CN108299294A - A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity - Google Patents
A kind of pleasure is cut down for the preparation method of Buddhist nun's impurity Download PDFInfo
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- CN108299294A CN108299294A CN201810021418.9A CN201810021418A CN108299294A CN 108299294 A CN108299294 A CN 108299294A CN 201810021418 A CN201810021418 A CN 201810021418A CN 108299294 A CN108299294 A CN 108299294A
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- 0 COC(CC(C1=C2)N=CC=C1Oc(cc1Cl)ccc1NC(NC1CC1)=O)=C2C(C*)=O Chemical compound COC(CC(C1=C2)N=CC=C1Oc(cc1Cl)ccc1NC(NC1CC1)=O)=C2C(C*)=O 0.000 description 1
- ZBTVNIDMGKZSGC-UHFFFAOYSA-N COc1cc2nccc(Cl)c2cc1C(N)=O Chemical compound COc1cc2nccc(Cl)c2cc1C(N)=O ZBTVNIDMGKZSGC-UHFFFAOYSA-N 0.000 description 1
- OFQLBCBNNWFEPV-UHFFFAOYSA-N COc1cc2nccc(Oc(cc3Cl)ccc3N)c2cc1C(N)=O Chemical compound COc1cc2nccc(Oc(cc3Cl)ccc3N)c2cc1C(N)=O OFQLBCBNNWFEPV-UHFFFAOYSA-N 0.000 description 1
- PNLPXABQLXSICH-UHFFFAOYSA-N Nc(c(Cl)c1)ccc1O Chemical compound Nc(c(Cl)c1)ccc1O PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 description 1
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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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
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- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of pleasures to cut down for the preparation method of Buddhist nun's impurity.Specifically, the present invention provides pleasures to cut down for Buddhist nun's impurity 4,4'[4,4' carbonyls bis- (urea diyls) are bis- (3 chlorine, 4,1 phenylene)] preparation method of bis- (oxygen) bis- (7 methoxy quinoline, 6 carboxylic acid amides).
Description
Technical field
The invention belongs to medicinal chemistry art, it is related to a kind of pleasure and cuts down for the preparation method of Buddhist nun's impurity.
Background technology
Happy cut down for Buddhist nun is that a kind of small molecule takes orally multiple target point inhibitor, act on VEGFR2 (vascular endothelial cell growth because
Sub- receptor 2) (KDR)/VEGFR3 (Flt-4) is most effective, and IC50 4nM/5.2 are slightly weak to VEGFR1/Flt-1 function and effect, make
It is compared to 10 times or so of the PDGFR α/βs high selectivity for FGFR1 (fibroblast growth factor acceptor 1) for VEGFR2/3.
It is defended treatment of material (Eisai) company exploitation for kinds cancer, such as a kind of more tyrosine kinase inhibitors (TKI)
Filter blocking and papillary thyroid carcinoma, hepatocellular carcinoma (HCC), carcinoma of endometrium, melanoma, oophoroma, clear-cell carcinoma
(RCC), non-small cell lung cancer (NSCLC) and glioma.
Happy to cut down for Buddhist nun, chemical name is 4- [3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen] -7- methoxyl groups -6-
Quinoline formyl amine, concrete structure such as Formulas I -2,
US7253286 discloses the method for producing quinoline, in embodiment, by 4- amino -3- chlorophenates
Hydrochlorate and the chloro- 7- methoxy-auinolins -6- formamides of 4-, then by the 4- (4- amino -3- chlorobenzenes of phenyl chloroformate and gained
Oxygroup) after -7- methoxy-auinolin -6- formamides, separation obtains N- [4- (agent of 6- formamide -7- methoxyl group -4- quinoline)
Amidocarbonic acid phenyl ester], it is then reacted with cyclopropylamine, to obtain compound 4- [3- chloro- 4- (Cyclopropylaminocarbonyl) amido benzene oxygen
Base] -7- methoxyl group -6- quinoline-carboxamides, as follows：
It is described in US2007004773, US2007004849, US2007078159 and US20070117842 with 4- ammonia
Base -3- chlorophenols or N- [4- (agent of 6- formamide -7- methoxyl group -4- quinoline) amidocarbonic acid phenyl ester] are starting material one-step synthesis
The method for obtaining target product 4- [3- chloro- 4- (Cyclopropylaminocarbonyl) amidos phenoxy group] -7- methoxyl group -6- quinoline-carboxamides.
In US2007004773 and US20070117842, reaction equation is as follows：
In US2007004849 and US2007078159, reaction equation is as follows：
WO2016031841 then discloses a kind of new pleasure and cuts down for Buddhist nun's synthesis technology, which can preferably avoid aforementioned
The impurity generated in the technique of the descriptions such as US2007004773, US2007004849 and US2007078159 is obtained with high-purity
The pleasure of degree is cut down for Buddhist nun, and reaction is as follows：
Research staff invents the generation impurity compound of formula I that above-mentioned preparation process will necessarily be more or less, if produced miscellaneous
When the super certain limit of quality, such as chromatographed based on conventional purification method, crystallization is to be difficult to remove.Researcher has had been surprisingly found that one
The new production technology of kind can reduce impurity I and generate, and provide impurity I contents and be less than -2 compound of 350ppm or lower Formulas I；Together
When develop preparation of compounds of formula I or the synthetic route of its salt, a large amount of impurity reference substances are obtained, for the happy quality research cut down for Buddhist nun
Work provides facility,
Invention content
The present invention provides preparation of compounds of formula I or the method for its salt, this method to include：- 2 compound or its salt of Formulas I with
The step of -3 compound or its salt of Formulas I progress aminolysis reaction, acquisition compound of formula I or its salt,
In embodiments, aminolysis reaction solvent for use of the present invention is selected from dimethyl sulfoxide, N, N'- dimethylformamides, N,
N '-dimethyl acetamide, N-Methyl pyrrolidone, dioxane, preferably N, N'- dimethylformamides.Further, one
In a little embodiments, aminolysis reaction can select alkali to accelerate reaction process as accelerating agent, and the accelerating agent is art technology
Personnel are known or confirmable, selected from but not limited to cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, the tert-butyl alcohol
At least one of lithium, sodium hydroxide, potassium hydroxide preferably are selected from cesium carbonate, potassium tert-butoxide.
Further, mole of aminolysis reaction Chinese style I-2 compound or its salts and I-3 compound or its salts of the present invention
Than being 1:1~1:2, preferably 1:1.2~1:1.5, can be 1:1.2、1:1.3、1:1.4、1:1.5.
In order to ensure that aminolysis reaction effectively carries out, the aminolysis reaction temperature be 50 DEG C~120 DEG C, preferably 70 DEG C~
110 DEG C, in embodiments, which can be 70,80,90,100,110 DEG C, more preferably 90~100 DEG C.
In embodiments, -2 compound or its salt of Formulas I of the present invention through decarboxylation obtain -3 compound of Formulas I or its
Salt,
In embodiments, the de-carbonyl reaction solvent for use is selected from dimethyl sulfoxide, N, N '-dimethyl formamide, N,
N '-dimethyl acetamide, N-Methyl pyrrolidone, dioxane, preferably N, N '-dimethyl formamide.In preferred implementation side
In case, be used as accelerating agent quickening reaction process by adding alkali, the accelerating agent is well known to those skilled in the art or can be with
Confirm, selected from but not limited to cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, sodium hydroxide,
At least one of potassium hydroxide, preferably cesium carbonate.
Further, de-carbonyl reaction temperature of the present invention be 90~140 DEG C, preferably 100~120 DEG C, embodiment party
Can be 100,105,110,115,120 DEG C in case.
The method of above-mentioned preparation of compounds of formula I or its salt, including：- 2 compound or its salt of Formulas I is obtained into formula through decarbonylation base
I-3 compounds, -3 compound of subsequent Formulas I carry out aminolysis reaction with -2 compound or its salt of Formulas I again.In embodiments, this hair
The bright method using separate operations detaches after obtaining -3 compound of Formulas I, then reacted with -2 compound or its salt of Formulas I.Preferred
In embodiment, the present invention may be used " one pot of two-step method " and be cut down for Buddhist nun's Formulas I impurity to prepare pleasure, specifically, being changed with Formulas I -2
It is starting material to close object or its salt, promotes decarboxylation reaction to obtain -3 compound of Formulas I by alkali, purifies, be further continued for without isolation
With -2 compound of unreacted Formulas I or add -2 compound or its salt of suitable Formulas I carry out aminolysis reaction, to obtain Formulas I chemical combination
Object.
The present invention also provides compound of formula I or its salt,
Compound of formula I of the present invention or its salt can be used as standard items or reference substance.
The present invention also provides the bulk pharmaceutical chemicals of Formulas I -2, wherein containing compound of formula I or its salt, compound of formula I or its salt phase
350ppm, preferably shorter than 250ppm or less are less than for the content of -2 compound or its salt of Formulas I.In embodiments, Formulas I
Content can be 350ppm, 330ppm, 300ppm, 280ppm, 250ppm, 220ppm, 200ppm, 180ppm, 150ppm,
120ppm, 100ppm, 80ppm, 50ppm or lower, to reduce side effect when -2 compound or its salt of Formulas I treats disease, especially
It is genotoxicity.
The method for preparing -2 bulk pharmaceutical chemicals of above-mentioned Formulas I can refer to embodiment 3 or its full text in US2007004773 and introduce this hair
In bright specification, in embodiments, this method is included in 60 ± 2 DEG C, compound A and the step of compound B addition reactions,
The reaction condition can guarantee that the content of impurity compound of formula I or its salt is less than 350ppm or less, obtain high quality
- 2 bulk pharmaceutical chemicals of Formulas I.
Wherein, the molar ratio of compound A and compound B is 1 in the reaction:1~1:2, reaction dissolvent is selected from N, N '-two
Methylformamide, N, N '-dimethyl acetamide, N-Methyl pyrrolidone, dioxane, preferably N, N '-dimethyl formamide.
Further, in the reaction compound A a concentration of 0.3~0.6M (mol/L), preferably 0.35M~0.4M, in favor of anti-
The intermolecular substitution reaction of compound A and B in system is answered to carry out.
- 2 compound of Formulas I of the present invention can be described as pleasure and cut down for Buddhist nun.
Compound (such as compound of formula I, -2 compound of Formulas I, -3 compound of Formulas I) of the present invention is alkali compounds, can
With corresponding acid at salt, the acid it is known to those skilled in the art or it is believed that be selected from but not limited to hydrochloric acid, sulfuric acid,
Methanesulfonic acid, benzene sulfonic acid, toluenesulfonic acid, maleic acid, acetic acid, trifluoroacetic acid.
Detailed description of the invention
The measurement of MS uses FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model：Finnigan LCQ
advantage MAX)；The measurement of HPLC uses 1200 liquid phase of Waters 2695Alliance liquid chromatographs or Agilent
Chromatograph.Testing conditions：Octadecylsilane chemically bonded silica is filler (Waters XTerra MS C18), with triethylamine and
Acetonitrile solution is that mobile phase is eluted, and compounds of formula I relative retention time is about 1.24.
Related substance or content of material of the present invention can be detected by HPLC and be obtained.
Of the present invention to be obtained by commercial sources with reagent, compound 4- amino -3- chlorophenate hydrochlorates pass through
Commercial sources obtain, and compound 4- (4- amino -3- chlorophenoxies) -7- methoxy-auinolin -6- formamides can be according to
US7253286 the methods are obtained or are bought by commercial sources.
Specific implementation mode
The present invention is explained in detail below with reference to specific embodiment so that this is more fully understood in those skilled in the art
Invention, specific embodiment or experimental example are only used to illustrate the technical scheme of the present invention, and do not limit the present invention in any way.
Embodiment 1
In reaction bulb, pleasure is added and cuts down for Buddhist nun (20mmol, 8.54g), 19.55g cesium carbonates and 100ml dimethyl sulfoxides, magnetic
Power stirs, and is warming up to 100 DEG C and reacts 12 hours.After reaction, it is cooled to room temperature, 200mL pure water is added into reaction solution and stirs
It mixes, filters, obtain 4- (4- amino -3- chlorophenoxies) -7- methoxy-auinolin -6- crude formamides.It (is washed through column chromatography purifying
De- agent：Methylene chloride/methanol=80:1~40:1) 5.82g, yield 84.6%, purity 99.2% are obtained.
Embodiment 2
In reaction bulb, it is added by implementing 1 4- (4- amino -3- chlorophenoxies) -7- methoxy-auinolins -6- obtained
Formamide (3.44g, 10mmol), pleasure are cut down for Buddhist nun (4.27g, 10mmol), 9.78g cesium carbonates and 30mL dimethyl sulfoxides, magnetic force
It is stirred to react, is warming up to 100 DEG C and reacts 6 hours.After reaction, it is cooled to room temperature, 100mL purifying is added into reaction solution
Water, stirring filter, and obtain compound of formula I crude product.Through silica gel column separating purification (eluant, eluent：Methylene chloride/methanol=50:1~
30:1) 5.45g, yield 76.4%, purity 99.1% are obtained.
ESI-MS(m/z):C35H26Cl2N6O7,713.03[M+H]+。
1H-NMR(BRUKER-400M,DMSO-d6):δ 4.05 (s, 6H), 6.59 (d, J=4.2,2H), 7.33 (dd, J=
2.4, J=9.2,2H), 7.54 (s, 2H), 7.60 (d, J=2.4,2H), 7.80 (brs, 2H), 7.90 (brs, 2H), 8.24 (d,
), J=9.2,2H 8.69-8.71 (m, 4H), 9.20 (s, 2H).
13C-NMR(BRUKER-100M,DMSO-d6):δ56.67,103.72,108.41,114.94,120.85,
122.55,124.16,124.23,125.21,125.57,134.16,149.16,152.14,152.81,153.84,158.54,
161.86,166.24。
Embodiment 3
In reaction bulb, addition 4- (4- amino -3- chlorophenoxies) -7- methoxy-auinolin -6- formamides (6.88g,
20mmol), happy to cut down for Buddhist nun (10.25g, 24mmol), 19.6g cesium carbonates and 60mL dimethyl sulfoxides, magnetic agitation reaction, heating
It is reacted 8 hours to 90 DEG C.After reaction, it is cooled to room temperature, 200mL water is added to reaction solution, it is thick that suction filtration obtains compound of formula I
Product.Through silica gel column separating purification (eluant, eluent：Methylene chloride/methanol=50:1~30:1) 9.98g is obtained, yield 70.0% is pure
Degree 98.6%.
Embodiment 4
In reaction bulb, -3 compound of Formulas I (3.44g, 10mmol) is added, pleasure is cut down for Buddhist nun (4.27g, 10mmol), 9.78g
Cesium carbonate and 30ml N, N '-dimethyl formamide, magnetic agitation reaction are warming up to 100 DEG C and react 6 hours.After reaction,
It is cooled to room temperature, filters, filtrate removes N by reduced pressure, and N '-dimethyl formamide obtains compound of formula I crude product.Through silicon
Rubber column gel column isolates and purifies (eluant, eluent：Methylene chloride/methanol=50:1~30:1) 4.68g target products are obtained, yield 65.6% is pure
Degree 98.5%.
Embodiment 5
In reaction bulb, -3 compound of Formulas I (3.44g, 10mmol) is added, pleasure is cut down for Buddhist nun (4.27g, 10mmol), 3.37g
Potassium tert-butoxide and 30ml dimethyl sulfoxides, magnetic agitation reaction are warming up to 100 DEG C and react 6 hours.After reaction, it is cooled to room
100mL purified waters are added into reaction solution, filter to obtain compound of formula I crude product for temperature.Through silica gel column separating purification (eluant, eluent：Dichloro
Methane/methanol=50:1~30:1) purifying obtains 5.62g target products, yield 78.8%, purity 99.3%.
Embodiment 6
In reaction bulb, pleasure is added and cuts down for Buddhist nun (4.27g, 10mmol), 9.78g cesium carbonates and 30ml dimethyl sulfoxides, magnetic force
It is stirred to react, is warming up to 100 DEG C and reacts 18 hours.After reaction, it is cooled to room temperature, filters, 100mL purified waters are added, use
Ethyl acetate extracts, saturated brine washing, then concentrated obtains compound of formula I crude product.Through silica gel column separating purification (eluant, eluent：
Methylene chloride/methanol=50:1~30:1) purifying obtains 1.85g, yield 51.9%, purity 98.3%.
Embodiment 7
15.0L n,N-Dimethylformamide is added into reaction kettle, 730.0g is sequentially added under stirring condition
The chloro- 7- methoxy quinolines -6- formamides of (3.08mol) 4-, 837.0g (3.7mol) 1- (2- chloro-4-hydroxyls phenyl) -3- rings third
Base urea and 2.0kg (6.16mol) cesium carbonate are stirred to react 26h at 60 DEG C, and the reaction was complete for TLC detections.Stirring cooling, will react
Liquid is rushed into suitable quantity of water, is filtered to find pleasure in and be cut down for Buddhist nun's crude product, is 0.32% through HPLC checked for impurities compound of formula I contents.
27.0L methanol is added into reaction kettle, is heated to reflux, then under agitation, is added into kettle and walks wet product,
Reflux dissolving, stirring and crystallizing.Filtering, obtained solid 1.85g, yield 51.9%, the wherein impurity compound of formula I of purity 98.3% contain
Amount is 0.04%.
Embodiment 8
With reference to the method in example 7 prepare it is happy cut down different reaction conditions is screened for Buddhist nun so as to obtain prepare it is miscellaneous containing Formulas I
Quality cuts down the method for Buddhist nun less than 350ppm or lower pleasures, and researcher has found that temperature of reaction system is to influence pleasure to cut down for Buddhist nun's matter
The key of amount, and consersion unit volume is big in big production, mode of heating is steam heating, is easy to local heating occur excessively high
Situation, the present invention select slightly lower temperature to carry out synthesis pleasure and cut down for Buddhist nun, and the content to ensure Formulas I impurity in finished product is substantially zeroed；
It is happy to cut down when being more than 0.35% for the content of Buddhist nun's crude product compounds of formula I simultaneously through test of many times data verification, through regular refiner side
Method (such as utilizing methanol, ethyl alcohol, ethyl acetate, acetone/water single solvent or mixed solvent) can not be by Formulas I chemical combination in finished product
The content of object is down to 0.1% hereinafter, to meet the quality requirement in relation to raw material in Chinese Pharmacopoeia or United States Pharmacopeia, and specific data are such as
Under：
Table 1
| Experimental example | A and B molar ratios | Temperature | Reaction time | Formulas I contenta |
| 1 | 1:1 | 90±2℃ | 10~12h | 30% |
| 2 | 1:1.1 | 70±2℃ | 16~17h | 0.45% |
| 3 | 1:1.2 | 60±2℃ | 20~22h | 0.34% |
| 4b | 1:1 | 50±2℃ | More than 35h | 0.10% |
Note：A pleasures are cut down for the content of Buddhist nun (- 2 compound of Formulas I) crude product compounds of formula I；
The reaction time of b experimental examples 4 is more than 35h, still has 20% raw material compound A to fail to participate in reaction through HPLC monitoring,
Generate a large amount of by-products, such as the oxide of compound B simultaneously.
Happy cut down of 1~4 gained of above-mentioned experimental example is refining to obtain finished product through methanol or acetone/water for Buddhist nun's crude product, and detects finished product
The content of middle Formulas I, specific data are as follows：
Table 2
| Experimental examplea | Formulas I content in crude product | Process for purification/condition | Formulas I content in finished product |
| 5 | 30% | Methanol | 10% |
| 6 | 0.45% | Acetone/water | 0.21% |
| 7 | 0.34% | Methanol | 0.04% |
| 8 | 0.10% | Methanol | 0.02% |
Note：Crude product used comes from above-mentioned experimental example 1~4 in a experimental examples 5~8.
Claims (13)
1. the method for preparation of compounds of formula I or its salt, including：- 2 compound or its salt of Formulas I is carried out with -3 compound or its salt of Formulas I
The step of aminolysis reaction, acquisition compound of formula I or its salt,
2. the method for preparation of compounds of formula I according to claim 1 or its salt, it is characterised in that the aminolysis reaction also makes
Use alkali as accelerating agent, the accelerating agent be selected from cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium,
At least one of sodium hydroxide, potassium hydroxide preferably are selected from cesium carbonate, potassium tert-butoxide.
3. the method for preparation of compounds of formula I according to claim 1 or 2 or its salt, it is characterised in that the aminolysis reaction
Solvent for use is selected from dimethyl sulfoxide, N, N'- dimethylformamides, N, N'- dimethylacetylamides, N-Methyl pyrrolidone, dioxy
Six rings, preferably N, N'- dimethylformamides.
4. the method for preparation of compounds of formula I according to claim 1 or 2 or its salt, it is characterised in that the aminolysis reaction
The molar ratio of Chinese style I-2 compound or its salts and I-3 compound or its salts is 1:1~1:2, preferably 1:1.2~1:1.5.
5. the method for preparation of compounds of formula I according to claim 1 or 2 or its salt, it is characterised in that -2 compound of Formulas I or
Its salt obtains -3 compound or its salt of Formulas I through decarboxylation,
6. described according to the method described in claim 5, it is characterized in that the de-carbonyl reaction also uses alkali as accelerating agent
Accelerating agent is in cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, tert-butyl alcohol lithium, sodium hydroxide, potassium hydroxide
At least one, preferably cesium carbonate.
7. method according to claim 5 or 6, it is characterised in that it is sub- that the de-carbonyl reaction solvent for use is selected from diformazan
Sulfone, N, N'- dimethylformamides, N, N'- dimethylacetylamides, N-Methyl pyrrolidone, dioxane, preferably N, N'- bis-
Methylformamide；It is preferred that the de-carbonyl reaction temperature is 90~140 DEG C, more preferably 100~120 DEG C.
8. the method for preparation of compounds of formula I according to claim 1 or 2 or its salt, it is characterised in that the aminolysis reaction
Temperature is 50~120 DEG C, preferably 70~110 DEG C.
9. according to claim 1-8 any one of them methods, it is characterised in that the method includes：By -2 compound of Formulas I or
Its salt obtains -3 compound of Formulas I through decarbonylation base, and -3 compound of subsequent Formulas I carries out aminolysis with compound or its salt shown in Formulas I -2 again
The step of reaction；It is preferred that the method is realized by " one pot of two-step method ".
10. a kind of compound of formula I or its salt,
11. a kind of bulk pharmaceutical chemicals of Formulas I -2,
It is characterized in that containing compound of formula I or its salt in the bulk pharmaceutical chemicals of Formulas I -2, the compound of formula I or its salt are relative to formula
The content of I-2 compound or its salts is less than 350ppm, preferably shorter than 250ppm or lower,
12. compound of formula I or its salt are used as the application of standard items or reference substance according to claim 10.
13. a kind of method of -2 bulk pharmaceutical chemicals of Formulas I prepared described in claim 11, including：Under the conditions of 60 ± 2 DEG C, compound A
The step of with compound B addition reactions,
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111320580A (en) * | 2018-12-14 | 2020-06-23 | 江苏先声药业有限公司 | Preparation method of Lunvatinib intermediate |
| CN112654603A (en) * | 2018-09-07 | 2021-04-13 | 因德纳有限公司 | Preparation method of lenvatinib |
| CN113226316A (en) * | 2018-10-04 | 2021-08-06 | 斯索恩有限公司 | Crystalline forms and processes of lenvatinib besylate |
| 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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| WO2016031841A1 (en) * | 2014-08-28 | 2016-03-03 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | High-purity quinoline derivative and method for manufacturing same |
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| 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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