CN105237540A - Preparation method, detection method and application for ticagrelor-related substances - Google Patents
Preparation method, detection method and application for ticagrelor-related substances Download PDFInfo
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- CN105237540A CN105237540A CN201510605513.XA CN201510605513A CN105237540A CN 105237540 A CN105237540 A CN 105237540A CN 201510605513 A CN201510605513 A CN 201510605513A CN 105237540 A CN105237540 A CN 105237540A
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- toluene
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- BVBICPVTPHUTNI-UHFFFAOYSA-N CCCS(c(nc1NC(CC2OCCO)C3C2OC(C)(C)C3)nc(NC2CC2)c1N)(=O)=O Chemical compound CCCS(c(nc1NC(CC2OCCO)C3C2OC(C)(C)C3)nc(NC2CC2)c1N)(=O)=O BVBICPVTPHUTNI-UHFFFAOYSA-N 0.000 description 1
- 0 CCC[Os](c(cc1NC(CC2)C3OC(C)(C)O[C@]23OCCO)nc(NC(C2)[C@@]2C(C=C(C23)F)=CC2C3F)c1N)=* Chemical compound CCC[Os](c(cc1NC(CC2)C3OC(C)(C)O[C@]23OCCO)nc(NC(C2)[C@@]2C(C=C(C23)F)=CC2C3F)c1N)=* 0.000 description 1
- GOYDNIKZWGIXJT-UHFFFAOYSA-N Fc(cccc1)c1F Chemical compound Fc(cccc1)c1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- QVUBIQNXHRPJKK-IMTBSYHQSA-N N[C@H](C1)[C@@H]1c(cc1F)ccc1F Chemical compound N[C@H](C1)[C@@H]1c(cc1F)ccc1F QVUBIQNXHRPJKK-IMTBSYHQSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N OC(C(O)=O)c1ccccc1 Chemical compound OC(C(O)=O)c1ccccc1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
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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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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
Abstract
The invention provides a preparation method and detection method for oxides of ticagrelor, i.e., (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3.4-difluorophenyl)cyclopropyl]amino}-5-(propylthionyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol and (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3.4-difluorophenyl)cyclopropyl]amino}-5-(propylthioacyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol, and application of the oxides in the quality control research of ticagrelor.
Description
Technical field
The invention belongs to medical art, relate to the oxide compound of one group of ticagrelor, and preparation method thereof, detection method and purposes.
Background technology
Ticagrelor (Ticagrelor), chemical name: (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3.4-difluorobenzene) cyclopropyl] is amino }-5-(propyl sulfo-)-3H-[1,2,3] triazolo-[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1,2-glycol is Novel anti-platelet agent thing, by Selective depression P2Y12 acceptor, thus inhibition thrombosis.Compare with clopidogrel, ticagrelor can sooner, more by force, more stable suppression P2Y12 acceptor, the incidence of the death that remarkable reduction blood vessel reason causes, myocardial infarction or cerebral apoplexy, thus the generation reducing thrombotic cardiovascular event, concrete structure formula is as follows.
At present, the document in ticagrelor pharmacy is quite abundant, mainly concentrates on the synthetic route of bulk drug and intermediate thereof and the crystal formation of ticagrelor, in the related substance of ticagrelor, then rarely has report.
In the oxidative degradation test of ticagrelor, the oxidized derivative generating sulfoxide and sulfone of sulphur, i.e. (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3.4-difluorophenyl) cyclopropyl] amino-5-(propyl group sulfinyl)-3H-[1, 2, 3] triazolo-[4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1, 2-glycol (ticagrelor sulfoxide, structural formula I) and (1S, 2S, 3R, 5S)-3-[7-{ [(1R, 2S)-2-(3.4-difluorophenyl) cyclopropyl] amino-5-(propylthio acyl group)-3H-[1, 2, 3] triazolo-[4, 5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1, 2-glycol (ticagrelor sulfone, structural formula II), HassaneSadouYaye etc. report the oxidative degradation mechanism of ticagrelor in Identificationofthemajordegradationpathwaysofticagrelor, but for the concrete preparation method of oxidation impurities, document is not disclosed.
Ticagrelor tablet is that chemical drug registers 3 classes, comparative study need be carried out with former triturate during research, in synchronism stability investigation process, the impurity spectrum of commercially available product is not quite similar with from grinding sample, but same exist this oxidation impurities, by the preparation of oxidation impurities compound and structural identification, reference substance can be provided for the analysis of ticagrelor related substance, thus improving the quality standard of ticagrelor, the safe medication for ticagrelor provides important directive significance.
Summary of the invention
Oxide compound (I), (II) pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, and parsing gained compound structure is as follows:
It is as follows that each method resolves the data obtained:
Compound (I):
MS(ESI):m/z[M-H]
-=537.3;m/z[M+Na]
+=561.2
Table 1
1h-NMR (500MHzDMSO) data
Chemical shift (ppm) | Proton number | Peak type | Ownership |
9.5715-9.8373 | 1H | d | H 24 |
7.2424-7.3884 | 2H | m | H 32,H 33 |
7.0708 | 1H | s | H 36 |
5.0739-5.1942 | 3H | m | H 11,H 12,H 15 |
4.6062 | 2H | s | H 26 |
3.9799 | 1H | s | H 4 |
3.7955 | 1H | s | H 8 |
3.5241 | 4H | t | H 13,H 14 |
3.2221-3.3317 | 1H | m | H 7 |
2.9283-3.0958 | 1H | m | H 6 |
2.8468-2.8954 | 1H | t | H 5 |
2.6688-2.7664 | 1H | m | H 5 |
2.0215-2.3238 | 2H | m | H 2 |
1.3656-1.7924 | 4H | m | H 27,H 29, 30 |
0.8190-1.0174 | 3H | m | H 28 |
Compound (II):
MS(ESI):m/z[M-H]
-=553.3;m/z[M+Na]
+=577.3
Table 2
1h-NMR (500MHzDMSO) data
Chemical shift (ppm) | Proton number | Peak type | Ownership |
9.7932-10.0624 | 1H | d | H 22 |
7.2435-7.3885 | 2H | d | H 30,H 31 |
7.0712-7.1367 | 1H | q | H 34 |
5.0693-5.1943 | 3H | q | H 9,H 10,H 13 |
4.5956 | 2H | s | H 2,H 6 |
3.9765 | 1H | s | H 5 |
3.7973 | 1H | s | H 4 |
3.5233 | 4H | s | H 11,H 12 |
3.3221 | 2H | s | H 23 |
3.2327 | 1H | s | H 3 |
2.6806-2.7816 | 1H | m | H 3 |
2.2114 | 1H | s | H 37 |
2.0258-2.0881 | 1H | m | H 37 |
1.6914-1.7896 | 1H | m | H 27 |
1.5150-1.6676 | 2H | m | H 25 |
1.4320-1.4562 | 1H | m | H 28 |
0.8053-1.0396 | 3H | m | H 26 |
Prove that this compound conforms to the chemical structure of target compound by structural identification.
The object of the invention is the preparation method providing oxidation impurities ticagrelor sulfoxide and ticagrelor sulfone.Its synthetic route is as follows:
The preparation method of compound (I), (II) is as follows:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole also [4,5-D] pyrimidin-3-yl] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in non-proton organic solvent and reacts with oxygenant, reaction is finished, and directly carries out next step reaction;
Wherein, described non-proton organic solvent is selected from the one in methylene dichloride, chloroform, benzene,toluene,xylene, wherein preferred toluene;
Described oxygenant is selected from the one in metachloroperbenzoic acid, potassium bichromate, potassium permanganate, Potcrate, hydrogen peroxide, wherein preferred metachloroperbenzoic acid.
B () adds (1R in the organic solvent of the compound V, VI of step (a), 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate, drip the aqueous solution stirring reaction of alkaline matter, reaction terminates rear stratification, generate compound III, IV be dissolved in machine mutually in
Wherein said alkaline matter is selected from the one in salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, preferred salt of wormwood.
C drip the organic solvent of concentrated hydrochloric acid in () organic phase, reaction terminates rear stratification, concentrate drying aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively; White solid 1 aftertreatment is obtained chemical compounds I sterling; Faint yellow solid aftertreatment is obtained compound ii sterling.
Wherein said organic solvent is water-soluble organic solvent, is selected from the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol acetone, tetrahydrofuran (THF), dme, acetic acid, wherein particular methanol.
Preferably, the preparation method of chemical combination I, II is as follows:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole also [4,5-D] pyrimidin-3-yl] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in toluene, and the toluene solution dripping metachloroperbenzoic acid makes it be oxidized.
B () adds (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate in reaction solution, drip K
2cO
3aqueous solution stirring reaction, reaction terminates rear stratification, gets toluene for next step reaction.
C () toluene is the middle methanol solution dripping concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrate drying aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively.
D (), by white solid 1 with after methyl alcohol heating for dissolving, white solid 2 is separated out in cooling, and namely suction filtration obtains chemical compounds I sterling.
F faint yellow solid water is at room temperature pulled an oar by (), suction filtration obtains white solid 3.
F white solid 3 is dried by () in vacuum drying oven, rear use preparation liquid phase separation obtains compound ii sterling.
Further, preferred preparation method comprises the following steps:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole is [4,5-D] pyrimidin-3-yl also] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in toluene, ice-water bath is cooled to 5 DEG C ~-5 DEG C, drips the metachloroperbenzoic acid toluene solution of 2 ~ 5 times of molar equivalents, is incubated 0 DEG C ~-5 DEG C and stirs 1-5 hour.
B () adds (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (the R)-mandelate of 0.5 ~ 2 times of molar equivalent in reaction solution, drip the K of 0.6 ~ 1mol/L
2cO
3aqueous solution stirring reaction 5 ~ 8 hours, reaction terminates rear stratification, gets toluene for next step reaction.
C () toluene is the middle methanol solution dripping 0.2 ~ 0.5mol/L concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively.
D white solid 1 is dried by () in vacuum drying oven, then dissolve by the methyl alcohol reflux of 60 ~ 80 times amount, room temperature environment borehole cooling to 40 ~ 50 DEG C, suction filtration obtains chemical compounds I sterling.
E the hydroecium temperature of faint yellow solid by 5 ~ 8 times of weight is pulled an oar 1 ~ 3 hour by (), suction filtration obtains white solid 3.
F white solid 3 is dried by () in vacuum drying oven, rear use preparation liquid phase separation.Preparation liquid phase separation condition: take octadecyl silane as weighting agent (250*50mm, 10 μm); With acetonitrile-water (volume ratio is: 3 ~ 5:7 ~ 5) for moving phase; Determined wavelength is 242nm; Flow velocity: 50 ~ 80ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling.
Further, preferred preparation method comprises the following steps:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole is [4,5-D] pyrimidin-3-yl also] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in toluene, ice-water bath is cooled to-2 DEG C, drips the metachloroperbenzoic acid toluene solution of 2 ~ 4 times of molar equivalents, is incubated 0 DEG C and stirs 2 hours.
B () adds (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (the R)-mandelate of 0.5 ~ 1 times of molar equivalent in reaction solution, drip the K of 0.8mol/L
2cO
3aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, gets toluene for next step reaction.
C () toluene is the middle methanol solution dripping 0.3mol/L concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively.
D white solid 1 is dried by () in vacuum drying oven, then dissolve by the methyl alcohol reflux of 70 times amount, room temperature environment borehole cooling to 45 ~ 50 DEG C, suction filtration obtains chemical compounds I sterling.
E the hydroecium temperature of faint yellow solid by 7 times of weight is pulled an oar 2 hours by (), suction filtration obtains white solid 3.
F white solid 3 is dried by () in vacuum drying oven, rear use preparation liquid phase separation.Preparation liquid phase separation condition: take octadecyl silane as weighting agent (250*50mm, 10 μm); With acetonitrile-water (volume ratio is for 4:6) for moving phase; Determined wavelength is 242nm; Flow velocity: 60ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling.
Present invention also offers two kinds of impurity compounds purposes as impurity reference substance when ticagrelor Related substances separation.
HPLC condition during ticagrelor Related substances separation is:
Take octadecyl silane as weighting agent; With acetonitrile-water-phosphate buffered saline buffer for moving phase; Determined wavelength is 237 ~ 245nm; Flow velocity: 1.0ml/min; Sample size: 10 ~ 20 μ l; Column temperature: 40 ~ 55 DEG C.
Further, preferred HPLC condition is:
Take octadecyl silane as weighting agent; With acetonitrile-water-phosphate buffered saline buffer for moving phase; Determined wavelength is 242nm; Flow velocity: 1.0ml/min; Sample size: 20 μ l; Column temperature: 55 DEG C.
Measuring according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D), is weighting agent with octadecylsilane chemically bonded silica, with phosphate buffered saline buffer
(1)-acetonitrile (90:10) is mobile phase A, with phosphate buffered saline buffer
(2)-acetonitrile (30:70) is Mobile phase B, carries out gradient elution by table 3; Flow velocity is 1.0ml/min, and column temperature is 55 DEG C, and determined wavelength is 242nm.Precision measures system suitability solution 10 μ l, injection liquid chromatography, and record color atlas, number of theoretical plate should be not less than 10000 in ticagrelor, and the tailing factor at ticagrelor peak should be not more than 1.5, and the resolution between ticagrelor and each impurity should meet the requirements.If any impurity peaks in the color atlas of need testing solution, oxidation impurities I, II peak area must not be greater than contrast solution main peak area (0.2%), other single impurity peak area must not be greater than contrast solution main peak area (0.2%), each impurity peak area and 3.5 times (0.7%) of contrast solution main peak area must not be greater than.
Table 3 gradient elution program
Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
0 | 90 | 10 |
7 | 35 | 65 |
15 | 35 | 65 |
16 | 0 | 100 |
23 | 0 | 100 |
25 | 90 | 10 |
30 | 90 | 10 |
Phosphate buffered saline buffer
(1): get 1.0mol/l sodium dihydrogen phosphate (with phosphoric acid adjust pH to 3.0) 10ml, add water to 900ml, shake up.
Phosphate buffered saline buffer
(2): get 1.0mol/l sodium dihydrogen phosphate (with phosphoric acid adjust pH to 3.0) 10ml, add water to 300ml, shake up.
Compared with prior art, the beneficial effect of ticagrelor oxidation impurities compound that the present invention relates to and preparation method thereof, detection method and purposes is: disclose the important oxidation impurities compound that ticagrelor produces in production, storage and transport process, how much content of this impurity compound directly affects the medicine quality of ticagrelor.The present invention obtains this compound by chemical synthesis, and structural identification is carried out to it thus confirms the structure of this compound, and the impurity reference substance disclosed when HPLC detection method it can be used as ticagrelor Related substances separation, thus the related substance in effective monitoring ticagrelor.Of the present inventionly implement the raising helping ticagrelor quality standard, thus better control the quality product of ticagrelor, people's safe medication is had great importance.
Accompanying drawing explanation
The mass spectrum of Fig. 1 ticagrelor oxidation impurities chemical compounds I;
Fig. 2 ticagrelor oxidation impurities chemical compounds I
1h-NMR spectrogram;
The mass spectrum of Fig. 3 ticagrelor oxidation impurities compound ii;
Fig. 4 ticagrelor oxidation impurities compound ii
1h-NMR spectrogram;
The HPLC of Fig. 5 ticagrelor oxidation impurities chemical compounds I detects collection of illustrative plates;
The HPLC of Fig. 6 ticagrelor oxidation impurities compound ii detects collection of illustrative plates.
Embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is further described, but protection scope of the present invention is not limited to these embodiments.Every do not deviate from the present invention's design change or equivalent substituting include within protection scope of the present invention.
Embodiment 1 ticagrelor oxidation impurities chemical compounds I, II preparation
(1) be dissolved in 225mL toluene by 15g intermediate, ice-water bath is cooled to-2 DEG C, drips the toluene solution that 210mL is dissolved with 18.06g metachloroperbenzoic acid, is incubated 0 DEG C and stirs 2.5 hours.
(2) in reaction solution, add 6.8g (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate, drip the K of 150mL0.8mol/L
2cO
3aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, gets toluene for next step reaction.
(3) the toluene middle concentrated hydrochloric acid methanol solution dripping 120mL0.3mol/L mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid 7.9g and white solid 1 respectively.
(4) 11.4g is obtained after being dried in vacuum drying oven by white solid 1, then dissolve by 700mL methyl alcohol reflux, room temperature environment borehole cooling to 48 DEG C, suction filtration obtains 8.2g sterling, yield 43.64%, HPLC detects purity 74.08% (referring to accompanying drawing 5).Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 1.
(5) by the hydroecium temperature of faint yellow solid 55mL making beating 2 hours, suction filtration obtains white solid 3.
(6) obtain 7.03g after being dried in vacuum drying oven by solid for white 3 bodies, liquid phase separation is prepared in rear use.Preparation liquid phase separation condition: take octadecyl silane as weighting agent; With acetonitrile-water (volume ratio is for 4:6) for moving phase; Determined wavelength is 242nm; Flow velocity: 60ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling 6.04g, and yield 31.21%, HPLC detects purity 99.75% (referring to accompanying drawing 6).Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 2.
Embodiment 2 ticagrelor oxidation impurities chemical compounds I, II preparation
(1) be dissolved in 225mL toluene by 15g intermediate, ice-water bath is cooled to-2 DEG C, drips the toluene solution that 320mL is dissolved with 30g metachloroperbenzoic acid, is incubated 0 DEG C and stirs 1 hour.
(2) in reaction solution, add 11g (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate, drip the K of 120mL0.8mol/L
2cO
3aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, gets toluene for next step reaction.
(3) the toluene middle methanol solution dripping 220mL0.6mol/L concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid 14.9g and white solid 1 respectively.
(4) obtain 5.92g after being dried in vacuum drying oven by white solid 1, then dissolve by the methyl alcohol reflux of 360mL, room temperature environment borehole cooling to 50 DEG C, suction filtration obtains sterling 4.2g, yield 22.34%.Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 1.
(5) by faint yellow solid 120mL hydroecium temperature making beating 1 hour, suction filtration obtains white solid 3.
(6) obtain 12.21g after being dried in vacuum drying oven by white solid 3, liquid phase separation is prepared in rear use.Preparation liquid phase separation condition: take octadecyl silane as weighting agent; With acetonitrile-water (volume ratio is for 3:7) for moving phase; Determined wavelength is 242nm; Flow velocity: 80ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling 10.02g, yield 51.8%.Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 2.
Embodiment 3 ticagrelor oxidation impurities chemical compounds I, II preparation
(1) be dissolved in 225mL toluene by 15g intermediate, ice-water bath is cooled to-2 DEG C, drips the methanol solution that 150mL is dissolved with 12g metachloroperbenzoic acid, is incubated 0 DEG C and stirs 5 hours.
(2) in reaction solution, add 5.6g (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate, drip the K of 120mL1mol/L
2cO
3aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, gets toluene for next step reaction.
(3) the toluene middle methanol solution dripping 80mL0.5mol/L concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid 4.02g and white solid 1 respectively.
(4) obtain 15.7g after being dried in vacuum drying oven by white solid 1, then dissolve by 1000mL methyl alcohol reflux, room temperature environment borehole cooling to 40 DEG C, suction filtration obtains sterling 11.2g, yield 59.6%.Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 1.
(5) by faint yellow solid 20mL hydroecium temperature making beating 3 hours, suction filtration obtains white solid 3.
(6) obtain 3.6g after being dried in vacuum drying oven by white solid, liquid phase separation is prepared in rear use.Preparation liquid phase separation condition: take octadecyl silane as weighting agent; With acetonitrile-water (volume ratio is for 5:5) for moving phase; Determined wavelength is 242nm; Flow velocity: 50ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling 3.03g, yield 15.5%.Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 2.
Embodiment 4 ticagrelor oxidation impurities chemical compounds I, II preparation
(1) be dissolved in 250mL dimethylbenzene by 15g intermediate, ice-water bath is cooled to-2 DEG C, drips the methanol solution that 220mL is dissolved with 10g potassium permanganate, is incubated 0 DEG C and stirs 5 hours.
(2) in reaction solution, add 11.1g (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate, drip the Na of 70mL0.8mol/L
2cO
3aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, gets toluene for next step reaction.
(3) the dimethylbenzene middle methanol solution dripping 100mL0.3mol/L concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively.
(4) dried in vacuum drying oven by white solid 1, then dissolve by the methyl alcohol reflux of 80 times amount, room temperature environment borehole cooling to 40 DEG C, suction filtration obtains sterling.Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 1.
(5) the hydroecium temperature of faint yellow solid by 5 times of weight pulled an oar 3 hours, suction filtration obtains white solid 3.
(6) white solid is dried in vacuum drying oven, rear use preparation liquid phase separation.Preparation liquid phase separation condition: take octadecyl silane as weighting agent; With acetonitrile-water (volume ratio is for 5:5) for moving phase; Determined wavelength is 242nm; Flow velocity: 50ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling.Pass through
1h-NMR spectrum, mass spectrum etc. have carried out structural identification, resolve the data obtained in table 2.
Embodiment 5 ticagrelor oxidation impurities I, II when ticagrelor Related substances separation as the application of impurity reference substance
Chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica, with phosphate buffered saline buffer
(1)-acetonitrile (90:10) is mobile phase A, with phosphate buffered saline buffer
(2)-acetonitrile (30:70) is Mobile phase B, carries out gradient elution by table 3; Flow velocity is 1.0ml/min, and column temperature is 55 DEG C, and determined wavelength is 242nm.
Experimental procedure: accurately weighed ticagrelor product to be tested 10.01mg, in 100mL volumetric flask, adds 35% acetonitrile and dissolves and be diluted to scale, as need testing solution; Precision measures oxidation impurities I reference substance 10.17mg and oxidation impurities II reference substance 10.24mg, in 100mL volumetric flask, dissolves and is diluted to scale, shake up with 35% acetonitrile, in contrast product solution.Precision takes ticagrelor reference substance 50.12mg, oxidation impurities I 50.32mg, oxidation impurities II 50.23mg, add 35% acetonitrile dissolve and dilute the mixing solutions made and contain ticagrelor 501.2 μ g, oxidation impurities I 503.2 μ g, oxidation impurities II 502.3 μ g in every 1ml respectively, as system suitability solution.Precision measures system suitability solution 10 μ l, injection liquid chromatography, and record color atlas, number of theoretical plate should be not less than 10000 in ticagrelor, and the tailing factor at ticagrelor peak should be not more than 1.5, and the resolution between ticagrelor and each impurity should meet the requirements.Precision measures reference substance solution and each 10 μ l of need testing solution, respectively injection liquid chromatography, record color atlas.
Its related substances check result that oxidation impurities compound measures ticagrelor as reference substance during Related substances separation is as follows:
Result is known as shown above, all has the existence of related oxidized impurity in the finished product of ticagrelor.
Claims (7)
1. a preparation method for ticagrelor oxide compound I and oxide compound II, is characterized in that, reaction scheme is as follows:
Concrete reactions steps is as follows:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole also [4,5-D] pyrimidin-3-yl] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in non-proton organic solvent and reacts with oxygenant, reaction is finished, and directly carries out next step reaction;
B () adds (1R in the organic solvent of the compound V, VI of step (a), 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate, drip the aqueous solution stirring reaction of alkaline matter, reaction terminates rear stratification, the compound III, IV of generation be dissolved in machine mutually in;
C drip the organic solvent of concentrated hydrochloric acid in () organic phase, reaction terminates rear stratification, concentrate drying aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively; White solid 1 aftertreatment is obtained chemical compounds I sterling; Faint yellow solid aftertreatment is obtained compound ii sterling;
Wherein, the described non-proton organic solvent of step (a) is selected from the one in methylene dichloride, chloroform, benzene,toluene,xylene, and described oxygenant is selected from the one in metachloroperbenzoic acid, potassium bichromate, potassium permanganate, Potcrate, hydrogen peroxide;
The described alkaline matter of step (b) is selected from the one in salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide;
The described organic solvent of step (c) is selected from the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol acetone, tetrahydrofuran (THF), dme, acetic acid.
2. the preparation method of a kind of ticagrelor oxide compound according to claim 1, it is characterized in that, concrete steps are as follows:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole also [4,5-D] pyrimidin-3-yl] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in toluene, and the toluene solution dripping metachloroperbenzoic acid makes it be oxidized;
B () adds (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate in reaction solution, drip K
2cO
3aqueous solution stirring reaction, reaction terminates rear stratification, gets toluene for next step reaction;
C () toluene is the middle methanol solution dripping concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrate drying aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively;
D (), by white solid 1 with after methyl alcohol heating for dissolving, white solid 2 is separated out in cooling, and namely suction filtration obtains chemical compounds I sterling;
E faint yellow solid water is at room temperature pulled an oar by (), suction filtration obtains white solid 3;
F white solid 3 is dried by () in vacuum drying oven, rear use preparation liquid phase separation obtains compound ii sterling.
3. the preparation method of a kind of ticagrelor oxide compound according to claim 1, it is characterized in that, concrete steps are as follows:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole is [4,5-D] pyrimidin-3-yl also] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in toluene, ice-water bath is cooled to 5 DEG C ~-5 DEG C, drips the metachloroperbenzoic acid toluene solution of 2 ~ 5 times of molar equivalents, is incubated 0 DEG C ~-5 DEG C and stirs 1-5 hour;
B () adds (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (the R)-mandelate of 0.5 ~ 2 times of molar equivalent in reaction solution, drip the K of 0.6 ~ 1mol/L
2cO
3aqueous solution stirring reaction 5 ~ 8 hours, reaction terminates rear stratification, gets toluene for next step reaction;
C () toluene is the middle methanol solution dripping 0.2 ~ 0.5mol/L concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively;
D white solid 1 is dried by () in vacuum drying oven, then dissolve by the methyl alcohol reflux of 60 ~ 80 times amount, room temperature environment borehole cooling to 40 ~ 50 DEG C, suction filtration obtains chemical compounds I sterling;
E the hydroecium temperature of faint yellow solid by 5 ~ 8 times of weight is pulled an oar 1 ~ 3 hour by (), suction filtration obtains white solid 3;
F white solid 3 is dried by () in vacuum drying oven, rear use preparation liquid phase separation.Preparation liquid phase separation condition: take octadecyl silane as weighting agent (250*50mm, 10 μm); With acetonitrile-water (volume ratio is: 3 ~ 5:7 ~ 5) for moving phase; Determined wavelength is 242nm; Flow velocity: 50 ~ 80ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling.
4. the preparation method of a kind of ticagrelor oxide compound according to claim 1, it is characterized in that, concrete reactions steps is as follows:
A () is by 2-[[(3AR, 4S, 6R, 6AS)-6-[the chloro-5-of 7-(rosickyite base)-3H-1,2,3-triazole is [4,5-D] pyrimidin-3-yl also] tetrahydrochysene-2,2-dimethyl-4H-cyclopenta-1,3-bis-dislikes luxuriant-4-base] oxygen base] ethanol is dissolved in toluene, ice-water bath is cooled to-2 DEG C, drips the metachloroperbenzoic acid toluene solution of 2 ~ 4 times of molar equivalents, is incubated 0 DEG C and stirs 2 hours;
B () adds (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (the R)-mandelate of 0.5 ~ 1 times of molar equivalent in reaction solution, drip the K of 0.8mol/L
2cO
3aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, gets toluene for next step reaction;
C () toluene is the middle methanol solution dripping 0.3mol/L concentrated hydrochloric acid mutually, reaction terminates rear stratification, and concentrated evaporate to dryness aqueous phase and organic phase, obtain faint yellow solid and white solid 1 respectively;
D white solid 1 is dried by () in vacuum drying oven, then dissolve by the methyl alcohol reflux of 70 times amount, room temperature environment borehole cooling to 45 ~ 50 DEG C, suction filtration obtains chemical compounds I sterling;
E the hydroecium temperature of faint yellow solid by 7 times of weight is pulled an oar 2 hours by (), suction filtration obtains white solid 3;
F white solid 3 is dried by () in vacuum drying oven, rear use preparation liquid phase separation.Preparation liquid phase separation condition: take octadecyl silane as weighting agent (250*50mm, 10 μm); With acetonitrile-water (volume ratio is for 4:6) for moving phase; Determined wavelength is 242nm; Flow velocity: 60ml/min; Sample size: 10ml; Column temperature is room temperature.Receive the elutriant containing compound ii, namely concentrate drying obtains sterling.
5. the HPLC detection method of ticagrelor oxide compound, is characterized in that, concrete chromatographic condition is as follows:
Weighting agent: with octadecyl silane;
Mobile phase A: mixture of acetonitrile-phosphate buffer (80 ~ 90:10 ~ 20), wherein, phosphate buffered liquid and preparation method thereof---get 1.0mol/l sodium dihydrogen phosphate (with phosphoric acid adjust pH to 3.0) 10ml, add water to 900ml, shake up;
Mobile phase B: mixture of acetonitrile-phosphate buffer (20 ~ 30:60 ~ 70), wherein, phosphate buffered liquid and preparation method thereof---get 1.0mol/l sodium dihydrogen phosphate (with phosphoric acid adjust pH to 3.0) 10ml, add water to 300ml, shake up;
Determined wavelength: 237 ~ 245nm; Flow velocity: 1.0ml/min; Sample size: 10 ~ 20 μ l; Column temperature: 40 ~ 55 DEG C.
6. the HPLC detection method of ticagrelor oxide compound according to claim 5, is characterized in that, concrete chromatographic condition is as follows:
Weighting agent: octadecyl silane is weighting agent;
Mobile phase A: mixture of acetonitrile-phosphate buffer (90:10), wherein, phosphate buffered liquid and preparation method thereof---get 1.0mol/l sodium dihydrogen phosphate (with phosphoric acid adjust pH to 3.0) 10ml, add water to 900ml, shake up;
Mobile phase B: mixture of acetonitrile-phosphate buffer (30:70), wherein, phosphate buffered liquid and preparation method thereof---get 1.0mol/l sodium dihydrogen phosphate (with phosphoric acid adjust pH to 3.0) 10ml, add water to 300ml, shake up;
Gradient program:
Determined wavelength is 242nm; Flow velocity: 1.0ml/min; Sample size: 20 μ l; Column temperature: 55 DEG C.
7. ticagrelor oxide compound I and oxide compound II when ticagrelor Related substances separation as the purposes of impurity reference substance.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000034283A1 (en) * | 1998-12-04 | 2000-06-15 | Astrazeneca Ab | Novel triazolo(4,5-d)pyrimidine compounds |
WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
CN104672242A (en) * | 2015-02-09 | 2015-06-03 | 扬子江药业集团有限公司 | Preparation method of Ticagrelor |
-
2015
- 2015-09-21 CN CN201510605513.XA patent/CN105237540B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000034283A1 (en) * | 1998-12-04 | 2000-06-15 | Astrazeneca Ab | Novel triazolo(4,5-d)pyrimidine compounds |
CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
CN104672242A (en) * | 2015-02-09 | 2015-06-03 | 扬子江药业集团有限公司 | Preparation method of Ticagrelor |
Non-Patent Citations (2)
Title |
---|
L. KALYANI ET AL.: ""A VALIDATED STABILITY-INDICATING HPLC METHOD FOR DETERMINATION OF TICAGRELOR IN BULK AND ITS FORMULATION"", 《INTERNATIONAL JOURNAL OF PHARMACY》 * |
TICAGRELORHASSANE SADOU YAYE ET AL.: ""Identification of the major degradation pathways of ticagrelor"", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
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