CN107266363A - Methanesulfonic acid pleasure is cut down for the preparation method of Buddhist nun's impurity of the drug - Google Patents
Methanesulfonic acid pleasure is cut down for the preparation method of Buddhist nun's impurity of the drug Download PDFInfo
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- CN107266363A CN107266363A CN201610210759.1A CN201610210759A CN107266363A CN 107266363 A CN107266363 A CN 107266363A CN 201610210759 A CN201610210759 A CN 201610210759A CN 107266363 A CN107266363 A CN 107266363A
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- Prior art keywords
- impurity
- buddhist nun
- methanesulfonic acid
- cut down
- pleasure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/067—Preparation by reaction, e.g. derivatising the sample
Abstract
The invention belongs to pharmaceutical synthesis field, it is related to impurity in production of raw medicine technique and preparation method thereof, more particularly to a kind of medicine methanesulfonic acid pleasure for the intractable thyroid cancer of therapeutic radiation iodine is cut down cuts down the purposes for Buddhist nun's quality research for process contaminants A, B of Buddhist nun's (carboxylic acid amide mesylate of i.e. 4 (3 chlorine 4 (N ' cyclopropylureidos) phenoxy group) 7 methoxy quinoline 6) and C preparation method and applications in methanesulfonic acid pleasure.It is that first passage chemical synthesis obtains process contaminants A, B and C by methods described, and can be separated efficiently and rapidly and obtains target compound
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be related to bulk drug methanesulfonic acid pleasure cut down for process contaminants in Buddhist nun's production process and its
Prepare.More particularly to methanesulfonic acid pleasure is cut down for Buddhist nun's process contaminants and preparation method thereof.
Background technology
What Lenvatinib was developed and developed by Wei Cai companies, the Chinese translation of standard, therefore the applicant are there is no at present
It is herein " pleasure is cut down for Buddhist nun " by its transliteration.The medicine obtained U.S. FDA approval in 2 months 2015, partly recurs or turns for having
Move, progressivity, the treatment of the intractable patients with differentiated thyroid carcinoma of radioiodine, trade name LENVIMA.In March, 2015, first sulphur
Happy cut down of acid is ratified to list for Buddhist nun by Japanese health ministry, as treatment irresectability thyroid cancer (including differentiated thyroid carcinoma,
Medullary carcinoma of thyroid gland, undifferentiated type thyroid cancer) first molecular targeted therapy；In May, 2015, by European Food medicine
Surveillance Authority's approval listing.It is a kind of polyceptor EGFR-TK (RTK) inhibitor that methanesulfonic acid pleasure, which is cut down for Buddhist nun, with novelty
Binding pattern, in addition to other Angiogensis RTK related to oncogenic signals path for suppressing to participate in tumor proliferation, additionally it is possible to select
Property suppress VEGF (VEGF) acceptor kinase activity.LENVIMA is a kind of molecular targeted system of oral administration
Agent.
According to material official information is defended, in one large-scale III phases SELECT are studied, compared with placebo, lenvatinib
Significantly extend the progression free survival phase (PFS of the intractable differentiated thyroid carcinoma of radioiodine：18.3 months vs 3.6 months)；
Meanwhile, the patient that there are significantly higher ratio in lenvatinib treatment groups realizes tumor mass reduction (65%vs 2%).In addition,
During another II phase that Japan carries out is studied, lenvatinib is also showed for medullary carcinoma of thyroid gland and undifferentiated type thyroid cancer
Good curative effect and tolerance are gone out.
At present, defend material and also assess treatments of the lenvatinib for other types tumour, including liver cancer, nephrocyte
Cancer, non-small cell lung cancer etc., in July, 2015, methanesulfonic acid pleasure is cut down obtains the breakthrough medicine qualifications of FDA for Buddhist nun (Lenvima),
For late period and/or the possibility indication of metastatic renal cell cancer.
Methanesulfonic acid pleasure is cut down is for the chemical name of Buddhist nun：4- (the chloro- 4- of 3- (N '-cyclopropylureido) phenoxy group) -7- methoxyl groups
QUINOLINE-6-CARBOXYLIC ACID's acid amides methanesulfonic acid, structural formula is：
Prior art discloses three kinds of process contaminants or degradation impurity, and they are during synthesizing methanesulfonic acid pleasure is cut down for Buddhist nun
Obtain, but FDA officials evaluate the knot in a series of impurity announced in report and interior metabolism product to above-mentioned three kinds of impurity
Structure is not described：
Methanesulfonic acid pleasure is cut down to be reported for the synthesis route of Buddhist nun in patent CN101024627, and the route is：It is chloro- with 4-
7- methoxy quinoline -6- carboxylic acid amides (SM1) and 4- amino -3- chlorophenols (SM2) are initiation material, in the effect of potassium tert-butoxide
Under, progress nucleophilic substitution obtains intermediate -1 in dimethyl sulphoxide solution：4- (4- amino -3- chlorophenoxies) -7- first
Phenoxyl quinoline -6- carboxylic acid amides (LVTN-1), intermediate -1 is in 1-METHYLPYRROLIDONE, using pyridine as alkali, with chloro-carbonic acid
Phenyl ester is condensed to yield intermediate -2：(4- ((6- acid methylamide base -7- methoxy quinoline -4- bases) oxygen) -2- chlorphenyls) amino
Phenyl formate (LVIN-2).Intermediate -2 by the substitution reaction with cyclopropylamine, obtains intermediate -3 again：4- (the chloro- 4- of 3- (N '-
Cyclopropylureido) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides (LVTN-3, pleasure is cut down for Buddhist nun's free alkali).Happy cut down is swum for Buddhist nun
From alkali in acetum, with methanesulfonic acid into salt, crystallization, then be beaten by ethanol, turn crystalline substance, be made methanesulfonic acid pleasure cut down for Buddhist nun into
Product,
The route, which is one, has the synthetic route of industrial production value, and the process contaminants on this production line are still
Without report.
The content of the invention
Impurity research is the important content during drug research and development, and impurity is studied through drug research and development all the time, directly
Imitation medicine and original is had influence on to grind medicine whether with original to grind medicine in terms of quality and security consistent.In order to be cut down to methanesulfonic acid pleasure for Buddhist nun and
Find pleasure in containing methanesulfonic acid and the relevant material reference substance of quality research offer of the preparation for Buddhist nun is provided, improve methanesulfonic acid pleasure and cuts down for Buddhist nun and contain
Methanesulfonic acid pleasure is cut down for the quality standard of Buddhist nun's preparation, is that methanesulfonic acid pleasure cuts down safe medication and imitation medicine Conformance Assessment for Buddhist nun's preparation
Important guidance is provided.The present invention studies and has synthesized methanesulfonic acid pleasure and cuts down for the new process contaminants in Buddhist nun's production line, and right
These impurity have carried out structural identification.
The methanesulfonic acid pleasure of patent CN101024627 reports cuts down the preparation technology route for Buddhist nun, can produce a series of technique
Impurity, also evaluates the partial impurities disclosed in report including FDA officials, and patent of the present invention only lists technique do not report, new
Impurity, its chemical name and chemical structural formula see the table below：
The mechanism that three kinds of impurity in patent of the present invention are produced is as follows：
Impurity A：In methanesulfonic acid pleasure cuts down the step 2 for Buddhist nun preparation technology, after intermediate LVTN-2 is generated, due to activity
The presence of reaction site phenyl isocyanate, occurs substitution reaction, generation with still unreacted intermediate LVTN-1 in reaction system
Impurity A, reaction equation is as follows：
Impurity B：Methanesulfonic acid pleasure is cut down for two step DMFs after Buddhist nun preparation technology as solvent, in the solvent
Containing a small amount of dimethylamine, with cyclopropylamine formation competitive reaction in the 3rd step substitution reaction, impurity B is generated, reaction equation is such as
Under：
Impurity C：Cut down in methanesulfonic acid pleasure in the step salt-forming reaction of Buddhist nun preparation technology the 4th, under acid condition, intermediate -3
(LVTN-3) impurity C is generated by etoh solvent attack
In specific embodiments, above-claimed cpd A-C is unpack format, is preferably substantially pure form, more preferably
With greater than about 95% purity.
On the other hand, cut down for Buddhist nun or contain in detection methanesulfonic acid pleasure the present invention relates to the one or more of above-claimed cpd A-C
There is methanesulfonic acid pleasure to cut down the application in the sample purity for the pharmaceutical preparation of Buddhist nun as reference standard or reference substance, wherein methanesulfonic acid is found pleasure in
The chemical name cut down for Buddhist nun is 4- (the chloro- 4- of 3- (N '-cyclopropylureido) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amide first
Sulfonate, structural formula is：
Brief description of the drawings
Fig. 1：Impurity A：4,4 '-(((carbonyl is double (urea diyl)) double (chloro- 4, the 1- phenyl of 3-)) double (epoxides)) double (7- methoxies
Base quinoline -6- formamides)1H-NMR；
Fig. 2：Impurity A：4,4 '-(((carbonyl is double (urea diyl)) double (chloro- 4, the 1- phenyl of 3-)) double (epoxides)) double (7- methoxies
Base quinoline -6- formamides)13C-NMR；
Fig. 3：Impurity A：4,4 '-(((carbonyl is double (urea diyl)) double (chloro- 4, the 1- phenyl of 3-)) double (epoxides)) double (7- methoxies
Base quinoline -6- formamides) high resolution mass spectrum (ESI-HRMS)；
Fig. 4：Impurity B：4- (the chloro- 4- of 3- (3,3- dimethyl urea groups) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides
's1H-NMR；
Fig. 5：Impurity B：4- (the chloro- 4- of 3- (3,3- dimethyl urea groups) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides
High resolution mass spectrum (ESI-HRMS)；
Fig. 6：Impurity C：4- ethyoxyl -7- methoxy quinoline -6- formamides1H-NMR；
Fig. 7：Impurity C：4- ethyoxyl -7- methoxy quinoline -6- formamides13C-NMR；
Fig. 8：Impurity C：The high resolution mass spectrum (ESI-HRMS) of 4- ethyoxyl -7- methoxy quinoline -6- formamides.
Embodiment
In order to which further the present invention will be described, it will be illustrated below by specific embodiment, but following reality
Example is applied to be not limited in any way protection scope of the present invention.
Embodiment 1：The synthesis of impurity A
Impurity A, 4,4 '-(((carbonyl is double (urea diyl)) double (chloro- 4, the 1- phenyl of 3-)) double (epoxides)) double (7- methoxyl group quinolines
Quinoline -6- formamides) synthesis
20ml 1-METHYLPYRROLIDONEs are added into 100mL there-necked flask, 1.00g LVTN-1 are sequentially added under stirring,
0.92g pyridines, nitrogen protection, are cooled to 0~10 DEG C, start that 1.46g phenyl chloroformates are added dropwise, drop finishes, continue to stir 20~30
Minute, 60 DEG C are warming up to, is stirred overnight；Sample TLC detections (methanol: dichloromethane=1: 10) raw material disappears.Add water 20ml, has
A large amount of solids are separated out, and continue to stir 30 minutes.Filtering, is drained, 40 DEG C of forced air dryings 30 minutes, is obtained solid crude product, will be obtained
Crude product carries out column chromatography purifying, and elution ratio is：Methanol: dichloromethane=1: 50, the collection common 160mL of eluent, temperature control 30~
40 DEG C, vacuum：- 0.08MPa, vacuum distillation is evaporated off solvent to being steamed without cut, obtains faint yellow solid 105mg, yield：
5.05%, that is, obtain impurity A：4,4 '-(((carbonyl is double (urea diyl)) double (chloro- 4, the 1- phenyl of 3-)) double (epoxides)) double (7- first
Phenoxyl quinoline -6- formamides).
Impurity A
The structural identification of impurity A is as follows：
The impurity A of table 11H-NMR and13C-NMR test datas (DMSO-d6) and ownership
The ESI-HRMS spectrograms of impurity A show molecular ion peak [M+H]+Mass-to-charge ratio be 713.13146, corresponding point
Son amount is consistent with the structural formula calculated value (713.12400) provided.Absolute error is 0.26ppm, in defined error model
Within enclosing.
Impurity A1H NMR、13C NMR and ESI-HRMS spectrogram are shown in accompanying drawing 1~3 respectively.
Embodiment 2：The synthesis of impurity B
The conjunction of impurity B, i.e. 4- (the chloro- 4- of 3- (3,3- dimethyl urea groups) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides
Into.
463.87mg methanesulfonic acids pleasure is added into 50ml there-necked flask to cut down for Buddhist nun's intermediate LVTN-2 and 9mL N- methyl pyrroles
Pyrrolidone.Controlling reaction temperature adds 99.18mg dimethylamine into reaction system at 0~10 DEG C, continues to stir 30 minutes, TLC
Monitor (dichloromethane: methanol=10: 1), reaction terminates.80% acetone/water (V/V) mixed solvent is added into reaction system
18mL, has a large amount of solids to separate out, after stirring 30 minutes, and filtering, 60 DEG C of forced air dryings obtain impurity B crude product.The crude product is carried out
Column chromatography is purified, and solvent and ratio are：Methanol: dichloromethane=1: 20 (V/V), the collection common 150mL of eluent, temperature control 30~
40 DEG C, vacuum：- 0.08MPa, vacuum distillation, to being steamed without cut, obtains pale pink solid 153.04mg, yield：36.89%,
Obtain impurity B：4- (the chloro- 4- of 3- (3,3- dimethyl urea groups) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides.1H-NMR
(400Mz, CDCl3)δ：8.709 (d, J=3.2Hz, 1H), 8.678 (s, 1H), 7.981 (s, 2H), 7.874 (s, 1H), 7.724
(d, J=6.0Hz, 1H), 7.544 (s, 1H), 7.274 (dd, J=2.0Hz, J=6.0Hz, 1H), 7.266 (d, J=2.0Hz,
1H), 6.559 (d, J=3.2Hz, 1H), 4.051 (s, 3H), 2.978 (s, 6H) (referring to accompanying drawing 4).ESI-HRMS spectrograms are shown
Molecular ion peak m/z=415.11742 [M+H]+, corresponding molecular weight and the structural formula calculated value of offer
(414.84226) it is consistent.Absolute error is 1.60ppm, and (accompanying drawing 5 is referred to) within high resolution mass spectrum error range.
Embodiment 3：Impurity C synthesis
Impurity C, i.e. 4- ethyoxyls -7- methoxy quinolines -6- formamides synthesis
2.00g methanesulfonic acids pleasure is added into 100ml there-necked flask to cut down for Buddhist nun, 50mL ethanol.Return stirring 72 hours, TLC
Monitoring (methanol: dichloromethane=1: 10, there is new point to produce).Remove solvent under reduced pressure, crude product will be obtained and carry out column chromatography purifying, washed
De- ratio is：Methanol: dichloromethane=1: 20, collect the common 60mL of eluent, 30~40 DEG C of temperature control, vacuum：- 0.08MPa, subtracts
Pressure distillation, is evaporated off solvent to being steamed without cut, obtains pale pink solid 122mg, yield：6.10%, that is, obtain impurity C：4- ethoxies
Base -7- methoxy quinoline -6- formamides.
Impurity C
Impurity C structural identification see the table below：
The impurity C's of table 21H-NMR and13C-NMR test datas (DMSO-d6) and ownership
Impurity C ESI-HRMS spectrograms show molecular ion peak [M+H]+Mass-to-charge ratio be 247.10872, [2M+Na+H]+
Mass-to-charge ratio be 515.19080, corresponding molecular weight is consistent with the structural formula calculated value (247.10044) of offer.Absolutely
It is 4.08ppm to error, within defined error range.
Impurity C's1H NMR、13C NMR and ESI-HRMS spectrogram are shown in accompanying drawing 6~8 respectively.
Embodiment 4：Methanesulfonic acid pleasure cuts down the preparation for Buddhist nun
(1) synthesis of 4- (4- amino -3- chlorophenoxies) -7- methoxy quinoline -6- carboxylic acid amides (LVTN-1).
Under nitrogen protection, into 500mL there-necked flask, 200mL dimethyl sulfoxide (DMSO)s are added, stirring is opened, sequentially adds
The chloro- 7- methoxy quinolines -6- carboxylic acid amides (SM1) of 20.00g 4-, 18.20g 4- amino -3- chlorophenols (SM2) and 14.22g
Potassium tert-butoxide.Charging is finished, and is warming up to 65 DEG C, insulated and stirred 19 hours.Above-mentioned reaction system is poured into pure water, there is big
Measure solid to separate out, filtering, the pure water wash of filter cake, under the conditions of 60 DEG C, forced air drying 1~2 hour obtains brown solid
25.07g 4- (4- amino -3- chlorophenoxies) -7- methoxy quinoline -6- carboxylic acid amides (LVTN-1), yield：86.32%.
(2) 4- (the chloro- 4- of 3- (N '-cyclopropylureido) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides (LVTN-3) are happy
Cut down the synthesis for Buddhist nun
250mL 1-METHYLPYRROLIDONEs are added into 500mL there-necked flasks, stirring is opened, sequentially adds 11.50g pyridines
With 25.00g 4- (4- amino -3- chlorophenoxies) -7- methoxy quinoline -6- carboxylic acid amides (LVTN-1).Under ice-water bath, Xiang Ti
It is added dropwise in system after 4.94g phenyl chloroformates, completion of dropping, system is warming up to room temperature.Pure water is added dropwise into reaction system, drips
1~2 hour between added-time, filter, elution, forced air drying 2 hours under the conditions of 60 DEG C obtain 33.74g (4- ((6- carboxylic acid formyls
Amido -7- methoxy quinoline -4- bases) oxygen) -2- chlorphenyls) phenyl carbamate (LVTN-2) brown ceramic powder.Yield：
81.26%.
300mL 1-METHYLPYRROLIDONEs are added into 1000mL there-necked flasks, stirring is opened, adds 30.00g (4- ((6-
Acid methylamide base -7- methoxy quinoline -4- bases) oxygen) -2- chlorphenyls) phenyl carbamate (LVTN-2).At room temperature, Xiang Ti
4.43g cyclopropylamines, time for adding 1 hour are added dropwise in system.After completion of dropping, continue insulated and stirred and stay overnight.Add into reaction system
Enter 300mL pure water, stirring continues to stir 1 hour, filtered to there are a large amount of solids to separate out (about 1~2 hour), elution, in 60 DEG C
Under the conditions of forced air drying 12 hours, obtain 27.50g crude products, obtaining 21.08g off-white powders 4- through ethyl alcohol recrystallization, (3- is chloro-
4- (N '-cyclopropylureido) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides (LVTN-3), yield：76.35%
(3) methanesulfonic acid pleasure cuts down the preparation for Buddhist nun, 4- (the chloro- 4- of 3- (N '-cyclopropylureido) phenoxy group) -7- methoxyl group quinolines
The preparation of quinoline -6- carboxylic acid amide mesylates
Under nitrogen protection, 100mL acetic acid and 2.70g methanesulfonic acids, 40 DEG C of conditions of temperature control are sequentially added into 250mL there-necked flasks
Under, then into system 10.00g LVTN-3 are added, stir 1~2 hour, mother liquor is collected in filtering, by tri- mouthfuls of mother liquor transferase 45 00mL
In bottle, under nitrogen protection, 170mL normal propyl alcohols, control time for adding 1~2 hour are added dropwise into system for 40 DEG C of temperature control.Filtering, filter
Cake 70mL normal propyl alcohols, elution, obtain methanesulfonic acid pleasure and cut down acetic acid compound for Buddhist nun.Under nitrogen protection, add into 250mL there-necked flasks
Enter 100mL ethanol, open under the conditions of stirring, 40 DEG C of temperature control, add methanesulfonic acid pleasure and cut down for Buddhist nun's acetic acid compound, it is small that continuation stirs 36
When, filtering, filter cake ethanol rinse, under the conditions of 60 DEG C, forced air drying 12 hours obtains methanesulfonic acid pleasure and cut down for Buddhist nun's finished product
10.23g, is off-white powder, yield：83.49%.
Embodiment 5：Impurity A-C in relevant material during methanesulfonic acid is found pleasure in and cut down for Buddhist nun's bulk drug is detected as reference substance application
(1) preparation of impurity A-C contrast solutions：
Take the impurity A-C of above-mentioned preparation appropriate, it is accurately weighed, put respectively in 100ml volumetric flasks, plus appropriate acetonitrile ultrasound makes
Dissolving, then add dilution in acetonitrile to scale, shake up, then precision measures each solution about 0.5ml, puts in 100ml volumetric flasks, plus 50% second
Nitrile-water is diluted to scale, shakes up, and every 1ml is respectively prepared containing about the solution that compound A~C is respectively 0.5 μ g, each impurity is used as
Contrast solution.
(2) preparation of need testing solution：
The methanesulfonic acid pleasure of above-mentioned preparation is cut down for the preparation of Buddhist nun's crude product need testing solution：The first sulphur for taking above-described embodiment 4 to prepare
Acid pleasure is cut down for Buddhist nun's crude product about 10mg, accurately weighed, puts in 20ml volumetric flasks, plus diluent (dimethyl sulfoxide (DMSO)：Acetonitrile: A (2: 4:
4, V/V/V) dissolve and be diluted to scale, shake up, every 1ml is made and is cut down containing pleasure for Buddhist nun about 0.5mg solution, cut down as methanesulfonic acid pleasure
For Buddhist nun's need testing solution.
(3) chromatographic condition
Chromatographic column：Waters XBridge BEH Shield RP18 posts, 4.6 × 150mm, 2.5 μm
Mobile phase：A phases：0.03mol/L ammonium acetates (acetic acid adjusts pH value to 5.0)-acetonitrile (92：8, V/V), B phases：Acetonitrile
Column temperature：40℃；
Detection wavelength：252nm
Flow velocity：0.9ml/min
Need testing solution：0.5mg/ml (is cut down in terms of Buddhist nun) by pleasure
Sampling volume：10μl
Solvent：DMSO：ACN：H2O=2：4：4(V/V/V)
Gradient elution program：
(4) test procedure：Above-mentioned impurity contrast solution and the μ l of need testing solution 10 are taken, liquid chromatograph (purchase is injected separately into
From Waters, US, model：Acquity H-Class UPLC), or LC-MS instrument (Agilent companies of the U.S.,
Agilent 6120) record chromatogram.Calculate impurity A-C's according to external standard method (Chinese Pharmacopoeia version in 2010, two, annex VD)
Content.
(5) result of the test：
The methanesulfonic acid pleasure prepared according to embodiment 4 cuts down the impurity analysis of spectrum for Buddhist nun's crude product
| Sequence number | Content (%) | [MW+H]+ | Impurity belongs to | Relative retention time |
| The impurity 1 detected | 0.03 | 247.0 | C | 0.46 |
| The impurity 2 detected | 0.04 | 472.9 | Unknown impuritie | 0.70 |
| The impurity 3 detected | 0.08 | 414.9 | B | 0.79 |
| The impurity 4 detected | 0.03 | 386.9 | Unknown impuritie | 0.92 |
| The impurity 5 detected | 0.02 | 343.9 | LVTN-1 | 0.97 |
| The impurity 6 detected | 0.05 | 393.9 | Unknown impuritie | 1.49 |
| The impurity 7 detected | 0.02 | 712.8 | A | 1.85 |
| The impurity 8 detected | 0.04 | 441.9 | Unknown impuritie | 2.08 |
It should be noted that all documents referred in the present invention are incorporated as reference in this application, just as each
Piece document is individually recited as with reference to such.In addition, it is to be understood that above-described is that the specific implementation of the present invention is arranged and transported
Technical principle, after present disclosure has been read, those skilled in the art can do various changes or repair to the present invention
Change without departing from spirit and scope of the invention, these equivalent form of values are also fallen within the scope of the present invention.
Claims (7)
1. compound A, chemical name is：4,4 '-(((carbonyl is double (urea diyl)) double (chloro- 4, the 1- phenyl of 3-)) double (epoxides)) are double
(7- methoxy quinoline -6- formamides), and with following structure：
2. compound B, chemical name is：4- (the chloro- 4- of 3- (3,3- dimethyl urea groups) phenoxy group) -7- methoxy quinoline -6- carboxylics
Sour acid amides, and with following structure：
3. compound C, chemical name is：4- ethyoxyl -7- methoxy quinoline -6- formamides, and with following structure：
4. it is unpack format according to compound according to any one of claims 1 to 3.
5. the compound according to claim any one of 1-3, it is substantially pure form.
6. the compound according to claim any one of 1-3, it has the purity higher than 95%.
7. according to compound according to any one of claims 1 to 6 it is one or more cut down for Buddhist nun in detection methanesulfonic acid pleasure or
The application in the sample purity for the pharmaceutical preparation of Buddhist nun as reference standard or reference substance, wherein methanesulfonic acid are cut down containing methanesulfonic acid pleasure
Happy cut down for the chemical name of Buddhist nun is 4- (the chloro- 4- of 3- (N '-cyclopropylureido) phenoxy group) -7- methoxy quinoline -6- carboxylic acid amides
Mesylate, its chemical structural formula is：
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610210759.1A CN107266363A (en) | 2016-04-06 | 2016-04-06 | Methanesulfonic acid pleasure is cut down for the preparation method of Buddhist nun's impurity of the drug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610210759.1A CN107266363A (en) | 2016-04-06 | 2016-04-06 | Methanesulfonic acid pleasure is cut down for the preparation method of Buddhist nun's impurity of the drug |
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| Publication Number | Publication Date |
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| CN107266363A true CN107266363A (en) | 2017-10-20 |
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| CN201610210759.1A Pending CN107266363A (en) | 2016-04-06 | 2016-04-06 | Methanesulfonic acid pleasure is cut down for the preparation method of Buddhist nun's impurity of the drug |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107305202A (en) * | 2016-04-22 | 2017-10-31 | 北京睿创康泰医药研究院有限公司 | The HPLC methods and impurity that analysis methanesulfonic acid pleasure is cut down for Buddhist nun and its preparation impurity make the purposes of reference standard |
| CN107739335A (en) * | 2017-12-01 | 2018-02-27 | 南京奇可药业有限公司 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
| CN108299294A (en) * | 2017-01-11 | 2018-07-20 | 江苏恒瑞医药股份有限公司 | A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity |
| CN109824590A (en) * | 2019-02-21 | 2019-05-31 | 扬子江药业集团有限公司 | Logical sequence cuts down the preparation method for Buddhist nun and its salt |
| CN110117255A (en) * | 2019-06-10 | 2019-08-13 | 湖北扬信医药科技有限公司 | A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof |
| WO2019228485A1 (en) * | 2018-06-01 | 2019-12-05 | 成都苑东生物制药股份有限公司 | New crystal form of lenvatinib mesylate and preparation method therefor |
| EP3620452A1 (en) | 2018-09-07 | 2020-03-11 | Indena S.p.A. | Process for the preparation of lenvatinib |
| CN111377864A (en) * | 2018-12-27 | 2020-07-07 | 江苏先声药业有限公司 | Lovatinib impurity and preparation method and application thereof |
| CN114634446A (en) * | 2020-12-15 | 2022-06-17 | 南京方生和医药科技有限公司 | Levatinib impurity and preparation method thereof |
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| CN107305202A (en) * | 2016-04-22 | 2017-10-31 | 北京睿创康泰医药研究院有限公司 | The HPLC methods and impurity that analysis methanesulfonic acid pleasure is cut down for Buddhist nun and its preparation impurity make the purposes of reference standard |
| CN107305202B (en) * | 2016-04-22 | 2020-04-17 | 北京睿创康泰医药研究院有限公司 | HPLC method for analyzing impurities of levovatinib mesylate and preparation thereof and application of impurities as reference standard |
| CN108299294A (en) * | 2017-01-11 | 2018-07-20 | 江苏恒瑞医药股份有限公司 | A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity |
| CN107739335A (en) * | 2017-12-01 | 2018-02-27 | 南京奇可药业有限公司 | A kind of pleasure cuts down the synthetic method for Buddhist nun |
| US11634388B2 (en) | 2018-06-01 | 2023-04-25 | Chengdu Easton Biopharmaceuticals Co., Ltd. | Crystal form of lenvatinib mesylate and preparation method therefor |
| CN112204011A (en) * | 2018-06-01 | 2021-01-08 | 成都苑东生物制药股份有限公司 | New crystal form of levofloxacin mesylate and preparation method thereof |
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| EP3620452A1 (en) | 2018-09-07 | 2020-03-11 | Indena S.p.A. | Process for the preparation of lenvatinib |
| WO2020048963A1 (en) | 2018-09-07 | 2020-03-12 | Indena S.P.A. | Process for the preparation of lenvatinib |
| CN111377864A (en) * | 2018-12-27 | 2020-07-07 | 江苏先声药业有限公司 | Lovatinib impurity and preparation method and application thereof |
| CN111377864B (en) * | 2018-12-27 | 2022-03-18 | 江苏先声药业有限公司 | Lovatinib impurity and preparation method and application thereof |
| CN109824590B (en) * | 2019-02-21 | 2022-03-22 | 扬子江药业集团有限公司 | Preparation method of Lovatinib and salt thereof |
| CN109824590A (en) * | 2019-02-21 | 2019-05-31 | 扬子江药业集团有限公司 | Logical sequence cuts down the preparation method for Buddhist nun and its salt |
| CN110117255A (en) * | 2019-06-10 | 2019-08-13 | 湖北扬信医药科技有限公司 | A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof |
| CN114634446A (en) * | 2020-12-15 | 2022-06-17 | 南京方生和医药科技有限公司 | Levatinib impurity and preparation method thereof |
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