CN106916147A - Compound and its production and use - Google Patents
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- CN106916147A CN106916147A CN201510999659.7A CN201510999659A CN106916147A CN 106916147 A CN106916147 A CN 106916147A CN 201510999659 A CN201510999659 A CN 201510999659A CN 106916147 A CN106916147 A CN 106916147A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention relates to compound and its production and use, specifically, the compound is compound described in formula 1, and there is provided the method for compound shown in a kind of formula 1, the method is included, in organic solvent, N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [[(3S)-tetrahydrochysene -3- furyls] epoxide] -6- quinazolyls] -4- (dimethylamino) -2- crotonamides are contacted with alkaline aqueous solution, to obtain compound shown in formula 1.Present invention process is easy to operate, and post-treated rear directly filtering just obtains white powder product, and product purity is high, reaches more than 99%, can directly be used as impurity reference substance during Afatinib bulk drug quality research.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, specifically, the present invention relates to a kind of Afatinib degradation impurity and
Preparation Method And The Use.
Background technology
Afatinib (Afatinib) is by a kind of the oral of Mutiple Targets of German Boehringer Ingelheim company research and development
Small-molecule drug, is EGF-R ELISA (EGFR) and human epidermal growth factor receptor 2 (HER2)
The irreversible inhibitor of EGFR-TK, is also the tyrosine-kinase enzyme level of second generation efficient double non reversibility
Agent.The medicine is in the examination ＆ approval by U.S. FDA on the 12nd of July in 2013, trade name Gilotrif.Ah method replaces
The Major Basic degradation impurity of Buddhist nun is compound shown in formula 1, frequently as the quality research of Afatinib drug products
And impurity quantitatively control in reference substance.
At present, the method for Afatinib degradation impurity shown in the compound of formula 1, still has much room for improvement.
The content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent or providing a kind of
Useful business selection.Therefore, the method it is an object of the present invention to propose compound shown in formula 1,
Using the method, compound shown in high-purity formula 1 can be efficiently prepared, the compound is Afatinib alkalescence drop
Solution impurity.
According to an aspect of the present invention, the invention provides compound shown in a kind of formula 1.It is of the invention
Some embodiments, compound shown in the formula 1 is Afatinib degradation impurity.
According to another aspect of the present invention, the invention provides the method for compound shown in a kind of formula 1.
According to some embodiments of the invention, the method includes：
In organic solvent, compound shown in formula 2 is contacted with alkaline aqueous solution, to obtain shownization of formula 1
Compound.
Afatinib is conventionally synthesized technique i.e. by { [4- (the chloro- 4- Fluorophenylaminos of 3-) -7- (s)-tetrahydrofuran -3-
Base oxygen)-quinazoline -6- bases carbamyl]-methyl-phosphonate diethyl ester and (dimethylamino)-acetaldehyde-diethyl contracting
Aldehyde or its sodium bisulfite adduct are coupled obtain compound 2 in the basic conditions：(4- [(the chloro- 4- fluorophenyls of 3-)
Amino] -6- { [4- (N, N- dimethylamino) -1- oxos -2- butene-1s-yl] amino -7- ((s)-tetrahydrofuran -3- base oxygen
Base) }.However, inventor is when Afatinib is researched and developed, through many experiments find synthesis technique this is important
In step, alkaline bleach liquor degradation impurity (compound shown in formula 1) is easily created, the Afatinib of step synthesis herein
In the case that the quality of free state is not well controlled, the alkaline bleach liquor degradation impurity easily takes next step reaction to
In.Similar reactive functionality and reactivity is had based on itself and Afatinib, compound shown in formula 1 is likely to
Participate in further salt-forming reaction, and be changed into the alkaline bleach liquor degradation impurity of the maleate form in finished product, therefore
The content to compound 1 in finished product is needed to be controlled.
Afatinib alkaline bleach liquor degradation impurity, i.e., compound shown in formula 1,4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- { [4-
Hydroxyl -1- oxos -2- butene-1s-yl] amino -7- ((s)-tetrahydrofuran -3- bases epoxide)-quinazoline, in technique productions mistake
It is easily formed in journey and is increased, be very important technique alkaline bleach liquor degradation impurity, is easy to be further carried to finished product
In.When quality research is carried out to Afatinib bulk drug, it has been found that this alkaline bleach liquor degradation impurity.Therefore
We need to obtain the reference substance of this alkaline bleach liquor degradation impurity, preferably to study and to control Afatinib raw material
The quality of medicine, medicinal requirements are met to ensure to prepare, and can be used in preparing safely and effectively pharmaceutical preparation
Bulk drug.The invention provides a kind of method that can prepare compound shown in purity formula 1 higher.
The term " contact " for being used herein should be interpreted broadly, and it can be any energy so that at least two
The mode that reactant chemically reacts, for example, can be to be mixed two kinds of reactants under suitable condition
Close.Herein, " compound N " is otherwise referred to as " compound shown in formula N " herein, N herein
It is the arbitrary integer of 1-9, such as " compound 2 " is referred to as " compound shown in formula 2 " herein.
In the description of the invention, it is to be understood that term " first ", " second " are only used for describing purpose,
And it is not intended that indicating or implying relative importance or the implicit quantity for indicating indicated technical characteristic.By
This, defines " first ", one or more spy can be expressed or be implicitly included to the feature of " second "
Levy.In the description of the invention, " multiple " is meant that two or more, unless otherwise clearly specific
Limit.
The method of preparation compound as shown in the compound of formula 1 of the specific embodiment of the invention is described below in detail.
Some embodiments of the invention, the alkali in the alkaline aqueous solution is potassium hydroxide or NaOH.
Thus, it is possible to ensure that the intensity of reaction system alkali is suitable, beneficial to the carrying out of reaction.If using weaker alkali,
Reaction carries out slow；If using stronger alkali, being easily caused reaction system and becoming miscellaneous.
Some embodiments of the invention, the organic solvent is methyl alcohol or ethanol.Thus, it is possible to ensure anti-
Substrate good dissolubility is answered, reaction speed is faster.
Some embodiments of the invention, the volume mass of the organic solvent and compound shown in the formula 2
Than being 20ml/g~30ml/g, preferably 25ml/g.Thus the content for obtaining target compound is higher, it is easy to point
From purifying.
Some embodiments of the invention, the mass fraction of the alkaline aqueous solution is 10%~30%, preferably
It is 20%.Thus reaction system is obtained simple, beneficial to isolating and purifying.
Some embodiments of the invention, the volume matter of the alkaline aqueous solution and compound shown in the formula 2
Amount is than being 5ml/g~15ml/g, preferably 10ml/g.Product assay is high in thus obtained reaction, high income.
Some embodiments of the invention, under 40~60 degrees celsius, in organic solvent, by formula 2
Shown compound is contacted with alkaline aqueous solution.Thus, the product content for obtaining is higher.If reaction temperature
Too high, product assay is relatively low, and accessory substance becomes many, and reaction temperature is too low, then react slack-off, starting material left mistake
It is many.
Some embodiments of the invention, in organic solvent, compound connects with alkaline aqueous solution shown in formula 2
Touch, and after reacting certain hour, room temperature is down to, to obtain compound shown in formula 1, by shown in the formula 1
Compound carries out column chromatography purifying, to obtain compound shown in formula 1 after purification.Thus, by column chromatography
Purifying further improves the purity of target impurity.
In the third aspect of the present invention, the present invention proposes compound shown in above-mentioned formula 1 or prepared by the above method
Purposes of the compound shown in the formula 1 of acquisition in the control of Afatinib drug product quality, wherein the institute of the formula 1
Show compound Afatinib drug product quality control in as Afatinib medicine degradation impurity standard
Product or reference substance.
Some embodiments of the invention, the method for compound shown in the formula 1, it is possible to achieve following
At least one advantage：
1st, the method for compound can be prepared efficiently such as the institute of formula 1 shown in formula 1 according to embodiments of the present invention
Show compound, the compound can be used as the alkaline bleach liquor degradation impurity of Afatinib；
2nd, the method for compound as shown in Equation 1 according to embodiments of the present invention, initiation material is cheap and easy to get, work
Skill easily-controlled operation, production efficiency is high, can amplify and meet quality research.
3rd, the method for compound as shown in Equation 1 according to embodiments of the present invention, operation process is simple, not
It is related to special consersion unit.
4th, the method for compound as shown in Equation 1 according to embodiments of the present invention, post-reaction treatment is simple, it is only necessary to
Other impurity in compound 1 are removed by silica gel column chromatography, is not required to by preparative liquid chromatograph and costliness
Prepare post separation.
5th, the method provided using the present invention makes the synthesis of the alkaline bleach liquor degradation impurity realize that beam system is standby, is industry
The quality research of metaplasia product Afatinib product and alkaline bleach liquor degradation impurity quantitatively control miscellaneous there is provided reliably degrading
Matter reference substance.
6th, the compound of formula 1 that products therefrom liquid phase purity more than 99% of the present invention, therefore the present invention is prepared
Shown alkaline bleach liquor degradation impurity can make as reference substance for relevant material research during Afatinib quality research
With.
Brief description of the drawings
Fig. 1 shows embodiments in accordance with the present invention 5, the high-efficient liquid phase chromatogram of gained compound 1；
Fig. 2 shows embodiments in accordance with the present invention 5, the mass spectrogram of gained compound 1；
Fig. 3 shows embodiments in accordance with the present invention 5, the hydrogen nuclear magnetic resonance spectrogram of gained compound 1；
Fig. 4 shows embodiments in accordance with the present invention 5, the carbon-13 nmr spectra figure of gained compound 1.
Specific embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining
The present invention, and be not considered as limiting the invention.Unreceipted particular technique or condition, press in embodiment
Carried out according to the technology or condition described by document in the art or according to product description.Agents useful for same or instrument
The unreceipted production firm person of device, be can by city available from conventional products.
The conventional method of compound shown in synthesis type 2
Compound 1 is as follows：
Embodiment 1
The step of synthesis compound 5, is as follows：
(1) to (S) -3- hydroxyl tetrahydrofurans of addition 125.1g compounds 4 in there-necked flask, 1200ml DMF,
Start stirring, ice-water bath cools to 0 DEG C, adds 160g potassium tert-butoxides, stirs 1h；
(2) 120g compounds 3 (N- (the chloro- 4- fluorophenyls of 3-) the fluoro- 6- nitros -4- quinazolines amine of -7-) is added, in room
2~6h of the lower reaction of temperature.
(3) sample, add water and middle control is quenched, reaction solution is poured into water, with salt acid for adjusting pH to 7, filter,
Wash with water, dry, obtain the yield 95% of 137g compounds 5.
The hydrogen nuclear magnetic resonance modal data of compound 5：1H-NMR(DMSO-d6):δ 2.04-2.07 (t, J=6.8Hz
1H), 2.31-2.36 (d, J=6.0,13.6Hz, 1H), 3.78-3.90 (m, 3H), 3.95-3.98 (m, 1H), 5.42 (s,
1H), 7.42-7.46 (t, J=10.8Hz, 2H), 7.77-7.79 (t, J=2.8Hz, 1H), 8.13-8.14 (d, J=4.8Hz,
1H),8.65(s,1H),9.20(s,1H),10.14(s,1H)。
Embodiment 2
The step of synthesis compound 6, is as follows：
(1) to addition 100g compounds 5 in there-necked flask：(4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitros -7- ((S) -
Tetrahydrofuran -3- bases epoxide)-quinazoline), 2500mL ethyl acetate, stirring is lower to add 500ml glacial acetic acid, 500ml
Water, 56g iron powders are warmed up to 70 DEG C of reaction 1h；
(2) react complete, cold filtration, filter cake is washed with ethyl acetate, and filtrate stratification, water is mutually retained,
Organic phase is placed；
(3) water is added to ethyl acetate, and extraction point liquid, organic phase merges；
(4) it is organic to be added to 2L water, adjust pH=8, stratification, water with sodium hydroxide solution under cooling
Wash, brine It, stratification, anhydrous sodium sulfate drying filtering.Filtrate is concentrated to dryness and obtains 84gization
Compound 6：(4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- amino -7- ((S)-tetrahydrofuran -3- bases epoxide)-quinazoline), receives
Rate 90.7%.
Embodiment 3
The step of synthesis compound 8, is as follows：
(1) to 350mL tetrahydrofurans are added in three mouthfuls of reaction bulbs, stirring is opened, adds 54.3g 1,1-
Dicarbapentaborane imidazoles, is white suspension.40 DEG C are warming up to, 57.1g diethyl phosphorus acetic acid is dissolved in tetrahydrochysene
In furans, it is added dropwise in system, 40 DEG C of 30~45min of stirring.Above-mentioned reactant mixture is solution A；
(2) to 420mL tetrahydrofurans are added in three mouthfuls of reaction bulbs, stirring is opened, adds 84.0g chemical combination
Thing 6, is paleturquoise solution.40 DEG C of above-mentioned solution are warming up to for B, above-mentioned solution A is added drop-wise to solution
In B, interior temperature drop reacts to 30 degrees Celsius after adding；
(3) stir 2 hours, reaction is complete.Add methyl tertiary butyl ether(MTBE) 420mL and be cooled to room temperature,
After persistently stirring 30 minutes, by above-mentioned white suspension suction filtration.
(4) 420mL (tetrahydrofurans/methyl tertiary butyl ether(MTBE)=1 are used：1, volume ratio) washing suction filtration gained
Solid, then use 1.7L water washings.Suction filtration is to dry.Dry 82.0g compounds 8, yield 66.2%.
The hydrogen nuclear magnetic resonance modal data of compound 8：1H-NMR(CDCl3):δ1.37-1.40(m,6H),
2.33-2.44 (m, 2H), 3.10-3.15 (d, J=20.4Hz, 2H), 3.92-3.97 (m, 1H), 4.06-4.14 (m,
2H),4.18-4.27(m,5H),5.11(m,1H),7.16-7.20(m,2H),7.51-7.57(m,2H),
7.95-7.97(m,1H),8.67(s,1H),8.98(s,1H),9.57(s,1H)。
Embodiment 4
The step of synthesis compound 2, is as follows：
(1) in there-necked flask, concentrated hydrochloric acid (120g), water (50ml).Dimethylamino contracting two is added dropwise under low temperature
Ethanol (100g) is heated to 30-40 DEG C of reaction 3h, is down to room temperature, less than 20 DEG C dropwise addition 106g sulfurous acid
Hydrogen sodium water solution, stirs 1h at such a temperature, is subsequently adding 500ml ethanol, and stirring, filtering, filter cake is used
Ethanol rinse, dry compound 9.107g, yield 90%, sealing preserve after drying.
(2) solution that 48g compounds 9 are dissolved in 480ml water is solution C, and 80gization is added in there-necked flask
Compound 8,600ml ethanol adds 6.1g anhydrous Lithium chlorides, and stirring cools to less than -10 DEG C.
(3) solution D：The potassium hydroxide aqueous solutions of 80g 45%, solution D is added drop-wise in reactant mixture.Control
Nei Wen -10 DEG C, then solution C be slowly dropped in reaction solution, keep less than -10 DEG C react two hours, instead
Reactant mixture is added after answering completely in 2.0 liters of water of stirring, form white suspension.Suction filtration, washing,
Drain, dry.Yield about 95%, purity 96.5% is white solid.
(4) above-mentioned solid is dissolved in butyl acetate, is heated to 70 DEG C of interior temperature, hexamethylene is added dropwise, dripped
After cool down, suction filtration obtains faint yellow solid, is dried to obtain product.It is small that the said goods are beaten 8 in 5V ethanol
When, it is cooled to room temperature.Then suction filtration, ethanol washing, drain and obtain solid, are dried to obtain 40g chemical combination
Thing 2, yield 60%, purity 99.5%.
The hydrogen nuclear magnetic resonance modal data of compound 2：1H-NMR(CD3OD):δ2.27-2.43(m,2H),2.34
(s, 6H), 3.23 (d, J=6.0Hz, 2H), 3.90-3.96 (m, 2H), 4.03-4.11 (m, 2H), 4.17-4.19 (d,
J=10.0Hz, 1H), 5.27-5.28 (d, J=4.4Hz, 1H), 6.51-6.55 (d, J=15.6Hz, 1H), 6.99-7.06
(m, 1H), 7.16 (s, 1H), 7.23-7.28 (t, J=8.8Hz, 1H), 7.66-7.70 (m, 1H), 8.02-8.04 (m,
1H),8.48(s,1H),8.90(s,1H)。
Embodiment 5
The step of synthesis compound 1, is as follows：
(1) by 2g (4.1mmol) compound 2,2mol/L sodium hydrate aqueous solutions (10mL) and 20
ML methyl alcohol, is added in tri- mouthfuls of reaction bulbs of 100mL, is warming up to 50 degrees Celsius, reacts 24h；
(2) reaction solution is cooled to 25 DEG C, is diluted with water, pH value to 7 is adjusted with 10% hydrochloric acid, add 100mL
Ethyl acetate is extracted；
(3) with methyl alcohol and dichloromethane as eluent, silica gel column separating purification obtains compound after purification excessively
1, yield 43%, efficient liquid phase detects its purity 99.5%, and its collection of illustrative plates is as shown in Figure 1.
The mass spectrum of compound 1, proton nmr spectra and carbon spectrogram are as shown in Figure 2-4.
Embodiment 6
The method for synthesizing compound 1 is as follows：
(1) by 2g (4.1mmol) compound 2,2mol/L potassium hydroxide aqueous solutions (10mL) and 20
ML ethanol, is added in tri- mouthfuls of reaction bulbs of 100mL, is warming up to 50 degrees Celsius, reacts 24h；
(2) reaction solution is cooled to 25 degrees Celsius, adds water dilution, pH value is adjusted to 7 with 10% hydrochloric acid,
Add the extraction of 100ml ethyl acetate；
(3) with methyl alcohol and dichloromethane as eluent, silica gel column separating purification obtains compound after purification excessively
1, yield 37.6%, efficient liquid phase detects its purity 99.3%.
Embodiment 7
The method for synthesizing compound 1 is as follows：
(1) by 2g (4.1mmol) compound 2,2mol/L sodium hydrate aqueous solutions (5mL) and 20mL
Methyl alcohol, is added in tri- mouthfuls of reaction bulbs of 100mL, is warming up to 50 degrees Celsius, reacts 24h；
(2) reaction solution is cooled to 25 DEG C, is diluted with water, pH value to 7 is adjusted with 10% hydrochloric acid, add 100ml
Ethyl acetate is extracted；
(3) with methyl alcohol and dichloromethane as eluent, silica gel column separating purification obtains compound after purification excessively
1, yield 30.6%, efficient liquid phase detects its purity 99.1%.
Embodiment 8
The method for synthesizing compound 1 is as follows：
(1) by 2g (4.1mmol) compound 2,2mol/L sodium hydrate aqueous solutions (15mL) and 20
ML methyl alcohol, is added in tri- mouthfuls of reaction bulbs of 100mL, is warming up to 50 degrees Celsius, reacts 24h；
(2) reaction solution is cooled to 25 DEG C, is diluted with water, pH value to 7 is adjusted with 10% hydrochloric acid, add 100ml
Ethyl acetate is extracted；
(3) with methyl alcohol and dichloromethane as eluent, silica gel column separating purification obtains compound after purification excessively
1, yield 32.6%, efficient liquid phase detects its purity 99.0%.
Embodiment 9
The method for synthesizing compound 1 is as follows：
(1) by 2g (4.1mmol) compound 2,2mol/L sodium hydrate aqueous solutions (15mL) and 20
ML methyl alcohol, is added in tri- mouthfuls of reaction bulbs of 100mL, is warming up to 40 degrees Celsius, reacts 24h；
(2) reaction solution is cooled to 25 DEG C, is diluted with water, pH value to 7 is adjusted with 10% hydrochloric acid, add 100ml
Ethyl acetate is extracted；
(3) with methyl alcohol and dichloromethane as eluent, silica gel column separating purification obtains compound after purification excessively
1, yield 28.6%, efficient liquid phase detects its purity 99.2%.
Embodiment 10
The method for synthesizing compound 1 is as follows：
(1) by 2g (4.1mmol) compound 2,2mol/L sodium hydrate aqueous solutions (15mL) and 20
ML methyl alcohol, is added in tri- mouthfuls of reaction bulbs of 100mL, is warming up to 60 degrees Celsius, reacts 24h；
(2) reaction solution is cooled to 25 DEG C, is diluted with water, pH value to 7 is adjusted with 10% hydrochloric acid, add 100ml
Ethyl acetate is extracted；
(3) with methyl alcohol and dichloromethane as eluent, silica gel column separating purification obtains compound after purification excessively
1, yield 27.2%, efficient liquid phase detects its purity 99.4%.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " tool
The description of body example " or " some examples " etc. means to combine specific features, the knot that the embodiment or example are described
Structure, material or feature are contained at least one embodiment of the invention or example.In this manual, it is right
The schematic representation of above-mentioned term is necessarily directed to identical embodiment or example.And, description it is specific
Feature, structure, material or feature can in an appropriate manner be tied in any one or more embodiments or example
Close.Additionally, in the case of not conflicting, those skilled in the art can be by described in this specification
The feature of different embodiments or example and different embodiments or example is combined and combines.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is
Exemplary, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art is in the scope of the present invention
It is interior above-described embodiment to be changed, changed, replaced and modification.
Claims (10)
1. a kind of compound, it is compound shown in formula 1.
2. the method for compound shown in a kind of formula 1, it is characterised in that include：
In organic solvent, compound shown in formula 2 is contacted with alkaline aqueous solution, to obtain shownization of formula 1
Compound.
3. method according to claim 2, it is characterised in that the alkali in the alkaline aqueous solution is hydrogen
Potassium oxide or NaOH.
4. method according to claim 2, it is characterised in that the organic solvent is methyl alcohol or ethanol.
5. method according to claim 2, it is characterised in that the organic solvent and the institute of the formula 2
The volume mass ratio for showing compound is 20ml/g~30ml/g, preferably 25ml/g.
6. method according to claim 3, it is characterised in that the quality of alkali in the alkaline aqueous solution
Fraction is 10%~30%, preferably 20%.
7. method according to claim 2, it is characterised in that the alkaline aqueous solution and the formula 2
The volume mass ratio of shown compound is 5ml/g~15ml/g, preferably 10ml/g.
8. method according to claim 2, it is characterised in that under 40~60 degrees celsius,
In the organic solvent, compound shown in the formula 2 is contacted with alkaline aqueous solution, to obtain the formula 1
Shown compound.
9. method according to claim 2, it is characterised in that further include：By the institute of the formula 1
Show that compound carries out column chromatography purifying, to obtain compound shown in formula 1 after purification.
10. compound shown in formula 1 described in claim 1 or claim 2-9 any one methods described systems
Purposes of the compound in the control of Afatinib drug product quality shown in the standby formula 1 for obtaining, wherein the formula 1
Shown compound Afatinib drug product quality control in as Afatinib medicine degradation impurity mark
Quasi- product or reference substance.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510999659.7A CN106916147A (en) | 2015-12-25 | 2015-12-25 | Compound and its production and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510999659.7A CN106916147A (en) | 2015-12-25 | 2015-12-25 | Compound and its production and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106916147A true CN106916147A (en) | 2017-07-04 |
Family
ID=59454914
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510999659.7A Pending CN106916147A (en) | 2015-12-25 | 2015-12-25 | Compound and its production and use |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947986A (en) * | 2018-06-27 | 2018-12-07 | 苏州市贝克生物科技有限公司 | The synthetic method of Afatinib degradation impurity |
| CN110590754A (en) * | 2019-09-21 | 2019-12-20 | 广东安诺药业股份有限公司 | Preparation method of afatinib maleate intermediate |
| CN115304587A (en) * | 2021-05-06 | 2022-11-08 | 北京康派森医药科技有限公司 | Preparation method of afatinib impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| WO2015103456A1 (en) * | 2014-01-02 | 2015-07-09 | Teva Pharmaceuticals International Gmbh | Crystalline forms of afatinib di-maleate |
-
2015
- 2015-12-25 CN CN201510999659.7A patent/CN106916147A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1867564A (en) * | 2003-10-17 | 2006-11-22 | 贝林格尔·英格海姆国际有限公司 | Process for preparing amino crotonyl compounds |
| WO2015103456A1 (en) * | 2014-01-02 | 2015-07-09 | Teva Pharmaceuticals International Gmbh | Crystalline forms of afatinib di-maleate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947986A (en) * | 2018-06-27 | 2018-12-07 | 苏州市贝克生物科技有限公司 | The synthetic method of Afatinib degradation impurity |
| CN110590754A (en) * | 2019-09-21 | 2019-12-20 | 广东安诺药业股份有限公司 | Preparation method of afatinib maleate intermediate |
| CN115304587A (en) * | 2021-05-06 | 2022-11-08 | 北京康派森医药科技有限公司 | Preparation method of afatinib impurity |
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