CN106018655B - A kind of detection method of the Pabuk former times profit cloth raw material about material - Google Patents
A kind of detection method of the Pabuk former times profit cloth raw material about material Download PDFInfo
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- CN106018655B CN106018655B CN201610618387.6A CN201610618387A CN106018655B CN 106018655 B CN106018655 B CN 106018655B CN 201610618387 A CN201610618387 A CN 201610618387A CN 106018655 B CN106018655 B CN 106018655B
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- G—PHYSICS
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- 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
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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
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Abstract
The present invention provides a kind of detection method of the Pabuk former times profit cloth raw material about material, and this method is carried out using high performance liquid chromatography, comprised the steps：（1）Prepare Pabuk former times profit cloth sample solution；With（2）By step（1）Gained sample solution injects high performance liquid chromatograph, carries out gradient elution as mobile phase using mobile phase A and Mobile phase B, and record chromatogram；Wherein, the chromatographic column fixed phase filler of the high performance liquid chromatography is fluorophenyl bonded silica gel or phenyl bonded silica；The concentration for being formulated as acidic buffer of mobile phase A is 0.05% ~ 0.3% deionized water solution；Mobile phase B is formulated as acidic buffer volume：Methanol volume=0 ~ 10：100 ~ 90 methanol.The detection method of the present invention determines the relevant material of Pabuk former times profit cloth determination of raw material under same liquid-phase condition, and the detection method is easy to operate, separating degree is high, assay method specificity is strong, testing result is accurately credible.
Description
Technical field
The invention belongs to Pharmaceutical Analysis field.Specifically, the present invention relates to one kind to use high effective liquid chromatography for measuring
Detection method of the Pabuk former times profit cloth raw material about material.
Technical background
Pabuk former times profit cloth（Palbociclib）It is a kind of the thin of high selectivity for being researched and developed by Pfizer pharmaceutical Co. Ltd
Born of the same parents' cyclin-dependent kinase CDK4 and CDK6 invertibity antagonist.Its entitled 6- acetyl group -8- cyclopenta -5- first of chemistry
Base -2- { [5-（1- piperazinyls）- 2- pyridine radicals] amino } -7,8- dihydroquinazoline -7- ketone, the entitled 6-acetyl- of English language Chemical
8-cyclopentyl-5-methyl-2 - {[5- (1-piperazinyl) -2-pyridinyl] amino} -7,8-
Dihydro-quinazolin-7 ketone, its molecular weight are 447.53, molecular formula C24H29N7O2。
Pabuk former times profit cloth can block the cell cycle, to the process of S phases, to be closed from the G1 phases so as to suppress DNA by suppressing CDK4/6
Into.There is tumour cell to subtract the effect of going out and suppress cell growth effect by preclinical study as shown by data, Palbociclib, be
First Breast cancer immunotherapy medicine of the current listing by FDA approvals in 2015, it is above-mentioned for conventional capsule agent at present（Rule
Lattice 75mg, 100mg and 125mg）.
Breast cancer is breast glandular epithelium under the effect of a variety of carcinogens, producer mutation, causes normal cell
It is changed into cancer cell.The pernicious increment of cancer cell causes the normal configuration of breast tissue to be destroyed, and extrudes and corrodes normal structure.Breast
Gland cancer is one of most common malignant tumour of women（Male is rare but exists）, uterine cancer is only second to, it also can spread other
Position, and seriously endanger patient's physical and mental health, the major disease of the social medical burden of increase.
The early treatment of breast cancer includes operative treatment, endocrine therapy, chemotherapy, radiotherapy and molecular targeted therapy, although
In this way, still there is many patients to shift and recur, its main mechanism includes tumor drug resistance, the activation of signal path and cancer base
Activation of cause etc..At present, tumor microenvironment and the relation of host are focused in more research, and wherein immune system is important composition
One of part.Therefore for the immune system of patient, breast is turned into tumour for the effect in alleviation and host by adjusting it
The foundation of gland cancer successive treatment.Pabuk former times profit cloth blocks the cell cycle from the G1 phases to the process of S phases by suppressing CDK4/6, so that
Suppress DNA synthesis.There is tumour cell to subtract the effect of going out and suppress cell life for its preclinical test as shown by data Pabuk former times profit cloth
Long effect.
At present in Pabuk former times profit cloth Material synthesis technique, initiation material, the intermediate that may contain in final raw produce
And the known impurities of degraded share 7, respectively 4- (6- aminopyridine -3- bases) piperazine -1- carboxylic acid tert-butyl esters（SM1）, 6- it is bromo-
The chloro- 8- cyclopenta -5- methvl-pyridiniums of 2- simultaneously [2,3-D] pyrimidine -7 (8H) -one（SM2）, tert-butyl group 4-（6-（The bromo- 8- rings penta of 6-
Base -5- methyl -7- oxygen -7,8- dihydropyridines [2,3-d] pyrimidine -2-yl amino）Pyridine -3-yl）Piperazine -1- carboxylates
（PALB01）, tert-butyl group 4-（6-（6-（1- vinyl butyl ethers）- 8- cyclopenta -5- methyl -7- oxygen -7,8- dihydropyridines [2,3-
D] pyrimidine -2-yl amino）Pyridine -3-yl）Piperazine -1- carboxylates（PALB02）, 8- cyclopenta-5- methyl-2-（（5-（Piperazine
Piperazine -1- bases）Pyridine -2- bases）Amino）- 6- vinylpyridines simultaneously [2,3-d] pyrimidine -7（8H）- ketone（PF-06651464）、8-
Cyclopenta -5- methyl -2-（5- piperazines -1- bases-pyridine -2- base amino）- 8H- pyridos [2,3-d] pyrimidin-7-ones（PF-
00447880）、4- [6-（6- acetyl group -8- cyclopenta -5- methyl -7- oxo -7,8- dihydro pyrido [2,3-d] pyrimidines -2-
Base amino）- pyridin-3-yl]-piperazine -1- carboxylates（PF-00310864）.
Detection method of a kind of Pabuk former times profit cloth raw material about material involved in the present invention primarily directed to more than wherein
Pabuk former times profit cloth known impurities effectively detect and separate.Wherein, 4- (6- aminopyridine -3- bases) piperazine -1- carboxylic acid uncles
Simultaneously [2,3-D] pyrimidine -7 (8H) -one is initiation material to the chloro- 8- cyclopenta -5- methvl-pyridiniums of the bromo- 2- of butyl ester, 6-；Tert-butyl group 4-
（6-（Bromo- 8- cyclopenta -5- methyl -7- oxygen -7,8- dihydropyridines [2,3-d] pyrimidine -2-yl amino of 6-）Pyridine -3-yl）Piperazine
Piperazine -1- carboxylates, tert-butyl group 4-（6-（6-（1- vinyl butyl ethers）- 8- cyclopenta -5- methyl -7- oxygen -7,8- dihydropyridines [2,
3-d] pyrimidine -2-yl amino）Pyridine -3-yl）Piperazine -1- carboxylates are synthetic intermediate；8- cyclopenta-5- methyl-2-
（（5-（Piperazine -1- bases）Pyridine -2- bases）Amino）- 6- vinylpyridines simultaneously [2,3-d] pyrimidine -7（8H）- ketone, 8- cyclopenta-
5- methyl -2-（5- piperazines -1- bases-pyridine -2- base amino）- 8H- pyridos [2,3-d] pyrimidin-7-ones, 4- [6-（6- second
Acyl group-8- cyclopenta-5- methyl-7- oxo-7,8- dihydro pyridos [2,3-d] pyrimidine -2 --amino）- pyridin-3-yl]-
Piperazine -1- carboxylates are catabolite.
At present, Chinese Pharmacopoeia and foreign pharmacopeia do not include the relevant substance-measuring method of Pabuk former times profit cloth raw material.Disclosed
Patent in, do not inquire the related testing conditions about material.The A of Chinese patent application CN 105541832 disclose one kind
The preparation method of isethionate Pabuk former times profit cloth, another A of Chinese patent application CN 105418603 disclose a kind of high-purity
The preparation method of degree Pabuk former times profit cloth and its reaction intermediate, the A of Chinese patent CN 105748435 disclose a kind of Pabuk former times profit
Cloth pharmaceutical composition and preparation method thereof, the A of Chinese patent CN 104887641 disclose a kind of Pabuk former times profit cloth gastric floating tablet
And preparation method thereof.Four patents of the above are not studied and explained to the relevant substance detecting method of Pabuk former times profit cloth bulk drug
State.In addition, in PCT Patent Application WO/2016/0662420A1, WO/2016/0662429A1, US20160024084 etc.
The relevant substance-measuring method of Pabuk former times profit cloth bulk drug is not studied.Detection method provided by the present invention can be to above-mentioned seven
One or more progress effective detections in kind impurity.
The content of the invention
It is an object of the invention to provide one kind to use the relevant material of high effective liquid chromatography for measuring Pabuk former times profit cloth bulk drug
Detection method, so as to accurate and effective measure Pabuk former times profit cloth raw material in relevant material, precisely control product quality.
For above-mentioned purpose, it is as follows that the present invention provides technical scheme：
The present invention provides a kind of detection method of the Pabuk former times profit cloth about material, wherein the relevant material of the Pabuk former times profit cloth
Including 4- (6- aminopyridine -3- bases) piperazine -1- carboxylic acid tert-butyl esters, the chloro- 8- cyclopenta -5- methvl-pyridiniums of the bromo- 2- of 6- simultaneously [2,
3-D] pyrimidine -7 (8H) -one, tert-butyl group 4-（6-（The bromo- 8- cyclopenta -5- methyl -7- oxygen -7,8- dihydropyridines [2,3-d] of 6- are phonetic
Pyridine -2-yl amino）Pyridine -3-yl）Piperazine -1- carboxylates, tert-butyl group 4-（6-（6-（1- vinyl butyl ethers）- 8- cyclopenta -5-
Methyl -7- oxygen -7,8- dihydropyridines [2,3-d] pyrimidine -2-yl amino）Pyridine -3-yl）Piperazine -1- carboxylates are, 8- rings penta
Base-5- methyl-2-（（5-（Piperazine -1- bases）Pyridine -2- bases）Amino）- 6- vinylpyridines simultaneously [2,3-d] pyrimidine -7（8H）
- ketone（PF-06651464）, 8- cyclopenta -5- methyl -2-（5- piperazines -1- bases-pyridine -2- base amino）- 8H- pyridos
[2,3-d] pyrimidin-7-ones（PF-00447880）、4- [6-（6- acetyl group -8- cyclopenta -5- methyl -7- oxo -7,8- dihydros
Pyrido [2,3-d] pyrimidine -2 --amino）- pyridin-3-yl]-piperazine -1- carboxylates（PF-00310864）In
One or more, this method are carried out using high performance liquid chromatography, comprised the steps：
（1）Pabuk former times profit cloth sample solution is prepared, described Pabuk former times profit cloth sample solution includes need testing solution；
（2）By step（1）Gained sample solution injects high performance liquid chromatograph, using mobile phase A and Mobile phase B as stream
It is dynamic mutually to carry out gradient elution, and record chromatogram；
Wherein, the preparation method of the need testing solution comprises the steps：Precision weighs Pabuk former times profit cloth bulk drug sample
Product, the concentration for adding dilution to dissolve and being diluted to Pabuk former times profit cloth is 0.2mg/ml~2mg/ml, obtains need testing solution；
The chromatographic column fixed phase filler of the high performance liquid chromatography is fluorophenyl bonded silica gel or phenyl bonded silica,
It is preferred that stationary phase filler is fluorophenyl bonded silica gel；
The gradient elution order of wherein described high performance liquid chromatography is as follows：
Mobile phase is at 0 minute：The volume % Mobile phase Bs of 90~100 volume % mobile phase As+0~10；
Mobile phase is during 0-30 minutes：The volume % Mobile phase Bs of 45~55 volume % mobile phase As+45~55；
Mobile phase is during 30-45 minutes：The volume % Mobile phase Bs of 0~10 volume % mobile phase As+90~100；
Mobile phase is during 45-55 minutes：The volume % Mobile phase Bs of 90~100 volume % mobile phase As+0~10；
Preferably, the gradient elution order of the high performance liquid chromatography is as follows：
Mobile phase is at 0 minute：The volume % Mobile phase Bs of 97 volume % mobile phase As+3；
Mobile phase is during 0-30 minutes：The volume % Mobile phase Bs of 50 volume % mobile phase As+50；
Mobile phase is during 30-45 minutes：The volume % Mobile phase Bs of 3 volume % mobile phase As+97；
Mobile phase is during 45- 55 minutes：The volume % Mobile phase Bs of 97 volume % mobile phase As+3.
The chromatographic column column temperature of the high performance liquid chromatography is 40~65 DEG C, preferably 55 DEG C；
Preferably, auto injection room temperature is 4 ~ 30 DEG C, preferably 25 DEG C；
Preferably, Detection wavelength 220nm.
The Pabuk former times profit cloth sample solution also includes own control solution and/or impurity sample-adding solution；
The preparation method of the own control solution comprises the steps：Precision measures need testing solution 1ml, puts 100ml
In volumetric flask, diluted is added to shake up to scale, obtain own control solution；
The preparation method of the impurity sample-adding solution comprises the steps：Precision weighs Pabuk former times profit cloth reference substance, adds dilute
It is 20ug/ml~5mg/ml to release liquid and dissolve and be diluted to the concentration of Pabuk former times profit cloth, obtains Pabuk former times profit cloth reference substance deposit
Liquid；Separately 4- (6- aminopyridine -3- bases) piperazine -1- carboxylic acid tert-butyl esters, the chloro- 8- cyclopenta -5- methyl-pyrroles of the bromo- 2- of 6- are taken respectively
Pyridine simultaneously [2,3-D] pyrimidine -7 (8H) -one, tert-butyl group 4-（6-（The bromo- 8- cyclopenta -5- methyl -7- oxygen -7,8- dihydropyridines of 6-
[2,3-d] pyrimidine -2-yl amino）Pyridine -3-yl）Piperazine -1- carboxylates, tert-butyl group 4-（6-（6-（1- vinyl butyl ethers）-8-
Cyclopenta -5- methyl -7- oxygen -7,8- dihydropyridines [2,3-d] pyrimidine -2-yl amino）Pyridine -3-yl）Piperazine -1- carboxylates
For, 8- cyclopenta-5- methyl-2-（（5-（Piperazine -1- bases）Pyridine -2- bases）Amino）Simultaneously [2,3-d] is phonetic for -6- vinylpyridines
Pyridine -7（8H）- ketone, 8- cyclopenta -5- methyl -2-（5- piperazines -1- bases-pyridine -2- base amino）- 8H- pyridos [2,3-
D] pyrimidin-7-ones, 4- [6-（6- acetyl group -8- cyclopenta -5- methyl -7- oxo -7,8- dihydro pyridos [2,3-d] pyrimidine -
2- base amino）- pyridin-3-yl]-piperazine -1- carboxylate's standard items, it is accurately weighed, respectively with dilution dissolving simultaneously
It is 20ug/ml~5mg/ml to be diluted to concentration, obtains each impurity reference substance solution mother liquor；Precision measures Pabuk former times profit cloth reference substance
Storing solution and each impurity reference substance mother liquor of Pabuk former times profit cloth, mixing, add diluted, and it is molten to obtain Pabuk former times profit cloth impurity sample-adding
Liquid；
Preferably, wherein the dilution is water：Acetonitrile：Perchloric acid=60：40：0.05.
Preferably, the concentration of Pabuk former times profit cloth is 1.0mg/ml wherein in Pabuk former times profit cloth need testing solution.
Preferably, wherein each impurity reference substance mother liquid concentration of Pabuk former times profit cloth is 100ug/ml.
Preferably, in high performance liquid chromatography detecting step（2）In, own control solution is injected into liquid chromatogram first
Instrument, contrast solution is injected into liquid chromatograph first, adjust detection sensitivity, the peak height for making principal component chromatographic peak is full scale
20%；Need testing solution and impurity sample-adding solution are injected separately into liquid chromatograph again, using mobile phase A and Mobile phase B as stream
It is dynamic mutually to carry out gradient elution, and record chromatogram；Preferably, the amount for injecting sample solution in liquid chromatograph is 2ul.
The detection method of the present invention determines the relevant material in Pabuk former times profit cloth raw material, the inspection under same liquid-phase condition
Survey method is easy to operate, and Pabuk former times profit cloth main peak retention time is more suitable, and wherein known impurities can obtain effective detection, point
High from degree, assay method specificity is strong, and testing result is accurately credible, is quality control, the impurity research of Pabuk former times profit cloth raw material
Provide a kind of easy rational detection method.The inventive method measure about material suitable for Pabuk former times profit cloth bulk drug
And sample survey.
Embodiment
The following example is being explained further and illustrate to the present invention, but is not intended to it and limits this hair in any way
Bright scope.
By many experiments and exploration, detection method of the Pabuk former times profit cloth raw material about material of the invention can effectively be divided
Seven kinds of known impurities relative from Pabuk former times profit cloth, method is reliable, and measure is accurate.
Embodiment 1
The relevant substance detecting method of Pabuk former times profit cloth raw material of the present invention
1. detecting instrument and testing conditions
Instrument：Wear peace Ultimate3000；Wear peace VWD-3100
Chromatographic column：Fluorobenzene pilum（1.7um, 2.1mm × 100mm）
Mobile phase：A：0.05%（v/v）High chloro acid solution
B：Methanol
Flow velocity：0.4ml/min；Detection wavelength：220nm；
Column temperature：55℃；Automatic sampler temperature is 25 DEG C.
2. solution is prepared：Pabuk former times profit cloth material sample is taken, adds diluent dissolving that every 1ml is made containing about Pabuk former times profit cloth
1mg need testing solution.
Precision measures need testing solution 1ml, puts in 100ml volumetric flasks, is diluted to scale with mobile phase A, shakes up, as certainly
Body contrast solution.
Pabuk former times profit cloth reference substance about 100mg is taken, is put in 50ml measuring bottles, is dissolved with diluent and be diluted to scale, shaken up,
As Pabuk former times profit cloth reference substance storing solution；Separately SM1, SM2, PALB01, PALB02, PF-06651464, PF- are taken respectively
00447880th, each 10mg of PF-00310864 standard items, it is accurately weighed, put in 10ml measuring bottles, dissolved with dilution and be diluted to quarter
Degree, shakes up, as each dirt solution mother liquor；Precision measures Pabuk former times profit cloth reference substance storing solution 5.0ml and each dirt solution is female
Liquid 1.0ml, put in 10ml measuring bottles and mix, with diluted to scale, shake up, be worth Pabuk former times profit cloth impurity sample-adding solution.
3. assay method：Go own control solution 2ul to inject liquid chromatograph, adjust detection sensitivity, make principal component color
The peak height of spectral peak is about the 20% of recorder full scale.It is another to take need testing solution and impurity to be loaded each 2ul injections liquid chromatogram of solution
Instrument, gradient elution is carried out according to table 1, record chromatogram is to 3 ~ 4 times of principal component peak retention time.
The present invention is easy to operate, and Pabuk former times profit cloth main peak retention time is about 11 minutes or so, and detection time is more suitable,
Seven kinds of known impurities can be detected effectively, and separating degree meets the requirements（More than 1.5）, assay method specificity is strong, inspection
It is accurately credible to survey result.
Claims (14)
- A kind of 1. detection method of the relevant material in Pabuk former times profit cloth raw material, wherein relevant in the Pabuk former times profit cloth raw material Material includes 8- cyclopenta -5- methyl -2-（5- piperazines -1- bases-pyridine -2- base amino）- 8H- pyridos [2,3-d] pyrimidine- 7- ketone, 8- cyclopenta-5- methyl-2-（（5-（Piperazine -1- bases）Pyridine -2- bases）Amino）- 6- vinylpyridines are simultaneously [2,3-d] Pyrimidine -7（8H）- ketone, 4- [6-（6- acetyl group -8- cyclopenta -5- methyl -7- oxo -7,8- dihydro pyridos [2,3-d] Pyrimidine -2 --amino）- pyridin-3-yl]-piperazine -1- carboxylates one or more, this method is to use efficient liquid What phase chromatography was carried out, comprise the steps：（1）Pabuk former times profit cloth sample solution is prepared, the Pabuk former times profit cloth sample solution includes need testing solution；（2）By step（1）Gained sample solution injects high performance liquid chromatograph, using mobile phase A and Mobile phase B as flowing Gradient elution is mutually carried out, and records chromatogram；Wherein, the preparation method of the need testing solution comprises the steps：Precision weighs Pabuk former times profit cloth material sample, adds dilute It is 0.2mg/ml~2.0mg/ml to release liquid and dissolve and be diluted to the concentration of Pabuk former times profit cloth, obtains need testing solution；The chromatographic column fixed phase filler of the high performance liquid chromatography is fluorophenyl bonded silica gel or phenyl bonded silica,Mobile phase A is 0.05% acid solution；Mobile phase B is methanol；The gradient elution order of wherein described high performance liquid chromatography is as follows：Mobile phase is at 0 minute：The volume % Mobile phase Bs of 90~100 volume % mobile phase As+0~10；Mobile phase is during 0-30 minutes：The volume % Mobile phase Bs of 45~55 volume % mobile phase As+45~55；Mobile phase is during 30-45 minutes：The volume % Mobile phase Bs of 0~10 volume % mobile phase As+90~100；Mobile phase is during 45-55 minutes：The volume % Mobile phase Bs of 90~100 volume % mobile phase As+0~10.
- 2. detection method according to claim 1, it is characterised in that the chromatographic column fixed phase of the high performance liquid chromatography Filler is fluorophenyl bonded silica gel.
- 3. detection method according to claim 1, wherein,The gradient elution order of the high performance liquid chromatography is as follows：Mobile phase is at 0 minute：The volume % Mobile phase Bs of 97 volume % mobile phase As+3；Mobile phase is during 0-30 minutes：The volume % Mobile phase Bs of 50 volume % mobile phase As+50；Mobile phase is during 30-45 minutes：The volume % Mobile phase Bs of 3 volume % mobile phase As+97；Mobile phase is during 45- 55 minutes：The volume % Mobile phase Bs of 97 volume % mobile phase As+3.
- 4. the detection method according to any one of claim 1 to 3, wherein the acid of described acid solution be perchloric acid, Phosphoric acid or trifluoroacetic acid；The pH of acid solution is 2.0 ~ 7.0；The flow velocity of mobile phase is 0.3~0.5ml/min.
- 5. detection method according to claim 4, it is characterised in that the pH of described mobile phase is 2.3.
- 6. detection method according to claim 4, it is characterised in that the acid of described acid solution is perchloric acid；Mobile phase Flow velocity be 0.4ml/min.
- 7. detection method according to any one of claim 1 to 3, wherein the chromatographic column of the high performance liquid chromatography Column temperature is 40~65 DEG C；Auto injection room temperature is 4 ~ 30 DEG C；Detection wavelength is 220nm.
- 8. detection method according to claim 7, it is characterised in that the chromatographic column post of wherein described high performance liquid chromatography Temperature is 55 DEG C；Auto injection room temperature is 25 DEG C.
- 9. the detection method according to any one of claim 1 to 3, wherein the Pabuk former times profit cloth sample solution also wraps Include own control solution and/or impurity sample-adding solution；The preparation method of the own control solution comprises the steps：Precision measures need testing solution 1ml, puts 100ml capacity In bottle, diluted is added to shake up to scale, obtain own control solution；The preparation method of the impurity sample-adding solution comprises the steps：Precision weighs Pabuk former times profit cloth reference substance, adds dilution The concentration for dissolving and being diluted to Pabuk former times profit cloth is 0.2mg/ml~2mg/ml, obtains Pabuk former times profit cloth reference substance storing solution； Separately 8- cyclopenta -5- methyl -2- is taken respectively（5- piperazines -1- bases-pyridine -2- base amino）- 8H- pyridos [2,3-d] are phonetic Pyridine-7- ketone, 8- cyclopenta-5- methyl-2-（（5-（Piperazine -1- bases）Pyridine -2- bases）Amino）- 6- vinylpyridines simultaneously [2 , 3-d] and pyrimidine -7（8H）-one, 4- [6-（6- acetyl group -8- cyclopenta -5- methyl -7- oxos -7,8- dihydro pyrido [2 , 3-d] and pyrimidine -2 --amino）- pyridin-3-yl]-piperazine -1- carboxylates, it is accurately weighed, it is molten with dilution respectively It is 20 μ g/ml~5mg/ml to solve and be diluted to concentration, obtains each impurity reference substance solution mother liquor；Precision measures Pabuk former times profit cloth Reference substance storing solution and each impurity reference substance solution mother liquor of Pabuk former times profit cloth, mixing, add diluted, obtain Pabuk former times profit cloth Impurity is loaded solution.
- 10. detection method according to claim 9, it is characterised in that the dilution is water：Acetonitrile：Perchloric acid=60： 40：0.05.
- 11. pa in the detection method according to any one of claim 1 to 3, wherein Pabuk former times profit cloth need testing solution Cloth former times profit cloth concentration is 1mg/ml.
- 12. detection method according to claim 9, wherein each impurity reference substance solution mother liquid concentration of Pabuk former times profit cloth are 100μg/ml。
- 13. detection method according to claim 9, wherein, in high performance liquid chromatography detecting step（2）In, first will Sample own control solution injects liquid chromatograph, adjusts detector sensitivity, the peak height for making principal component chromatographic peak is recorder The 20% of full scale；Need testing solution and impurity sample-adding solution are injected separately into liquid chromatograph again, using mobile phase A and stream Dynamic phase B carries out gradient elution as mobile phase, and records chromatogram.
- 14. detection method according to claim 13, it is characterised in that the amount of sample solution is equal in injection liquid chromatograph For 2 μ l.
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| CN106970177B (en) * | 2017-06-06 | 2018-05-15 | 北京元延医药科技股份有限公司 | The analyzing detecting method of Pa Boxini intermediates and its impurity |
| CN111239299B (en) * | 2020-03-30 | 2022-05-27 | 重庆三圣实业股份有限公司 | Method for separating and measuring palbociclib and impurities thereof |
| CN114544847B (en) * | 2022-03-09 | 2023-11-03 | 上海皓元医药股份有限公司 | Method for detecting genotoxic impurities in starting raw material for synthesizing piperaquine Bai Xi |
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| WO2016030439A1 (en) * | 2014-08-28 | 2016-03-03 | Ratiopharm Gmbh | Method of producing palbociclib and pharmaceutical compositions comprising the same |
| CN104892604B (en) * | 2015-06-19 | 2016-08-24 | 北京康立生医药技术开发有限公司 | A kind of synthetic method of CDK4 inhibitor |
| CN105418603A (en) * | 2015-11-17 | 2016-03-23 | 重庆莱美药业股份有限公司 | Method for preparing high-purity palbociclib and reaction intermediate of palbociclib |
| CN105524059A (en) * | 2016-01-06 | 2016-04-27 | 北京修正创新药物研究院有限公司 | Palbociclib impurity preparation method |
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