CN105061410B - A kind of Afatinib and its preparation method and application - Google Patents
A kind of Afatinib and its preparation method and application Download PDFInfo
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Abstract
The present invention provides a kind of Afatinib and its preparation method and application, the method is using carbon tetrabromide and organic phosphorus compound as condensation reagent, with dimethylamino crotonic acid and/or dimethylamino cronate and N4 (3 chlorine, 4 fluorophenyl) 7 (3 base oxygen of (S) tetrahydrofuran) quinazoline 4,6 diamines are raw material, condensation reaction is carried out, generates Afatinib.The preparation method of the present invention is used as condensation reagent by the use of carbon tetrabromide and organic phosphorus compound, Afatinib can be obtained by by a step condensation reaction, technique is simple, and widen and prepared during Afatinib to the range of choice of condensation reagent, reaction yield can reach more than 90%, and product purity is more than 95%.
Description
Technical field
The present invention relates to medicinal chemistry arts, in particular it relates to a kind of Afatinib and preparation method thereof and should
With.
Background technology
Afatinib (Afatinib), is a kind of anti cancer target medicine of innovation, i.e. the oral targeting medicine of a new generation, is
The first kind in the whole world irreversibly combine ErbB families (include four kinds of different cancer cell EGF-R ELISAs, as EGFR,
HER2, ErbB3 and ErbB4) anti cancer target medicine, and then more effectively and pointedly block the news for triggering growth of cancer cells
Number, reduce or delay the hyperplasia of cancer cell.Afatinib in the U.S., the more countries and regions in Europe and Taiwan are granted is used as a line
Medicine, is treated applied to the non-small cell lung cancer (NSCLC) with EGF-R ELISA (EGFR) mutated cancer cells,
It is oral target therapeutic agent once a day.
Afatinib is researched and developed by German Boehringer Ingelheim company, by multinomial large-scale clinical verification, is chosen as breaking through by FDA
Property treatment.Afatinib was respectively " Gilotrif " and " Giotrif " in the U.S. and Europe listing, trade name in 2013；
Middle culture-commerce's name is respectively " appropriate multiple gram " and " mark must reach " in Taiwan and Hong Kong.
Afatinib is by suppressing the signal transductions of above-mentioned ErbB families, for preventing tumour growth and diffusion from taking on key
The role of property.The effect of Afatinib can be combined irreversibly with ErbB family receptors, downstream information conduction be interrupted, so as to hinder
Only growth of cancer cells, and cancer cell specific induction of apoptosis (programmed death).Therefore, compared to other targeted drugs, Afatinib with
The characteristic that ErbB family receptors irreversibly combine is capable of providing more lasting, selectivity, covalent and fully interruption passes through
The Information Conduction of cancer cell, so as to bring the anticancer therapy benefit of uniqueness, more potentiality are disinthibited the tumour cell of wide class
Increase, its curative effect is also more notable.
Its chemical name of Afatinib is N- [4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- [[(3S)-tetrahydrochysene -3- furans
Base] epoxide] -6- quinazolyls] -4- (dimethylamino) -2- crotonamides；English name is (S, E)-N- (4- (3-
chloro-4-fluorophenylamino)-7-(tetrahydro-furan-3-yloxy)quinazolin-6-yl)-4-
(dimethylamino)but-2-enamide；Molecular formula is C24H25ClFN5O3；Relative molecular weight is 485.9；CAS registration numbers
It is as follows for 439081-18-2, structural formula：
At present, the known route of synthesis of Afatinib mainly has following 3 kinds：
Preparation method disclosed in US20050085495 is to be lived with diethylphosphoryl acetic acid by 1,1- carbonyl dimidazoles
Change, with afatinib intermediate N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
Reaction, obtained { [4- (the chloro- 4- fluoro-phenyls amino of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen)-quinazoline -6- base carbamyls
Base]-methyl } p diethylaminobenzoic acid base ester, then Horner- occurs for dimethylamino acetal after being hydrolyzed by aqueous hydrochloric acid solution
Wadsworth-Emmons reaction, obtains Afatinib.The a large amount of phosphatizations larger to environmental hazard can be generated using this method
Compound.
The synthetic method that CN1277822 has disclosed Afatinib a kind of：Bromo crotonic acid and oxalyl chloride are reacted, obtained
Acyl chlorides and afatinib intermediate N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6-
Diamines is acylated, and then adds dimethylamine, obtains Afatinib.This method low yield (at most only has 50%), needs in addition
By column chromatography for separation, large-scale industrial production is not suitable for.
CN103755688 is disclosed by dimethylamino cronate hydrochlorate, and reagent (1,1- carbonyl, two miaow is connected by acid amides
Azoles) activation after or chlorination (oxalyl chloride) after, with N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinoline azoles
Afatinib is made in quinoline -4,6- diamine reactants.This method will could first must carry out after dimethylamino cronate acid salt activating
Follow-up condensation reaction, adds operating procedure, and the yield of product is relatively low.
Therefore, in the art, it is expected that to develop that a kind of technological operation is simple, the side of Afatinib is obtained through single step reaction
Method, and it is desirable to obtain the Afatinib with high-purity in high yield.
The content of the invention
In view of the deficiencies of the prior art, it is an object of the invention to provide a kind of Afatinib and preparation method thereof and should
With.The preparation method of the present invention is condensed anti-by the use of carbon tetrabromide and organic phosphorus compound as amide condensed reagent by a step
Afatinib should be can be obtained by, technique is simple, high income, and product purity is high.
For this purpose, the present invention uses following technical scheme：
On the one hand, the present invention provides a kind of preparation method of Afatinib, and the method is with carbon tetrabromide and organic phosphatization
Compound is condensation reagent, with dimethylamino crotonic acid and/or dimethylamino cronate and N4- (the chloro- 4- fluoro-phenyls of 3-) -7-
((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines is raw material, carries out condensation reaction, generates Afatinib.
In the present invention, a kind of new condensation reagent (i.e. the combination of carbon tetrabromide and organic phosphorus compound) is make use of, it is real
Existing dimethylamino crotonic acid and/or dimethylamino cronate and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3-
Base oxygen) amide condensed reaction between quinazoline -4,6- diamines, widen the choosing prepared during Afatinib to condensation reagent
Scope is selected, reaction yield is high, and product purity is high.
In the present invention, carbon tetrabromide and organic phosphorus compound, which must be used cooperatively, could be used as condensation reagent, react
During carbon tetrabromide and organic phosphorus compound form phosphonium salt, make dimethylamino crotonic acid and/or dimethylamino cronate
Amide condensed reaction occurs with N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines,
If this cannot be played the role of using only one of which.
In the preparation method of Afatinib of the present invention, the organic phosphorus compound is trialkyl phosphine or triphenyl
Phosphine, triphenylphosphine.
Preferably, trialkyl phosphine is any one in trimethyl-phosphine, triethyl phosphine, tripropyl phosphine or tributylphosphine.
Preferably, the dimethylamino cronate is dimethylamino cronate hydrochlorate.
The preparation method of Afatinib of the present invention comprises the following steps：
(1) by dimethylamino crotonic acid and/or dimethylamino cronate, N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S) -
Tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines, organic amine and carbon tetrabromide be dissolved in organic solvent, stir it is lower add it is organic
Phosphorus compound, is reacted；
(2) filter after reaction, filtrate washing, organic layer concentration, is recrystallized to give Afatinib.
In the preparation method of Afatinib of the present invention, the organic solvent is aprotic organic solvent, preferably two
Chloromethanes and/or chloroform.Due to the activity of the condensation reagent (combination of carbon tetrabromide and organic phosphorus compound) of the present invention
It is higher, it can react with protonic solvent (such as water, methanol), therefore the present invention can ensure four using aprotic organic solvent
Bromination carbon and organic phosphorus compound have greater activity so that the efficiency that the present invention reacts is higher.
In the preparation method of Afatinib of the present invention, step (1) the dimethylamino crotonic acid and/or diformazan ammonia
Mole of base cronate and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
The ratio between amount is (1~1.1):1, such as 1:1、1:1.01、1:1.02、1:1.03、1:1.04、1:1.05、1:1.06、1:1.07、
1:1.08、1:1.09 or 1:1.1, preferably (1~1.05):1.
Dimethylamino crotonic acid and/or dimethylamino cronate of the present invention and N4- (the chloro- 4- fluoro-phenyls of 3-) -7-
The ratio between mole of ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines, refers to comprise only dimethylamino bar in raw material
Beans acid and dimethylamino cronate in it is a kind of when, then the ratio between the mole refers to dimethylamino crotonic acid or dimethylamino bar
The mole of beans hydrochlorate and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines it
Than if use dimethylamino crotonic acid and dimethylamino cronate at the same time in raw material, the ratio between mole refers to diformazan
The sum of amount of substance of amino crotonic acid and dimethylamino cronate and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysene furans
The ratio between mutter -3- bases oxygen) mole of quinazoline -4,6- diamines.
Preferably, step (1) described organic amine is any one in diethylamine, triethylamine or ethylenediamine or at least two
Combination, preferred triethylamine.
Preferably, the mole of step (1) organic amine and dimethylamino crotonic acid and/or dimethylamino cronate
The ratio between be (2~2.2):1, such as 2:1、2.03:1、2.05:1、2.08:1、2.1:1、2.12:1、2.14:1、2.16:1、
2.18:1 or 2.2:1, preferably (2~2.1):1.
Preferably, step (1) carbon tetrabromide and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases
Oxygen) the ratio between the mole of quinazoline -4,6- diamines is (1~1.1):1, such as 1:1、1:1.01、1:1.02、1:1.03、1:
1.04、1:1.05、1:1.06、1:1.07、1:1.08、1:1.09 or 1:1.1, preferably (1~1.05):1.
The purpose for adding organic amine in the present invention is to provide alkaline environment for reaction, when raw material is dimethylamino crotonic acid
During hydrochloride, the hydrochloric part of institute in raw material dimethylamino cronate hydrochlorate is neutralized using organic amine, obtains diformazan ammonia
Base crotonic acid, to occur with N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
Reaction.
In the preparation method of Afatinib of the present invention, relative to 1g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S) -
Tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines, the dosage of step (1) described organic solvent is 10~20mL, such as 10mL,
11mL, 12mL, 13mL, 14mL, 15mL, 16mL, 17mL, 18mL, 19mL or 20mL, preferably 12~18mL.
Preferably, step (1) organic phosphorus compound and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -
3- bases oxygen) the ratio between the mole of quinazoline -4,6- diamines is (1~1.1):1, such as 1:1、1:1.01、1:1.02、1:1.03、
1:1.04、1:1.05、1:1.06、1:1.07、1:1.08、1:1.09 or 1:1.1, preferably (1~1.05):1.
When adding organic phosphorus compound in the present invention, heat generation is had, overheat is brought dangerous or produced in order to prevent
Side reaction, is added slowly with stirring organic phosphorus compound.
In the preparation method of Afatinib of the present invention, the temperature of step (1) described reaction is 20~30 DEG C, such as
20 DEG C, 21 DEG C, 22 DEG C, 23 DEG C, 24 DEG C, 25 DEG C, 26 DEG C, 27 DEG C, 28 DEG C, 29 DEG C or 30 DEG C, preferably 20~25 DEG C.
Preferably, the time of step (1) described reaction is 30~90min, for example, 30min, 35min, 40min, 45min,
50min, 55min, 60min, 65min, 70min, 75min, 80min, 85min or 90min, preferably 40~60min.
Preferably, step (2) concentration is to be concentrated under reduced pressure.
Preferably, step (2) recrystallization is to use recrystallisation from isopropanol.
As the preferred technical solution of the present invention, the preparation method of the Afatinib comprises the following steps：
(1) will rub with N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
The ratio between your amount is (1~1.1):1 dimethylamino crotonic acid and/or dimethylamino cronate, with dimethylamino crotonic acid and/
Or the ratio between mole of dimethylamino cronate is (2~2.2):1 organic amine and with N4- (the chloro- 4- fluoro-phenyls of 3-) -7-
The ratio between mole of ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines is (1~1.1):1 carbon tetrabromide, which is dissolved in, to be had
In solvent, lower add and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- bis- is stirred
The ratio between mole of amine is (1~1.1):1 organic phosphorus compound, 20~30 DEG C of 30~90min of reaction；
(2) filter after reaction, filtrate washing, organic layer is concentrated under reduced pressure, and Afatinib is obtained with recrystallisation from isopropanol.
The technical solution further preferred as the present invention, the preparation method of the Afatinib comprise the following steps：
(1) will rub with N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
The ratio between your amount is (1~1.05):1 dimethylamino crotonic acid and/or dimethylamino cronate and dimethylamino crotonic acid
And/or the ratio between mole of dimethylamino cronate is (2~2.1):1 organic amine and with N4- (the chloro- 4- fluoro-phenyls of 3-)-
The ratio between mole of 7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines is (1~1.05):1 carbon tetrabromide is dissolved in
In aprotic organic solvent, lower add and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinoline azoles is stirred
The ratio between mole of quinoline -4,6- diamines is (1~1.05):1 organic phosphorus compound, 20~25 DEG C of 40~60min of reaction；
(2) filter after reaction, filtrate washing, organic layer is concentrated under reduced pressure, and Afatinib is obtained with recrystallisation from isopropanol.
On the other hand, the present invention provides the Afatinib that preparation method as described in relation to the first aspect is prepared.
On the other hand, the application the present invention provides Afatinib of the present invention in anticancer targeting medicine is prepared.
The Afatinib of the present invention can be used as anti cancer target medicine, blocks effectively and pointedly and triggers cancer cell
The signal of growth, reduces or delays the hyperplasia of cancer cell.
Relative to the prior art, the invention has the advantages that：
The preparation method of the present invention is condensed anti-by the use of carbon tetrabromide and organic phosphorus compound as condensation reagent by a step
Afatinib should be can be obtained by, technique is simple, and has widened and prepared selection model to condensation reagent during Afatinib
Enclose, reaction yield can reach more than 90%, and product purity is more than 95%.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright
, the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
Embodiment 1
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 24.3g dimethylamino cronates hydrochlorate, 55.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysene furans
Mutter -3- bases oxygen) quinazoline -4,6- diamines, 40.8mL triethylamines and 48.7g carbon tetrabromides be dissolved in dry 660mL dichloromethane
In, 38.5g triphenylphosphines are slowly added under 20 DEG C of stirrings, reacts and terminates after 45min, are filtered, filtrate washing (700mL × 2 time),
Organic layer is concentrated under reduced pressure into dry, and residue obtains 64.2g Afatinibs with 200mL recrystallisation from isopropanol, and molar yield is
90.1%, product purity 97%.
1H NMR(DMSO-d6)δ(ppm):11.08 (s, 1H), 9.90 (s, 1H), 9.79 (s, 1H), 8.94 (s, 1H),
8.56 (s, 1H), 8.14 (dd, 1H), 7.82 (dd, 1H), 7.43 (t, 1H), 7.27 (s, 1H), 6.88 (m, 1H), 6.78 (d,
1H), 5.31 (s, 1H), 3.98 (m, 5H), 3.80 (m, 1H), 2.76 (s, 6H), 2.37 (m, 1H), 2.14 (m, 1H), LC-MS
(ESI)：486.0 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 2
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 50.1g dimethylamino cronates hydrochlorate, 108.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysene furans
Mutter -3- bases oxygen) quinazoline -4,6- diamines, 84.2mL triethylamines and 100.3g carbon tetrabromides be dissolved in dry 1944mL dichloromethanes
In alkane, 79.4g triphenylphosphines are added portionwise under 25 DEG C of stirrings, is reacted after 60min and terminates to filter, filtrate washing (1900mL × 2
It is secondary), organic layer is concentrated under reduced pressure into dry, and residue obtains 130.2g Afatinibs with 390mL recrystallisation from isopropanol, and molar yield is
93%, product purity 98%.
Through1H NMR and LC-MS (ESI)：486.2 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 3
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 39.0g dimethylaminos crotonic acid, 108.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases
Oxygen) quinazoline -4,6- diamines, 40.5mL ethylenediamines and 100.3g carbon tetrabromides be dissolved in dry 1944mL dichloromethane, and 25
Be added portionwise 79.4g triphenylphosphines under DEG C stirring, after 60min reaction terminate to filter, filtrate washing (1900mL × 2 time) is organic
Layer is concentrated under reduced pressure into dry, and residue obtains 126g Afatinibs with 390mL recrystallisation from isopropanol, and molar yield is 90%, product
Purity is 95%.
Through1H NMR and LC-MS (ESI)：486.2 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 4
By 52.7g dimethylamino cronates hydrochlorate, 117.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysene furans
Mutter -3- bases oxygen) quinazoline -4,6- diamines, 88.6mL triethylamines and 105.6g carbon tetrabromides be dissolved in dry 1870mL dichloromethanes
In alkane, 83.5g trimethyl-phosphines are slowly added under 23 DEG C of stirrings, is reacted after 65min and terminates to filter, filtrate washing (1800mL × 2
It is secondary), organic layer is concentrated under reduced pressure into dry, and residue obtains 138.0g Afatinibs with 455mL recrystallisation from isopropanol, and molar yield is
91%, product purity 96%.
Through1H NMR and LC-MS (ESI)：486.1 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 5
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 26.7g dimethylamino cronates hydrochlorate, 55.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysene furans
Mutter -3- bases oxygen) quinazoline -4,6- diamines, 49.1mL diethylamine and 53.5g carbon tetrabromides be dissolved in dry 1100mL dichloromethane
In, 42.3g triphenylphosphines are slowly added under 20 DEG C of stirrings, reacts and terminates after 30min, are filtered, filtrate washing (800mL × 2 time),
Organic layer is concentrated under reduced pressure into dry, and residue obtains 64.2g Afatinibs with 200mL recrystallisation from isopropanol, and molar yield is 90%,
Product purity is 97%.
Through1H NMR and LC-MS (ESI)：486.0 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 6
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 53g dimethylamino cronates hydrochlorate, 120.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -
3- bases oxygen) quinazoline -4,6- diamines, 93mL triethylamines and 111.4g carbon tetrabromides be dissolved in dry 1800mL dichloromethane,
25.5g trimethyl-phosphines are slowly added under 25 DEG C of stirrings, is reacted after 90min and terminates to filter, filtrate washing (1800mL × 2 time), has
Machine layer is concentrated under reduced pressure into dry, and residue obtains 140g Afatinibs with 400mL recrystallisation from isopropanol, and molar yield is 90%, production
Thing purity is 95%.
Through1H NMR and LC-MS (ESI)：486.1 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 7
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 25.8g dimethylaminos crotonic acid and 19.86g dimethylamino cronates hydrochlorate, 120.0g N4- (the chloro- 4- of 3-
Fluoro-phenyl) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines, 93mL triethylamines and 111.4g carbon tetrabromides it is molten
In dry 1800mL dichloromethane, 67.9g tributylphosphines are slowly added under 25 DEG C of stirrings, is reacted after 90min and terminates to filter,
Filtrate washes (1800mL × 2 time), organic layer be concentrated under reduced pressure into it is dry, residue with 400mL recrystallisation from isopropanol obtain 140g Ah
Method replaces Buddhist nun, and molar yield is 90%, product purity 96%.
Through1H NMR and LC-MS (ESI)：486.1 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 8
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 52.4g dimethylamino cronates hydrochlorate, 108.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysene furans
Mutter -3- bases oxygen) quinazoline -4,6- diamines, 54.7mL ethylenediamines and 103.1g carbon tetrabromides be dissolved in dry 1080mL dichloromethanes
In alkane, 80.8g triphenylphosphines are added portionwise under 25 DEG C of stirrings, is reacted after 40min and terminates to filter, filtrate washing (1900mL × 2
It is secondary), organic layer is concentrated under reduced pressure into dry, and residue obtains 130.2g Afatinibs with 390mL recrystallisation from isopropanol, and molar yield is
93%, product purity 97%.
Through1H NMR and LC-MS (ESI)：486.1 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Embodiment 9
In the present embodiment, Afatinib is prepared by the following method, the described method comprises the following steps：
By 51.5g dimethylamino cronates hydrochlorate, 108.0g N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysene furans
Mutter -3- bases oxygen) quinazoline -4,6- diamines, 94.7mL triethylamines and 103.1g carbon tetrabromides be dissolved in dry 1080mL dichloromethanes
In alkane, 80.8g triphenylphosphines are added portionwise under 25 DEG C of stirrings, is reacted after 40min and terminates to filter, filtrate washing (1900mL × 2
It is secondary), organic layer is concentrated under reduced pressure into dry, and residue obtains 128.7g Afatinibs with 390mL recrystallisation from isopropanol, and molar yield is
92%, product purity 96%.
Through1H NMR and LC-MS (ESI)：486.2 [M+H]+, it is Afatinib to illustrate material manufactured in the present embodiment.
Comparative example 1
The comparative example difference from Example 1 is, during the reaction, for condensation reagent, only adds and real
The identical carbon tetrabromide of 1 dosage of example is applied, and does not add any organic phosphorus compound, remaining raw material and raw material dosage and reaction bar
Part is same as Example 1.Through1H NMR and LC-MS (ESI) characterization find that this comparative example cannot get Afatinib, says at all
Bright carbon tetrabromide, which individually cannot function as condensation reagent, makes raw material that condensation reaction occur, and only coordinating with organic phosphorus compound to send out
Wave its effect.
Comparative example 2
The comparative example difference from Example 1 is, during the reaction, for condensation reagent, only adds and real
Apply the identical triphenylphosphine of 1 dosage of example, and do not add carbon tetrabromide, remaining raw material and raw material dosage and reaction condition with reality
It is identical to apply example 1.Through1H NMR and LC-MS (ESI) characterization find that this comparative example cannot get Afatinib, illustrates triphenyl at all
Phosphine, which individually cannot function as condensation reagent, makes raw material that condensation reaction occur, and changes triphenylphosphine into other organic phosphorus compounds, and not
Carbon tetrabromide is added, still cannot get Afatinib.
Comparative example 3
The comparative example difference from Example 2 is, by carbon tetrabromide and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S) -
Tetrahydrofuran -3- bases oxygen) the ratio between the mole of quinazoline -4,6- diamines is respectively set as 0.9:1 and 1.2:1 (is separately added into
86g carbon tetrabromides and 114.6g carbon tetrabromides), remaining raw material and raw material dosage and reaction condition are same as Example 2, point
Not carry out Afatinib preparation.In carbon tetrabromide and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen)
The ratio between mole of quinazoline -4,6- diamines is respectively 0.9:1 and 1.2:The molar yield of the Afatinib obtained when 1 is respectively
70% and 72%, product purity is respectively 73% and 75%.
Comparative example 4
The comparative example difference from Example 3 is, by triphenylphosphine and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S) -
Tetrahydrofuran -3- bases oxygen) the ratio between the mole of quinazoline -4,6- diamines is respectively set as 0.9:1 and 1.2:1 (is separately added into
67.9g triphenylphosphines and 90.5g triphenylphosphines), remaining raw material and raw material dosage and reaction condition are same as Example 3,
The preparation of Afatinib is carried out respectively.In triphenylphosphine and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases
Oxygen) the ratio between the mole of quinazoline -4,6- diamines is respectively set as 0.9:1 and 1.2:When 1, mole receipts of obtained Afatinib
Rate is 71% and 73% respectively, and product purity is respectively 75% and 78%.
As seen from the above embodiment, on the one hand the method for the invention has expanded the optional scope of amide condensed reagent, separately
On the one hand by " one kettle way " react, simplify the preparation method of Afatinib, at the same be prepared high quality, in high yield Ah
Method replaces Buddhist nun.Afatinib prepared by the present invention can be used as anti cancer target medicine, blocks effectively and pointedly and triggers cancer
The signal of cell growth, reduces or delays the hyperplasia of cancer cell.
Applicant states that the present invention is illustrated Afatinib of the present invention and preparation method thereof and answered by above-described embodiment
With, but the invention is not limited in above-described embodiment, that is, do not mean that the present invention has to rely on above-described embodiment and could implement.Institute
Belong to those skilled in the art it will be clearly understood that any improvement in the present invention, to the equivalence replacement of each raw material of product of the present invention
And the addition of auxiliary element, selection of concrete mode etc., all fall within protection scope of the present invention and the open scope.
Claims (23)
1. a kind of preparation method of Afatinib, it is characterised in that the method is using carbon tetrabromide and organic phosphorus compound as contracting
Reagent is closed, with dimethylamino crotonic acid and/or dimethylamino cronate and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysenes
Furans -3- bases oxygen) quinazoline -4,6- diamines is raw material, carries out condensation reaction, generate Afatinib；
(1) by dimethylamino crotonic acid and/or dimethylamino cronate, N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrochysenes
Furans -3- bases oxygen) quinazoline -4,6- diamines, organic amine and carbon tetrabromide be dissolved in organic solvent, and stir and lower add organic phosphatization
Compound, is reacted；
(2) filter after reaction, filtrate washing, organic layer concentration, is recrystallized to give Afatinib；
Step (1) carbon tetrabromide and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,
The ratio between mole of 6- diamines is (1~1.1):1；
Step (1) organic phosphorus compound and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinoline azoles
The ratio between mole of quinoline -4,6- diamines is (1~1.1):1.
2. preparation method according to claim 1, it is characterised in that the organic phosphorus compound is trialkyl phosphine or triphen
Base phosphine.
3. preparation method according to claim 2, it is characterised in that the organic phosphorus compound is triphenylphosphine.
4. preparation method according to claim 2, it is characterised in that the trialkyl phosphine for trimethyl-phosphine, triethyl phosphine,
Any one in tripropyl phosphine or tributylphosphine.
5. preparation method according to claim 1, it is characterised in that the dimethylamino cronate is dimethylamino bar
Beans acid hydrochloride.
6. preparation method according to claim 1, it is characterised in that step (1) described organic solvent is non-proton organic
Solvent.
7. preparation method according to claim 6, it is characterised in that step (1) described organic solvent for dichloromethane and/
Or chloroform.
8. preparation method according to claim 1, it is characterised in that step (1) the dimethylamino crotonic acid and/or two
Methylamino cronate and N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
The ratio between mole is (1~1.05):1.
9. preparation method according to claim 1, it is characterised in that step (1) described organic amine is diethylamine, triethylamine
In ethylenediamine any one or at least two combination.
10. preparation method according to claim 9, it is characterised in that step (1) described organic amine is triethylamine.
11. preparation method according to claim 1, it is characterised in that step (1) organic amine and dimethylamino crotons
The ratio between mole of acid and/or dimethylamino cronate is (2~2.2):1.
12. preparation method according to claim 11, it is characterised in that step (1) organic amine and dimethylamino bar
The ratio between mole of beans acid and/or dimethylamino cronate is (2~2.1):1.
13. preparation method according to claim 1, it is characterised in that (3- is chloro- with N4- for step (1) described carbon tetrabromide
4- fluoro-phenyls) the ratio between the mole of -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines is (1~1.05):1.
14. preparation method according to claim 1, it is characterised in that relative to 1g N4- (the chloro- 4- fluoro-phenyls of 3-) -7-
((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines, the dosage of step (1) described organic solvent is 10~20mL.
15. preparation method according to claim 14, it is characterised in that relative to 1g N4- (the chloro- 4- fluoro-phenyls of 3-)-
7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines, the dosage of step (1) described organic solvent is 12~18mL.
16. preparation method according to claim 1, it is characterised in that step (1) organic phosphorus compound and N4- (3-
Chloro- 4- fluoro-phenyls) the ratio between the mole of -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines is (1~1.05):
1。
17. preparation method according to claim 1, it is characterised in that the temperature of step (1) described reaction is 20~30
℃。
18. preparation method according to claim 17, it is characterised in that the temperature of step (1) described reaction is 20~25
℃。
19. preparation method according to claim 1, it is characterised in that the time of step (1) described reaction for 30~
90min。
20. preparation method according to claim 19, it is characterised in that the time of step (1) described reaction for 40~
60min。
21. preparation method according to claim 1, it is characterised in that step (2) concentration is to be concentrated under reduced pressure.
22. preparation method according to claim 1, it is characterised in that step (2) recrystallization is to be tied again with isopropanol
It is brilliant.
23. preparation method according to claim 1, it is characterised in that the preparation method comprises the following steps：
(1) will be with the mole of N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
The ratio between be (1~1.1):1 dimethylamino crotonic acid and/or dimethylamino cronate and dimethylamino crotonic acid and/or two
The ratio between mole of methylamino cronate is (2~2.2):1 organic amine and with N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S) -
Tetrahydrofuran -3- bases oxygen) the ratio between the mole of quinazoline -4,6- diamines is (1~1.1):1 carbon tetrabromide is dissolved in organic solvent
In, stir lower add and rub with N4- (the chloro- 4- fluoro-phenyls of 3-) -7- ((S)-tetrahydrofuran -3- bases oxygen) quinazoline -4,6- diamines
The ratio between your amount is (1~1.1):1 organic phosphorus compound, 20~30 DEG C of 30~90min of reaction；
(2) filter after reaction, filtrate washing, organic layer is concentrated under reduced pressure, and Afatinib is obtained with recrystallisation from isopropanol.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101874022A (en) * | 2007-09-28 | 2010-10-27 | 田边三菱制药株式会社 | Indazole acrylic acid amide compound |
| WO2013052157A1 (en) * | 2011-10-06 | 2013-04-11 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN103304552A (en) * | 2012-03-09 | 2013-09-18 | 广东东阳光药业有限公司 | Substituted pyridine compounds and methods and uses thereof |
| CN103755688A (en) * | 2013-12-24 | 2014-04-30 | 江苏奥赛康药业股份有限公司 | Preparation method for afatinib compound |
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2015
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101874022A (en) * | 2007-09-28 | 2010-10-27 | 田边三菱制药株式会社 | Indazole acrylic acid amide compound |
| WO2013052157A1 (en) * | 2011-10-06 | 2013-04-11 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN103304552A (en) * | 2012-03-09 | 2013-09-18 | 广东东阳光药业有限公司 | Substituted pyridine compounds and methods and uses thereof |
| CN103755688A (en) * | 2013-12-24 | 2014-04-30 | 江苏奥赛康药业股份有限公司 | Preparation method for afatinib compound |
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