CN105237540B - Preparation method, detection method and purposes of a kind of ticagrelor about material - Google Patents

Preparation method, detection method and purposes of a kind of ticagrelor about material Download PDF

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CN105237540B
CN105237540B CN201510605513.XA CN201510605513A CN105237540B CN 105237540 B CN105237540 B CN 105237540B CN 201510605513 A CN201510605513 A CN 201510605513A CN 105237540 B CN105237540 B CN 105237540B
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white solid
phase
toluene
reaction
added dropwise
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CN105237540A (en
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李志华
吴舰
钱修文
柴雨柱
朱谧
徐丹
朱春霞
田舟山
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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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
    • 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 present invention provides the oxide (1S of ticagrelor, 2S, 3R, 5S) 3 [7 { [(1R, 2S) 2 (3.4 difluorophenyl) cyclopropyl] amino } 5 (propyl group sulfinyl) 3H [1, 2, 3] triazol [4, 5 d] 3 base of pyrimidine] 5 (2 hydroxyl-oxethyl) pentamethylene 1, 2 glycol and (1S, 2S, 3R, 5S) 3 [7 { [(1R, 2S) 2 (3.4 difluorophenyl) cyclopropyl] amino } 5 (propyl group sulfonyl) 3H [1, 2, 3] triazol [4, 5 d] 3 base of pyrimidine] 5 (2 hydroxyl-oxethyl) pentamethylene 1, the preparation method of 2 glycol, detection method and application of the oxide in ticagrelor quality controling research.

Description

Preparation method, detection method and purposes of a kind of ticagrelor about material
Technical field
The invention belongs to pharmaceutical technology field, be related to the oxide 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- difluoros Benzene) cyclopropyl] amino } -5- (propyl is thio) -3H- [1,2,3] triazol-[4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl second Epoxide) pentamethylene -1,2- glycol is Novel anti-platelet agent thing, by selective depression P2Y12 acceptors, so as to suppress thrombus Formed.Compared with clopidogrel, the suppression P2Y12 acceptors that ticagrelor can faster, stronger, more stable significantly reduce blood vessel Dead, myocardial infarction or the incidence of cerebral apoplexy caused by reason, so that the generation of thrombotic cardiovascular event is reduced, specific knot Structure formula is as follows.
At present, the document in terms of ticagrelor pharmacy quite enriches, and is concentrated mainly on bulk drug and its intermediate On the crystal formation of synthetic route and ticagrelor, then it is rarely reported in terms of the relevant material of ticagrelor.
In the oxidative degradation experiment of ticagrelor, sulphur, which is oxidized, can generate the derivative of sulfoxide and sulfone, i.e., (1S, 2S, 3R, 5S) -3- [7- { [(1R, 2S) -2- (3.4- difluorophenyls) cyclopropyl] amino } -5- (propyl group sulfinyl) -3H- [1,2, 3] triazol-[4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol (ticagrelor sulfoxide, structure Formula I) and (1S, 2S, 3R, 5S) -3- [7- { [(1R, 2S) -2- (3.4- difluorophenyls) cyclopropyl] amino } -5- (propyl group sulfonyls Base) -3H- [1,2,3] triazol-[4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol (and for lattice it is auspicious Lip river sulfone, structural formula II), HassaneSadouYaye etc. is in Identification of the major degradation The oxidative degradation mechanism of ticagrelor is reported in pathways ofticagrelor, but for the specific system of oxidation impurities Preparation Method, not document give disclosure.
Ticagrelor tablet is that chemical drug registers 3 classes, need to carry out comparative study with former triturate during research, be examined in synchronism stability During examining, the impurity spectrum of commercially available product is not quite similar with grinding sample certainly, but equally exists the oxidation impurities, by oxidation impurities The preparation of compound and structural identification, analysis that can be for ticagrelor about material provide reference substance, so as to improve for lattice The quality standard of auspicious Lip river, important directive significance is provided for the safe medication of ticagrelor.
The content of the invention
Oxide (I), (II) pass through1H-NMR spectrums, mass spectrum etc. have carried out structural identification, and parsing gained compound structure is such as Under：
Each method parsing the data obtained is as follows：
Compound (I)：
MS(ESI)：m/z[M-H]-=537.3；m/z[M+Na]+=561.2
Table 11H-NMR (500MHz DMSO) data
Chemical shift (ppm) Proton number Peak type Ownership
9.5715-9.8373 1H d H24
7.2424-7.3884 2H m H32,H33
7.0708 1H s H36
5.0739-5.1942 3H m H11,H12,H15
4.6062 2H s H26
3.9799 1H s H4
3.7955 1H s H8
3.5241 4H t H13,H14
3.2221-3.3317 1H m H7
2.9283-3.0958 1H m H6
2.8468-2.8954 1H t H5
2.6688-2.7664 1H m H5
2.0215-2.3238 2H m H2
1.3656-1.7924 4H m H27,H29,30
0.8190-1.0174 3H m H28
Compound (II)：
MS(ESI)：m/z[M-H]-=553.3；m/z[M+Na]+=577.3
Table 21H-NMR (500MHz DMSO) data
Chemical shift (ppm) Proton number Peak type Ownership
9.7932-10.0624 1H d H22
7.2435-7.3885 2H d H30,H31
7.0712-7.1367 1H q H34
5.0693-5.1943 3H q H9,H10,H13
4.5956 2H s H2,H6
3.9765 1H s H5
3.7973 1H s H4
3.5233 4H s H11,H12
3.3221 2H s H23
3.2327 1H s H3
2.6806-2.7816 1H m H3
2.2114 1H s H37
2.0258-2.0881 1H m H37
1.6914-1.7896 1H m H27
1.5150-1.6676 2H m H25
1.4320-1.4562 1H m H28
0.8053-1.0396 3H m H26
Prove that the compound is consistent with the chemical constitution of target compound by structural identification.
Present invention aims at the preparation method for providing oxidation impurities ticagrelor sulfoxide and ticagrelor sulfone.It synthesizes road Line is as follows：
Compound (I), the preparation method of (II) are as follows：
(a) by 2-, [[[the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles are simultaneously [4,5-D] by (3AR, 4S, 6R, 6AS) -6- Pyrimidin-3-yl] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- two dislikes cyclopentadienyl -4- bases] epoxide] ethanol is dissolved in aprotic has Reacted in machine solvent with oxidant, reaction is finished, directly carry out next step reaction；
Wherein, the non-proton organic solvent is selected from one in dichloromethane, chloroform, benzene,toluene,xylene Kind, wherein it is preferred that toluene；
The oxidant in metachloroperbenzoic acid, potassium bichromate, potassium permanganate, potassium chlorate, hydrogen peroxide one Kind, wherein it is preferred that metachloroperbenzoic acid.
(b) (1R, 2S) -2- (3,4- difluorophenyl) ring third is added into the organic solvent of the compound V, VI of step (a) Amine (R)-mandelate, is added dropwise the aqueous solution stirring reaction of alkaline matter, and reaction terminates rear stratification, the compound of generation IIIth, IV is dissolved in machine phase,
The one kind of wherein described alkaline matter in potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, preferably carbonic acid Potassium.
(c) in organic phase be added dropwise concentrated hydrochloric acid organic solvent, reaction terminate rear stratification, respectively be concentrated and dried aqueous phase and Organic phase, obtains faint yellow solid and white solid 1；White solid 1 is post-processed into obtain chemical compounds I sterling；After faint yellow solid Handle to obtain compound ii sterling.
Wherein described organic solvent is the organic solvent for being dissolved in water, selected from methanol, ethanol, normal propyl alcohol, isopropanol acetone, four One kind in hydrogen furans, dimethyl ether, acetic acid, wherein it is preferred that methanol.
Preferably, the preparation method of chemical combination I, II is as follows：
(a) by 2-, [[[the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles are simultaneously [4,5-D] by (3AR, 4S, 6R, 6AS) -6- Pyrimidin-3-yl] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- bis- dislike cyclopentadienyl -4- bases] epoxide] ethanol is dissolved in toluene, drips Plus the toluene solution of metachloroperbenzoic acid aoxidizes it.
(b) (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-mandelate is added into reaction solution, K is added dropwise2CO3 Aqueous solution stirring reaction, reaction terminates rear stratification, takes toluene to be mutually used for next step and reacts.
(c) in toluene phase be added dropwise concentrated hydrochloric acid methanol solution, reaction terminate rear stratification, respectively be concentrated and dried aqueous phase and Organic phase, obtains faint yellow solid and white solid 1.
(d) after white solid 1 is dissolved by heating with methanol, cooling separates out white solid 2, and suction filtration produces chemical compounds I sterling.
(f) faint yellow solid is beaten at room temperature with water, suction filtration obtains white solid 3.
(f) white solid 3 is dried in vacuum drying chamber, it is rear to obtain compound ii sterling using preparation liquid phase separation.
Further, it is preferable to preparation method comprise the following steps：
(a) by 2-, [[[the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles are simultaneously [4,5-D] by (3AR, 4S, 6R, 6AS) -6- Pyrimidin-3-yl] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- bis- dislike cyclopentadienyl -4- bases] epoxide] ethanol is dissolved in toluene, ice Water-bath is cooled to 5 DEG C~-5 DEG C, and the metachloroperbenzoic acid toluene solution of 2~5 times of molar equivalents is added dropwise, and is incubated 0 DEG C~-5 DEG C Stirring 1-5 hours.
(b) into reaction solution add 0.5~2 times of molar equivalent (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R) - Mandelate, is added dropwise 0.6~1mol/L K2CO3Aqueous solution stirring reaction 5~8 hours, reaction terminates rear stratification, takes first Benzene is mutually used for next step and reacted.
(c) methanol solution of 0.2~0.5mol/L concentrated hydrochloric acids is added dropwise in toluene phase, reaction terminates rear stratification, respectively Concentration is evaporated aqueous phase and organic phase, obtains faint yellow solid and white solid 1.
(d) white solid 1 is dried in vacuum drying chamber, is then heated to reflux dissolving with the methanol of 60~80 times of amounts, 40~50 DEG C are cooled under room temperature environment, suction filtration obtains chemical compounds I sterling.
(e) faint yellow solid is beaten 1~3 hour with the hydroecium temperature of 5~8 times of weight, suction filtration obtains white solid 3.
(f) white solid 3 is dried in vacuum drying chamber, it is rear to use preparation liquid phase separation.Preparation solution phase separation： Using octadecyl silane as filler (250*50mm, 10 μm)；Using acetonitrile-water (volume ratio as：3~5:7~5) for flowing Phase；Detection wavelength is 242nm；Flow velocity：50~80ml/min；Sample size：10ml；Column temperature is room temperature.Receive containing compound ii Eluent, concentrate drying produces sterling.
Further, preparation method preferably comprises the following steps：
(a) by 2-, [[[the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles are simultaneously [4,5-D] by (3AR, 4S, 6R, 6AS) -6- Pyrimidin-3-yl] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- bis- dislike cyclopentadienyl -4- bases] epoxide] ethanol is dissolved in toluene, ice Water-bath is cooled to -2 DEG C, and the metachloroperbenzoic acid toluene solution of 2~4 times of molar equivalents is added dropwise, and is incubated 0 DEG C and stirs 2 hours.
(b) into reaction solution add 0.5~1 times of molar equivalent (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R) - Mandelate, is added dropwise 0.8mol/L K2CO3Aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, takes toluene mutually to use In next step reaction.
(c) methanol solution of 0.3mol/L concentrated hydrochloric acids is added dropwise in toluene phase, reaction terminates rear stratification, concentration respectively is steamed Solid carbon dioxide phase and organic phase, obtain faint yellow solid and white solid 1.
(d) white solid 1 is dried in vacuum drying chamber, is then heated to reflux dissolving, room temperature with the methanol of 70 times of amounts 45~50 DEG C are cooled under environment, suction filtration obtains chemical compounds I sterling.
(e) faint yellow solid is beaten 2 hours with the hydroecium temperature of 7 times of weight, suction filtration obtains white solid 3.
(f) white solid 3 is dried in vacuum drying chamber, it is rear to use preparation liquid phase separation.Preparation solution phase separation： Using octadecyl silane as filler (250*50mm, 10 μm)；Using acetonitrile-water, (volume ratio is 4：6) it is mobile phase；Detection Wavelength is 242nm；Flow velocity：60ml/min；Sample size：10ml；Column temperature is room temperature.Receive the eluent containing compound ii, concentration It is drying to obtain sterling.
Present invention also offers two kinds of impurity compounds impurity reference substance is used as in ticagrelor Related substances separation Purposes.
HPLC conditions during ticagrelor Related substances separation are：
Using octadecyl silane as filler；Using acetonitrile-water-phosphate buffer as mobile phase；Detection wavelength is 237~245nm；Flow velocity：1.0ml/min；Sample size：10~20 μ l；Column temperature：40~55 DEG C.
Further, HPLC conditions preferably are：
Using octadecyl silane as filler；Using acetonitrile-water-phosphate buffer as mobile phase；Detection wavelength is 242nm；Flow velocity：1.0ml/min；Sample size：20μl；Column temperature：55℃.
Determine, be bonded with octadecylsilane according to high performance liquid chromatography (two D of annex V of Chinese Pharmacopoeia version in 2010) Silica gel is filler, with phosphate buffer(1)- acetonitrile (90:10) it is mobile phase A, with phosphate buffer(2)- acetonitrile (30: 70) it is Mobile phase B, gradient elution is carried out by table 3；Flow velocity is 1.0ml/min, and column temperature is 55 DEG C, and Detection wavelength is 242nm.Essence It is close to measure the μ l of system suitability solution 10, liquid chromatograph is injected, chromatogram is recorded, number of theoretical plate should not be low in terms of ticagrelor In 10000, the tailing factor at ticagrelor peak should be not more than 1.5, and the separating degree between ticagrelor and each impurity should meet the requirements. If any impurity peaks in the chromatogram of need testing solution, oxidation impurities I, II peak area cannot be greater than contrast solution main peak area (0.2%), other single impurity peak areas cannot be greater than contrast solution main peak area (0.2%), each impurity peak area and not It must be more than 3.5 times (0.7%) of contrast solution main peak area.
The gradient elution program of table 3
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 buffer(1)：1.0mol/l sodium dihydrogen phosphates (adjusting pH value to 3.0 with phosphoric acid) 10ml is taken, is added water to 900ml, shakes up.
Phosphate buffer(2)：1.0mol/l sodium dihydrogen phosphates (adjusting pH value to 3.0 with phosphoric acid) 10ml is taken, is added water to 300ml, shakes up.
Compared with prior art, ticagrelor oxidation impurities compound of the present invention and preparation method thereof, detection side The beneficial effect of method and purposes is：Disclose the important oxidation impurities that ticagrelor is produced in production, storage and transport process How much compound, the content of this impurity compound directly affects the medicine quality of ticagrelor.The present invention is obtained by chemical synthesis Take the compound, and structural identification carried out to it so as to confirming the structure of the compound, and disclose HPLC detection methods by its As impurity reference substance during ticagrelor Related substances separation, so that the effectively relevant material in monitoring ticagrelor.This The implementation of invention contributes to the raising of ticagrelor quality standard, so that the product quality of ticagrelor is preferably controlled, to people People's masses'safety medication has great importance.
Brief description of the drawings
The mass spectrogram of Fig. 1 ticagrelor oxidation impurities chemical compounds Is；
Fig. 2 ticagrelor oxidation impurities chemical compounds Is1H-NMR spectrum；
The mass spectrogram of Fig. 3 ticagrelor oxidation impurities compound iis；
Fig. 4 ticagrelor oxidation impurities compound iis1H-NMR spectrum；
The HPLC detection collection of illustrative plates of Fig. 5 ticagrelor oxidation impurities chemical compounds Is；
The HPLC detection collection of illustrative plates of Fig. 6 ticagrelor oxidation impurities compound iis.
Embodiment
The following is the specific embodiment of the present invention, technical scheme is further described, but it is of the invention Protection domain be not limited to these embodiments.Every change or equivalent substitute without departing substantially from present inventive concept is included in this hair Within bright protection domain.
The ticagrelor oxidation impurities chemical compounds I of embodiment 1, II preparation
(1) 15g intermediates are dissolved in 225mL toluene, ice-water bath is cooled to -2 DEG C, 210mL is added dropwise dissolved between 18.06g The toluene solution of chloroperoxybenzoic acid, is incubated 0 DEG C and stirs 2.5 hours.
(2) 6.8g (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-mandelate is added into reaction solution, is added dropwise 150mL 0.8mol/L K2CO3Aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, takes toluene to be mutually used for next step Reaction.
(3) 120mL 0.3mol/L concentrated hydrochloric acid methanol solution is added dropwise in toluene phase, reaction terminates rear stratification, respectively Concentration is evaporated aqueous phase and organic phase, obtains faint yellow solid 7.9g and white solid 1.
(4) 11.4g is obtained after white solid 1 is dried in vacuum drying chamber, is then heated to reflux with 700mL methanol molten 48 DEG C are cooled under solution, room temperature environment, suction filtration obtains 8.2g sterlings, yield 43.64%, HPLC detections purity 74.08% (is referred to attached Fig. 5).Pass through1H-NMR spectrums, mass spectrum etc. have carried out structural identification, and parsing the data obtained is shown in Table 1.
(5) faint yellow solid is beaten 2 hours with 55mL hydroecium temperature, suction filtration obtains white solid 3.
(6) 7.03g is obtained after solid 3 bodies of white are dried in vacuum drying chamber, rear use prepares liquid phase separation.Prepare liquid phase Separation condition：Using octadecyl silane as filler；Using acetonitrile-water, (volume ratio is 4：6) it is mobile phase；Detection wavelength is 242nm；Flow velocity：60ml/min；Sample size：10ml；Column temperature is room temperature.The eluent containing compound ii is received, concentrate drying is Obtain sterling 6.04g, yield 31.21%, HPLC detection purity 99.75% (referring to accompanying drawing 6).Pass through1H-NMR spectrums, mass spectrum etc. enter Structural identification is gone, parsing the data obtained is shown in Table 2.
The ticagrelor oxidation impurities chemical compounds I of embodiment 2, II preparation
(1) 15g intermediates are dissolved in 225mL toluene, ice-water bath is cooled to -2 DEG C, 320mL is added dropwise dissolved with 30g m-chloro mistakes The toluene solution of oxybenzoic acid, is incubated 0 DEG C and stirs 1 hour.
(2) 11g (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-mandelate is added into reaction solution, is added dropwise 120mL 0.8mol/L K2CO3Aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, takes toluene to be mutually used for next step Reaction.
(3) methanol solution of 220mL 0.6mol/L concentrated hydrochloric acids is added dropwise in toluene phase, reaction terminates rear stratification, respectively Concentration is evaporated aqueous phase and organic phase, obtains faint yellow solid 14.9g and white solid 1.
(4) 5.92g is obtained after white solid 1 is dried in vacuum drying chamber, is then heated to reflux with 360mL methanol molten 50 DEG C are cooled under solution, room temperature environment, suction filtration obtains sterling 4.2g, yield 22.34%.Pass through1H-NMR spectrums, mass spectrum etc. are carried out Structural identification, parsing the data obtained is shown in Table 1.
(5) faint yellow solid is beaten 1 hour with 120mL hydroeciums temperature, suction filtration obtains white solid 3.
(6) 12.21g is obtained after white solid 3 is dried in vacuum drying chamber, it is rear to use preparation liquid phase separation.Preparation solution Phase separation：Using octadecyl silane as filler；Using acetonitrile-water, (volume ratio is 3：7) it is mobile phase；Detection wavelength For 242nm；Flow velocity：80ml/min；Sample size：10ml；Column temperature is room temperature.The eluent containing compound ii is received, is concentrated and dried Produce sterling 10.02g, yield 51.8%.Pass through1H-NMR spectrums, mass spectrum etc. have carried out structural identification, and parsing the data obtained is shown in Table 2。
The ticagrelor oxidation impurities chemical compounds I of embodiment 3, II preparation
(1) 15g intermediates are dissolved in 225mL toluene, ice-water bath is cooled to -2 DEG C, 150mL is added dropwise dissolved with 12g m-chloro mistakes The methanol solution of oxybenzoic acid, is incubated 0 DEG C and stirs 5 hours.
(2) 5.6g (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-mandelate is added into reaction solution, is added dropwise 120mL 1mol/L K2CO3Aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, takes toluene to be mutually used for next step anti- Should.
(3) methanol solution of 80mL 0.5mol/L concentrated hydrochloric acids is added dropwise in toluene phase, reaction terminates rear stratification, respectively Concentration is evaporated aqueous phase and organic phase, obtains faint yellow solid 4.02g and white solid 1.
(4) 15.7g is obtained after white solid 1 is dried in vacuum drying chamber, is then heated to reflux with 1000mL methanol molten 40 DEG C are cooled under solution, room temperature environment, suction filtration obtains sterling 11.2g, yield 59.6%.Pass through1H-NMR spectrums, mass spectrum etc. are carried out Structural identification, parsing the data obtained is shown in Table 1.
(5) faint yellow solid is beaten 3 hours with 20mL hydroeciums temperature, suction filtration obtains white solid 3.
(6) 3.6g is obtained after white solid is dried in vacuum drying chamber, it is rear to use preparation liquid phase separation.Prepare liquid phase point From condition：Using octadecyl silane as filler；Using acetonitrile-water, (volume ratio is 5：5) it is mobile phase；Detection wavelength is 242nm；Flow velocity：50ml/min；Sample size：10ml；Column temperature is room temperature.The eluent containing compound ii is received, concentrate drying is Obtain sterling 3.03g, yield 15.5%.Pass through1H-NMR spectrums, mass spectrum etc. have carried out structural identification, and parsing the data obtained is shown in Table 2.
The ticagrelor oxidation impurities chemical compounds I of embodiment 4, II preparation
(1) 15g intermediates are dissolved in 250mL dimethylbenzene, ice-water bath is cooled to -2 DEG C, 220mL is added dropwise dissolved with 10g Gao Meng The methanol solution of sour potassium, is incubated 0 DEG C and stirs 5 hours.
(2) 11.1g (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-mandelate is added into reaction solution, is added dropwise 70mL 0.8mol/L Na2CO3Aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, takes toluene to be mutually used for next step Reaction.
(3) methanol solution of 100mL 0.3mol/L concentrated hydrochloric acids is added dropwise in dimethylbenzene phase, reaction terminates rear stratification, point Aqueous phase and organic phase Nong Suo be evaporated, faint yellow solid and white solid 1 is obtained.
(4) white solid 1 is dried in vacuum drying chamber, is then heated to reflux dissolving, room temperature with the methanol of 80 times of amounts 40 DEG C are cooled under environment, suction filtration obtains sterling.Pass through1H-NMR spectrums, mass spectrum etc. have carried out structural identification, and parsing the data obtained is shown in Table 1.
(5) faint yellow solid is beaten 3 hours with the hydroecium temperature of 5 times of weight, suction filtration obtains white solid 3.
(6) white solid is dried in vacuum drying chamber, it is rear to use preparation liquid phase separation.Preparation solution phase separation： Using octadecyl silane as filler；Using acetonitrile-water, (volume ratio is 5：5) it is mobile phase；Detection wavelength is 242nm；Stream Speed：50ml/min；Sample size：10ml；Column temperature is room temperature.The eluent containing compound ii is received, concentrate drying produces sterling.It is logical Cross1H-NMR spectrums, mass spectrum etc. have carried out structural identification, and parsing the data obtained is shown in Table 2.
The ticagrelor oxidation impurities I, II of embodiment 5 answering as impurity reference substance in ticagrelor Related substances separation With
Chromatographic condition：Using octadecylsilane chemically bonded silica as filler, with phosphate buffer(1)- acetonitrile (90:10) For mobile phase A, with phosphate buffer(2)- acetonitrile (30:70) it is Mobile phase B, gradient elution is carried out by table 3；Flow velocity is 1.0ml/min, column temperature is 55 DEG C, and Detection wavelength is 242nm.
Experimental procedure：Accurately weighed ticagrelor product to be tested 10.01mg, into 100mL volumetric flasks, plus the dissolving of 35% acetonitrile And scale is diluted to, it is used as need testing solution；Precision measures the reference substance 10.17mg of oxidation impurities I and the reference substance of oxidation impurities II 10.24mg, into 100mL volumetric flasks, is dissolved with 35% acetonitrile and is diluted to scale, shaken up, be used as reference substance solution.Precision claims Ticagrelor reference substance 50.12mg, the 50.32mg of oxidation impurities I, the 50.23mg of oxidation impurities II, plus 35% acetonitrile is taken to dissolve and dilute Release the mixing being made in every 1ml respectively containing the μ g of ticagrelor 501.2, the μ g of oxidation impurities I 503.2, the μ g of oxidation impurities II 502.3 molten Liquid, is used as system suitability solution.Precision measures the μ l of system suitability solution 10, injects liquid chromatograph, records chromatogram, reason 10000 should be not less than in terms of ticagrelor by plate number, the tailing factor at ticagrelor peak should be not more than 1.5, ticagrelor with it is each Separating degree between impurity should meet the requirements.Precision measures reference substance solution and each 10 μ l of need testing solution, is injected separately into liquid phase color Spectrometer, records chromatogram.
The relevant content of material that oxidation impurities compound determines ticagrelor as reference substance during Related substances separation is examined The fruit that comes to an end is as follows：
Result is understood as shown above, there is the presence of related oxidized impurity in the finished product of ticagrelor.

Claims (4)

1. the preparation method of a kind of ticagrelor oxide I and oxide II, it is characterised in that reaction scheme is as follows：
Specific reactions steps are as follows：
(a) by 2- [[(3AR, 4S, 6R, 6AS) -6- [and the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles simultaneously [4,5-D] pyrimidine - 3- yls] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- two dislikes cyclopentadienyl -4- bases] epoxide] to be dissolved in aprotic organic molten for ethanol Reacted in agent with oxidant, reaction is finished, directly carry out next step reaction；
(b) (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine is added into the organic solvent of the compound V, VI of step (a) (R)-mandelate, is added dropwise the aqueous solution stirring reaction of alkaline matter, reacts and terminates rear stratification, the compound III of generation, IV is dissolved in organic phase；
(c) organic solvent of concentrated hydrochloric acid is added dropwise in organic phase, reaction terminates rear stratification, aqueous phase is concentrated and dried respectively and organic Phase, obtains faint yellow solid and white solid 1；White solid 1 is post-processed into obtain chemical compounds I sterling；Faint yellow solid is post-processed Obtain compound ii sterling；
Wherein, the one kind of step (a) non-proton organic solvent in dichloromethane, chloroform, benzene,toluene,xylene, The one kind of the oxidant in metachloroperbenzoic acid, potassium bichromate, potassium permanganate, potassium chlorate, hydrogen peroxide；
The one kind of step (b) alkaline matter in potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide；
Step (c) organic solvent is selected from methanol, ethanol, normal propyl alcohol, isopropanol, acetone, tetrahydrofuran, dimethyl ether, acetic acid In one kind.
2. the preparation method of a kind of ticagrelor oxide according to claim 1, it is characterised in that specific steps are such as Under：
(a) by 2- [[(3AR, 4S, 6R, 6AS) -6- [and the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles simultaneously [4,5-D] pyrimidine - 3- yls] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- bis- dislike cyclopentadienyl -4- bases] epoxide] ethanol is dissolved in toluene, and m-chloro is added dropwise The toluene solution of benzoyl hydroperoxide aoxidizes it；
(b) (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-mandelate is added into reaction solution, K is added dropwise2CO3It is water-soluble Liquid stirring reaction, reaction terminates rear stratification, takes toluene to be mutually used for next step and reacts；
(c) methanol solution of concentrated hydrochloric acid is added dropwise in toluene phase, reaction terminates rear stratification, aqueous phase is concentrated and dried respectively and organic Phase, obtains faint yellow solid and white solid 1；
(d) after white solid 1 is dissolved by heating with methanol, cooling separates out white solid 2, and suction filtration produces chemical compounds I sterling；
(e) faint yellow solid is beaten at room temperature with water, suction filtration obtains white solid 3；
(f) white solid 3 is dried in vacuum drying chamber, it is rear to obtain compound ii sterling using preparation liquid phase separation.
3. the preparation method of a kind of ticagrelor oxide according to claim 1, it is characterised in that specific steps are such as Under：
(a) by 2- [[(3AR, 4S, 6R, 6AS) -6- [and the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles simultaneously [4,5-D] pyrimidine - 3- yls] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- bis- dislike cyclopentadienyl -4- bases] epoxide] ethanol is dissolved in toluene, ice-water bath is cold But to 5 DEG C~-5 DEG C, the metachloroperbenzoic acid toluene solution of 2~5 times of molar equivalents is added dropwise, 0 DEG C~-5 DEG C stirring 1-5 are incubated Hour；
(b) (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-almond of 0.5~2 times of molar equivalent is added into reaction solution Hydrochlorate, is added dropwise 0.6~1mol/L K2CO3Aqueous solution stirring reaction 5~8 hours, reaction terminates rear stratification, takes toluene phase For next step reaction；
(c) methanol solution of 0.2~0.5mol/L concentrated hydrochloric acids is added dropwise in toluene phase, reaction terminates rear stratification, concentrated respectively Aqueous phase and organic phase are evaporated, faint yellow solid and white solid 1 is obtained；
(d) white solid 1 is dried in vacuum drying chamber, is then heated to reflux dissolving, room temperature with the methanol of 60~80 times of amounts 40~50 DEG C are cooled under environment, suction filtration obtains chemical compounds I sterling；
(e) faint yellow solid is beaten 1~3 hour with the hydroecium temperature of 5~8 times of weight, suction filtration obtains white solid 3；
(f) white solid 3 is dried in vacuum drying chamber, it is rear to use preparation liquid phase separation, preparation solution phase separation：With ten Eight alkyl linked silica gel are filler, and column length * internal diameters are 250*50mm, and fixed phase stuffing particle diameter is 10 μm；Using acetonitrile-water as stream The volume ratio of dynamic phase, acetonitrile and water is：3~5:7~5；Detection wavelength is 242nm；Flow velocity：50~80ml/min；Sample size： 10ml；Column temperature is room temperature, receives the eluent containing compound ii, and concentrate drying produces sterling.
4. a kind of preparation method of ticagrelor oxide according to claim 1, it is characterised in that specific reactions steps It is as follows：
(a) by 2- [[(3AR, 4S, 6R, 6AS) -6- [and the chloro- 5- of 7- (rosickyite base) -3H-1,2,3- triazoles simultaneously [4,5-D] pyrimidine - 3- yls] tetrahydrochysene -2,2- dimethyl -4H- cyclopentas -1,3- bis- dislike cyclopentadienyl -4- bases] epoxide] ethanol is dissolved in toluene, ice-water bath is cold But to -2 DEG C, the metachloroperbenzoic acid toluene solution of 2~4 times of molar equivalents is added dropwise, is incubated 0 DEG C and stirs 2 hours；
(b) (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (R)-almond of 0.5~1 times of molar equivalent is added into reaction solution Hydrochlorate, is added dropwise 0.8mol/L K2CO3Aqueous solution stirring reaction 6 hours, reaction terminates rear stratification, under taking toluene to be mutually used for Single step reaction；
(c) methanol solution of 0.3mol/L concentrated hydrochloric acids is added dropwise in toluene phase, reaction terminates rear stratification, concentration respectively is evaporated water Phase and organic phase, obtain faint yellow solid and white solid 1；
(d) white solid 1 is dried in vacuum drying chamber, is then heated to reflux dissolving, room temperature environment with the methanol of 70 times of amounts Under be cooled to 45~50 DEG C, suction filtration obtains chemical compounds I sterling；
(e) faint yellow solid is beaten 2 hours with the hydroecium temperature of 7 times of weight, suction filtration obtains white solid 3；
(f) white solid 3 is dried in vacuum drying chamber, it is rear to use preparation liquid phase separation, preparation solution phase separation：With ten Eight alkyl linked silica gel are filler, and column length * internal diameters are 250*50mm, and fixed phase stuffing particle diameter is 10 μm；Using acetonitrile-water as stream The volume ratio of dynamic phase, acetonitrile and water is 4：6；Detection wavelength is 242nm；Flow velocity：60ml/min；Sample size：10ml；Column temperature is room Temperature, receives the eluent containing compound ii, and concentrate drying produces sterling.
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CN105510482B (en) * 2016-01-29 2018-02-02 成都百裕制药股份有限公司 The detection method of isomer impurities content in a kind of ticagrelor raw material
CN105606741A (en) * 2016-03-10 2016-05-25 天津红日药业股份有限公司 Method for detecting content of relevant substances of Ticagrelor
CN107513066A (en) * 2016-06-15 2017-12-26 武汉武药科技有限公司 A kind of preparation method of defluorinate type ticagrelor derivative
CN107778312A (en) * 2016-08-30 2018-03-09 重庆植恩药业有限公司 Ticagrelor impurity and its production and use
CN109387578A (en) * 2017-08-11 2019-02-26 四川海思科制药有限公司 The method for detecting (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine in ticagrelor
CN107976497B (en) * 2017-11-23 2020-11-10 重庆华邦制药有限公司 Method for determining synthesis reaction degree of ticagrelor intermediate 1 and application thereof
CN108542891A (en) * 2018-06-07 2018-09-18 董贵雨 A kind of solid composite medicament containing ticagrelor
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CN110746428A (en) * 2019-10-29 2020-02-04 株洲千金药业股份有限公司 Preparation method of R-type chiral sulfoxide compound
CN110642862B (en) * 2019-10-29 2021-01-26 株洲千金药业股份有限公司 Preparation method of ticagrelor ethylated impurity
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