l of contrast solution and injects liquid chromatograph, records chromatogram, principal component color
The signal-to-noise ratio of spectral peak should be greater than 10.It is accurate again to measure each 5 μ l of test solution and control solution, it is injected separately into liquid chromatogram
View records chromatogram, and after deducting solvent peak, if any impurity peaks in the chromatogram of test solution, the peak area of impurity must not be big
In 1.5 times (0.15%) of contrast solution main peak area, unknown single impurity peak area is not greater than the main peak face of contrast solution
Product (0.1%), the sum of each impurity peak area are not greater than 10 times (1.0%) of contrast solution main peak area.
2 gradient mobile phase of table
Conclusion: preparation method of the present invention obtains in ticagrelor raw material impurity P content less than 0.15%.
Claims (4)
1. a kind of preparation method of ticagrelor, it is characterised in that:
(1) (C is prepared17H24CIN5O4S) toluene solution: raw material (C is taken17H27CIN4O4S), toluene, acetic acid, sodium nitrite is added
Aqueous solution, until (C in reaction system17H27CIN4O4S) less than 0.5%, wet chemical is added, adds water extraction, is retained
Organic phase are as follows: (C17H24CIN5O4S) toluene solution；
(2) (C is prepared26H32F2N6O4S) toluene solution: taking potassium carbonate and water to be made into clarified solution, is cooled to room temperature in advance, spare；It negates
Formula-(1R, 2S) -2- (3,4- difluorophenyl)-cyclopropylamine hydrochloride (C9H10CIF2N) it is added to the water, it is spare；In step (1)
(C17H24CIN5O4S) toluene solution adds spare wet chemical, adds spare trans--(1R, 2S) -2- (3,4- difluorophenyl) -
Cyclopropylamine hydrochloric acid (C9H10CIF2N) aqueous solution, reaction terminate；Liquid separation is stood, lower layer's water phase discards；Organic phase is with by ice second
The mixed liquor extraction that acid, sodium chloride and water are made into；Organic phase is extracted with saturated sodium chloride solution primary again；Gained upper organic phase
For (C26H32F2N6O4S) toluene solution；
(3) it prepares ticagrelor: taking step (2) (C26H32F2N6O4S) in toluene solution, methanol is added, stirs evenly；It is added dropwise dense
Hydrochloric acid；Drop finishes, and it is anti-to continue stirring；Methanol is added, is stirred, stirring is stopped, being stood, upper toluene is recycled in liquid separation, takes lower layer's first
Alcohol-water phase is added ethyl acetate, stirs evenly, and the rear aqueous solution that potassium carbonate is added dropwise, drop finishes, continues to stir；It stands, liquid separation, under
Layer water phase discards；Organic phase washed once with saturated sodium chloride solution again, stand split-phase；Lower layer's water phase discards, and filtrate is simultaneously shifted
Into enrichment facility；Be concentrated under reduced pressure organic phase to a large amount of solids be precipitated after, add ethyl acetate to be concentrated before scale, be added dropwise just oneself
Alkane, drop is complete, continues to stir, and is centrifuged, and filter cake is rinsed once with ethyl acetate/n-hexane, then is rinsed once with n-hexane；Filter cake subtracts
It press dry dry, obtains ticagrelor (C23H28F2N6O4S)。
2. the preparation method of a kind of ticagrelor according to claim 1, wherein preparing (C17H24CIN5O4S) toluene solution
Method are as follows:
Toluene, (C are added into reaction kettle17H27CIN4O4S), stir, after be added at one time acetic acid, be stirred well to
System clarification, rear system cooling；The aqueous solution of sodium nitrite is added dropwise at -10 DEG C ± 20 DEG C in temperature in control system；Drop finishes, control
Temperature continues to be stirred to react at -10 DEG C ± 10 DEG C in system；Reaction is until (C17H27CIN4O4S) less than 0.5%, as reaction is whole
Point；The solution prepared in advance by potassium carbonate and water is added dropwise in Xiang Shangshu system in control system Nei Wen -10 ± 10 DEG C；Drop finishes, and keeps
5 ± 15 DEG C of temperature continues to stir 30min in system, and rear water supplement is extracted, and upper organic phase is (C17H24CIN5O4S) toluene is molten
Liquid.
3. the preparation method according to claim 1 for preparing a kind of ticagrelor, wherein preparing (C26H32F2N6O4S) toluene
The method of solution are as follows:
Potassium carbonate and water are made into clarified solution, are cooled to room temperature in advance, it is spare；At 100 ± 10 DEG C, by trans--(1R, 2S) -2- (3,4-
Difluorophenyl)-cyclopropylamine hydrochloride (C9H10CIF2N) it is added to the water, yellow clarified solution is spare；Take (C17H24CIN5O4S) first
Spare wet chemical is added dropwise in benzole soln, 25 ± 15 DEG C of temperature in control system, and drop finishes, and stirs 10min；It is warm in control system
25 ± 15 DEG C, spare trans--(1R, 2S) -2- (3,4- difluorophenyl)-cyclopropylamine hydrochloride (C is added dropwise9H10CIF2N) water-soluble
Liquid, drop finish, 25 ± 15 DEG C of control system temperature, continue that reaction is sufficiently stirred, reaction terminates；Stand 30min, liquid separation, lower water
Mutually discard；Organic phase is extracted with the mixed liquor being made by glacial acetic acid, sodium chloride and water；Organic phase is extracted with saturated sodium chloride solution again
It takes primary；Gained upper organic phase (C26H32F2N6O4S) toluene solution.
4. a kind of preparation method of ticagrelor according to claim 1, wherein ticagrelor the preparation method comprises the following steps:
Take (C26H32F2N6O4S) toluene solution is added methanol, stirs；Reaction kettle cools down, warm 10 in control system ±
10 DEG C, concentrated hydrochloric acid is added dropwise；Drop finishes, and 10 ± 10 DEG C of temperature, continues to be stirred to react 6h~12h in control system；React finishing control body
10 ± 10 DEG C of temperature in system, adds methanol, stirs 10min-30min, stops stirring, stands 30min, and upper toluene is returned in liquid separation
It receives, takes lower layer's methanol-water phase, control system Nei Wen -10 ± 10 DEG C are added ethyl acetate, stir evenly, rear dropwise addition potassium carbonate
Aqueous solution, drop finish, and continue to stir 30min；It stands, liquid separation, lower layer's water phase discards；Organic phase is washed with saturated sodium chloride solution again
Once, split-phase is stood；Lower layer's water phase discards, and filtrate is simultaneously transferred in enrichment facility；Reduced pressure organic phase (45 ± 5 DEG C, vacuum
Degree≤- 0.07MPa) be precipitated to a large amount of solids after, add ethyl acetate scale to before being concentrated, 50 ± 5 DEG C of temperature makes in control system
System clarification, be added dropwise n-hexane, drop finish, in control system temperature 25 ± 5 DEG C, continue stir 12h, centrifugation, filter cake with ethyl acetate/
N-hexane rinsing is primary, then is rinsed once with n-hexane；Filter cake is dried under reduced pressure 8h (50 ± 5 DEG C, vacuum degree≤- 0.07Mpa), obtains
Ticagrelor raw material.
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